ISSN 1883-9606

2020

Vol.141

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2019 ---- March 2020

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2019-March 2020

Introduction
This is volume 141(the edition of year 2020) 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.

Nobuhito Saito, Dean
Graduate School of Medicine and Faculty of Medicine
The University of Tokyo
October, 2020

i

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

1

Department of Cell Biology and Anatomy ···································································

2

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

4

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

6

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

8

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

9

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

13

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

16

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

19

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

21

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

22

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

24

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

28

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

30

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

31

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

33

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

37

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

38

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

42

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

46

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

47

ii

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

50

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

53

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

54

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

58

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

59

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

65

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

66

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

70

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

72

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

75

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

78

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

79

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

82

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

88

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

89

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

91

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

92

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

97

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

104

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

110

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

111

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

114

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

120

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

121

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

124

iii

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

128

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

129

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

133

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

137

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

142

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

143

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

149

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

155

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

159

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

162

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

165

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

167

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.464] )Department of Transfusion Medicine ·········································································

168

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

171

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

172

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

175

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

177

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

179

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

182

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

183

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

190

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

193

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

194

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

198

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

199

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

203

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

208

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

211

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

214

iv

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

219

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

225

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

229

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

231

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

232

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

235

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

239

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

244

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

253

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

256

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

261

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

264

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

265

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

268

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

272

Department of Health Sociology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.342] )Department of Mental Health ··················································································

273

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

276

Department of Social Gerontology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.342] )Department of Biomedical Ethics & Department of Health Promotion Sciences ·······················

280

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

283

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

284

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

287

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

290

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

293

Department of Gerontological Home Care and Long-term Care Nursing/Palliative Care Nursing ···294

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

297

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

300

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

303

v

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

310

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

311

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

314

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

318

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

319

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

321

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

324

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

328

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

330

Department of Biostatistics(See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.276] )Department of Social and Preventive Epidemiology ························································

331

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

333

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

338

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

341

Department of Mental Health (See Department of Mental Health [P.273] )Department of Health Sociology and Health Education(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.342] )Departments of Health and Social Behavior & Health Education and Health Sociology ···············

342

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.280] )3. Health Services Sciences ·························································································

348

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.114] )Department of Healthcare Informatics (See Department of Biomedical Informatics [ P.124] )Department of Clinical Information Engineering ····························································

349

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.121] )Department of Global Environmental Health ································································

351

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

353

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

354

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

357

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

359

Science for joint reconstruction (See Department of Orthopaedic Surgery [P.244] )viDepartment of Medical Genomics ·············································································

363

Department of Bone & Cartilage Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.536] )Department of Osteoimmunology ··············································································

367

Department of Continence Medicine ··········································································

371

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

373

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

375

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

377

Laboratory for New Generation Drug Discovery (See Laboratory of Molecular Biomedicine
for Pathogenesis [P.550] )Department of Biostatistics and Bioinformatics ·······························································

381

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

385

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

389

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

391

Department of medical and pharmaceutical community healthcare ········································

393

Department of Cartilage & Bone Regeneration (Fujisoft)(See Central Clinical Facilities Division of Tissue Engineering [P.536] )Department of Molecular Structure and Dynamics ·························································

397

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

399

Department of Molecular Sciences on Diabetes ·····························································

403

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

405

Department of Immunotherapy Management ································································

408

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

410

Department of Life Support Technology (Molten) ··························································

412

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

415

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

419

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

421

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

422

Department of Imaging nursing Science ·······································································

425

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

428

Voice Analysis pf Pathophysiology ············································································

437

Department of Ubiquitous Health Informatics ·······························································

439

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

442

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

445

Bariatric and Metabolic Care
(See Department of Gastrointestinal Surgery [P.208]
Department of Innovative Dementia Prevention ······························································

447

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

450

vii

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

454

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

458

University Hospital
Clinical Divisions ····································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.129] )Respiratory Medicine (See Department of Respiratory Medicine [P.133] )Gastroenterology (See Department of Gastroenterology [P.137] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.143] )Diabetes and Metabolic Diseases (See Department of Diabetes and Metabolic Diseases [P.149] )Hematology and Oncology (See Department of Hematology and Oncology [P.155] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.159] )Infectious Diseases (See Department of Infectious Diseases (Internal Medicine) [P.162] )Neurology (See Department of Neurology [P.97] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.194] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.165] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.208] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.219] )Hepatobiliary Pancreatic Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.211] )Vascular Surgery (See Department of Vascular Surgery [P.225] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.229] )Artificial Organ and Transplantation Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.211] )Cardiovascular Surgery (See Department of Cardiac Surgery [P.203] )Thoracic Surgery (See Department of Thoracic Surgery [P.199] )Neurosurgery (See Department of Neurosurgery [P.104] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.265] )Urology and Andrology (See Department of Urology [P.214] )

462

viii

Gynecologic Surgery (See Obstetrics and Gynecology [P.171] )Sensory and Motor System Medicine
Dermatology (See Department of Dermatology [P.232] )Ophthalmology (See Department of Ophthalmology [P.253] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.244] )Otorhinolaryngology and Head and Neck Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.256] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.261] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.235] )Oral-Maxillofacial Surgery and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.239] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.183] )Pediatrics Surgery (See Department of Pediatric Surgery [P.190] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.172,175,177] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.92] )Radiology
Radiology (See Department of Radiology [P.59] )Acute Medicine
Acute Medicine(See Department of Acute Medicine [P.268] )Central Clinical Facilities ···························································································

463

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

464

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

469

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

472

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

474

Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.168] )Rehabilitation Center ····························································································

478

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

481

Department of Intensive Care Unit
(See Department of Acute Medicine [P.268] )ix

Division of Diagnostic Pathology ··············································································

483

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

487

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

489

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

492

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

495

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

498

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.50] )Department of Planning, Information, and Management(See Department of Biomedical Informatics [P.124] )University Hospital Medical Information Network (UMIN) Center ······································

500

Organ Transplantation Service ·················································································

503

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

504

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

506

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

509

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

510

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

514

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

517

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

519

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

521

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

522

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

527

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

529

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

536

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

540

Genomic Research Support Center (GresCent) ······························································

547

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

549

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

550

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

553

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

556

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

559

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

564

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

569

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

572

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

575

x

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

578

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

579

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

580

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

582

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

586

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

588

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

591

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

593

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

595

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

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. 140, October 2020

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. 141, October 2020

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.

xiv

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

Organization Chart
Cell Biology

Cell Biology and Anatomy

Structural Biology
Structural Cell Biology
Cellular Neurobiology

Molecular Cell Biology

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

Cellular and Molecular Physiology
Neurophysiology

Functional Biology

Pharmacology

Collaborative Department

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

Pathology

Molecular Pathology
Surgical Pathology

Microbiology
Pathology, Immunology
and Microbiology
Immunology

Microbiology
Infection Control and Prevention
Immunology
Clinical Immunology
Infection Pathology

Collaborative Department

T umor Pathology
Molecular Oncology
Diagnoatic Radiology

Radiology

Radiotherapy
Nuclear Medicine

Radiology and Biomedical
Engineering

System Physiology
Biomedical Engineering

Chemical Biology and Molecular Imaging
Biosystem Construction and Control
Neuropathology

Basic Neuroscience

Neurochemistry
Neurobiology
Developmental Neuroscience

Neuroscience

Integrativ Medical Neurosciences

Cognitive Neuroscience
Systems Medical Neuroscience
Child Neuropsychiatry
Neuropsychiatry

Clinical Neuroscience

Neurology
Neurosurgery

Collaborative Department

Biomedical Neural Dynamics

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

Preventive Medicine
Occupational, Environmental andPreventive Medicine

Public HealthRadiological HealthSocial Medicine

Forensic Medicine, and Medical
Informatics and Economics

Forensic Medicine
Medical Informatics
Cancer Control Policy and Research

Collaborative Department

Cancer Epidemiology
Cancer Communication
Cardiovascular Medicine
Vascular Biology

Medicine I

Respiratory Medicine
Gastroenterology
Nephrology
Endocrinology
Nutrition and Metabolism

Internal Medicine
Medicine II

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

Clinical Laboratory Medicine
and Pathology
Collaborative Department

Clinical Laboratory Medicine
T ransfusion Medicine
Molecular Diabetology
Reproductive Endocrinology

Obstetrics and Gynecology

Gynecological Oncology
Perinatal Medicine
Molecular Reproductive Endocrinology
Pediatrics

Reproductive,
Developmental andAging Sciences

Pediatric Sciences

Developmental Pediatrics
Pediatric Surgery
Pediatric Oncology

Aging Sciences

Geriatrics
Aging Research
Health Policy for Children and Families

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

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

xv

xvi

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

Surgical Sciences

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

Orthopaedic Surgery
Ophthalmology
Otolaryngology and Head and Neck
Surgery
Rehabilitation Medicine

Vital Care Medicine

Anesthesiology
Emergency and Critical Care Medicine
Health Sociology
Mental Health

Health Sciences

Epidemiology and Preventive Health
Sciences
Social Gerontology
Health Promotion Sciences
Biostatistics

Graduate School of
Medicine

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

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

Clinical Nursing

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

Collaborative Department

International Social Medicine

International HealthPublic Mental Health Policy
Global Health Policy
Community and Global Health
Human Genetics

International Biomedical Sciences

Medical Science (Master’s Program)

Epidemiology and Health Sciences

Developmental Medical Sciences
Human Ecology
Biomedical Chemistry
Biostatistics
Social and Preventive Epidemiology
Health Economics and Epidemiology Research
Health Communication
Mental Health
Health Sociology and Health Education

School of Public HealthBehavioral Health Sciences

Health and Social Behavior
Health Promotion Science
Biomedical Ethics

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

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

Center for Disease
Biology and Integrative
medicine

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

International ResearchCenter for Medical
Education
Global Nursing ResearchCenterLaboratory of Molecular Radiology

Section of Animal Research

Division of Research Resources and Support

Section of Radiation Biology

Department of Medical Education Studies

Section of Bioinformatics

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

Institution

Office for Human Research Studies
Office for Life Science Research Equipment
SupprtLife Sciences Core Facility
Office for Clinical Practice and Medical
Education
Advisory Office for Conflicts of interest
Bone & Cartilage Regenerative Medicine
Department of Cell & T issue
Engineering(Fujisoft)
Immunotherapeutics

Endowed Department

Advanced Clinical Science and T herapeutics
Computational Diagnostic Radiology andPreventive Medicine
Department of Molecular Neurology
Clinical T rial Data Management
Ubiquitous Preventive Medicine
Science for Joint Reconstruction
T herapeutic Strategy for Heart Failure
Molecular Structure and Dynamics
Department of Life Support T echnology(Molten)
Department of Home Care Medicine
Department of Advanced T ranslational Researchand Medicine in Management of Pulmonary
Hypertension
Department of Advanced Cardiology
Department of medical research andmanagement for musculoskeletal pain

xvii

xviiiThe Tokyo Journal of Medical Sciences. Vol. 141, October 2020

Department of Molecular Science on Diabetes
Department of Osteoimmunology
Department of medical and pharmaceuticalcommunity healthcare
Health Economy and Society Policy
Departmento of Biostatics and Bioinformatics
Department of Preventive Medicine for
Locomotive Organ Disorders
Laboratory for New Generation Drug Discovery
Laboratory for Advanced Research on
Pathophysiology of Metabolic Diseases
Artificial Intelligence in Healthcare
Department of Lipidomics
Social Cooperation
ProgramAdvanced Nursing T echnology
T issue stem cell / life dentistry
Verbal analysis of pathophysiology
Department of Health Services Research
Skincare Science

General Affairs Office

Imaging Nursing Science

Personnel Office

Department of Healthcare Quality Assessment

Research Support Office

Bariatric & Metabolic Care

Educational Affairs

Department of Innovative Dementia Prevention

Graduate Student Affairs

Department of Functional Genomics and
Immunological Diseases

Finance Office

Department of Prevention of Diabetes and Lifestyle Related Disease

Faculty of
Medicine
Graduate School of
Medicine

External Fund Management Office

Department of Next-Generation
Pathology Information Networking

Finance Office

Chronic kidney disease pathophysiology

Facilities Office

Administrative officeAcquisition Office Medical Library
Cataloging Office Medical Library

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

School of Medicine
Faculty of
Medicine

Contract Office

Microbiology
Immunology
Radiology
Biomedical Engineering
Basic Neuroscience
Speech and Cognitive Sciences
Clinical Neuroscience
Occupational, Environmental and Preventive
Medicine
Medical Principles and Medical Ethics

Administrative Office

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

xix

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 l Internal Medicine
Cardiovascular Medicine
Respiratory Medicine
Gastroenterology
Nephrology and Endocrinology
Diabetes and Metabolic Medicine
Hematology and Oncology
Allergy and Rheumatology
Infectious Diseases
Neurology
Geriatric Medicine

Clinical Divisions

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

University
Hospital

Vascular Surgery
Breast and Endocrine Surgery
Surgery

Artificial Organ and T ransplantation Surgery
Cardiothoracic Surgery
T horacic Surgery
Neurosurgery
Anesthesiology and Pain Relief Center
Urology and Andrology
Gynecologic Surgery

xx

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

Dermatology
Ophthalmology
Orthopaedic Surgery and Spinal Surgery
Sensory and Motor System Medicine

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

Pediatrics, Perinatal and
Women's Medicine

Pediatric Surgery
Obstetrics and Gynecology

Central ClinicalFacilities

Neuropsychiatry

NeuropsychiatryRadiology

Radiology

Acute Medicine

Acute Medicine

Pharmaceutical Department

Office of General Administration

Nursing Department

Office of Procurement andFacility Management

Administration Office

Office of Management Planning

Department of Clinical Laboratory

Office of Research Support

Surgical Center

Office of Medical Management

Radiology Center

Office of Medical Accounting

Department of Blood T ransfusion
Perinatal Center
Rehabilitation Center
Department of Medial Engineering
Central Supply Service
Intensive Care Unit
Pathology
Department of Corneal T ransplantation
Department of Cell a T herapy andT ransplantation Medicine
Department of Endoscopy and Endoscopic
Surgery
Department of Hemodialysis and Apheresis
Infection Control and Prevention Service
Department of Planning, Information, andManagement
University Hospital Medical Information
Network Center
Organ T ransplantation Service
Labor Safety and Health Management Office
Staff Wellness Consulting RoomChild Psychiatry
T issue Bank
Center for Epidemiology and Preventive
Medicine
Center for Liaison and Public Relations
Database Center of the National University
Hospitals
Department of Chemotherapy

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

xxi

Department of Medical Record Management
Critical Care and Emergency Medical
Center/Emergency Room
Department of Pain and Palliative Medicine
Children's Medical Center
Department of Disaster Medical Management
International Medical Center
Department of Clinical Nutrition T herapy
Department of Pediatric and Neonatal Intensive
Care
Department of Clinical Genomics
Department of Clinical Genomics
Clinical Research Promotion Center
22nd Century Medical and Research Center
Department of T issue Engineering
Clinical Research
Division

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

Medical Specialists T raining Center
Office of Performance Monitoring

Department of Performance Monitoring and
Risk Management
Organization ofClinical Management

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

Department of Education and Staff
Development

General Education Center
Hospitality Center

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

Outpatient Services
Administration
Central Clinical Services
Administration

Department of Clinical Research Governance
Admission and Discharge Center
Cancer Board
Ｖａｓｃｕｌａｒ Board
Perioperative Assessment Center
Epilepsy Center
Immunotherapy Center
SSc Center
Osteoporosis Center
Hip Fracture Board
Palliative Care Consulation T eam
Nutrition Support T eam

Division of patient support services

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

xxii

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

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

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

Noriko Yamamoto

Director, Medical Library

Hideo Yasunaga

Director General, University Hospital

Yasuyuki Seto

Director, Center for Disease Biology and Integrative Medicine

Masanobu Kano

Director, International Research Center for Medical Education

Tatsuya Yamasoba

Director, Global Nursing Research Center

Hiromi Sanada

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

Professor

Yasushi Okada

Professor

Masahide Kikkawa

Professor

Shigeo Okabe

Professor

Noboru Mizushima

Professor

Makoto Murakami

Professor

Hiroki Kurihara

Professor

DANEV RADOSTIN

Professor

Kenichi Ohki

Professor

Masanori Matsuzaki

Professor

Masanobu Kano

Professor

Kenzo Hirose

Professor

Hiroki Ueda

Professor

Tetsuo Ushiku

Professor

Kohei Miyazono

Professor

Masanori Hatakeyama

Professor

Kyoji Moriya

Professor

Hiroshi Takayanagi

Department of Radiology

Professor

Osamu Abe

Department of Biomedical Engineering

Professor

Kiyoshi Miyagawa

Professor

Yasuteru Urano

Department of Biochemistry and Molecular Biology

Functional Biology
Department of Physiology

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

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

xxiii

Professor

Katsutoshi Oda

Professor

Takeshi Iwatsubo

Professor

Haruhiko Bito

Professor

Kiyoto Kasai

Professor

Tatsushi Toda

Professor

Nobuhito Saito

Department of Occupational, Environmental and Preventive

Professor

Shumpei Ishikawa

Medicine

Professor

Yasuki Kobayashi

Department of Forensic Medicine, and Medical Informatics

Professor

Hirotaro Iwase

and Economics

Professor

Kazuhiko Ohe

Professor

Issei Komuro

Professor

Takahide Nagase

Professor

Kazuhiko koike

Professor

Masaomi Nangaku

Professor

Toshimasa Yamauchi

Professor

Mineo Kurokawa

Professor

Keishi Fujio

Professor

Kyoji Moriya

Professor

Yutaka Yatomi

Professor

Hitoshi Okazaki

Professor

Tomoyuki Fujii

Professor

Yutaka Osuga

Department of Pediatric Science

Professor

Akira Oka

Department of Pediatric Surgery

Professor

Jun Fujishiro

Department of Aging Science

Professor

Masahiro Akishita

Professor

Jun Nakajima

Professor

Minoru Ono

Professor

Yasuyuki Seto

Professor

Kiyoshi Hasegawa

Professor

Haruki Kume

Professor

Soichiro Ishihara

Professor

Shinichi Sato

Professor

Mutsumi Okazaki

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

Social Medicine

Internal Medicine
Department of Medicine I

Department of Medicine II

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

Surgical Sciences
Department of Surgery

Department of Sensory and Motor System Medicine

xxiv

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

Professor

Kazuto Hoshi

Professor

Sakae Tanaka

Professor

Makoto Aihara

Professor

Tatsuya Yamasoba

Professor

Nobuhiko Haga

Professor

Kanji Uchida

Professor

Naoto Morimura

Professor

Norito Kawakami

Professor

Yutaka Matsuyama

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Department of Preventive and Administrative Nursing

Professor

Kiyoko Kamibeppu

Department of Clinical Nursing

Professor

Noriko Yamamoto

Professor

Megumi Haruna

Professor

Norito Kawakami

Professor

Hiromi Sanada

Professor

Masahiro Hashizume

Professor

Masamine Jinba

Professor

Akihiro Fujimoto

Professor

Masashi Mizuguchi

Professor

Masahiro Umezaki

Professor

Tomoyoshi Nozaki

Professor

Yutaka Matsuyama

Professor

Satoshi Sasaki

Professor

Hideo Yasunaga

Professor

Takahiro Kiuchi

Professor

Norito Kawakami

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Professor

Yasuki Kobayashi

Professor

Kazuhiko Ohe

Professor

Hiroshi Oyama

Professor

Hirotaro Iwase

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

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

xxv

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

Professor

Toru Miyazaki

Laboratory of Structural Physiology

Professor

Haruo Kasai

Laboratory of Clinical Biotechnology

Professor

Ungil Chung

Laboratory of Environmental and Metabolic Health Sciences

Professor

Makoto MurakamiLaboratory of Animal Resources

Professor

Atsu Aiba

Laboratory of Molecular Radiology

Professor

Kiyoshi Miyagawa

International Research Center for Medical Education

Professor

Masato Eto

Global Nursing Research Center

Professor

Hiromi Sanada

Medical LibraryProfessor

Hideo Yasunaga

International Academic Affairs

Professor

Shinichi Sato

Medical Scientist Training Program

Professor

Haruhiko Bito

Museum of Health and Medicine

Professor

Kazuhiko Ohe

Office for Human Research Studies

Professor

Masaomi Nangaku

Life Sciences Core Facility

Associate Professor

Yoshihiro Kita

Office for Clinical Practice and Medical Education

Professor

Masato Eto

Division of Research Resources and Support

Endowed Departments
Artificial Intelligence in Healthcare

Project Associate professor

Yoshimasa Kawazoe

Department of Bone & Cartilage Regenerative Medicine

Project Associate professor

Fumiko Yano

Cell & Tissue Engineering(Fujisoft)

Project Associate professor

Atsuhiko Hikita

Immunotherapeutics

Project Professor

Kazuhiro Kakimi

Department of Advanced Clinical Science andProject Associate professor

Mutsuo Harada

Project Professor

Naoto Hayashi

Ubiquitous Preventive Medicine

Project Associate professor

Yuichi Ikeda

Science for joint reconstruction

Project Associate professor

Toru Moro

Therapeutic Strategy for Heart Failure

Project Associate professor

Masaru Hatano

Department of Molecular Structure and Dynamics

Project Professor

Nobutaka Hirokawa

Department of Life Support Technology (Molten)

Project Professor

Taketoshi Mori

Department of Advanced Translational Research andProject Associate professor

Haruhiro Toko

Department of medical research and management for

Project Professor

Koh Matsudaira

musculoskeletal painDepartment of Osteoimmunology

Project Associate professor

Kazuo Okamoto

Department of medical and pharmaceutical community

Project Professor

Hirohisa Imai

Therapeutics
Computational Diagnostic Radiology and Preventive
Medicine
Clinical Trial Data Management

Medicine in Management of Pulmonary Hypertension

healthcare

xxvi

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

Health Economy and Society Policy

Project Professor

Tomoyuki Takura

Department of Biostatistics and Bioinformatics

Project Professor

Daisuke Koide

Department of Preventive Medicine for Locomotive

Project Professor

Noriko Yoshimura

Laboratory for New Generation Drug Discovery

Project Associate Professor

Hideaki Ando

Department of Molecular Neurology

Project Professor

Syoji Tsuji

Laboratory for Advanced Research on Pathophysiology

Project Associate Professor

Miki Iwabu

Department of Home Care Medicine

Project Associate Professor

Takashi Yamanaka

Department of Advanced Cardiology

Project Associate Professor

Katsuhito Fujiu

Department of Lipidomics

Project Professor

Yoshiya Oda

Advanced Nursing Technology

Project Associate professor

Ryoko Murayama

Department of Health Services Research

Project Associate professor

Taisuke Jo

Skincare Science

Project Associate professor

Takeo Minematsu

Imaging Nursing Science

Project Associate professor

Nao Tamai

Department of Healthcare Quality Assessment

Project Professor

Hiroaki Miyata

Bariatric & Metabolic Care

Project Associate professor

Susumu Aiko

Department of Innovative Dementia Prevention

Project Associate professor

Tadafumi Hashimoto

Department of Next-Generation Pathology Information

Project Professor

Takeshi Sasaki

Project Professor

Takashi Kadowaki

Chronic Kidney Disease Pathophysiology

Project Professor

Reiko Inagi

Department of Functional Genomics andProject Associate professor

Tomohisa Okamura

Project Professor

Makoto Komura

General Medicine

Head

Issei Komuro

Cardiovascular Medicine

Head

Issei Komuro

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Kazuhiko Koike

Nephrology and Endocrinology

Head

Masaomi Nangaku

Diabetes and Metabolic Medicine

Head

Toshimasa Yamauchi

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Keishi Fujio

Organ Disordersof Metabolic Diseases

Social Cooperation Program

Networking
Department of Prevention of Diabetes andLifestyle-Related Diseases

Immunological Diseases
Tissue stem cell / life dentistry
University Hospital
Clinical Divisions

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

xxvii

Infectious Diseases

Head

Kyoji Moriya

Neurology

Head

Tatsushi Toda

Geriatric Medicine

Head

Masahiro Akishita

Psychosomatic Medicine

Head

Kazuhiro Yoshiuchi

General Surgery

HeadSoichiro Ishihara

Stomach and Esophagus Surgery

Head

Yasuyuki Seto

Colon and Rectal Surgery

HeadSoichiro Ishihara

Hepatobiliary Pancreatic Surgery

HeadKiyoshi Hasegawa

Vascular Surgery

HeadSoichiro Ishihara

Breast and Endocrine Surgery

Head

Masahiko Tanabe

Artificial organ and Transplantation Surgery

HeadKiyoshi Hasegawa

Cardiovascular Surgery

HeadMinoru Ono

Thoracic Surgery

Head

Jun Nakajima

Neurosurgery

Head

Hirofumi Nakatomi

Anesthesiology and Pain Relief Center

Head

Kanji Uchida

Urology and Andrology

Head

Haruki Kume

Gynecologic Surgery

Head

Yutaka Ohsuga

Dermatology

HeadShinichi Sato

Ophthalmology

Head

Makoto Aihara

Orthopaedic Surgery and Spinal Surgery

Head

Sakae Tanaka

Otorhinolaryngology and Head and Neck Surgery

Head

Tatsuya Yamasoba

Rehabilitation Medicine

Head

Nobuhiko Haga

Plastic, Reconstructive and Aesthetic Surgery

Head

Mutsumi Okazaki

Oral-Maxillofacial Surgery and Orthodontics

Head

Kazuto Hoshi

Pediatrics

Head

Akira Oka

Pediatric Surgery

Head

Jun Fujishiro

Obstetrics and Gynecology

HeadTomoyuki Fujii

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Osamu Abe

Acute Medicine

Head

Naoto Morimura

Pharmaceutical Department

Head

Hiroshi Suzuki

Department of Clinical Laboratory

Head

Yutaka Yatomi

Surgical Center

Head

Kazuhiko Fukatsu

Radiology Center

Head

Osamu Abe

Department of Blood Transfusion

Head

Hitoshi Okazaki

Perinatal Center

Head

Tomoyuki Fujii

Rehabilitation Center

Head

Nobuhiko Haga

Department of Medical Engineering

Head

Kento Doi

Central Clinical Facilites

xxviii

The Tokyo Journal of Medical Sciences. Vol. 141, October 2020

Central Supply Service

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Naoto Morimura

Pathology

Head

Tetsuo Ushiku

Department of Corneal Transplantation

Head

Makoto Aihara

Department of Cell Therapy and Transplantation Medicine

Head

Mineo Kurokawa

Department of Endoscopy and Endoscopic Surgery

Head

Yousuke Nakai

Department of Hemodialysis and Apheresis

Head

Masaomi Nangaku

Infection Control and Prevention Service

Head

Kyoji Moriya

Department of Healthcare Information Management

Head

Kazuhiko Ohe

Organ Transplantation Service

Head

Kiyoshi Hasegawa

Labor Safety and Health Management Office

HeadTomotaka Yamamoto

Child Psychiatry

Head

Yukiko Kano

Tissue Bank

Head

Sumihito Tamura

Epidemiology and Preventive Medicine

Head

Nobutake Yamamichi

Center for Liaison and Public Relations

Head

Yutaka Osuga

Department of Chemotherapy

HeadKiyoshi Miyagawa

Department of Medical Record Management

Head

Kazuhiko Ohe

Critical Care Center

Head

Naoto Morimura

Department of Pain and Palliative Medicine

Head

Masahiko SumitaniChildren’s Medical Center

Head

Akira Oka

Department of Disaster Medical Management

Head

Naoto MorimuraInternational Medical Center

Head

Sumihito Tamura

Department of Clinical Nutrition Therapy

Head

Naoto Kubota

Department of Pediatric and Neonatal Intensive Care

Head

Naoto Takahashi

Department of Clinical Genomics

Head

Katsutoshi Oda

Clinical Research Promotion Center

Head

Takashi Moritoyo

22nd Century Medical and Research Center

Head

Yutaka Osuga

Department of Tissue Engineering

Head

Kazuto Hoshi

Cooperative Unit of Medicine and Engineering Research

Head

Minoru Ono

Translational Research Center

Head

Takeshi Iwatsubo

Genomic Research Support Center

Head

Yutaka Osuga

Unit for Early and Exploratory Clinical Development

Head

Takeshi Iwatsubo

The University of Tokyo,
Graduate School of Medicine

Molecular Cell Biology
1. Cell Biology and Anatomy

2

Department of Cell Biology andAnatomyAssociate Professor
Yoshimitsu Kanai, M. D.

Lecturer
Yosuke Tanaka, M. D.

Research Associate
Tadayuki Ogawa, Ph. D.

Home page

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

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

Research activities
Our research field covers the molecular cell biologyof the cytoskeleton. We focus on the molecularmechanisms of cell morphogenesis and intracellulartransports.
Our laboratory studies molecular architecture,dynamics and function of the neuronal cytoskeleton
using various new molecular cell biologicalapproaches including new electron microscopy suchas the quick freeze deep etch electron microscopy,
cryoelectron microscopy at atomic resolution, andcryoultramicrotomy,
biochemistry,
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.

3

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. Ichinose, S., T. Ogawa, X. Jiang, and N.
Hirokawa. The Spatiotemporal Construction of
the Axon Initial Segment via KIF3/KAP3/TRIM46
Transport under MARK2 Signaling.
Cell
Reports 28 (9): 2413-2426. 2019. (Published
Online: August 27, 2019). https://doi.org/10.1016/
j.celrep.2019.07.093
2. Toyoshima M., Jiang X., Ogawa T., Ohnishi T.,
Yoshihara S., Balan S., Yoshikawa T., and N.
Hirokawa. Enhanced carbonyl stress induces
irreversible multimerization of CRMP2 inschizophrenia pathogenesis. Life Sci Alliance.
2019 Oct 7;2(5). pii: e201900478. doi: 10.26508/
lsa.201900478. Print 2019 Oct.
3. Alsabban AH., Morikawa M., Tanaka Y., Takei Y.,
and N. Hirokawa.
Kinesin Kif3b mutation
reduces NMDAR subunit NR2A trafficking andcauses schizophrenia-like phenotypes in mice.
EMBO Journal . 2019 Nov 20:e101090. doi:
10.15252/embj.2018101090. [Epub ahead of print]
4. Yoshihara S., Jiang X., Morikawa M., Ogawa T.,
Ichinose S., Yabe H., Kakita A., Toyoshima M.,
Kunii Ya, Yoshikawa T., Tanaka Y., and N.
Hirokawa. Betaine ameliorates schizophrenic
traits by functionally compaensating KIF3-based
CRMP2 transport. Cell Reports in press
5. Iwata S., Morikawa M., Takei, Y., and N.
Hirokawa. An activity-dependent local transport
regulation via degradation and synthesis of KIF17
underlying cognitive flexibility. Science Advances
2020 6: eabc8355

4

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

LecturerHaruaki Yanagisawa, Ph.D.

Project Lecturer
Yoshiyuki Fukuda, Ph.D.

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

Project Research Associate
Akihisa Tsutsumi, Ph. D

Homepage

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

Introduction and Organization
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), Motohiro Morikawa,Yuta Komori, and Shuohang Gao (MSTP students),
Akiko Oosakaya, Ayako Ogasawara, Koshi Chiba(technical assistant), Kazuhiro Nakamura (Advanced
Academic Specialist), and Mikako Yanagiuchi and
Aiko Shibata(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 of
eukaryotic flagella/cilia. Flagella/cilia is both“propeller” and “antenna” of cells, whose diameter isabout 250 nm. From the recent studies, it is becoming
clear that flagella/cilia are involved in various
important cell functions.
To study the functions of flagella/cilia, we employ
various imaging techniques, including cryo-electron
microscopy and 3D-tracking microscope incombination with genetic manipulations.
Cryo-electron microscopy and cryo-electron
tomography
One of our strength is in the high-resolution
cryo-electron microscopy (cryo-EM). This technique

5enables preserving biological samples by quickly
freezing them and observing the frozen samples
without staining. Using electron microscopy, we areable
toobtainnano-meter
resolutionofmacromolecular complexes such as axonemes. We
have been developing new techniques, such asasymmetric helical reconstruction and Ruby-Helix
software.
A new project for cryo-electron microscopy started in
October 2017 with a grant from AMED (Japan
Agency for Medical Research and Development). This
project is intended to make cryo-EM techniques
available to many biological/medical researchers. New
state-of-the-art cryo-electron microscopes are used bymany researchers in Japan, including external users.
Model Organism
Our lab currently uses Chlamydomonas, zebrafish, andmice as a model organism for studying cilia/flagella.
To identify molecules that are involved in regulating
dynein, we use various genetic tools, includingclassical mutagenesis, siRNA.
In addition, we are also developing 3D-tracking
microscopy in collaboration with Dr. Oku in
Department of Engineering. We are trying to track
Chlamydomonas cells and simultaneously record
flagella movement to elucidate the mechanism offlagella regulation.

References
1. N. Nishida, Y. Komori, O. Takarada, A. Watanabe,
S. Tamura, S. Kubo, I. Shimada, and M. Kikkawa.
Structural basis for two-way communication
between dynein and microtubules. Nat Commun,
11(1):1038, 2020.
2 Y. Araiso, A. Tsutsumi, J. Qiu, K. Imai, T. Shiota,
J. Song, C. Lindau, L. S. Wenz, H. Sakaue, K.
Yunoki, S. Kawano, J. Suzuki, M. Wischnewski,
C. Schutze, H. Ariyama, T. Ando, T. Becker, T.
Lithgow, N. Wiedemann, N. Pfanner, M. Kikkawa,and T. Endo. Structure of the mitochondrial
import gate reveals distinct preprotein paths.
Nature, 575(7782):395–401, 2019.
3 C. Ito, H. Akutsu, R. Yao, K. Yoshida, K.
Yamatoya, T. Mutoh, T. Makino, K. Aoyama, H.
Ishikawa, K. Kunimoto, S. Tsukita, T. Noda, M.
Kikkawa,andK.
Toshimori.
Odf2
haploinsufficiency causes a new type of
decapitatedanddecaudated
spermatozoa,
Odf2-DDS, in mice. Sci Rep, 9(1):14249, 2019.
4 K. Sasaki, K. Shiba, A. Nakamura, N. Kawano, Y.
Satouh, H. Yamaguchi, M. Morikawa, D. Shibata,
R. Yanase, K. Jokura, M. Nomura, M. Miyado, S.
Takada, H. Ueno, S. Nonaka, T. Baba, M. Ikawa,
M. Kikkawa, K. Miyado, and K. Inaba. Calaxin isrequired for cilia-driven determination ofvertebrate laterality. Commun Biol, 2:226, 2019.
5 R. Danev, H. Yanagisawa, and M. Kikkawa.
Cryo-Electron Microscopy Methodology: Current
Aspects and Future Directions. Trends Biochem
Sci, 44(10):837–848, 2019.
6. M. Owa, T. Uchihashi, H. A. Yanagisawa, T.
Yamano, H. Iguchi, H. Fukuzawa, K. I.
Wakabayashi, T. Ando, and M. Kikkawa. Inner
lumen proteins stabilize doublet microtubules incilia and flagella. Nat Commun, 10(1):1143, 2019.

6

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

Research Associate
Yutaro Kashiwagi, Ph.D., Hisato Maruoka, Ph.D., Shinichiro Tsutsumi, M.D., 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 28 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

7

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

Publications
1. Urata, S., Iida, T., Yamamoto, M., Mizushima, Y.,
Fujimoto, C., Matsumoto, Y., Yamasoba, T. and S.
Okabe Cellular cartography of the organ of Corti
based on optical tissue clearing and machinelearning. eLIFE 2019 8. pii: e40946. doi: 10.
7554/eLife.40946.
2. Takahashi, A., Parajuli, L.M., Iwasaki, H., Tanaka,S., and S. Okabe Ultrastructural observation of
glutamatergic synapses by focused ion beamscanning electron microscopy (FIB/SEM)
Methods in Molecular Biology 2019 1941, 17-27.
doi: 10.1007/978-1-4939-9077-1_2.
3. Miller, C., Hale, M.E., Okano, H., Okabe, S., andMitra, P. Comparative principles for nextgeneration neuroscience Frontiers in Behavioral
Neuroscience 2019 13, 12. doi: 10.3389/fnbeh.
2019.00012.
4. Sadato, N., Morita, K., Kasai, K., Fukushi, T.,
Nakamura, K., Nakazawa, E., Okano, H., and S.
Okabe. Neuroethical issues of the Brain/MINDS
project of Japan Neuron 2019 101, 385-389. doi:
10.1016/j.neuron.2019.01.006.
5. Koebis M, Urata S, Shinoda Y, Okabe S,
Yamasoba T, Nakao K, Aiba A, and T. Furuichi.
LAMP5 in presynaptic inhibitory terminals in thehindbrain and spinal cord: a role in startle
response and auditory processing. MolecularBrain 2019 12, 20. doi: 10.1186/s13041-0190437-4.
6. Kashiwagi, Y., Higashi, T., Obashi, K., Sato, Y.,
Komiyama, N., Grant, S. G. N. and S. Okabe
Computational geometry analysis of dendritic
spines by structured illumination microscopy
Nature Communications 2019 10, 1285. doi: 10.
1038/s41467-019-09337-0.
7. Obashi, K., Matsuda, A., Inoue, Y., and S. Okabe
Precise temporal regulation of molecular
diffusion within dendritic spines by actin
polymers during structural plasticity. Cell Reports

2019 27, 1503-1515. e8. doi: 10.1016/j.celrep.
2019.04.006.
8. Li, J., Sekine-Aizawa, Y., Ebrahimi, S., Tanaka,S., and S. Okabe Tumor suppressor protein
CYLD regulates morphogenesis of dendrites andspines. European Journal of Neuroscience 201950(4):2722-2739. doi: 10.1111/ejn.14421.
9. Iguchi, R., Tanaka, S., and S. Okabe Neonatalsocial isolation increases the proportion of theimmature spines in the layer 2/3 pyramidal
neurons of the somatosensory cortex. Neuroscience Research 2020 154:27-34. doi: 10.1016/j.
neures.2019.05.004.
10. Cho, T., Kashiwagi, Y., and S. Okabe

Temporalsequences of synapse disintegration triggered byafferent axon transection, Time-lapse imaging
study of presynaptic and postsynaptic molecules.
eNeuro. 2019 4; 6(5). pii: ENEURO.0459-18.
2019. doi: 10.1523/ENEURO.0459-18.2019.
11. Iwasaki,

K.,

Obashi,

K.,

and

S.

Okabe

Vasodilator-stimulated phosphoprotein (VASP) is
recruited into dendritic spines via G-actindependent mechanism and contributes to spine
enlargement and stabilization.

Eur J Neurosci.

2020 51(3):806-821. doi: 10.1111/ejn.14634.
12. International Brain Initiative: An innovative
framework for coordinated global brain research
efforts.

International Brain Initiative (J. Bjaalie

and S. Okabe corresponding authors) Neuron
2020 105(2):212-216. doi: 10.1016/j.neuron.2020.
01.002.
13. Tanaka S, Masuda Y, Harada A, Okabe S.
Impaired actin dynamics and suppression of
Shank2-mediated spine enlargement in cortactin
knockout mice. Microscopy (Oxf). 2020 Mar 9;
69(1):44-52. doi: 10.1093/jmicro/dfaa001.
14. Okabe, S. Recent advances in computational
methods for measurement of dendritic spines
imaged by light microscopy. Microscopy (Oxf).
2020 Jul 30;69(4):196-213. doi: 10.1093/jmicro/
dfaa016.

Molecular Cell Biology
2. Biochemistry and Molecular Biology

9Department of Molecular Biology
Professor
Noboru Mizushima, M.D., Ph.D.

Lecturer
Hayashi Yamamoto, Ph.D.

Research Associate
Hideaki Morishita, M.D., Ph.D. (~Aug 2019), Yuji Sakai, Ph.D.

Project Associate Professor
Chieko Saito, Ph.D.

Project Lecturer
Ikuko Koyama-Honda, Ph.D.

Project Research Associate
Junichi Sakamaki, Ph.D., Takeshi Sugawara, Ph.D., Seiichi Koike, Ph.D., Roland Knorr,
Ph.D. (~Jan 2019), Tomoya Eguchi, M.D., Ph.D.

Homepagehttps://molbiolut.jp/en/

Introduction and Organization
Established in 1893 as a part of Department of
Physiology, this Department became independent in
1897. It was renamed Department of Biochemistry in
1927, First Department of Biochemistry in 1974, andDepartment of Molecular Biology in 1997, according
to the creation of new related departments and thereorganization of Faculty of Medicine. This
Department has been headed by seven professors,each of whom made significant contributions to thedevelopment of biochemistry, nutrition, and molecularbiology in Japan.
Professor
Muneo
Kumagawa,
whoestablished this Biochemistry or Medical Chemistry
Department for the first time in Japan, graduated fromThe University of Tokyo Faculty of Medicine in 1882.
In 1884 he went to Germany to study in Departmentof Pathology, The University of Berlin headed by Dr.
Rudolf Virchow under the supervision of Dr. Ernst
Salkowski. After returning to Japan, he became
Lecturer and was promoted to Professor of thisDepartment. In 1908, he discovered a lack ofglycogenecity in lipids, which has been firmly
established besides some exceptions, and succeeded inpurification of vitamin B1, which had been discoveredby Dr. C. Eijkman in 1906. His lab produced many
famous researchers including Dr. Masahiro Sakaguchi,
who developed a world-famous colorimetric method
for arginine and Dr. Takaoki Sasaki, who firstsucceeded in generating liver cancer with chemicals.
Professor Samuro Kakiuchi graduated fromthe Imperial University of Tokyo, Faculty of Medicine
in 1906 and studied under Professor Kumagawa. After
studying in the US, he came back to succeed the late
Kumagawa. He launched the Journal of Biochemistry
and founded the Japanese Society of Biochemistry.
His students included Professors Kodama andShimazono.
Professor Keizo Kodama graduated from theImperial University of Tokyo in 1918. After studying
at Cambridge University, he became Professor of
Biochemistry at Kyushu Imperial University. In 1943,

10

he took up a professorship at this Department. His
research was on oxidation and reduction, andnutrition.
Professor Norio Shimazono, a graduate of
the Imperial University of Tokyo Faculty of Medicine
in 1928, became a professor at Niigata Medical
School. In 1952 he succeeded Professor Kodama. He
studied vitamin B1/ cocarboxylase, ketoacid
metabolism and hexose metabolism.
Professor Tamio Yamakawa graduated fromthe Imperial University of Tokyo Faculty of Medicine,and began studies at the Institute for Infectious
Diseases, the University of Tokyo. He took up a
professorship to succeed Professor Shimazono. He
was a pioneer in glycolipid research and discovered
the involvement of sialic acid in the ABO blood typeantigens.
Professor Masami Muramatsu graduatedfrom the University of Tokyo Faculty of Medicine in
1955. He began studies at the Department of Internal
Medicine, and then went to Baylor College ofMedicine to study under Dr. H. Busch. After comingback to Japan, he took a position at the Cancer
Institute and the took up a professorship at Tokushima
University School of Medicine. In 1982, he succeeded
Professor Yamakawa. He studied ribosomal RNA andcloned interferon and p450 genes.
Professor Hiroto Okayama graduated from
Kumamoto University School of Medicine in 1973.
After taking a Ph.D. degree at Kyoto University
School of Medicine, he went to Stanford University to
study under Dr. P. Berg. After working at the NIH,
USA, he became Professor of Molecular Genetics, atOsaka University Institute for Infectious Diseases. In
1993 he succeeded Professor Muramatsu. At Stanford
and the NIH, he studied gene cloning and developed afull-length cDNA cloning method and a cDNA
expression cloning vector system, and, after returning
to Japan, he studied cell cycle control and cancer.
Professor Noboru Mizushima graduatedfrom Tokyo Medical and Dental University, Faculty of
Medicine in 1991. After receiving Ph.D., he studied at
National Institute for Basic Biology in Okazaki andstarted works on autophagy in yeast and mammals at
Dr. Yoshinori Ohsumi’s laboratory. Taking a position
as a PI at the Tokyo Metropolitan Institute of Medical
Science in 2004, he started studies on physiologicalroles of autophagy. He was promoted to Professor of
Physiology and Cell Biology, in Graduate School andFaculty of Medicine at Tokyo Medical and Dental
University in 2006, and succeeded Professor Okayama
in 2012.

Research Activities
Our current study focuses on the understanding of themolecular mechanism and physiological roles of
autophagy.
1. Molecular mechanism of autophagy
Autophagy is one of the major degradation
pathways in the cell. In autophagy, intracellularcomponents are sequestered by autophagosomes
and then degraded upon fusion with lysosomes.
Yeast genetic studies have identified more than 40
autophagy-related (ATG) genes. Many of thesegenes are conserved in higher eukaryotes, whichallow us to perform genetic analysis of autophagy
in mammals. We are currently addressing some of
the central questions remaining the autophagy
field and trying to elucidate the mechanisms of (1)regulation of autophagy, (2) initiation of
autophagosome formation, (3) elongation of the
autophagic membrane, (4) closure, fusion, anddegradation of the autophagosome (5) recognitionof selective substrates. In 2018, we reported thefollowing novel findings.
Autophagosome formation requires thecovalent attachment of the ubiquitin-like protein
ATG12 to ATG5. However, why both proteinsneed to be covalently bound has been unclear for
two decades. Unexpectedly, we found that the
Apicomplexanparasites
Plasmodium
andToxoplasma and the yeast Komagataella phaffii(former Pichia pastoris) do not possess the
enzyme required for covalent binding of ATG12and ATG5, and that ATG12 and ATG5 exist as astable, functional, non-covalent complex. That is,
ATG12 and ATG5 do not necessarily have to forma covalent complex, and the ATG12 system insome organisms may have evolved to a simpler,
non-covalent version (Pang et al. Nat Struct Mol
Biol 2019).
Autophay degrades intracellular components

11

not only nonselectively but also selectively. In the
search for novel molecules selectively degradedby autophagy, we identified TEX264. TEX264 ispresent on the endoplasmic reticulum membraneand binds to autophagosome LC3 at the carboxy
terminus. In cells lacking TEX264, thedegradation of endoplasmic reticulum by autophagy (called ER-phagy) was remarkably
suppressed. Thus, TEX264 functions as a novel
ER-phagy adaptor (Chino et al. Mol Cell 2019).
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.
Some of the autophagy-related factors havealso been found to have functions other than
autophagy. For example, using zebrafish and mice,
we found that the ER membrane protein VMP1 isrequired not only for autophagy but also for theprocess of lipoprotein detachment from the ER to
the lumen. Since autophagy, lipoprotein secretion,and lipid droplet formation involves dynamic
morphological changes of the ER, VMP1 may
play a role in the homeostasis and remodeling of
the ER membrane. Recently, an association
between single nucleotide polymorphisms (SNPs)
in the human VMP1 gene and blood cholesterollevels has been reported. Our results would
provide new insights into the mechanism oflipoprotein formation and secretion and contributeto the understanding of relevant diseases.
3. Methods for monitoring autophagic activity
Measuring autophagic activity is critical to dissect
molecular mechanisms and functions ofautophagy but remains challenging due to the lackof a definitive method. We have recently
developed a new fluorescent reporter, GFP-LC3RFP-LC3ΔG, to assess autophagic flux. We havegenerated a new mouse model ubiquitously

expressing this autophagy flux reporter.

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

Publication
1. Takahashi, S.S., Sou, Y.S., Saito, T., Kuma, A.,Yabe, T., Sugiura, Y., Lee, H.C., Suematsu, M.,
Yokomizo, T., Koike, M., Terai, S., Mizushima,N., Waguri, S., Komatsu, M. Loss of autophagy
impairs physiological steatosis by accumulationof NCoR1. Life Sci. Alliance 3. pii: e201900513(2019)
2. Morishita, H., Zhao, Y.G., Tamura, N., Nishimura,T., Kanda, Y., Sakamaki, Y., Okazaki, M., Li, D.,*Mizushima, N. A critical role of VMP1 inlipoprotein secretion. Elife 8. pii: e48834 (2019)
3. Chino, H., Hatta, T., Natsume, T., *Mizushima, N.
Intrinsically disordered protein TEX264 mediates
ER-phagy. Mol. Cell 74:909-921 (2019).
4. DeVorkin, L., Pavey, N., Carleton, G., Comber, A.,
Ho, C., Lim, J., McNamara, E., Huang, H., Kim,
P., Zacharias, L.G., Mizushima, N., Saitoh, T.,
Akira, S., Beckham, W., Lorzadeh, A., Moksa, M.,
Cao, Q., Murthy, A., Hirst, M., DeBerardinis, R.J.,*Lum, J.J. Autophagy Regulation of Metabolism
Is Required for CD8+ T Cell Anti-tumor
Immunity. Cell Rep. 27:502-513 (2019).
5. Saito, T., Kuma, A., Sugiura, Y., Ichimura, Y.,
Obata, M., Kitamura, H., Okuda, S., Lee, H.C.,
Ikeda, K., Kanegae, Y., Saito, I., Auwerx, J.,
Motohashi, H., Suematsu, M., Soga, T., Yokomizo,T., Waguri, S., Mizushima, N., *Komatsu, M.
Autophagy regulates lipid metabolism throughselective turnover of NCoR1. Nat Commun. 10:1567 (2019).
6. Pang, Y., Yamamoto, H., Sakamoto, H., Oku, M.,
Mutungi, J.K., Sahani, M.H, Kurikawa, Y., Kita,
K., Noda, N.N., Sakai, Y., *Jia, H., *Mizushima,
N. Evolution from covalent conjugation to12

non-covalent interaction in the ubiquitin-like
ATG12 system. Nat. Struct. Mol. Biol. 26:289296 (2019).
7. *Mizushima, N. The ATG conjugation systems in
autophagy. Curr. Opin. Cell Biol. (2019)
8. *Mizushima, N. The ubiquitin E2 enzyme
UBE2QL1 mediates lysophagy. EMBO Rep. 15:
e49104 (2019).
9. *Morishita, H., *Mizushima, N. Diverse cellularroles of autophagy. Annu. Rev. Cell Dev. Biol. 35:
453-475 (2019)
10. Morita, K., Hama, Y., *Mizushima, N. TMEM41B
functions with VMP1 in autophagosome
formation. Autophagy. 15:922-923 (2019)11. *Mizushima, N., Matsui, T., Yamamoto, H. YKT6
as a second SNARE protein of mammalian
autophagosomes. Autophagy. 15:176-177 (2019).

13

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

Assistant Professor
Yoshitaka Taketomi, Ph.D.

Home Page

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

Introduction
The Department of Cellular Signaling, belonging to
the Molecular Cell Biology, is organized by Murakami,
who is also a professor of the Laboratory ofMicroenvironmental and Metabolic Health Sciences,since August 2018. The laboratory is composed of one
professor and one assistant professor as well as themembers of the the Laboratory of Microenvironmental
and Metabolic Health Sciences.

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

1) Metabolic diseases
Polyunsaturated fatty acids (PUFAs) confer healthbenefits by preventing inflammation and obesity and
by increasing thermogenesis in brown and beige
adipocytes. As well as being supplied exogenously as
nutrients, PUFAs are largely stored in membrane
glycerophospholipids and released by phospholipase
A2s (PLA2s). However, the molecular identity of the
PLA2 subtype(s) that supplies endogenous PUFAs formetabolic homeostasis remains unclear. PLA2G2D, asecreted phospholipase A2 (sPLA2) isoform, isconstitutively expressed in M2 macrophages in white
adipose tissue (WAT) and shows a reciprocal
correlation with obesity. Studies using global andmacrophage-specific Pla2g2d-/- mice have revealed
that PLA2G2D ameliorates diet-induced obesity andinsulin resistance and counteracts the proinflammatory
M1 macrophage bias in WAT. Moreover, PLA2G2D
increases energy expenditure and thermogenesis byfacilitating
WAT
browning.
Mechanistically,
PLA2G2D constitutively supplies a pool of PUFAs,
3 in particular, in WAT. These results underscore thecontribution
of
the
M2
macrophage-driven
PLA2G2D-PUFA axis to metabolic health (Sato et al,
Cell Reports 2020).
Choline supplies methyl groups for regenerationof methionine and the universal methyl donor
S-adenosylmethionine (SAM) in the liver. Althoughphosphatidylcholine (PC) is the main cellularreservoir for choline, the pathway for hepatic PC
catabolism that generates free endogenous choline
remains unexplored. We found that PNPLA7, alysophospholipase that catalyzes the conversion of

14

lysophosphatidylcholine to glycerophosphocholine(GPC), is crucial for this pathway. Pnpla7-deficient
mice show marked decreases in hepatic GPC, choline,
betaine and SAM, accompanied by various signs ofmethionine insufficiency including impaired triglyceride storage and secretion, hypoglycemia, increased
energy expenditure, and reduced fat mass withadipocyte browning. Accordingly, mutant mice arelean, display growth retardation, and die prematurely.
Thus, the methyl group flux from choline endogenously generated through PC breakdown by the
PNPLA7 axis is crucial for liver functions and energy
homeostasis (manuscript in preparation).
2) Cardiovascular diseases
Aortic dissection is a life-threatening aortopathy
involving separation of the aortic wall, yet theunderlying mechanisms are still incompletely
understood. Epidemiological evidence suggests thebeneficial effects of unsaturated fatty acids on
cardiovascular health. Here we show that PLA2G5, asPLA2 isoform expressed in aortic endothelial cells,
plays a protective role against aortic dissection byendogenously mobilizing vasoprotective lipids. Global
and endothelial cell-specific Pla2g5-deficient micefrequently develop aortic dissection shortly after
infusion of angiotensin II (AT-II). In the AT-II-treatedaorta, endothelial PLA2G5 mobilizes oleic andlinoleic acids, which attenuate ER stress, increase theexpression of lysyl oxidase, and thereby stabilize theextracellular matrix in the aorta. The increased
susceptibility of Pla2g5-/- mice to aortic dissection
was rescued by dietary supplementation with oleic or
linoleic acid. These findings reveal an unexploredfunctional link between sPLA2-driven phospholipid
metabolism and aortic stability, possibly contributing
to the development of novel diagnostic and/or
therapeutic strategies for aortic dissection (Watanabe
et al, J Biol Chem 2020; selected as an Editors’ Pick).
3) Skin diseases
Lipids play crucial roles in skin homeostasis anddiseases. We have currently reported that PLA2G2F,
an epidermal sPLA2, mobilizes lysoplasmalogen, aunique lysophospholipid that promotes epidermal
hyperplasic diseases such as psoriasis and skin cancer(Yamamoto et al, J Exp Med 2015), and that PNPLA1,
a member of the intracellular iPLA2 family whose
mutations cause autosomal recessive congenitalichthyosis, acts as a transacylase to produce
ω-O-acylceramide, an essential lipid component forskin barrier function (Hirabayashi et al, Nat Commun2017). Furthermore, by phenotypic screening (withperturbation of skin barrier function as a readout)using a series of PLA2 knockout strains, as well as bygene expression profiling of PLA2-related genes inmouse and human skins, we have identified several
PLA2s that appear to be linked to skin diseases. Of
these, we found that PLA2G4E (cPLA2, which isexpressed in epidermal keratinocytes, exhibits aunique N-acyltransferase activity that transfers a fatty
acid from the sn-1 position of PC to the amino groupof phosphatidylethanolamine (PE) to give rise to
N-acyl PE (NAPE), a precursor of the non-canonicallipid mediator N-acylethanolamine (NAE) that has ananti-inflammatory function. Pla2g4e deficiency leadto exacerbation of psoriasis with marked reduction ofvarious NAE species, suggesting that PLA2G4E plays
a role in putting a brake on psoriasis by generating theanti-inflammatory lipid mediator NAE. This is thefirst demonstration of the role of PLA2G4E as an
N-acyltransferase in vivo (manuscript in preparation).
4) Allergic diseases
We have currently shown that PLA2G3, an sPLA2
isoform secreted from mast cells, promotes mast cellmaturation by driving the paracrine PGD2 circuit incooperation with microenvironmental fibroblasts(Taketomi et al, Nat Immunol 2013) and that
PAF-AH2, a unique PLA2 that hydrolyzes oxidized
phospholipids, ensures optimal mast cell activationand thereby allergic responses through producing
unique EPA/DHA metabolites (ω3 epoxides)(Shimanaka et al, Nat Med 2017). We are now
analyzing other PLA2 knockout strains that havealterations in allergic responses.
5) Neuronal diseases
Mutations in the PLA2G6 gene, which encodes
PLA2G6 or iPLA2, are responsible for PARK14linked Parkinson’s disease with -synucleinopathy.
However, it is unclear how PLA2G6 mutations lead to
dopaminergic (DA) neurodegeneration in association
with -synuclein (-Syn) aggregation. We found that
PLA2G6-deficient Drosophila exhibits degenerationof DA neurons, with defective neurotransmission andmotor ability. Lipidomics analysis of the brain reveals
that the acyl-chain length of phospholipids is15

shortened by PLA2G6 loss, which causes membrane
lipid disequilibrium-induced ER stress. Introductionof native human PLA2G6 or C19orf12, an orphan
protein residing in the mitochondria-ER contact site,in PLA2G6-deficient flies rescues the phenotypes
associated with altered lipid composition, ER stressand DA neurodegeneration, whereas that of a diseaseassociated missense mutant, PLA2G6 A80T, fails tosuppress these phenotypes. The acceleration of -Syn
aggregation by PLA2G6 deficiency or A80T
expression is suppressed by the administration oflinoleic acid, which corrects lipid composition in the
fly brain. These results suggest that membrane
remodeling by PLA2G6 is required for the survival of
DA neurons and -Syn stability (Mori et al, PNAS2019).

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

Publications
1. Mori A, Hatano T, Inoshita T, Shiba- Fukushima
K, Koinuma T, Meng H, Kubo SI, Spratt S, Cui C,
Yamashita C, Miki Y, Yamamoto K, Hirabayashi
T, Murakami M, Takahashi Y, Shindou H, Nonaka
T, Hasegawa M, Okuzumi A, Imai Y, Hattori N.
Parkinsin’s
disease-associated
iPLA2-VIA/
PLA2G6 regulates neuronal functions and αsynuclein stability through membrane remodeling.
Proc Natl Acad Sci U S A. 116, 20689-20699,
2019.

2. Jin F, Li X, Deng Y, Timilshina M, Huang B, Kim
DY, Chang JH, Ichinose H, Baek SH, Murakami
M, Lee YJ, Chang HW. The orphan nuclear
receptor NR4A1 promotes FcεRI-stimulated mastcell activation and anaphylaxis by counteracting
the inhibitory LKB1/AMPK axis. Allergy 74,1145-1156, 2019.
3. Murakami M. Novel functions of phospholipase
A2s: Overview. Biochim. Biophys. Acta 1864,
763-765, 2019. (Review, Guest Editor)
4. Murakami M, Miki Y, Sato H, Murase R,
Taketomi Y, Yamamoto K. Group IID, IIE, IIF and
III secreted phospholipase A2s. Biochim. Biophys.
Acta 1864, 803-818, 2019. (Review, Guest Editor)
5. Hirabayashi T, Murakami M, Kihara A. The roleof PNPLA1 in ω-O-acylceramide synthesis andskin barrier function. Biochim. Biophys. Acta
1864, 869-879, 2019. (Review, Guest Editor)
6. Sato H, Taketomi Y, Miki Y, Murase R,
Yamamoto K, Murakami M. Secreted phospholipase PLA2G2D contributes to metabolic health bymobilizing -3 polyunsaturated fatty acids inwhite adipose tissue. Cell Rep. 31, 107579, 2020.
7. Watanabe K, Taketomi Y, Miki Y, Kugiyama K,
Murakami M. Endothelial group V secreted
phospholipase A2 plays a protective role against
aortic dissection. J. Biol. Chem. 295, 1009210111, 2020. (selected as an Editors’ Pick)
8. Toda K, Tsukayama I, Nagasaki Y, Yuka K,
Tamenobu A, Ganeko N, Ito H, Kawakami Y,
Takahashi Y, Miki Y, Yamamoto K, Murakami M,
Yamamoto T. Red-kerneled rice proanthocyanidin
inhibits
arachidonate
5-lipoxygenase
anddecreases psoriasis-like skin inflammation. Arch.
Biochem. Biophys. 689, 108307, 2020.
9. Sano Y, Toyoshima S, Miki Y, Taketomi Y, Ito M,
Lee H, Saito S, Murakami M, Okayama Y.
Activation of inflammation and resolution
pathways of lipid mediators in synovial fluid frompatients with severe rheumatoid arthritis
compared with severe osteoarthritis. Asia Pac.
Allergy. 10, e21, 2020.

16

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

Lecturer
Yukiko Kurihara, M.D.

Research Associate
Kazuo Tonami, M.D.

Associate
Yasunobu Uchijima, Ph.D.

URL http://bio.m.u-tokyo.ac.jp/home-j.html
Introduction and Organization
The Department of Physiological Chemistry andNutrition, the predecessor of the present department,
was founded in 1952. Upon the restructuring of theuniversity system in 1997, the department was
renamed ‘Department of Physiological Chemistry andMetabolism’ as one unit of the Specialty of Molecular
Cell Biology. The present members include the above
stuffs, 2 postdoctoral fellow, 7 graduate students(doctor course) and 1 secretary. Professor Tomoichiro
Asano (Hiroshima University) is invited as a part-time
lecturer to instruct graduate students and give lecturesto undergraduate students.

Teaching Activities
We give a series of lectures and laboratory courses
on biochemistry and molecular biology forundergraduate students from Faculty of Medicine andFaculty of Science. We also accept undergraduate
students taking the MD-researcher developing
program, “Free Quarter” and “Early-Exposureto-Medicine” courses every year. Several students arestaying in our lab beyond the term to join our
research.
For graduate students, we hold progress-reportmeeting and journal club every week, and sometimes
invite established scientists for seminar to encourage
scientific discussion.

Research Activities
Our research is aimed at understanding molecularmechanisms underlying morphogenesis of the craniofacial and cardiovascular structures.
(1) Craniofacial development
The branchial (pharyngeal) arches are a segmental
series of bulging structures common and characteristic
for all vertebrate embryos. They are mainly formed bymigratory cranial neural crests, which give rise tovarious skeletal components including the jaw andmiddle ear structures. We have revealed that
endothelin-1 (ET-1), first identified as anendothelium-derived vasoconstrictor peptide, and its
receptor ETAR signaling acts as a molecular switchthat determines the lower jaw identity by using mouse
genetics. In another work, we clarified that the
tympanic membranes of mammals and reptiles/birds
are independently acquired as a product of convergent
evolution by showing that lower-to-upper jaw
transformation induced by inactivation of ET-1/ETAR17

signaling results in loss of the tympanic membrane inmouse, but causes duplication of the tympanic
membrane in chicken. Recently, human ETAR genemutations causing craniofacial abnormalities andalopecia were identified, and the causal relationshipwas confirmed by our experiments recapitulating thesame mutations in mice. We are now collaborating
researchers in the field of molecular dynamics toclarify the mechanisms underlying the pathogenic
mutations.
Furthermore, we verified that Hoxa2, a member ofthe Hox gene clusters, is sufficient for endowing
Hox-free pharyngeal arch tissues with the second
pharyngeal arch identity by introducing ectopic Hoxa2
expression. Hoxa2 gene manipulation also identified
the dorso-ventral boundary in the pharyngeal region,
together with experiments using mice carrying
mutations in ET-1/ETAR and its downstream genes
Dlx5 and Dlx6.
(2) Cardiac development
Recently, we found that the cranial neural crest
from the preotic region, rather than post-otic ‘cardiac’
neural crest cells, migrate into the heart anddifferentiate into coronary artery smooth muscle cells
in the proximal region. Ablation of the preotic neuralcrest in chick embryos causes abnormalities incoronary septal branch and orifice formation.
Appropriate migration and deployment of neural crest
cells and subsequent smooth muscle differentiation
require multicellular interactions involving ET-1/
ETAR signaling possibly through G12/13-mediated,
Dlx5/Dlx6-independet mechanisms, whereas ET-1/
ETAR signaling is involved in ventral identification of
the pharyngeal arches through Gq/11-mediated, Dlx5/
Dlx6-dependet mechanisms. These findings indicatethat the ET-1/ETAR signaling pathway is involved incraniofacial and cardiac development throughdifferent trimeric G-proteins.
(3) Angiogenesis
Angiogenesis is a morphogenetic process that
produces branching vascular structures during
embryogenesis and various (patho-)physiologicalconditions. We have identified characteristic cellularbehaviors in angiogenic processes, including dynamicchanges in forward-backward movement, tip cell

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

References
1. Maruyama K, Miyagawa-Tomita S, Mizukami K,
Matsuzaki F, Kurihara H. Isl1-expressing nonvenous cell lineage contributes to cardiac
lymphatic vessel development. Dev. Biol. 452(2):134-143, 2019.
2. Takubo N, Yura F, Naemura K, Yoshida R,
Tokunaga T, Tokihiro T, Kurihara H. Cohesive
and anisotropic vascular endothelial cell motility
driving angiogenic morphogenesis. Sci. Rep.
29(1):9304, 2019.
3. Fukushima Y, Nishiyama K, Kataoka H, Fruttiger
M, Fukuhara S, Nishida K, Mochizuki N,
Kurihara H, Nishikawa SI, Uemura A. Rho J
integrates attractive and repulsive cues in
directional migration of endothelial cells. EMBO
J. 29:e102930, 2020.
4. Saito R, Koebis M, Nagai T, Shimizu K, Liao J,
Wulaer B, Sugaya Y, Nagahama K, Uesaka N,
Kushima I, Mori D, Maruyama K, Nakao K,
Kurihara H, Yamada K, Kano M, Fukada Y, Ozaki
N, Aiba A. Comprehensive analysis of a novel
mouse model of the 22q11.2 deletion syndrome: amodel with the most common 3.0-Mb deletion at
the human 22q11.2 locus. Transl. Psychiatry.

18

10(1):35, 2020.
5. Higashijima Y, Nagai N, Yamamoto M, Kitazawa
T, Kawamura YK, Taguchi A, Nakada N,
Nangaku M, Furukawa T, Aburatani H, Kurihara
H, Wada Y, Kanki Y. Lysine demethylase 7aregulates murine anterior-posterior development
by modulating the transcription of Hox genecluster. Commun. Biol. 3(1):725, 2020.

19

Department ofAdvanced Structural Studies
Professor
Radostin Danev, Ph.D.

Homepage http://danevlab.m.u-tokyo.ac.jp
Introduction and Organization
Our laboratory was established in November 2018 aspart of an initiative to strengthen the molecular
structural biology research at the Graduate School of
Medicine. We are supported by grants from the Japan
Science and Technology Agency (JST), the Japan
Society for the Promotion of Science (JSPS) andTakeda Science Foundation. Our research also
benefits from indirect support through an
instrumentation facility grant from the Japan Agency
for Medical Research and Development (AMED). The
lab members are Radostin Danev (professor) and Isao
Takahashi (technical assistant).

Teaching activities
We conduct training and provide support for the usersof the recently opened cryo-electron microscopy(cryo-EM) facility at the Graduate School of Medicine.
This includes specialized lectures at cryo-EM courses
within the University of Tokyo and other research
institutions in Japan. We also gave introductorylectures about structural biology as part of thefollowing 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
structure-function relationships of proteins

the
and

cellular components. We hope to contribute to thegeneral knowledge of the molecular mechanisms
behind chronic diseases and thereby to help develop
effective treatments.
Currently, we are investigating an important class ofmembrane proteins called G protein-coupled receptors(GPCRs). GPCRs constitute the largest protein
superfamily in the human genome and are implicatedin numerous illnesses, such as diabetes, obesity,
nervous system disorders, asthma, allergies,
cardiovascular disorders, cancer, and others. As such,they also represent the biggest group of drug targets
and are the subject of approximately 30% of approved
drugs. For our structural investigations, we employ thepresently flourishing method of cryo-EM single
particle analysis to determine the atomic structure of
GPCRs in complex with both native and synthetic
ligands. We have an ongoing international
collaboration with a group from Monash University inAustralia that specializes in GPCR pharmacology andhas substantial experience in expression andpurification of target complexes. In the past year, ourresults comprise more than twenty sub-3 Å full-length
unmodified GPRC structures, one third of which are at
resolutions better than 2.5 Å. This is an unprecedented
achievement both in terms of resolution andthroughput. To reach such level of success, we
conducted a thorough optimization of theexperimental parameters for both sample preparationand cryo-EM data collection. We implemented ahighly efficient “tandem” approach that combined
methodology testing with actual data collection andtherefore did not require extra usage time on the costly

20

and heavily booked electron microscope equipment.
The exceptional results from our group and all othergroups that utilize the state-of-the-art equipment at thecryo-EM facility showcase both the accelerating
evolution of cryo-EM as a technique and the very
successful launch of the new cryo-EM facility at theGraduate School of Medicine.
Despite the exponential growth of the field in recent
years, there are still many areas where further
advances are possible and/or are highly desirable. In
addition to our structural studies, we are also working
on the development of new experimental methods forcryo-EM. One of the current projects aims to develop
and implement a high-speed real-time synchronous
modulation of the electron beam that will expand thecapabilities of the microscope. With the so-called
FADE method (fast and accurate defocus modulation),
we hope to transform the instrument from a static andrigid system into a dynamic and tunable opticalplatform. Other directions of our research include
improvement of the throughput and performance ofelectron cryo-tomography and cryo-EM experimentautomation. In the future, we plan to expand ourinvestigations towards state-of-the-art deep learning
experiment augmentation and improved dataprocessing algorithms.

References
1. Eisenstein F, Danev R, Pilhofer M. Improved
applicability and robustness of fast cryo-electron
tomography data acquisition. J. Struct. Biol. 208,
107-114 (2019).
2. Danev R, Yanagisawa H, Kikkawa M.
Cryo-Electron Microscopy Methodology: Current
Aspects and Future Directions. Trends Biochem
Sci 44 (2019) 837-848.

Functional Biology
1. Physiology

22

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

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

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

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

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system.
(1) Sensory inputs sparsely activate neurons in thesensory cortex, which is postulated to be an efficient
information coding. However, how sparsely active
neurons represent information and how the
information is optimally decoded from the sparse
representation have not been determined.
In the primary visual cortex (V1), simple cells
each have a receptive field (RF) structure that ismodeled by a two-dimensional (2D) Gabor function.
Theoretically, a single natural scene is represented bya relatively small number of neurons using Gabor-like23

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

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

References(1) Yoshida T, Ohki K. Natural images are reliably
represented by sparse andvariable populations ofneurons in visual cortex Nature Communications..2020.Feb13;11.872(2) Matsui T, Murakami T, Ohki K. Neuronal Originof the Temporal Dynamics of Spontaneous BOLD
Activity Correlation. Cereb Cortex. 2019 Apr 1;
29(4):1496-1508.
(3) 松井鉄平 大木研一
「神経‐グリア‐fMRI 信号を繋ぐ脳活動イ
メージング」, 実験医学増刊号「グリア」（松井広, 田中謙二編）（羊土社）, 2019 年 10 月
（和文）

24

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

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

Homepage

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

Introduction and Organization
The Department of Cellular and Molecular Physiology
succeeded the former ‘Second Department of Physiology’, and belongs to the Department of Physiology.
We participate in the teaching of physiology atundergraduate school and graduate school.
The present members include the above staff, 1secretary staff, 5 technical staff, 2 postdoctoral
researchers, 6 graduate students.

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

Research activities
Various firing patterns of many cortical neurons

represent information processing in the brain. The
microarchitecture of synaptic connections control
information processing in cortical circuits. The
structure and location of synapses determine andmodify the strength of this information processing.
The aim of our laboratory is to reveal how information
is formed, maintained, selected, and decoded in thebrain at the levels of single cells and of single
synapses. To do so, we mainly use two-photon
microscopy that allows us to see fluorescence signals
from deep within living tissue, developing novel
photostimulation methods and animal behavioral tasks.
The goals of our recent studies are to reveal how
voluntary movement is memorized and represented incortical circuits. In addition, we are working to apply
two-photon microscopy to a non-human primate, thecommon marmoset, in order to understand information processing in the brain, which is relevant tohigh cognitive functions.
(1) Arm movements induced by non-invasive
optogenetic stimulation of the motor cortex in thecommon marmoset
Which brain area drives hand/arm movements after
learning or brain injury? When does motor corticalactivity generate appropriate hand/arm movements?
To address these issues, it is necessary to manipulate
motor cortical activity in a controlled manner.

25

Optogenetics has been applied to manipulate theneuronal activity related to a variety of brain functions
in non-human primates and rodents. With regard to themotor control system of non-human primates,
saccadic eye movements were modulated by
optogenetic activation and/or inactivation of cerebral
cortical neurons. However, optogenetic stimulation
failed to induce or modulate any limb movements in
non-human primates. This is in contrast to mice, inwhich Channelrhodopsin-2 (ChR2) stimulation oflayer 5 neurons in multiple subregions of the motor
cortex successfully induced different types of complex
forelimb movements. This may be because the numberof photoactivated neurons in the non-human primate
did not reach a level sufficient to elicit hand/arm
movements, and/or because the activation patterns ofneurons and/or the types of activated neurons differ
between optogenetic and electrical stimulation.
We used the common marmoset (Callithrix jacchus) to
overcome these possible problems, as this New World
monkey has a smaller motor cortex than macaque andsquirrel monkeys. We therefore expected it to beeasier to photostimulate a relatively larger proportionof the motor cortical neurons dominating the hand/arm
movements. To do this, we used adeno-associatedviruses (AAVs) with a tetracycline-inducible gene
expression system that amplifies neuronal expressionof induced genes. We previously used this system
carrying the GCaMP gene to establish two-photon
calcium imaging of cortical neurons in anesthetizedand behaving marmosets. We also used a ChR2
variant (E123T/T159C) with fast kinetics that wasable to follow each high-frequency photostimulation,
as is commonly used in electrical stimulation(100–350 Hz). Furthermore, we used a cranial window
to permit stimulation of a larger area (diameter of 1–2mm) than is possible with an optical fiber inserted into
the cortex.
In an awake state, forelimb movements could be
induced when channelrhodopsin-2-expressing neurons
in the motor cortex were illuminated by blue laser
light with a spot diameter of 1 or 2 mm through acranial window without cortical invasion. Forelimbmuscles responded 10–50 ms after photostimulation
onset. Long-duration (500 ms) photostimulationinduced discrete forelimb movements that could bemarkerlessly tracked with CCD cameras and a

deep-learning algorithm. Long-duration photostimulation mapping revealed that the primary motor cortex isdivided into multiple domains that can induce handand elbow movements in different directions.
In the visually cued pole-pull task, weak 500 ms
photostimulation, which did not induce visible
forelimb movements at rest, at any time point inrespect to the cue onset caused the pole to be slightly
moved in the same direction as the movement inducedby the strong 500 ms stimulation. This suggests that
M1 neurons are more activated by and more sensitive
to photostimulation during a voluntary movement task,
than they are at rest. In two marmosets, thephotostimulation that started 1500 ms before the cue
onset did not affect the reward reaching time,suggesting that the preceding perturbation of the M1
activity can be amended for ~1 s before the onset ofthe voluntary movement. By contrast, when thephotostimulation started at the cue onset for one
marmoset, and 500 ms before the onset for anothermarmoset, the reward reaching time changed
according to the direction of the induced movement.
The difference in the effect of the time window
between the two marmosets might be due to thedifference in the extent of the photoactivation and/or
stimulation position. These results suggest that thevoluntary movement was biased toward the movement
dominated by the domain of M1 with high activity.
Combined with calcium imaging, all-opticalinterrogation of motor circuits should be possible inbehaving marmosets.
(2) Neural dynamics in the mouse secondary andprimary motor cortices during self-initiated andexternally triggered movements
Voluntary movements can be either self-initiated or
externally triggered. The higher motor cortex (M2) inprimates is activated differently in these scenarios.
However, little is known about whether the presenceor absence of an external cue primarily determines
which type of M2 neural activity is evoked when thesame movement is executed in both contexts. To
address this, we improved on previously developed
mouse forelimb movement tasks. We trained
head-fixed mice to perform a self-initiated lever-pull
task (SI) and an external cue-triggered lever-pull task
(ET). Blocks of these tasks (SI and ET blocks) were26

switched several times within one session. During task
performance, we conducted concurrent calcium
imaging of layer 2/3 neurons in M2 and M1 using a
super-wide-field two-photon microscope (Terada et al.,2018). As expected, the proportion of neurons thatexhibited movement-related activity specific to either
block was larger in M2 than in M1. Neural population
analysis showed that M2 population activity aroundthe onset of lever pull was markedly different between
the SI and ET blocks; this could not be explained byslight differences in body movement, including
forelimb and orofacial movements, between theblocks. By contrast, the difference in M1 population
activity was smaller than that in M2 population
activity and well explained by the behavioral
differences. In a majority of trials, M2 population
activity showed the post-switch block type
immediately after the block switch. However, in sometrials, M2 population activity showed the pre-switch
block type. In addition, during approximately half ofthe lever pulls that occurred mistakenly at the interval
between the external cues in the ET block, the M2
population exhibited ET block-type activity. These
results indicate that the type of M2 population activity
evoked depends on both the present and preceding
contexts. Both types of M2 population activity
presumably evocate the inseparable M1 ensemble
whose activity varies to the same extent that the body
movement varies.
(From abstract in Neuroscience 2019)(3) Value information that affects decision making istransmitted from the thalamus to the motor cortex
We can estimate the values of presented cues anddecide whether to act after each cue presentation
through operant conditioning. It is thought that thestriatum is a critical region to estimate such cue values
and that the motor cortex generates the motor
command for the appropriate action. However, it isunknown whether and how cue value information
estimated in the striatum is transmitted to the motor
cortex, including the secondary and primary motor
cortical areas (M2 and M1). Anatomically, the motor
thalamus receives the projection descending from thestriatum and sends axons to M2 and M1. We recently
reported movement-related activity in thalamocortical(TC) axons projecting from the motor thalamus to M1

in mice performing a self-initiated lever-pull task
(Tanaka et al., 2018). Here, we developed a new
reward-based lever-pull task. In this task, one of twocues with different sound frequencies (cues A and B)
was randomly presented in each trial. After a cue
period, the mice chose whether to pull the lever with
their right forelimb. When the mice pulled the lever, awater reward was delivered at a high probability in thecue A trial and a low probability in the cue B trial.
After training for this task, the mice pulled the levermore frequently in the cue A trial than in the cue B
trial. During the task, we conducted two-photon
calcium imaging of TC axons in the left M2 and M1.
Activity of a subset of TC axonal boutons increased
after cue A onset, while few boutons exhibited
increased activity after cue B onset. Linear
discriminant analysis revealed that the emergence ofcue information transmitted by M2-projecting TC
axonal boutons preceded that of cue informationtransmitted by M1-projecting ones. Channelrhodopsin-2 stimulation of M2-projecting TC axons during thecue period increased the frequency with which themice pulled the lever in the cue B trial. These results
suggest that M2-projecting axons of the motor
thalamus transmit cue value information that canaffect subsequent decision making.
(From abstract in Neuroscience 2019)(4) Development of a behavioral paradigm and amodel-based analysis with reinforcement learning
Animals choose something and act appropriately intheir daily life. They get something good and bad at
the same time through their choice. The former is the
reward such as food and water and the latter is the cost
and/or energy that inevitably accompany body
movements. Animals have to compute both of them
before they decide whether they act or not. However,
it is poorly understood how the rewards obtained byanimals’ action and the costs accompanying theiraction affect their decision-making and whether doing
nothing is actively chosen or not.
To address these issues, we developed a simple
behavioral task focusing on water reward and physicaleffort (forelimb movement) and performed amodel-based analysis with reinforcement learning, aframework using animal behavior and the outcomes.
In our task, mice were let to choose whether to pull

27

the lever or not in response to two different tones
associated with two different probabilities of water
delivery (reward probabilities) following a successful
lever pull. No reward was delivered after either tone
when the lever was not successfully pulled. After
two-week training sessions, most of the micefrequently pulled the lever after tones with higher
reward probability but infrequently did after tones
with lower one. This tendency was similarly observed
when different sets of reward probabilities were used.
We then fit the changes in their behavior during thetraining sessions by several models with different
free-parameter sets. In terms of the physical effort, we
assumed two cases: “cost model” and “saving-energy
model”. “Cost model” is that the mice get the cost(negative reward) when they choose ‘to pull’ because
they should get tired. “Saving-energy model” is thatthey get ‘rewarded’ when they choose ‘not to pull’because the mice could save the physical effort. We
compared these models with the use of Bayesian
information criterion and found that “saving-energy
model” described their learning process better than“cost model”.
These results suggested that the mice found something
good in the choice of ‘not to pull’ even though they
got no water reward. The mice might regard avoiding
the costs as ‘reward’, and they might actively choose‘not to pull’ rather than they just didn’t choose ‘topull’. This paradigm will help us to understand theactive choice of ‘doing nothing’ and how animals
evaluate the cost or energy.
(From abstract in the 43rd Annual Meeting of theJapan Neuroscience Meeting)

References
1. Ebina T, Obara K, Watakabe A, Masamizu Y,
Terada S, Matoba R, Takaji M, Hatanaka A,
Nambu A, Mizukami H, Yamamori T, Matsuzaki
M. Arm movements induced by non-invasive
optogenetic stimulation of the motor cortex in thecommon marmoset. Proc Natl Acad Sci USA.
2019 116: 22844-22850.
2. Tsutsumi S, Hidaka N, Isomura Y, Matsuzaki M,
Sakimura K, Kano M, Kitamura K. Modularorganization of cerebellar climbing fiber inputs

during goal-directed behavior. eLife 2019 8:
e470219.

28

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

Lecturer
Naofumi Uesaka, Ph.D.

Research Associate
Takaki Watanabe, 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), 4 postdoctoral fellows, 10 graduate
students, 4 research student and 5 technicians. We
teach neurophysiology for medical undergraduates andfor students in the Master and Ph.D. courses. Our
research aims at elucidating cellular and molecularmechanisms underlying regulation of synaptictransmission and postnatal development of neuronal
circuits.

Teaching activities
We teach neurophysiology for medical undergraduates in lectures and practical courses. Lectures
are designed for students to learn basic mechanisms
underlying the generation of electrical signals,
synaptic transmission and their regulations in the
nervous system and roles of the spinal cord, brain
stem and cerebellum in sensori-motor functions.
Students also learn how functional neural circuits inthe brain are formed and matured during postnatal
development. In the practical courses, students
perform two types of classical experiments ofneurophysiology. First, students make intracellular
recording from frog skeletal muscle fibers andexamine the endplate potential for understanding basic
properties of synaptic transmission. Second, students
record electromyogram (EMG) from human gastricnemius muscles and learn how the stretch reflex works.
We accept Free-Quarter students. Students areencouraged to experience patch-clamp recordings
from neurons either in brain slices or in dissociatedculture, or to experience recordings of neuronal
activities from living animals.
For the training of Master and Ph.D. course students,
we have a weekly conference for discussing current
research activities. A laboratory member summarizes
his/her recent experimental data or presents papers
closely related to his/her research. Moreover, formutual communication between the laboratories withsimilar interests in neuroscience, we have a weekly
joint seminar with Department of Cellular
Neurobiology, Division of Structural Physiology,
Department of Cellular and Molecular Physiology,
Department of Integrative Physiology, and Division ofAnimal Resources.

Research activities
The brain consists of neuronal circuits in which
neurons are connected through numerous synapses. To
understand the brain function, it is necessary to
elucidate mechanisms of synaptic transmission andthose underlying changes in synapses related todevelopment, learning and memory (synaptic
plasticity). We take various methodological ap-

29

proaches including electrophysiology, pharmacology,
morphology, and genetic engineering of mouse. We
particularly focus on observing neuronal activities inreal time in intact neurons. We use whole-cell patch
clamp recording, calcium imaging, two-photon imaging and their combinations in various preparations(cultured neurons, brain slices and intact animals) andinvestigate molecular mechanisms of synaptic transmission and plasticity.
The main subjects of our research are as follows(1) Refinement of synaptic organization during
cerebellar development:
In early postnatal days, all Purkinje cells in the
cerebellum are innervated by multiple climbing fibers.
These surplus climbing fibers are eliminatedeventually with the progress of postnatal development,
and most Purkinje cells become innervated by single
climbing fibers by the end of the third postnatal weekin mice. We investigate the mechanisms how single
climbing fibers are selected and how the surplus
climbing fibers are eliminated.
(2) Retrograde synaptic modulation mediated byendogenous cannabinoids:
We reported in 2001 that endogenous cannabinoids
are released from postsynaptic neurons in an activitydependent manner, act retrogradely onto presynaptic
cannabinoid receptors and suppress transmitter release.
Since then, we have been investigating themechanisms of this retrograde modulation. We arealso interested in elucidating the physiologicalsignificance of this phenomenon including learningand memory, addiction, and anxiety.
(3) Synaptic integration in intact animals:
To understand the physiological function ofsynapses in vivo, we analyze synaptic transmission
and integration in single neurons in the intact brain byusing in vivo two-photon imaging and whole-cellrecording. We also develop new methods toimplement these experiments.

References(1) Watanabe T, Suzuki H, Kano M. Postnatal
Development of Cerebellar Neural Circuits. Brain

Nerve. 2019 Dec;71(12):1373-1383. doi: 10.
11477/mf.1416201457.
(2) Tanigami H, Yoneda M, Tabata Y, Echigo R,
Kikuchi Y, Yamazaki M, Kishimoto Y, Sakimura
K, Kano M, Ohno-Shosaku T. Endocannabinoid
Signaling from 2-Arachidonoylglycerol to CB1Cannabinoid Receptor Facilitates Reward-based
Learning of Motor Sequence. Neuroscience. 2019
Nov 21; 421:1-16. doi: 10.1016/j.neuroscience.
2019.09.040. Epub 2019 Nov 1.
(3) Tsutsumi S, Hidaka N, Isomura Y, Matsuzaki M,
Sakimura K, Kano M, Kitamura K. Modularorganization of cerebellar climbing fiber inputs
during goal-directed behavior. Elife. 2019 Oct 9;
8:e47021. doi: 10.7554/eLife.47021.
(4) Kano M, Watanabe T. Developmental synapse
remodeling in the cerebellum and visual thalamus.
F1000Res. 2019 Jul 25;8:F1000 Faculty Rev-1191.
doi: 10.12688/f1000research.18903.1. eCollection
2019.
(5) Martínez-Torres S, Cutando L, Pastor A, Kato A,
Sakimura K, de la Torre R, Valjent E, Maldonado
R, Kano M, Ozaita A. Monoacylglycerol lipase
blockade impairs fine motor coordination andtriggers cerebellar neuroinflammation throughcyclooxygenase-2. Brain Behav Immun. 2019
Oct;81:399-409. doi: 10.1016/j.bbi.2019.06.036.
Epub 2019 Jun 25.
(6) Nakao H, Kishimoto Y, Hashimoto K, Kitamura K,
Yamasaki M, Nakao K, Watanabe M, Kano M,
Kirino Y, Aiba A. mGluR1 in cerebellar Purkinjecells is essential for the formation but not
expression of associative eyeblink memory. Sci
Rep. 2019 May 14;9(1):7353. doi: 10.1038/
s41598-019-43744-z.
(7)
Inoue M, Takeuchi A, Manita S, Horigane SI,
Sakamoto M, Kawakami R, Yamaguchi K, Otomo
K, Yokoyama H, Kim R, Yokoyama T, TakemotoKimura S, Abe M, Okamura M, Kondo Y, Quirin
S, Ramakrishnan C, Imamura T, Sakimura K,
Nemoto T, Kano M, Fujii H, Deisseroth K,
Kitamura K, Bito H. Rational Engineering of
XCaMPs, a Multicolor GECI Suite for In Vivo
Imaging of Complex Brain Circuit Dynamics.
Cell. 2019 May 16;177(5):1346-1360.e24. doi: 10.
1016/j.cell.2019.04.007. Epub 2019 May 9.

Functional Biology
2. Pharmacology

31

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

Lecturer
Shigeyuki Namiki, Ph. D.,

Yohei Okubo, Ph. D.

Research Associate
Daisuke Asanuma, Ph. D.

Homepage

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

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

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

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

1) Development of high-performance fluorescenceprobes for visualizing neurotransmitters
Imaging techniques which visualize neurotransmittersin living neurons are powerful methods to understandthe mechanism underlying synaptic transmission inneuronal circuits. To facilitate this process, wedeveloped a high-throughput screening system basedon 96-well plate format protocol. After screening, we
obtained high-performance glutamate probes showing
large fluorescence changes upon glutamate binding.
This result indicates that our screening system should
be applicable to develop fluorescence probes for
signaling molecules other than glutamate in shortperiods.
2) Study of the mechanism underlying the exocytosisof neurotransmitterFor understanding of regulation mechanism
underlying neuronal circuit in mammalian central
nervous system, elucidation of the neurotransmitter
release machinery is indispensable. Aiming at imaging
neurotransmitter glutamate, we developed a novel
optical glutamate probe by our high-throughput
screening system as described above. Using this probe,
we successfully visualized presynaptically released
glutamate with a single synapse resolution in cultured
hippocampal neurons. We quantitatively analyzed
released glutamate at individual synapses and revealed32that 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 technique revealed thatdynamics of neurotransmitter release is precisely
controlled by the highly coordinated nanoscale
molecular assemblies of presynaptic molecules. We
are also trying to identify the functional changes innanoscale molecular assemblies in psychiatric diseasemodel.

References
1. Okubo, Y. and Iino, M. Visualization of astrocytic
intracellular Ca2+ mobilization. J. Physiol. 589,
1671-1681 (2020)
2. Takahashi, S., Hanaoka, K., Okubo, Y., Echizen,
H., Ikeno, T., Komatsu, T., Ueno, T., Hirose, K.,
Iino, M., Nagano, T. and Urano, Y. Rational
design of a near-infrared fluorescence probe forCa2+ based on phosphorus-substituted rhodamines
utilizing photoinduced electron transfer. Chem.
Asian J. 15, 524-530 (2020)
3. Okubo, Y., Iino, M. and Hirose, K. Store-operated
Ca2+ entry-dependent Ca2+ refilling in theendoplasmic reticulum in astrocytes. Biochem.
Biophys. Res. Commun. 522, 1003-1008 (2020)

4. Okubo, Y., Kanemaru, K., Suzuki, J., Kobayashi,
K., Hirose, K. and Iino, M. Inositol
1,4,5-trisphosphate receptor type 2-independent
Ca2+ release from the endoplasmic reticulum inastrocytes. Glia 67, 113-124 (2019)

33

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

Associate Professor
Etsuo A, Susaki, M.D., Ph.D.

Lecturer
Koji L. Ode, Ph.D.

Associate
Shoi Shi, Ph.D.

Homepage

http://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 six invited lectures to cover specialized andcurrently highlighted fields in pharmacology. We offer
several laboratory courses, and all the members of thedepartment 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
With our members from different backgrounds, wewould like to realize experimental systems biology at
the organism level, leading to greater understanding
and even control of organismal pathophysiology. To
this end, we specifically focus on the cellular circuits
controlling the sleep/wake cycle and address thehourglass mechanism of sleep, a homeostatic- andcircadian-dependent regulation of sleep amount andtiming. We are also planning on multi-scale research
activities covering a series of length scales;
molecule-to-cell, cell-to-tissue, and tissue-to-organism
to envision such complicated underlying mechanism.
We have been devoting our research to twotechnological challenges; 1) next-generation mammalian reverse genetics, where we can produce
genetically modified mice in a high-throughput
fashion, 2) system-level identification and analysis ofcellular circuits in the whole-organ (especially, thewhole-brain) and whole-body, where we can identify
individual cells or cellular circuits in the whole-organ
and whole-body. Combined with these techniques, 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.
Additionally, we execute a comprehensive study to
examine dynamic properties of the biological system
inside cell-to-tissue scale, and their relations toorganism-level phenotypes.

341) 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 (Ukai et al. Nat Protoc. 2017;
Sumiyama et al. PLOS ONE 2019). Using thesemethods, we successfully generated knockout mice foracetylcholine muscarinic receptors and leak potassiumchannels and analyzed these sleep phenotypes in thefirst generation (Niwa et al., Cell Rep. 2018; Yoshida
et al., PNAS 2018).
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 imaging at single-cell resolution(represented by Susaki et al., Cell, 2014; Tainaka et al.,Cell Rep. 2018). Among our concerted efforts to
expand CUBIC technology, we recently applied thetissue clearing and 3D imaging to organs other thanthe brain (e.g., Hasegawa et al., Kidney Int. 2019),
whole mouse body (e.g., Tainaka et al. Cell 2014;
Kubota et al. Cell Rep. 2017), and human pathological
specimens (e.g., Nojima et al. Sci Rep. 2017). By
integrating the swelling-based clearing protocol(CUBIC-X) and high-throughput and high-resolution
light-sheet microscopy (MOVIE), we also succeededin generating a single-cell resolution whole mousebrain atlas (CUBIC-Atlas) (Murakami et al. Nature
Neurosci 2018; Murakami et al., Nat Protoc. 2019).
Furthermore, we have challenged developing a
versatile and efficient three-dimensional histopathological method (CUBIC-HistoVIsion) (Susaki et al.,Nat Commun. 2020).
Because of its rapid imaging capability of thewhole organ/body, CUBIC offers extraordinary novel
discoveries in life science and medical research.
Together with several major laboratories involving
tissue-clearing development, we introduced the latest
circumstances
regardingtheclearing-imaging
technology (Ueda et al., Nat Rev Neurosci. 2020;
Ueda et al., Neuron 2020).

353) Mechanism of dynamic homeostasis in sleep/wakecycle
Sleep amount during a day is under homeostatic
control, in which sleep pressure accumulates during
awake time and gradually decreases during sleep.
Sleep deprivation further promotes the accumulationof sleep pressure, resulting in the longer/deeper sleepin the next cycle. The required sleep duration in a day
is mostly determined genetically as evident from 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; Odeand Ueda. Cold Spring Harb. Perspect. Biol. 2018; Shi
and Ueda. BioEssays 2018; Yoshida et al. PNAS2019).
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. They also indicated that REM
sleep is not critical for the survival of animals.
Given our numerous studies of sleep, circadianrhythms, and related technologies, our findings willcontribute to our understanding of these diseases,
including psychiatric and neurodegenerative disorders.
We have proposed perspectives on human circadianrhythms, sleep, and genetics for future research (Odeand Ueda, Cold Spring Harb. Perspect. Biol. 2018;
Ode and Ueda, Mol. Syst. Biol. 2018; Ukai et al.,Current Opinion in Biotechnology 2019; Millius et al.,F1000Res. 2019) and are currently expanding ourapproach to human sleep phenotyping.

References
1. Bassett D.S., Cullen K.E., Eickhoff S.B., Farah
M.J., Goda Y., Haggard P., Hu H., Hurd Y.L.,
Josselyn S.A., Khakh B.S., Knoblich J.A., Poirazi
P., Poldrack R.A., Prinz M., Roelfsema P.R.,
Spires-Jones T.L., Sur M., Ueda H.R. Reflections
on the past two decades of neuroscience. Nat. Rev.
Neurosci. 21, 524-534 (2020)
2. Ogawa M., Shintani-Domoto Y., Nagashima Y.,
Ode K.L., Sato A., Shimizu Y., Ohashi K., Roehrl
M.H.A., Ushiku T., Ueda H.R., Fukayama M. Mass
Spectrometry-Based Absolute Quantification of
Amyloid Proteins in Pathology Tissue Specimens:
Merits and Limitations. PLOS ONE 15, e0235143(2020)
3. Urae S., Harita Y., Udagawa T., Ode K.L.,
Nagahama M., Kajiho Y., Kanda S., Saito A., Ueda
H.R., Nangaku M., Oka A. The cellular model ofalbumin endocytosis uncovers link between
membrane and nuclear proteins. J. Cell Sci. 133,
jcs242859 (2020)
4. Ueda H.R., Dodt H., Osten P., Economo M.N.,
Chandrashekar J., Keller P.J. Whole-Brain Profilingof Cells and Circuits in Mammals by Tissue
Clearing and Light-Sheet Microscopy. Neuron 106,369-387 (2020)
5. Susaki E.A., Shimizu C., Kuno A., Tainaka K., Li
X., Nishi K., Morishima K., Ono H., Ode K.L.,
Saeki Y., Miyamichi K., Isa K., Yokoyama C.,
Kitaura H., Ikemura M., Ushiku T., Shimizu Y.,
Saito T., Saido T.C., Fukayama M., Onoe H.,
Touhara K., Isa T., Kakita A., Shibayama M., Ueda
H.R. Versatile whole-organ/body staining andimaging based on electrolyte-gel properties of
biological tissues. Nat. Commun. 11, 1982 (2020)
6. Hasegawa S., Tanaka T., Saito T., Fukui K.,
Wakashima T., Susaki E.A., Ueda H.R., Nangaku
M. The oral hypoxia-inducible factor prolylhydroxylase inhibitor enarodustat counteracts
alterations in renal energy metabolism in the earlystages of diabetic kidney disease. Kidney Int. 97,
934-950 (2020)
7. Miyawaki T., Morikawa S., Susaki E.A.,
Nakashima A., Takeuchi H., Yamaguchi S., Ueda
H.R., Ikegaya Y. Visualization and molecularcharacterization of whole-brain vascular networks

36with capillary resolution. Nat. Commun. 11, 1104
(2020)
8. Yamada R.G., Ueda H.R. Molecular Mechanismsof REM Sleep. Front. Neurosci. 13, 1402 (2020)
9. Ueda H.R., Ertürk A., Chung K., Gradinaru V.,
Chédotal A., Tomancak P., Keller P.J. Tissue
clearing and its applications in neuroscience. Nat.
Rev. Neurosci. 21, 61–79 (2020)
10. Matsumoto K., Mitani T.T., Horiguchi S.A.,
Kaneshiro J., Murakami T.C., Mano T., Fujishima
H., Konno A., Watanabe T.M., Hirai H., Ueda H.R.
Advanced CUBIC tissue clearing for whole-organcell profiling. Nat. Protoc. 14, 3506-3537 (2019)11. Puelles V.G., Fleck D., Ortz L., Papadouri S.,
Strieder T., Böhner A.M.C., van der Wolde J.W.,
Vogt M., Saritas T., Kuppe C., Fuss A., Menzel S.,
Klinkhammer B.M., Müller-Newen G., HeymannF., Decker L., Braun F., Kretz O., Moeller M.J.
Novel 3D analysis using optical tissue clearing
documents the evolution of murine rapidly
progressive glomerulonephritis. Kidney Int. 96,
505-516 (2019)12. Millius A., Ode K.L., Ueda H.R. A period without
PER: understanding 24-h rhythms without classictranscription and translation feedback loops.
F1000Res. 8, 499 (2019)13. Hasegawa S., Susaki E.A., Tanaka T., Komaba H.,
Wada T., Fukagawa M., Ueda H.R., Nangaku M.
Comprehensive
three-dimensional
analysis(CUBIC-kidney) visualizes abnormal renal
sympathetic nerves after ischemia/reperfusion
injury. Kidney Int. 96, 129-138 (2019)14. Ukai H., Sumiyama K., Ueda H.R. Next-generation
human genetics for organism-level systems biology.
Curr. Opin. Biotechnol. 58, 137-145 (2019)

Pathology, Immunology andMicrobiology
1. Pathology

38

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, Chief,
Telepathology & Remote Diagnosis Promotion Center)

Lecturer
Masako Ikemura, M.D., Ph.D. (Office for “Promotion of CPC Education and General
Integrative Medicine”)
Aya Shinozaki-Ushiku*, M.D., Ph.D.
Hiroyuki Abe, M.D., Ph.D.

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

Homepage

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

Introduction and Organization
Department of Pathology and Diagnostic Pathology is
responsible for the practice of diagnostic pathology,
education, and research in cooperation with Divisionof Diagnostic Pathology of the University Hospital*.
Our aim is to perform pathology as an important partof clinical medicine as well as to establish“next-generation pathology incorporating cutting-edge
science and technology”.

After retirement of former Professor, Prof.
Fukayama, Dr. Testuo Ushiku was appointed to aprofessorship at the Department of Pathology and
Diagnostic Pathology of the University of Tokyo on
May 1st, 2019. Dr. Misumi moved to National Center
for Global Health and Medicine. Dr. Miyama become
an associate of the department and Dr. Rokutan
became an associate of the University of Tokyo
Hospital.
Two postgraduate students (Hakozaki and39

Furuhata) finished the course and received Ph.D. In
the new fiscal year, 2020, six new students (5 in the
doctoral course and one in the master’s course) willenter the postgraduate course, and there will be 24
postgraduates.
We are responsible for the pathology practice of
the University of Tokyo Hospital and are carrying
forward the morphology-based research targeting
human diseases. As for the education of the medical
students, we take charge of the following courses;
General Pathology Course for the 1st grade medical
students in collaboration with Department of
Molecular Pathology, Systemic Pathology for the 2nd
grade, Elective Clinical Clerkship for the 4th grade,
and Clinical Clerkship for the 3rd/4th grade students.
Programs for postgraduates and junior residents arealso included in our education activities.
"Tsunagu"Fukushima-Kanto
PathologyForensic Pathology Cooperation Program was plannedin collaboration with Fukushima Medical University
and Juntendo University, headed by Prof. Saito, thedean of Graduate School. The program has been
adopted as one of Activation Program of Basic
Researcher Training of the Ministry of Education,
Culture, Sports, Science and Technology. For the four
years since FY2018, in graduate school education, weplan to train pathologists, who are specialized in"death investigation, remote pathology diagnosis, andgenomic medicine" with the training system oriented
to region support by making them rotate among
universities.
We registered substantial cases of whole slide
images (WSI) in the research project of JapaneseSociety of Pathology “Database of Pathology-WSI for
Development of Artificial Intelligence (AI) Techniqueand AI-based Support System for Pathology
Diagnosis” in 2017. We also examined the problems
in image registration in the hospital with the
Departments of Radiology and Neurosurgery.

Teaching activities
We provide General Pathology Course for the 1st
grade of undergraduate students, especially in its
morphologic field.
Each class of Systemic Pathology Course andexercises are held in parallel with that of Systemic

Medicine Course. Handouts are available in every halfcourse of the pathologic exercises, and all slides usedin the course are accessible on our website as virtual
slides (digital images of the slides).
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
in-house as well as other hospitals.
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. One of our research developments
was obtained from genomic analysis of early-stage
gastric cancer done by Dr. Rokutan, which
demonstrated the mutation status in APC and TP53 isdiagnostically useful in differentiating malignant frombenign (ref 17). We also expand our research to cover
pathologically diverse gastric cancer.
Our department has pathologists with different
expertise, and they are engaged in specific research
projects. The research covers brain tumors andneurodegenerative disease (Drs. Ikemura and Saito),
Epstein-Barrvirus-associatedtumors(Drs.
Shinozaki-Ushiku, Abe and Hinata), pancreatobiliary
tumors (Drs. Tanaka and Yamauchi, ref 19), bone andsoft tissue tumors (Dr. Makise), and urinary tract
tumors (Dr. Miyama). We also collaborate with otherlaboratories in and outside the University to develop
new technologies such as AI (Drs. Abe and Hinata),
tissue clearing technique, and tissue processing robots
in pathology practice.

40

References(Case reports are listed in the section of Diagnostic
Pathology Division)
1. Aoki T, Yamada A, Takahashi M, Niikura R,
Toyama K, Ushiku T, Kurokawa M, Momose T,
Fukayama M, Koike K Development and internal
validation of a risk scoring system for gastrointestinal events requiring surgery in gastrointestinal lymphoma patients. J Gastroenterol Hepatol.
2019-4;34(4):693-699.
2. Fukayama
M,
Abe
H,
KunitaA,
Shinozaki-Ushiku A, Matsusaka K, Ushiku T,
Kaneda A. Thirty years of Epstein-Barr virusassociated gastric carcinoma. Virchows Arch
2019-12. [Epub ahead of print]
3. Furukawa T, Fukushima N, Itoi T, Ohike N,
Mitsuhashi T, Nakagohri T, Notohara K, Shimizu
M, Tajiri T, Tanaka M, Yamaguchi H,
Yanagisawa A, Sugiyama M, Okazaki K. A
Consensus Study of the Grading and Typing of
Intraductal Papillary Mucinous Neoplasms of the
Pancreas. Pancreas 2019-4;48(4):480-487.
4. Ishihara J, Ishihara A, Sasaki K, Lee SS, Williford
JM, Yasui M, Abe H, Potin L, Hosseinchi P,
Fukunaga K, Raczy MM, Gray LT, Mansurov A,
Katsumata K, Fukayama M, Kron SJ, Swartz MA,
Hubbell JA. Targeted antibody and cytokine
cancer immunotherapies through collagen affinity.
Sci Transl Med 2019-4; 11(487):eaau3259.
5. Ito Y, Miyauchi M, Nakamura T, Takahara N,
Nakai Y, Taoka K, Toyama K, Shinozaki-Ushiku
A, Koike K, Kurokawa M. Significance of biopsy
with ERCP for diagnosis of bile duct invasion of
DLBCL. Int J Hematol 2019-9;110(3):381-384.
6. Kage H, Kohsaka S, Shinozaki-Ushiku A,
Hiraishi Y, Sato J, Nagayama K, Ushiku T, Takai
D, Nakajima J, Miyagawa K, Aburatani H, Mano
H, Nagase T. Small Lung Tumor Biopsy Samples
Are Feasible for High Quality Targeted Next
Generation Sequencing. Cancer Sci 2019 -8;
110(8):2652-2657.
7. Kashima J, Okuma Y, Hosomi Y, Hishima T.
High serum soluble-CD27 level correlates withpoor performance status and reduced survival inpatients with advanced lung cancer. Oncol 201912;97(6): 365-372.

8. Ko T, Fujita K, Nomura S, Uemura Y, Yamada S,
Tobita T, Katoh M, Satoh M, Ito M, Domoto Y,
Hosoya Y, Amiya E, Hatano M, Morita H,
Fukayama M, Aburatani H, Komuro I.
Quantification of DNA Damage in Heart Tissue
as a Novel Prediction Tool for Therapeutic
Prognosis of Patients With Dilated Cardiomyopathy. JACC Basic Transl Sci. 2019-9;4(6):670-680.
9. Kobayashi H, Makise N, Ushiku T, Ito N, Koga
M, Shinoda Y, Tanaka S. Infiltrative nature oftumor-induced osteomalacia lesions in bone:
Correlation between radiological and histopathological features. J Orthop Sci. 2019-9; 24(5):900905.
10. Kohsaka S, Tatsuno K, Ueno T, Nagano M,
Shinozaki-Ushiku A, Ushiku T, Takai D, Ikegami
M, Kobayashi H, Kage H, Ando M, Hata K, Ueda
H, Yamamoto S, Kojima S, Oseto K, Akaike K,
Suehara Y, Hayashi T, Saito T, Takahashi F,
Takahashi K, Takamochi K, Suzuki K, Nagayama
S, Oda Y, Mimori K, Ishihara S, Yatomi Y,
Nagase T, Nakajima J, Tanaka S, Fukayama M,
Oda K, Nangaku M, Miyazono K, Miyagawa K,
Aburatani H, Mano H. Comprehensive assay forthe molecular profiling of cancer by target
enrichment
fromformalin-fixedparaffinembedded specimens. Cancer Sci 2019-4;110(4):1464-1479.
11. Mizushima I, Kasashima S, Fujinaga Y, Notohara
K, Saeki T, Zen Y, Inoue D, Yamamoto M,
Kasashima F, Matsumoto Y, Amiya E, Sato Y,
Yamada K, Domoto Y, Kawa S, Kawano M,
Ishizaka N. Clinical and Pathological Characteristics of IgG4-Related Periaortitis/Periarteritis andRetroperitoneal Fibrosis Diagnosed Based onExperts’ Diagnosis. Ann Vasc Dis 2019-12;12(4):460-472.
12. Nagata H, Ishihara S, Abe H, Ushiku T,
Kishikawa J, Tanaka T, Hata K, Kawai K,
Fukayama M, Nozawa H. LGR5 expression
predicts peritoneal recurrence after curative
resection of primary colon cancer. Br J Cancer
2019-5;120(10):996-1002.
13. Narui K, Ishikawa T, Shimizu D, Yamada A,
Tanabe M, Sasaki T, Oba MS, Morita S, Nawata
S, Kida K, Mogaki M, Doi T, Tsugawa K, Ogata

41

H, Ota T, Kosaka Y, Sengoku N, Kuranami M,
Niikura N, Saito Y, Suzuki Y, Suto A, Arioka H,
Chishima T, Ichikawa Y, Endo I, Tokuda Y.
Anthracycline could be essential for triplenegative breast cancer: A randomised phase II
study by the Kanagawa Breast Oncology Group(KBOG) 1101. Breast 2019-6;47:1-9.
14. Niikura R, Hayakawa Y, Hirata Y, Ogura K,
Fujishiro M, Yamada A, Ushiku T, Konishi M,
Fukayama M, Koike K. The Reduction in GastricAtrophy after Helicobacter pylori Eradication Is
Reduced by Treatment with Inhibitors of Gastric
Acid Secretion. Int J Mol Sci 2019-4;20(8):E1913.
15. Nozawa H, Hata K, Ushiku T, Kawai K, Tanaka T,
Shuno Y, Nishikawa T, Sasaki K, Emoto S,
Kaneko M, Murono K, Sonoda H, Ishihara S.
Accelerated perineural invasion in colitisassociated cancer: A retrospective cohort study.
Medicine (Baltimore). 2019-10;98(42):e17570.
16. Ogasawara A, Kamiya M, Sakamoto K, Kuriki Y,
Fujita K, Komatsu T, Ueno T, Hanaoka K,
Onoyama H, Abe H, Tsuji Y, Fujishiro M, Koike
K, Fukayama M, Seto Y, Urano Y. Red Fluorescence Probe Targeted to Dipeptidylpeptidase-IV
for Highly Sensitive Detection of Esophageal
Cancer. Bioconjug Chem 2019-4;30(4):10551060.
17. Rokutan H, Abe H, Nakamura H, Ushiku T,
Arakawa E, Hosoda F, Yachida S, Tsuji Y,
Fujishiro M, Koike K, Totoki Y, Fukayama M,
Shibata T. Initial and crucial genetic events inintestinal-type gastric intramucosal neoplasia. J
Pathol 2019-4;247(4):494-504.
18. Soroida Y, Nakatsuka T, Sato M, Nakagawa H,
Tanaka M, Yamauchi N, Wake T, Nakagomi R,
Kinoshita MN, Minami T, Uchino K, Enooku K,
Asaoka Y, Tanaka Y, Endo M, Nakamura A,
Kobayashi T, Kurihara M, Hikita H, Sato M,
Gotoh H, Iwai T, Fukayama M, Ikeda H, Tateishi
R, Yatomi Y, Koike K. A Novel Non-invasive
Method for Predicting Liver Fibrosis by
Quantifying the Hepatic Vein Waveform.
Ultrasound Med Biol. 2019-9;45(9):2363-2371.
19. Tanaka M, Yamauchi N, Ushiku T, Shibahara J,
Hayashi A, Misumi K, Yasunaga Y, Morikawa T,
Kokudo T, Arita J, Sakamoto Y, Hasegawa K,

Fukayama M. Tumor budding in intrahepaticcholangiocarcinoma: a predictor of post-surgery
outcomes. Am J Surg Pathol 2019-9;43(9):11801190.
20. Terada Y, Takahashi T, Morita S, Kashiwabara K,
Nagayama K, Nitadori JI, Anraku M, Sato M,
Shinozaki-Ushiku A, Nakajima J. Spread throughair spaces is an independent predictor ofrecurrence in stage III (N2) lung adenocarcinoma.
Interact Cardiovasc Thorac Surg 2019-9;29(3):442-448.
21. Yoshida Y, Manaka T, Nitadori JI, ShinozakiUshiku A, Doke T, Saito T, Sato J, Miyaji T,
Yamaguchi T, Oyama H, Fukayama M, Nakajima
Y, Nakajima J. A comparison between 2- and3-dimensional approaches to solid component
measurement as radiological criteria for sublobar
resection in lung adenocarcinoma ≤ 2 cm in size.
Surg Today 2019-10;49(10):828-835.

42

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

Associate Professor
Daizo Koinuma, M.D., Ph.D.; Shogo Ehata, M.D., Ph.D. (Environmental Science Center)

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

Homepage

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

Introduction and organization
Our department has a more than 100-year history
from its establishment as the Department of Pathology.
Kohei Miyazono is Professor of the Department of
Molecular Pathology from August 2000. In March
2020, the Department consists of a professor, two
associate professors, three assistant professors,
technical assistants, and some research fellows,
including four graduate students, a master course
student, and two post-doctoral fellows.

Teaching activities
Our department takes responsibility for lectures on“General Pathology” for undergraduate students of theFaculty of Medicine in collaboration with the
Department of Human Pathology. Teaching responsibilities include lectures on General Pathology related
to the mechanisms of diseases. Since we believe itvery important for medical students to study basic
oncology, we teach a basic tumor biology course in
our lectures of General Pathology. In addition, weoffer several laboratory courses for students frommolecular pathological points of view.
We also supervise research activities of the graduate
students of the Department. Our laboratory is locatedat the 11th floor at the Research Building of Graduate

School of Medicine. The laboratory is very convenientfor doing research, because most of the experiments
can be done on this floor. We have “Progress Meeting”
twice a month and “Monday Seminar” once a month.
We have been doing collaboration with Prof.
Carl-Henrik Heldin’s group, Uppsala University,
Sweden for more than 20 years.
Some of our graduate students had been supportedby the GPLLI Graduate Program for Leaders in Life
Innovation at the University of Tokyo from the
Ministry of Education, Culture, Sports, Science andTechnology, Japan (MEXT). From 2018, Worldleading INnovative Graduate School Program for Life
Science and Technology (WINGS-LST) has started.
These programs will stimulate interaction between
students and scientists in the programs as well as thosefrom other laboratories (square.umin.ac.jp/gplli/;
square.umin.ac.jp/wings-lf/)).

Research activities
Our major research interest is to elucidate how
members of the TGF-β (transforming growth factor-β)family transduce signals, and how they regulate
growth, differentiation, and apoptosis of various cells.
From 2015, our research is mainly supported by aGrant-in-Aid for Scientific Research (S) on

43“Transcriptional regulation by TGF-β signaling and its
relation to progression of cancer” (15H05774) fromthe Japanese Society for the Promotion of Science(JSPS). From 2017, our research is also supported by
a Grant-in-Aid for Scientific Research on Innovative
Area on Integrated Analysis and Regulation of
Cellular Diversity (17H06326) from MEXT.
Followings are some research results obtained at
our laboratory in 2019.
1) Roles of the BMPRII/ALK-1/SMAD/ATOH8 axis in
the development of pulmonary arterial hypertension
Perturbations of bone morphogenetic protein (BMP)signaling in endothelial cells are involved in vasculardiseases, such as pulmonary arterial hypertension(PAH). We demonstrated that the transcription factor
ATOH8 is a direct target of BMP signaling factors
Smad1/5, and it is induced in a BMP-dependent
manner. In zebrafish and mice, gene silencing of
Atoh8 failed to cause an arteriovenous malformation(AVM)-like phenotype, which is observed bymutations in Alk1 gene. In contrast, Atoh8-knockout
mice showed a PAH-like phenotype, such as increased
pulmonary arterial pressure and right ventricular
hypertrophy. Furthermore, expression levels of
ATOH8 were decreased in the lungs of PAH patients.
We revealed that ATOH8 physically associates withhypoxia-inducible factor 2α (HIF-2α) and decreases
its expression levels in cultured cells, leading toattenuation of the induction of HIF-2α target genes in
response to hypoxia. These findings suggest that the
BMP receptor type II/ALK-1/SMAD/ATOH8 axis
may attenuate hypoxic responses in endothelial cells
in the pulmonary circulation and may play animportant role in prevention of the development of
PAH (Morikawa et al. Sci Signal 2019).
2) Tyrosine kinase EPHA6 sensitizes glioma-initiating
cells towards BMP-induced apoptosis
BMP signaling plays critical roles in the developmentof glioblastoma multiforme (GBM). BMP suppresses
tumorigenicity of GBM cells through induction ofdifferentiation and apoptosis of glioma-initiating cells(GICs). However, BMP fails to induce tumor suppressive effects on some GICs. By a phosphoreceptor
tyrosine kinase array analysis, we found that
phosphorylation of EPHA6 (erythropoietin-producing
hepatocellular carcinoma receptor A6) was regulatedby BMP-2 in some GICs. Analysis of The Cancer
Genome Atlas (TCGA) dataset revealed that
expression levels of EPHA6 were lower in patientswith GBM than those in the normal brain; moreover,high EPHA6 expression was correlated with better
prognosis. Ectopic expression of EPHA6 increased thesusceptibility of GICs to apoptosis induced by BMP-2.
The cooperative effect on apoptosis induction by
EPHA6 and BMP signaling depended on the kinase
activity of BMP type I receptor, but not on the kinase
activity EPHA6. Overexpression of EPHA6 in GICs
induced the formation of a protein complex of EPHA6
and the BMP type I receptor ALK-2, which wascorrelated with BMP-induced apoptosis in GICs.
Intracranial injection of GICs into immunodeficient
mice demonstrated that gain-of-function of EPHA6
together with BMP-2 pretreatment attenuated thetumor progression of GBM in the mouse brain andprolonged the mouse survival. Thus, EPHA6 together
with BMP signaling leads to apoptotic cell death in
GICs, and thus possibly functions as a tumor
suppressor in GBM (Raja et al. Cancer Sci 2019).
3) FGF signals regulate TGF-β-induced endothelialmyofibroblast transition of tumor endothelial cells
Tumor microenvironment contains various components, including cancer cells, blood and lymphatic
vessels, and cancer-associated fibroblasts (CAFs).
CAFs are comprised of tumor-promoting myofibroblasts and tumor-suppressing fibroblasts. TGF-β is
known to induce the formation of myofibroblasts andother types of mesenchymal (non-myofibroblastic)
cells from vascular endothelial cells. Recent reports
showed that fibroblast growth factor 2 (FGF2)
regulates TGF-β-induced endothelial- mesenchymaltransition (EndMT), but the mechanisms that control
transcriptional networks for the formation of distinctgroups of fibroblasts remain unclear. We investigated
the roles of FGF2 in the regulation of TGF-β-induced
EndMT of tumor endothelial cells (TECs). We showedthat FGF signals in TECs inhibit TGF-β-induced
endothelial- myofibroblast transition (End-MyoT),
leading to suppressed formation of contractile
myofibroblast cells. However, FGF signals can alsocollaborate with TGF-β in promoting the formation ofactive fibroblastic cells with migratory andproliferative properties. FGF2 modulated formation of
myofibroblastic and non-myofibroblastic cells by44

TGF-β from TECs through transcriptional regulationof various mesenchymal markers and growth factors.
Moreover, TECs treated with TGF-β were morecompetent in promoting in vivo tumor growthcompared to TECs treated with TGF-β and FGF2. We
further showed that Elk1 regulated FGF2-induced
inhibition of End-MyoT through inhibition of
TGF-β-induced transcriptional activation of the
α-smooth muscle actin promoter by myocardin-relatedtranscription factor-A. These findings suggest that
TGF-β and FGF2 oppose and cooperate with eachother during the formation of myofibroblastic andnon-myofibroblastic cells from TECs, and thesefunctions of TGF-β and FGF2 determine thecharacteristics of mesenchymal cells in the tumor
microenvironment (Akatsu et al. Mol Oncol 2019).
4) Comparative analysis of TTF-1-binding DNA
regions in SCLC and non-SCLC
Thyroid transcription factor-1 (TTF-1, encoded by the
NKX2-1 gene) is highly expressed in both small-celllung carcinoma (SCLC) and non-small-cell lungcarcinoma (NSCLC). TTF-1 antagonizes the effect of
TGF-β in the induction of epithelial-mesenchymaltransition (EMT) in NSCLC. However, it still remains
to be elucidated how the functional roles of TTF-1
differ between SCLC and NSCLC. We compared the
genome-wide distributions of TTF-1 binding regions
and the transcriptional programs regulated by TTF-1
using a human SCLC cell line NCI-H209 (H209), anda human lung adenocarcinoma (NSCLC) cell line
NCI-H441 (H441), by ChIP-seq (chromatin
immunoprecipitation-sequencing)andRNA-seq(RNA-sequencing) analyses. TTF-1 binding regions in
H209 and H441 cells differed by 75.0% and E-box
motifs were highly enriched in the TTF-1 binding
regions of H209 SCLC cells. Transcriptome profilingshowed that TTF-1 is involved in neuroendocrine
differentiation in H209 SCLC cells. ASCL1 (alsoknown as ASH1) is an E-box binding basic helixloop-helix transcription factor, and a lineage-survival
oncogene of SCLC. We found that TTF-1 and ASCL1
were coexpressed and bound to adjacent sites on target
genes in SCLC, and cooperatively regulate transcripttion of them. Moreover, TTF-1 regulated expressionof the Bcl-2 apoptosis-related gene family and showedanti-apoptotic function in SCLC. These findings
suggest that TTF-1 promotes SCLC growth andcontributes to neuroendocrine and anti-apoptotic gene
expression by partly coordinating with ASCL1(Hokari et al. Mol Oncol 2019).

References
1. Harada, M., Morikawa, M., Ozawa, T., Kobayashi,M., Tamura, Y., Takahashi, K., Tanabe, M., Tada,
K., Seto, Y., Miyazono, K., and Koinuma, D.
(2019) Palbociclib enhances activin-SMADinduced cytostasis in estrogen receptor-positive
breast cancer. Cancer Science 110 (1), 209-220.
doi: 10.1111/cas.13841.
2. Nakai, Y., Okamoto, K., Terashima, A., Ehata, S.,
Nishida, J., Imamura, T., Ono, T., and Takayanagi,
H. (2019) Efficacy of an orally active
small-molecule inhibitor of RANKL in bonemetastasis. Bone Research 7, 1. doi: 10.1038/
s41413-018-0036-5.
3. Katsuno, Y., Meyer, D. S., Zhang, Z., Shokat, K.
M., Akhurst, R. J., Miyazono, K., and Derynck, R.
(2019) Chronic TGF-β exposure drives stabilized
EMT, tumor stemness, and cancer drug resistancewith vulnerability to bitopic mTOR inhibition.
Science Signaling 12 (570), pii:eaau8544. doi:
10.1126/scisignal.aau8544.
4. Kohsaka, S., Tatsuno, K., Ueno, T., Nagano, M.,
Shinozaki-Ushiku, A., Ushiku, T., Takai, D.,
Ikegami, M., Kobayashi, H., Kage, H., Ando, M.,
Hata, K., Ueda, H., Yamamoto, S., Kojima, S.,
Oseto, K., Akaike, K., Suehara, Y., Hayashi, T.,
Saito, T., Takahashi, F., Takahashi, K., Takamochi,
K., Suzuki, K., Nagayama, S., Oda, Y., Mimori,K., Ishihara, S., Yatomi, Y., Nagase, T., Nakajima,J., Tanaka, S., Fukayama, M., Oda, K., Nangaku,M., Miyazono, K., Miyagawa, K., Aburatani, H.,
and Mano, H. (2019) Comprehensive assay for themolecular profiling of cancer by target enrichment
fromformalin-fixedparaffin-embedded
specimens. Cancer Science 110 (4), 1464-1479.
doi: 10.1111/cas.13968.

45

5. Sekimata, K., Sato, T., Sakai, N., Watanabe, H.,
Mishima-Tsumagari, C., Taguri, T., Matsumoto, T.,
Fujii, Y., Handa, N., Honma, T., Tanaka, A.,
Shirouzu, M., Yokoyama, S., Miyazono, K.,
Hashizume, Y., and Koyama, H. (2019)
Bis-heteroaryl pyrazoles: Identification of orally
bioavailable inhibitors of activin receptor-likekinase-2 (R206H). Chemical and Pharmaceutical
Bulletin (Tokyo) 67 (3), 224-235. doi:
10.1248/cpb.c18-00598.
6. Taguchi, L., Miyakuni, K., Morishita, Y.,
Morikawa, T., Fukayama, M., Miyazono, K., andEhata, S. (2019) c-Ski accelerates renal cancer
progression by attenuating transforming growth
factor-β signaling. Cancer Science 110 (6),2063-2074. doi: 10.1111/cas.14018.
7. Akatsu, Y., Takahashi, N., Yoshimatsu, Y., Kimuro,S., Muramatsu, T., Katsura, A., Maishi, N., Suzuki,
H.I., Inazawa, J., Hida, K., Miyazono, K., and
Watabe, T. (2019) Fibroblast growth factor signals
regulate transforming growth factor-β-induced
endothelial-to-myofibroblast transition of tumor
endothelial cells via Elk1. Molecular Oncology
13(8),1706-1724.
doi:
10.1002/
1878-0261.12504.
8. Asano, T., Okamoto, K., Nakai, Y., Tsutsumi, M.,
Muro, R., Suematsu, A., Hashimoto, K., Okamura,T., Ehata, S., Nitta, T., and Takayanagi H. (2019)
Soluble RANKL is physiologically dispensable
but accelerates tumour metastasis to bone. Nature
Metabolism 1 (9), 868-875. doi: 10.1038/
s42255-019-0104-1.
9. Itoh, Y., Koinuma, D., Omata, C., Ogami, T.,
Motizuki, M., Yaguchi, S.I., Itoh, T., Miyake, K.,
Tsutsumi, S., Aburatani, H., Saitoh, M., Miyazono,
K., and Miyazawa, K. (2019) A comparative
analysis of Smad-responsive motifs identifies
multipleregulatory
inputsfor
TGF-βtranscriptional activation. The Journal of
Biological Chemistry 294 (42), 15466-15479. doi:
10.1074/jbc.RA119.009877.

10. Raja, E., Morikawa, M., Nishida, J., Tanabe, R.,
Takahashi, K., Seeherman, H.J., Saito, N., Todo,T., and Miyazono, K. (2019) Tyrosine kinase Ephreceptor A6 sensitizes glioma-initiating cells
towards bone morphogenetic protein-induced
apoptosis. Cancer Science 110 (11), 3486-3496.
doi: 10.1111/cas.14187.
11. Morikawa, M., Mitani, Y., Holmborn, K., Kato, T.,
Koinuma, D., Maruyama, J., Vasilaki, E., Sawada,
H., Kobayashi, M., Ozawa, T., Morishita, Y.,
Bessho, Y., Maeda, S., Ledin, J., Aburatani, H.,
Kageyama, R., Maruyama, K., Heldin, CH., andMiyazono, K. (2019) The ALK-1/SMAD/ATOH8
axis attenuates hypoxic responses and protects
against the development of pulmonary arterial
hypertension. Science Signaling 12 (607), pii:
eaay4430. doi: 10.1126/scisignal.aay4430.
12. Hokari, S., Tamura, Y., Kaneda, A., Katsura, A.,
Morikawa, M., Murai, F., Ehata, S., Tsutsumi, S.,
Ishikawa, Y., Aburatani, H., Kikuchi, T.,
Miyazono, K., and Koinuma, D. (2019)
Comparative analysis of TTF-1-binding DNA
regions in small cell lung cancer and non-small
cell lung cancer. Molecular Oncology 14 (2),277-293. doi: 10.1002/1878-0261.12608.

Pathology, Immunology andMicrobiology
2. Microbiology

47

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

Lecturer
Naoko Kamiya, Ph.D.

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

Homepage

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

Introduction and Organization

Research

Professor emeritus Akio Nomoto who had been thechief of the Department retired in 2008 and moved to
Microbial Chemistry Research Foundation as the
Chairman of Board. From 2009, new Department ofMicrobiology started with Professor Masanori
Hatakeyama as the new chief. The present Department
consists of 21 members; 1 professor (Dr. Hatakeyama),
1 senior lecturer (Dr. Kamiya), 2 research associates(Drs. Takahashi and Hayashi), 3 post-doctoral fellows(Drs. Nishikawa, Kikuchi, and Ooki), 2 academic
assistants (Ms. Sakamoto and Komatsu), 9 graduate
school students (Mr. and Ms. Knight, Wada, Imai,
Tahmina, Marrero, Wu, Wu, Hikawa, Yau), and 3
research students (Ms. Priscillia, Del Valle Lazarte,
Shrestha).

Gastric cancer is the third leading cause (10.4%) ofcancer death worldwide. It has now been wellestablished that infection with Helicobacter pylori (H.
pylori) is associated with the development of gastriccancer. Especially, infection with H. pylori strains
carrying a gene called cagA plays an essential role ingastric carcinogenesis. The cagA-positive H. pylori
delivers the cagA gene product, the CagA protein, into
the host gastric epithelial cells via the type IV
secretion system. Through a series of studies, we haveuncovered the molecular mechanisms by which
delivered CagA causes transformation of gastricepithelial cells.
East Asian countries such as Japan, Korea andChina, are known to show the highest incidence ofgastric cancer in the world. In Japan, for instance,
50,000 peoples are killed by gastric cancer each year.
Thus, establishment of new strategies for prevention
and treatment for gastric cancer is urgently required.
In our department, we are conducting cutting-edge
researches, ranging from molecular structural biology
to mouse genetics, to elucidate oncogenic mechanismsof the bacterial CagA protein. These researches will
provide an opportunity to develop molecular-targeting
methods that effectively prevent the development ofgastric cancer. We made substantial progress in thefollowing research during the current year.

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

48

1. High-molecular-weight hyaluronan is a Hippo
pathway ligand that directs cell densitydependent growth inhibition via PAR1b
The tumor-suppressive Hippo signaling pathway plays
a key role in organ size determination and tissue
homeostasis by regulating cell proliferation andapoptosis during organ development. In mammals,
upon Hippo signaling activation, two serine/threonine
kinases MST (MST1 and MST2) and LATS (LATS1
and LATS2) are sequentially activated, which in turn
phosphorylatesthetranscription
co-activator
Yes-associated protein (YAP) and the transcriptional
co-activator with PDZ-binding motif (TAZ) via
phosphorylation and thereby causes cytoplasmic
retention of YAP/TAZ. In the nucleus, YAP/TAZ
interact with numerous transcription factors including
TEAD and thereby transactivate cancer-predisposing
genes. A unique feature of the Hippo signaling is that
it is regulated by a variety of signaling events such as
cellular tension, cell-to-cell contact, cell polarity, andcell-extracellular matrix (ECM) interaction.
Hyaluronan (HA), a major component of the ECM,
is synthesized by hyaluronan synthases and degradedby hyaluronidases. High-molecular-weight hyaluronan(HMW-HA) (> 1,000 kDa) exhibits anti-proliferative
and anti-oncogenic actions by binding to its cellular
receptor CD44. In contrast, low-molecular-weighthyaluronan (LMW-HA) (10-250 kDa), which is
produced by hyaluronidase-mediated degradation of
HMW-HA,
exhibits
pro-proliferative
andpro-oncogenic actions by binding to CD44. However,
the mechanisms underlying the size-dependent
opposite bioactivities of HA remain uncertain.
In this study, we found that treatment with HMWHA stimulates Hippo signaling. Mechanistically, theextracellular association of HMW-HA with CD44
causes clustering of the CD44 extracellular domain,which leads to interaction of intracellular CD44 with
PAR1b (partitioning defective-1b)/MARK2 (microtubule affinity-regulating kinase 2). We found thatPAR1b inhibits MST1 and MST2 via phosphorylation
on Thr440 and Ser444, respectively. Upon HMW-HA
treatment, the Hippo signaling-inhibitory PAR1b-MST
complex is disrupted through CD44-PAR1b
interaction. Once liberated from PAR1b, MST
activates Hippo signaling. On the other hand,
LMW-HA inhibits Hippo signaling by competing with

HMW-HA for CD44 binding. Therefore, this study
revealed the mechanism by which hyaluronan
mediates opposing cellular responses depending on its
molecular size.
To evaluate the in vivo relevance to the
HMW-HA-mediated activation of Hippo signaling, we
conducted
immunohistochemical
anaysisofhyaluronidase-2 and YAP expression in surgicallyisolated breast cancer specimens. We also conducted
Kaplan-Meier analysis for disease-free survival rates
using the TCGA breast cancer dataset. Triple-negative
breast cancers with higher hyaluronidase-2 expression
show poorer prognosis than those with lower
hyaluronidase-2 expression. Consistently, inhibition of
hyaluronidase-2 expression is associated with reduced
tumorigenicity in a tumor xenograft model. Hence,
perturbation of HMW-HA-mediated Hippo signaling
activation contributes to cancer aggressiveness.
2. Inverse regulation of co-activator functions of
YAP and TAZ through tyrosine phosphorylation status of Parafibromin
Parafibromin is the human (mammalian) orthologue of
budding yeast Cdc73, a component of the RNA
polymerase II (Pol II)-associated factor (PAF)
complex. Absence of, or mutation in, the PAF
components results in alterations in gene expressionthat can lead to deregulation of developmental
programs and loss of control of cell growth anddifferentiation, thereby predisposing to various
diseases including cancer. Parafibromin regulates
multiple independent morphogen signaling pathways
such as -catenin signaling and Hedgehog signaling.
The transcriptional platform function of parafibrominis potentiated by tyrosine dephosphorylation,
mediated by SHP2 phosphatase, while it is attenuatedby tyrosine phosphorylation, mediated by PTK6
kinase.
In the present study, we found that Parafibromin
physically interacts with YAP and TAZ, thereby
potentiating their co-activator activities toward the
TEAD transcription factors. TAZ is functionallyactivatedthroughbindingwithtyrosinedephosphorylated Parafibromin. Furthermore, TAZ
and-catenin
interact
cooperatively
withdephosphorylated Parafibromin, which synergisticallystimulates the co-activator functions of TAZ and49

-catenin. On the other hand, YAP is selectively
activatedthroughbindingwithtyrosinephosphorylated Parafibromin, which does not interact
with -catenin and thus cannot co-activate YAP and-catenin. These findings indicate that Parafibromininversely stimulates the co-activator functions of YAP
and TAZ depending on its tyrosine phosphorylation
status. They also suggest that YAP and TAZ exert their
redundant and non-redundant biological actions
through mutually exclusive interaction with Parafibromin, which is regulated by a balance of kinaseand phosphatase activities toward Parafibromin.

Publications
1. Hatakeyama, M. Malignant Helicobacter pyloriassociated diseases: Gastric cancer and MALT
lymphoma. Adv. Exp. Med. Biol. 1-15 (2019)
2. Ooki, T., Murata-Kamiya, N., TakahashiKanemitsu, A., Wu, W. and Hatakeyama, M.
High-molecular-weight hyaluronan is a Hippo
pathway ligand that directs cell density-dependent
growth inhibition via PAR1b. Dev. Cell 49(4):590-604 (2019)
3. Knorr, J., Ricci, V., Hatakeyama, M., Backert, S.
Classification of Helicobacter pylori virulence
factors: Is CagA a toxin or not?. Trends in
Microbiol. 27(9): 731-8 (2019)
4. Yachida, S., Mizutani, S., Shiroma, H., Shiba, S.,
Nakajima, T., Sakamoto, T., Watanabe, H.,
Masuda, K., Nishimoto, Y., Kubo, M., Hosoda, F.,
Rokutan, H., Matsumoto, M., Takamaru, H.,
Yamada, M., Matsuda, T., Iwasaki, M., Yamaji, T.,
Yachida, T., Soga, T., Kurokawa, K., Toyoda, A.,
Ogura, Y., Hayashi, T., Hatakeyama, M.,
Nakagama, H., Saito, Y., Fukuda, S., Shibata, T.,
Yamada, T. Metagenomic and metabolomic
analyses reveal distinct stage-specific phenotypesof the gut microbiota in colorectal cancer. Nat.
Med. 25(6): 968-76 (2019)
5. Tsugawa, H., Kato, C., Mori, H., Matsuzaki, J.,
Kameyama, K., Saya, H., Hatakeyama, M.,
Suematsu, M., Suzuki, H. Cancer Stem-Cell
Marker CD44v9-Positive Cells Arise From
Helicobacter
pylori-Infected
CAPZA1overexpressing cells. Cell. Mol. Gastroenterol.
Hepatol. 8(3): 319-334 (2019)

50

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

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

Project Lecturer
Mahoko Ikeda, M.D., Ph.D.
Nobuhiko Satoh, M.D., Ph.D.

Research Associate
Yuka Kobayashi, MD., Ph.D.
Kazuya Okushin, MD., Ph.D.
Chihiro Minatsuki, MD., Ph.D.

Homepage

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

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

Clinical activities
Our daily activities are as follows:
1) Surveillance and control of hospital-acquired
infection, such as infection or colonization ofmethicillin-resistant Staphylococcus aureus andother drug-resistant microbes.
2) Investigation of trends in weekly bases andmonthly reports to all departments; Screening ofcolonization; monitoring of appropriate use ofantibiotics.
3) Microbiological investigation of wards andenvironment.
4) Detection, investigation, intervention and controlof the hospital infection outbreak.
5) Offering of information and advice on HIVinfected patients’ management.
6) Direct inquiries and advises on management ofpatients with various infections through ward
rounds every week.

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

51

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

Research
We have been mainly studying on following subjects:
Several studies are now going with the members of
department of pharmacy and of surgery.
1) Development of preemptive strategies for thecontrol of healthcare-associated infection2) Development of new methods in infection control
and treatment of viral hepatitis
3) Molecular pathogenesis of hepatocellular carcinoma in HCV infection4) Pathogenesis of progression of HIV infection5) Molecular pathogenesis of the mitochondrial
disturbances in viral infections
6) Molecular pathogenesis of hepatitis B viral infection7) Host defenses to microorganisms
8) Molecular analysis of innate immunity in microorganism infection
9) New detection method and pathogenesis of opportunistic cytomegaloviral infection10) Mechanisms and molecular epidemiology ofmulti-drug resistant microorganisms11) Epidemiology of Clostridioides difficile infection12) Clinical characteristics and molecular epidemiology of hypervirulent Klebsiella pnemoniae
infection

Publications
1. Wakabayashi Y, Jubishi D, Okamoto K, Ikeda M,
Tatsuno K, Mizoguchi M, Sato T, Okugawa S,
Moriya K. A rare case of a prostatic abscess,bacteremia and chronic granulomatous diseaseassociated with Klebsiella pneumoniae. J InfectChemother. 2019;25(5):365-367.
2. Yamamoto S, Okamoto K, Okugawa S, Moriya K.
Fusobacterium necrophorum septic pelvic thrombophlebitis after intrauterine device insertion. Int
J Gynaecol Obstet. 2019;145(1):122-123.
3. Miyashita H, Okamoto K, Kobayashi T,

Wakabayashi Y, Kitaura S, Ikeuchi K, Ishigaki K,
Nakai Y, Okugawa S, Koike K, Moriya K.
Bacterial peritonitis in a patient with malignant
ascites caused by pancreatic carcinoma: Case
report and review of literature. J Infect Chemother.
2019;25(6):473-476.
4. Kado A, Tsutsumi T, Enooku K, Fujinaga H,
Ikeuchi K, Okushin K, Moriya K, Yotsuyanagi H,
Koike K. Noninvasive diagnostic criteria fornonalcoholic steatohepatitis based on gene
expression levels in peripheral blood mononuclear
cells. J Gastroenterol. 2019;54(8):730-741.
5. Muto Y, Moroishi T, Ichihara K, Nishiyama M,
Shimizu H, Eguchi H, Moriya K, Koike K,
Mimori K, Mori M, Katayama Y, Nakayama KI.
Disruption of FBXL5-mediated cellular ironhomeostasis promotes liver carcinogenesis. J Exp
Med. 2019;216(4):950-965.
6. Wang X, Tanaka N, Hu X, Kimura T, Lu Y, Jia F,
Sato Y, Nakayama J, Moriya K, Koike K, Aoyama
T. A high-cholesterol diet promotes steatohepatitis
and liver tumorigenesis in HCV core genetransgenic mice. Arch Toxicol. 2019;93(6):17131725.
7. Harada S, Aoki K, Okamoto K, Kinoshita O,
Nawata K, Ishii Y, Tateda K, Sasaki M, Saga T,
Doi Y, Yotsuyanagi H, Moriya K, Ono M. Leftventricular assist device-associated endocarditis
involving multiple clones of Staphylococcus
aureus with distinct antimicrobial susceptibility
patterns. Int J Infect Dis. 2019;84:44-47.
8. Hu X, Wang X, Jia F, Tanaka N, Kimura T,
Nakajima T, Sato Y, Moriya K, Koike K,
Gonzalez FJ, Nakayama J, Aoyama T. A transfatty acid-rich diet promotes liver tumorigenesis
in HCV core gene transgenic mice. Carcinogenesis. 2020;41(2):159-170.
9. Midorikawa Y, Takayama T, Nakayama H, Higaki
T, Moriguchi M, Moriya K, Kanda T, Matsuoka S,
Moriyama M. Prior hepatitis B virus infection as a
co-factor of chronic hepatitis C patient survival
after resection of hepatocellular carcinoma. BMC
Gastroenterol. 2019;19(1):147.
10. Okamoto K, Asano S, Yamamoto T, Toyono T,
Yamaguchi R, Okada Y, Okugawa S, Suzuki H,
Moriya K, Aihara M. Poor penetration of
cefcapene into aqueous humor after oral

52

administration of cefcapene pivoxil to patients
undergoing cataract surgery. J Infect Chemother.
2020;26(2):312-315.
11. Enooku K, Tsutsumi T, Kondo M, Fujiwara N,
Sasako T, Shibahara J, Kado A, Okushin K,
Fujinaga H, Nakagomi R, Minami T, Sato M,
Uchino K, Nakagawa H, Kondo Y, Asaoka Y,
Tateishi R, Ueki K, Ikeda H, Yoshida H, Moriya K,
Yotsuyanagi H, Kadowaki T, Koike K. Hepatic
FATP5 expression is associated with histologicalprogression and loss of hepatic fat in NAFLD
patients. J Gastroenterol. 2020;55(2):227-243.
12. Nakamura M, Tsukada H, Seki G, Satoh N,
Mizuno T, Fujii W, Horita S, Moriya K, Sato Y,
Kume H, Nangaku M, Suzuki M. Insulin
promotes sodium transport but suppresses
gluconeogenesis via distinct cellular pathways inhuman and rat renal proximal tubules. Kidney Int.
2020;97(2):316-326.
13. Endo Y, Araoka H, Baba M, Okada C, Kimura M,
Higurashi Y, Sato T, Yatomi Y, Moriya K,
Yoneyama A. Matrix-assisted laser desorption
ionization-time of flight mass spectrometry can beused to identify Helicobacter cinaedi. Diagn
Microbiol Infect Dis. 2020;96(3):114964.
14. Shiraya T, Araki F, Ueta T, Fukunaga H, Totsuka
K, Arai T, Uemura A, Moriya K, Kato S.
Ursodeoxycholic Acid Attenuates the Retinal
Vascular Abnormalities in Anti-PDGFR-β
Antibody-Induced Pericyte Depletion Mouse
Models. Sci Rep. 2020;10(1):977.
15. Mizoguchi M, Matsumoto Y, Saito R, Sato T,
Moriya K. Direct antibiotic susceptibility testingof blood cultures of gram-negative bacilli using
the Drug Susceptibility Testing Microfluidic(DSTM) device. J Infect Chemother. 2020;26(6):554-562.
16. Tatsuno K, Ikeda M, Wakabayashi Y, Yanagimoto
S, Okugawa S, Moriya K. Clinical Features ofBloodstream
Infections
Associatedwith
Peripheral Versus Central Venous Catheters.
Infect Dis Ther. 2019;8(3):343-352.

Pathology, Immunology andMicrobiology
3. Immunology

54

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

Associate Professor
Takeshi Nitta, Ph.D.

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

Homepage

http://www.osteoimmunology.com/

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

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

generation of scientists. Undergraduate students of thefaculty take part in departmental class work throughlectures on immunobiology, immunochemistry andmolecular immunology as well as practical training by
way of laboratory courses on basic immunology
experimental techniques. The education of graduate
students is based on weekly seminars where students
present the progress of their own research projects,
discuss the future directions of their research and theresearch of others, and are exposed to the latest cuttingedge questions confronting the research field of
immunology. We also offer a special training course(called ‘free quarter’) of basic and advanced biologicaland immunological techniques to medical students. We
are also accepting undergraduate students as Medical
Scientist Training Program in faculty of medicine. In
fiscal year 2019, special lectures for undergraduate
students were given by internationally recognizedscientists, Dr. Shimon Sakaguchi (Osaka Univ.), Dr.
Hiroshi Kiyono (The Univ. of Tokyo), Dr. Hiroshi
Kawamoto (Kyoto Univ.), and Dr. Tadatsugu Taniguchi(The Univ. of Tokyo).

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

55

is to develop epoch-making strategies for the treatmentof immune disorders such as autoimmune diseases andsevere infectious diseases.
1) Osteoimmunology
The bone and immune systems share a variety ofmolecules and interact with each other underphysiological and pathological conditions, constituting
the “osteoimmune system” which functions as alocomotor organ and a mineral reservoir as well as a
primary lymphoid organ (Tsukasaki & Takayanagi. Nat
Rev Immunol, 2019). The bone marrow is a primary
lymphoid organ that plays a critical role in immune cell
development. The crucial stromal cell types that
support hematopoietic cell development in the bonemarrow have not been clarified. We reported the crucialrole of osteoblasts in supporting lymphoid lineage
development within the bone marrow microenvironment (Terashima et al., Immunity. 2016). The
mice genetically ablated for osteoblasts exhibited amarked reduction of the number of common lymphoidprogenitor cells in the bone marrow and mature
lymphocytes in the periphery. Our results showed that
osteoblasts play a pivotal role in maintenance ofcommon lymphoid progenitors through the productionof IL-7. Furthermore, using a mouse model of sepsis,
we showed that sepsis rapidly ablated osteoblasts,
which reduced the common lymphoid progenitor
number and thereby resulted in peripheral lymphopenia.
This study demonstrates a reciprocal interaction
between the immune and bone systems, in which acuteinflammation induces a defect in bone cells resulting inlymphopenia-associated immunodeficiency, suggesting that osteoblasts are a potential therapeutic target of
the treatment of inflammatory diseases.
Osteoclasts are polynuclear cells derived from themonocyte/macrophage lineage, which are responsible
for bone resorption. Aberrant osteoclast function anddevelopment is involved in the pathogenesis of several
diseases such as the inflammatory bone destruction
observed in rheumatoid arthritis as well as postmenopausal osteoporosis and osteopetrosis. Osteoclast
development is dependent on TNF family cytokine
receptor activator of nuclear factor kappa-B ligand(RANKL). We studied the receptor signal transduction
pathway for RANKL and identified nuclear factor of
activated T cells c1 (NFATc1) as a master regulator for

osteoclast differentiation (Takayanagi et al., Dev Cell.
2002; Asagiri et al., J. Exp. Med., 2005). We also
identified an ITAM-harboring co-receptor for RANK
(Koga et al., Nature 2004) and the importance ofbridging signal cascade between RANK and ITAM
via Btk for RANK dependent osteoclastogenesis(Shinohara et al., Cell. 2008; Shinohara et al., Bone.
2014). Our recent proteomic analysis identified
multiple target proteins phosphorylated upon
differentiation of osteoclasts (Sumiya et al., Biochem
Biophys Res Commun. 2015).
Furthermore, we have revealed the roles of
Semaphorin4D on osteoblast differentiation (NegishiKoga et al., Nature Med. 2011) and Semaphorin3A on
inhibition of bone resorption as well as promotion ofbone formation (Hayashi et al., Nature 2012; Hayashi
et al., Cell Metab. 2019). We also found that immune
complexes in serum activate osteoclastogenesis andcause bone loss through binding to Fc receptors(Negishi-Koga et al., Nat Commun. 2015). We also
reported that, using a bone-fracture model in mouse,
the cytokine IL-17 promotes bone fracture healing via
osteoblastic bone formation and that T cells are themajor source of IL-17 produced in the bone injury site
(Ono et al., Nat Commun. 2016). Although it has been
known that IL-17 enhances osteoclastic bone
resorption in certain pathological situations, our current
results clearly show the promoting effect of IL-17 onbone formation,
Most recently, we found that oral bacteria promote
the conversion of Foxp3+T cells into Th17 cells(exFoxp3Th17 cells) in periodontitis which is one of
the most common infectious diseases. exFoxp3Th17
cells were found to be the most potent bone-damaging
T cells. Interestingly, these bone-damaging
exFoxp3Th17 cells protect against oral bacteria in two
different ways. First, they elicit mucosal immune
responses mainly by the production of anti-bacterial
products. Second, they inhibit bacterial dissemination by removing the tooth. Thus, exFoxp3Th17 cells
play a beneficial role in the host defense against oral
bacteria. This investigation highlighted the notion that
T-cell-mediated bone damage, which was considered to
be an adverse consequence of inflammation, may havedeveloped to contribute to host defense against oral
bacteria (Tsukasaki et al., Nat Commun. 2018).
An anti-RANKL neutralizing antibody has been

56

introduced for the treatment of osteoporosis, skeletalrelated events by bone metastasis and bone destruction
in rheumatoid arthritis. We have demonstrated thatoral administration of the novel small-molecule
inhibitor against RANKL suppressed bone metastasis
using the mouse models, indicating the great efficacy
of RANKL inhibition with a small-molecule compoundin bone metastasis (Nakai et al., Bone Res. 2019).
RANKL is synthesized as membrane-bound molecule,and cleaved into its soluble form by proteases. We havereported that soluble RANKL is dispensable forphysiological regulation of bone and immune systems,
but has a distinct and pivotal role in the promotion ofbone metastasis (Asano et al., Nat Metab. 2019). Thesefindings provided a new paradigm for physiologicalinteraction between bone and immune system.
2) Lymphocyte development and lymphoid tissue
microenvironment
Thymus is the primary lymphoid organ that supports
development of useful T cells (positive selection) andeliminates self-reactive T cells (negative selection).
The microenvironment of the thymus is mainlycomposed of thymic epithelial cells that regulate
selections of developing T cells.
We have reported that the genetic variations ofhuman PSMB11 gene, which encodes 5t, a thymusspecific proteasome subunit, affected the MHC class Ibound peptide repertoire in the thymus and positive
selection of CD8 T cells (Nitta et al., Sci Immunol.
2017). One of the PSMB11 polymorphisms, G49S,
detected in the Japanese population at a high frequency,
was associated with a higher risk of Sjögren’s
syndrome. These results suggested that, in addition to
the MHC haplotype, genetic variations of proteasome
influence T cell repertoire selection and susceptibility
to autoimmunity.
We have also been studying on thymic developmentof T cells. We showed that the TCR signal
mediated by the Syk-PI3K pathway is essential forthymic development of IL-17-producing T cells(Muro et al., J Clin Invest. 2018). These findings
suggest that the Syk-PI3K pathway might be atherapeutic target of inflammatory diseases. Recently,
we generated mutant mice lacing all of the Skint family
genes (Skint1-11) that encode candidate thymic factors
for regulation of T cell development (Narita et al., Int

Immunol. 2018). These mice exhibited a marked
reduction of V5V1 T cells in the thymus and skin,
but had normal development of other T cell subsets
and leukocytes. This study indicates an exclusivefunction of Skint family genes in the development ofV5V1 T cells and provides a useful animal modelto analyze the mechanism for thymic education of Tcells.
Much attention has been paid to the development andfunction of the gut-associated lymphoid tissues(GALTs) and the symbiotic relationship between thegut microbiota and host immune system.
We
identified a previously unrecognized subset ofmesenchymal cells in the subepithelial dome of GALTs(Nagashima et al., Nat Immunol. 2017). These cells
expressed high levels of RANKL and directlyinteracted with the gut epithelium to induce microfold(M) cell differentiation and CCL20 expression. The
deletion of RANKL in mesenchymal cells impaired M
cell-dependent antigen sampling, which resulted in a
reduction in IgA production and a decrease in microbial
diversity, indicating that subepithelial RANKLexpressing mesenchymal cells (M cell inducer (MCi)cells) are key players in the maintenance of hostmicrobe symbiosis. Furthermore, we reported that
Col6a1-Cre driver mice are useful to study the functionof MCi cells (Nagashima et al., Biochem Biophys Res
Commun. 2017). Manipulation of MCi cells may
provide a molecular basis for novel treatments ofintestinal diseases such as inflammatory bowel
disorders and infectious diseases.
We have recently found that protein arginine
methylation, a post-translational modification, is an
essential regulator of T cell maintenance. T cellspecific deficiency of the arginine methyltransferase
PRMT5 led to a decrease in the number of peripheral
CD4, CD8 and regulatory T cells, and an almost
complete loss of iNKT cells.
PRMT5-mediatedarginine methylation was essential for the expression of
the cytokine-signal-transducing components, thecommon cytokine receptor γ-chain (γc) and JAK3,
which are required for the development of iNKT cells
and the proliferation and survival of peripheral T cells.
PRMT5 induced the arginine methylation of the
spliceosomal component SmD3 that promoted thesplicing of pre-mRNA encoding γc and JAK3. In
recent years, Jak inhibitors have attracted attention as

57

potential agents for the autoimmune diseases such as
rheumatoid arthritis. This study presented an entirely
new regulatory mechanism governing γc family
cytokine-Jak3 signaling in T cells (Inoue et al., Nat
Immunol. 2018).
3) Mechanism of autoimmune disease
The IL-17 producing helper T cell subset (Th17 cell)
plays critical roles in several autoimmune diseasemodels such as collagen induced arthritis (CIA) andexperimental encephalomyelitis (EAE). We haveidentified IBas an indispensable transcription factor
for Th17 cell differentiation (Okamoto et al., Nature.
2010). However, in both RA and EAE models, effector
mechanisms of Th17 cells have been unclear. Recently,
we identified a subset of Th17 cells that robustly
produces IL-17 and RANKL and exacerbates bothinflammation and bone destruction in CIA mice.
Interestingly these Th17 cells are the progeny of CD4
T cells expressing Foxp3, a master regulator for
immunosuppressive Treg cells (Komatsu et al., Nat
Med. 2014). We also reported that RANKL producedby synovial fibroblasts is primarily responsible for theformation of bone-destructive osteoclasts in inflammatory arthritis. These results show that the targetingthese cells and/or molecules could be effective inpreventing bone destruction in RA (Danks et al., Ann
Rheum Dis. 2016).
To elucidate a role of RANKL on T cells, we
generated T cell-specific RANKL-deficient mice.
These mice were protected from EAE, a mouse modelof multiple sclerosis, due to an impairment of
infiltration of pathogenic T cells into the central
nervous system (CNS). RANKL on T cells stimulates
the chemokine production by astrocytes, leading to thechronic inflammation in the CNS. Pharmacologicalinhibition of RANKL prevented the development of
EAE, indicating that RANKL is a potential therapeutictarget for treatment of multiple sclerosis (Guerrini et al.,Immunity. 2015).
We have also been studying the mechanism of T cell
tolerance induction, because a breakdown of T cell
tolerance induces autoimmune diseases. Self-toleranceof T cells is primarily established during theirdevelopment in the thymic medulla, where medullary
thymic epithelial cells (mTECs) ectopically express avariety of tissue-restricted antigens (TRAs) and thereby

TRA-reactive immature T cells are deleted. It has been
known that expression of a set of TRAs is regulated by
the transcriptional regulator Aire, although how theremaining TRAs are regulated has been unclear.
Recently, we identified a novel key transcription factor
Fezf2, which is highly expressed in mTECs andcontrols the expression of a large fraction of Aireindependent TRAs (Takaba et al., Cell. 2015). Micelacking Fezf2 in mTECs exhibited severe autoimmune
disorders in peripheral organs, and the spectrum of
autoimmunity in Fezf2-deficient mice differed fromthat in Aire-deficient mice. These results indicate that
two independent factors, Fezf2 and Aire, play nonredundant and mutually complementary roles in the
TRA expression to ensure T cell tolerance induction.
This study represented an important advance in our
understanding of the mechanisms underlying theimmune tolerance and autoimmune diseases.

References
1. Asano T, Okamoto K, Nakai Y, Tsutsumi M,
Muro R, Suematsu A, Hashimoto K, Okamura T,
Ehata S, Nitta T, Takayanagi H. Soluble RANKLis physiologically dispensable but accelerates
tumour metastasis to bone. Nat Metab, 1: 9 (2019)
2. Tsukasaki M, Takayanagi H. Osteoimmunology:
evolving concepts in bone-immune interactions inhealth and disease. Nat Rev Immunol. 19: 626-642(2019)
3. Nakai Y, Okamoto K, Terashima A, Ehata S,
Nishida J, Imamura T, Ono T, Takayanagi H.
Efficacy of an orally active small-molecule
inhibitor of RANKL in bone metastasis. Bone Res,
7: 1(2019)
4. Hayashi M, Nakashima T, Yoshimura N,
Okamoto K, Tanaka S, Takayanagi H. Autoregulation of Osteocyte Sema3A Orchestrates
Estrogen Action and Counteracts Bone Aging.
Cell Metab, 29: 627-637 (2019)
5. Muro R, Takayanagi H, Nitta T. T cell receptor
signaling for T cell development. Inflamm
Regen, 39: 6 (2019)

Radiology and Biomedical
Engineering
1. Radiology

59

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

Associate Professor
Keiichi Nakagawa, M.D., Ph.D., Harushi Mori, M.D., Ph.D., Hidemasa Takao, M.D., Ph.D.

Lecturer
Hideomi Yamashita M.D., Ph.D., Takeyuki Watadani, M.D., Ph.D.,
Toshihiro Furuta, M.D., Ph.D.

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

Assistant Professor
Mami Ogita, M.D., Wataru Gonoi, M.D., Ph.D.
Kouhei Kamiya, M.D., Ph.D., Wataru Takahashi, M.D., Ph.D., Taku Tajima, M.D.,
Naotoshi Ishida, M.D., Ph.D., Ryousuke Takenaka, M.D., Ph.D.,
Eisuke Shibata, M.D., Ph.D., Ryu Miyagawa, Ph.D.

Project Assistant Professor
Yudai Nakai M.D., Ph.D., Takatoshi Kubo, M.D., Ph.D.

Homepage

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

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

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

Service Department in cooperation with radiology
technologists and nurses.
In the section of Diagnostic Radiology, all CT
and MRI examinations are monitored and reported
by diagnostic radiologists. Diagnostic radiologists,
gastroenterologists, cardiologists, and neurosurgeons mainly perform interventional procedures.
In the section of Nuclear Medicine, twocyclotrons and several remote or processorcontrolled automated devices are installed, whichfacilitate standardized procedures in the PET tracer
production and the implementation of GMP in
PET-related work. There are two SPECT rooms andfour 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 most60

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

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

Research activities
Research activities in our department include
clinical research, animal experiments, and development of instruments as well as computer-based newtechnology
including
artificial
intelligence.
Diagnostic Radiology group in the department
promotes research activities aiming at efficacy
improvement of diagnostic imaging and expansionof its application. Multi-row detector helicalcomputed tomography (MDCT) enables us to taketomographic images in a three-dimensional (3D)fashion. Using the data acquired by MDCT, various
kinds of diseases in almost all parts of the body,from cerebral diseases to musculoskeletal diseases,
can be displayed in 3D images. New 3D softwaredeveloped in our departments is now widely used in
the field of the gastrointestinal tract, lung, andcentral nervous system. In addition, we haveopened a new laboratory section named Image
Computing and Analysis Laboratory with invitationof a new staff from the Faculty of Engineering, theUniversity of Tokyo. This section will contribute todevelopment of novel software including
convolutional neural network to abstract clinicallyuseful information from the 3D imaging data moresophisticatedly. In the field of magnetic resonance(MR) imaging, MR digital subtraction angiography,
perfusion imaging, and diffusion imaging are thefoci of research. These techniques are aggressively
applied to the investigation of vascular andneoplastic diseases of the brain.
Radiation oncology group promotes research
projects in two major fields; one is physicalengineering such as the optimization of dose
distribution in the radiation therapy (RT) and theother is reduction of injuries due to radiation
exposure in vitro and in vivo. This group pushes
forward studies mainly on a brain tumor, head andneck cancer, esophageal cancer, uterine cervicalcancer, prostate cancer in conformity with recent
EBM in the clinical study, and is active in studies ofthe physical engineering traditionally and plays amain role in the highly precise radiation therapy ofour country until now. With the purpose ofachieving precise external irradiation, a new linear
accelerator with multileaf collimator systems wasdeveloped and installed, which is utilized mainly
for non-coplanar radiation therapy in many patients
especially with brain tumor or head and neck tumor.
Dynamic conical conformal radiotherapy formetastatic brain tumors using the accelerator isunder evaluation. In addition to gamma knife
radiosurgery, this new accelerator based stereotactic
radiotherapy for brain diseases has been undergone,and stereotactic radiotherapy (SRT) for body tumors,such as head and neck cancer, prostate cancer, rectal
cancer and lung cancer, has been investigated(intensity modulation radiation therapy; IMRT) for61

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

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Amemiya S, Takao H, Abe O. Global vs.

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Network-Specific Regulations as the Source ofIntrinsic Coactivations in Resting-State Networks. Front Syst Neurosci 13: 65, 2019
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Andica C, Hagiwara A, Hori M, Kamagata K,
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Aoki S, Yamashita H, Takahashi W, Nawa K,
Ota T, Imae T, Ozaki S, Nozawa Y, Nakajima J,
Sato M, Anraku M, Nitadori J, Karasaki T, Abe
O, Nakagawa K. Salvage stereotactic body radiotherapy for post-operative oligo-recurrence of
non-small cell lung cancer: A single-institution
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Nakagawa K, Haga A. Development of amarkerless tumor-tracking algorithm using prior four-dimensional cone-beam computed tomography. J Radiat Res 60(1): 109-15, 2019
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Cohen-Adad J, Warntjes M, Maekawa T, Hori
M, Koshino S, Nakazawa M, Abe O, Aoki S.
Signal Intensity within Cerebral Venous Sinus-

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Fujita S, Nakazawa M, Hagiwara A, Ueda R,
Horita M, Maekawa T, Irie R, Andica C, Kumamaru K, Hori M, Aoki S. Estimation ofGadolinium-based Contrast Agent Concentration Using Quantitative Synthetic MRI and Its
Application to Brain Metastases: A Feasibility
Study. Magn Reson Med Sci 18(4): 260-4,
2019
Fujita S, Hagiwara A, Hori M, Warntjes M,
Kamagata K, Fukunaga I, Andica C, Maekawa
T, Irie R, Takemura M, Kumamaru K, Wada A,
Suzuki M, Ozaki Y, Abe O, Aoki S.
Three-dimensional high-resolution simultaneous quantitative mapping of the whole brain
with 3D-QALAS: An accuracy and repeatability study. Magn Reson Imaging 63: 235-43,
2019
Fujita S, Hagiwara A, Hori M, Warntjes M,
Kamagata K, Fukunaga I, Goto M, Takuya H,
Takasu K, Andica C, Maekawa T, Takemura
MY, Irie R, Wada A, Suzuki M, Aoki S. 3D
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thickness and subcortical brain volumes:
Scan-rescan repeatability and comparison withconventional T1 -weighted images. J Magn
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N, Hwang Ken-pin, Irie R, Andica C, Kamagata K, Akashi T, Kumamaru KK, Suzuki M,
Wada A, Abe O, Aoki S. Deep Learning Approach for Generating MRA Images From 3D
Quantitative Synthetic MRI Without Additional
Scans. Invest Radiol: Epub ahead of print,
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MRI and MR fingerprinting in routine neuroimaging protocol: What's the next step? J
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Gonoi W, Hayashi TY, Hayashi N, Abe O. Association between chronic asymptomatic pan-

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creatic hyperenzymemia and pancreatic ductal
anomalies: a magnetic resonance cholangiopancreatography study. Abdom Radiol (NY)
44(7): 2494-500, 2019
Gonoi W, Okuma H, Hayashi TY, Akahane M,
Nakai Y, Tateishi R, Mizuno S, Suzuki Y,
Mitsuda M, Matsuda K, Nakagawa K, Isayama
H, Miyagawa K, Koike K, Abe O. Development of pancreatic cancer during observation
for hepatocellular carcinoma: A retrospective
cohort study. Saudi J Gastroenterol 25(6):390-6, 2019
Goto M, Karima R, Hagiwara A, Hori M,
Kamagata K, Aoki S, Abe O. Measured volumes using segmented tissue probability dataobtained using statistical parametric mapping
12 were not influenced by the contrasts of analyzed images. J Clin Neurosci: Epub ahead ofprint, 2020
Goto M, Hagiwara A, Fujita S, Hori M, Kamagata K, Aoki S, Abe O, Sakamoto H, Sakano
Y, Kyogoku S, Daida H. Influence of MildWhite Matter Lesions on Voxel-based Morphometry. Magn Reson Med Sci: Epub aheadof print, 2020
Goto M, Hagiwara A, Kato A, Fujita S, Hori M,
Kamagata K, Aoki S, Abe O, Sakamoto H, Sakano Y, Kyogoku S, Daida H. Effect of changing the analyzed image contrast on the accuracy of intracranial volume extraction using
Brain Extraction Tool 2. Radiol Phys Technol
13(1): 76-82, 2020
Haga A, Takahashi W, Aoki S, Nawa K, Yamashita H, Abe O, Nakagawa K. Standardizationof imaging features for radiomics analysis. J
Med Invest 66(1.2): 35-7, 2019
Hagiwara A, Kamagata K, Shimoji K, Yokoyama K, Andica C, Hori M, Fujita S, Maekawa
T, Irie R, Akashi T, Wada A, Suzuki M, Abe O,
Hattori N, Aoki S. White Matter Abnormalities
in Multiple Sclerosis Evaluated by Quantitative
Synthetic MRI, Diffusion Tensor Imaging, andNeurite Orientation Dispersion and Density
Imaging. AJNR Am J Neuroradiol 40(10):1642-8, 2019
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aging: Monoparametric to Multiparametric
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2020
Hanaoka S, Nomura Y, Takenaga T, Murata M,
Nakao T, Miki S, Yoshikawa T, Hayashi N,
Abe O, Shimizu A. HoTPiG: a novel
graph-based 3-D image feature set and its applications to computer-assisted detection of
cerebral aneurysms and lung nodules. Int J
Comput Assist Radiol Surg 14(12): 2095-107,
2019
Hatayama K, Goto S, Yashiro M, Mori H, Fujimoto T, Hanaoka N, Tanaka-Taya K, Zuzan T,
Inoue M. Acute flaccid myelitis associated withenterovirus D68 in a non-epidemic setting.
IDCases 17: e00549, 2019
Hirakawa Y, Miura R, Sasaki Y, Yoshida Y,
Mimura I, Katsura M, Shintani-Domoto Y,
Ogawa M, Hayashi A, Nangaku M Nutcracker
Syndrome with the Superimposition of Thin
Basement Membrane Syndrome. Intern Med
58(3): 411-4, 2019
Hong SH, Goo HW, Maeda E, Choo KS, Tsai
IC; Asian Society of Cardiovascular Imaging
Congenital Heart Disease Study Group. User-Friendly Vendor-Specific Guideline for Pediatric Cardiothoracic Computed Tomography
Provided by the Asian Society of Cardiovascular Imaging Congenital Heart Disease Study
Group: Part 1. Imaging Techniques. Korean J
Radiol 20(2): 190-204, 2019
Hoshiai S, Masumoto T, Hanaoka S, Nomura Y,
Mori K, Hara T, Saida T, Okamoto Y, Minami
M. Clinical usefulness of temporal subtraction
CT in detecting vertebral bone metastases. Eur
J Radiol 118: 175-80, 2019
Imamura Y, Shinozaki T, Okada-Ogawa A,
Noma N, Shinoda M, Iwata K, Wada A, Abe O,
Wang K, Svensson P. An updated review onpathophysiology and management of burning
mouth syndrome with endocrinological, psychological and neuropathic perspectives. J Oral
Rehabil 46(6): 574-87, 2019
Inui S, Kondo H, Yamamoto M, Inoue M, Onozawa S, Furui S, Oba H. Intravascular Ultrasound-Guided Percutaneous Portal Vein Re-

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canalization for Chronic Portal Vein Obstruction. J Vasc Interv Radiol 30(10): 1628-31,
2019
Inui S, Sakurai K, Hashizume Y. Voxel-Based
Morphometry Analysis of Structural MRI for
Differentiation Between Dementia with Lewy
Bodies and Alzheimer's Disease [Letter]. Neuropsychiatr Dis Treat 16: 179-80, 2020
Inui S, Fujikawa A, Jitsu M, Kunishima N,
Watanabe S, Suzuki Y, Umeda S, Uwabe Y.
Chest CT Findings in Cases from the Cruise
Ship “Diamond Princess” with Coronavirus
Disease 2019 (COVID-19). Radiology: Cardiothoracic Imaging: Epub ahead of print, 2020
Irie R, Otsuka Y, Hagiwara A, Kamagata K,
Kamiya K, Suzuki M, Wada A, Maekawa T,
Fujita S, Kato S, Nakajima M, Miyajima M,
Motoi Y, Abe O, Aoki S. A Novel Deep Learning Approach with a 3D Convolutional Ladder
Network for Differential Diagnosis of Idiopathic Normal Pressure Hydrocephalus andAlzheimer’s Disease. Magn Reson Med Sci:
Epub ahead of print, 2020
Ito T, Hanafusa N, Iwase S, Noiri E, Nangaku
M, Nakagawa K, Miyagawa K. Ascitic IL-10
Concentration Predicts Prognosis of Patients
Undergoing Cell-Free and Concentrated Ascites Reinfusion Therapy. Ther Apher Dial: Epubahead of print, 2019
Iwashiro N, Takano Y, Natsubori T, Aoki Y,
Yahata N, Gonoi W, Kunimatsu A, Abe O, Kasai K, Yamasue H. Aberrant attentive and inattentive brain activity to auditory negative
words, and its relation to persecutory delusionin patients with schizophrenia. Neuropsychiatr
Dis Treat 15: 491-502, 2019
Kage H, Kohsaka S, Shinozaki-Ushiku A, Hiraishi Y, Sato J, Nagayama K, Ushiku T, Takai
D, Nakajima J, Miyagawa K, Aburatani H,
Mano H, Nagase T. Small lung tumor biopsy
samples are feasible for high quality targetednext generation sequencing. Cancer Sci 110(8):2652-7, 2019
Kakeda S, Watanabe K, Katsuki A, Sugimoto K,
Ueda I, Igata N, Kishi T, Iwata N, Abe O, Yoshimura R, Korogi Y. Genetic effects on whitematter integrity in drug-naive patients with

64

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major depressive disorder: a diffusion tensor
imaging study of 17 genetic loci associatedwith depressive symptoms. Neuropsychiatr
Dis Treat 15: 375-83, 2019
Kamiya K, Abe O. Imaging of PosttraumaticStress Disorder. Neuroimaging Clin N Am
30(1): 115-23, 2020 Kano Y, Inui S, Oguri T,
Kato H, Yuasa H, Morimoto S, Sakurai K.
Utility of T2-weighted high-resolution vessel
wall imaging for the diagnosis of isolated posterior inferior cerebellar artery dissection atacute and early subacute stages. J Neurol Sci:
Epub ahead of print, 2020
Katano A, Yamashita H, Nakagawa K. Successful definitive concurrent chemoradiotherapy in a patient with esophageal cancer andChild-Pugh B cirrhosis of the liver. J Cancer
Res Ther 15(1): 255-7, 2019
Kida S, Kaji S, Nawa K, Imae T, Nakamoto T,
Ozaki S, Ohta T, Nozawa Y, Nakagawa K.
Visual enhancement of Cone-beam CT by useof CycleGAN. Med Phys 47(3): 998-1010,
2020
Kiryu S, Yasaka K, Akai H, Nakata Y,
Sugomori Y, Hara S, Seo M, Abe O, Ohtomo K.
Deep learning to differentiate parkinsonian
disorders separately using single midsagittal
MR imaging: a proof of concept study. EurRadiol 29(12): 6891-9, 2019
Kodama S, Shirota Y, Hagiwara A, Otsuka J,
Sato K, Sugiyama Y, Mori H, Watanabe M,
Hamada M, Toda T. Multinodular and vacuolating neuronal tumor (MVNT): A presumably
incidental and asymptomatic case in an intractable epilepsy patient. Clin Neurophysiol Pract
4: 164-7, 2019
Kojima M, Yassin W, Owada K, Aoki Y, Kuwabara H, Natsubori T, Iwashiro N, Gonoi W,
Takao H, Kasai K, Abe O, Kano Y, Yamasue H.
Neuroanatomical Correlates of Advanced Paternal and Maternal Age at Birth in Autism
Spectrum Disorder. Cereb Cortex 29(6):2524-32, 2019
Koshiyama D, Fukunaga M, Okada N, Morita
K, Nemoto K, Usui K, Yamamori H, Yasuda Y,
Fujimoto M, Kudo N, Azechi H, Watanabe Y,
Hashimoto N, Narita H, Kusumi I, Ohi K,

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Shimada T, Kataoka Y, Yamamoto M, Ozaki N,
Okada G, Okamoto Y, Harada K, Matsuo K,
Yamasue H, Abe O, Hashimoto R, Takahashi T,
Hori T, Nakataki M, Onitsuka T, Holleran L,
Jahanshad N, van Erp TGM, Turner J,
Donohoe G, Thompson PM, Kasai K, Hashimoto R, COCORO. White matter microstructural alterations across four major psychiatricdisorders: mega-analysis study in 2937 individuals. Mol Psychiatry: Epub ahead of print,
2019
Kunimatsu A, Yasaka K, Akai H, Kunimatsu N,
Abe O. MRI findings in posttraumatic stressdisorder. J Magn Reson Imaging: Epub aheadof print, 2019
Kurokawa R, Maeda E, Mori H, Amemiya S,
Sato J, Ino K, Torigoe R, Abe O. Effect of bolus tracking region-of-interest position within
the descending aorta on luminal enhancementof coronary arteries in coronary computed tomography angiography. Medicine (Baltimore)
98(19): e15538, 2019
Kurokawa R, Maeda E, Mori H, Amemiya S,
Sato J, Ino K, Torigoe R, Abe O. Evaluation of
the depiction ability of the microanatomy of
the temporal bone in quarter-detector CT:
Model-based iterative reconstruction vs hybrid
iterative reconstruction. Medicine (Baltimore)
98(24): e15991, 2019
Kurokawa R, Amemiya S, Akashi K, Abe O.
Persistent collection of antibiotic ointment
masquerading as a lipoma arising at a surgicalsite. Radiol Case Rep 14(11): 1423-6, 2019

Ninety eight English articles in total, including
another 49, have been published from ourdepartment in 2019. Please refer to our homepage,
http://www.ut-radiology.umin.jp/publication/2018.html

Radiology and Biomedical
Engineering
2. Biomedical Engineering

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

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

Homepage

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

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

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

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

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migrated and proliferated in the denuded area, andcovered the denuded area. Shear stress enhanced theregenerative functions of ECs. Shear stress increased
the production of nitric oxide, a potent vasodilator, in
ECs in a dose-dependent manner. Shear stress also
increased the expression of thrombomodulin, an
antithrombotic molecule, in ECs. In contrast, it
decreased the expression of vascular cell adhesion,
which leads to the inhibition of leukocyte adhesion tovascular cell adhesion molecule-1 (VCAM-1). It was
shown that shear stress increases the levels of
adrenomedulin and C-type natriuretic peptide mRNA
which have vasodilating effects in addition to nitricoxide, and that it also augmented the expression oflectin like low density lipoprotein receptor (LOX-1) at
the protein and mRNA level.
2. Hemodynamic force-mediated gene regulation
We have demonstrated that shear stress regulates
endothelial gene expression transcriptionally and/or
posttranscriptionally. Shear stress downregulates
VCAM-1 gene transcription via the double AP-1
binding element (TGACTCA) in the promoter whichfunctions as a shear stress-responsive element. Shearstress has also been shown to increase the expression
level of granulocyte/macrophage-colony stimulating
factor (GM-CSF) via mRNA stabilization. Differential
display and DNA microarray analysis showed thataround 600 known and unknown transcripts were upor down-regulated in human umbilical vein ECs
exposed to a shear stress. From these shear stressresponsive genes, a cDNA encoding an unknown
G-protein coupled receptor was cloned. We showedthat the transcription factor SP1 is involved in theshear stress-induced down-regulation of P2X4 (anATP-gated cation channel) gene expression in ECs.
We also revealed that endothelial genes aredifferentially regulated by laminar and turbulent shear
stress. Laminar shear stress decreases the gene
expression of urokinase plasminogen activator (uPA),which plays a role in fibrinolysis and vascular remodeling, via both GATA6-mediated down-regulationof gene transcription and an acceleration of mRNAdegradation, while turbulent shear stress increases theuPA gene expression through mRNA stabilization. We
demonstrated that shear stress up-regulates the gene

expression of plasminogen activator inhibitor-1(PAI-1) through activation of transcription factors
Sp-1 and Ets-1 in human hepatocytes. We developed acompliant tube-type flow-loading device that allows
simultaneous application of physiological levels ofshear stress and cyclic strain to cultured cells andobserved that the response of endothelial genes toshear stress or cyclic strain depends on whether thetwo forces are applied separately or together.
3. Hemodynamic force-induced cell differentiation
We have revealed that endothelial progenitor cells(EPCs) circulating in human peripheral blood
proliferate and differentiate into mature ECs in
response to shear stress, thereby forming tube-likestructures in collagen gel. Moreover, we revealed thatshear stress increased the gene expression of thearterial EC marker ephrinB2 in EPCs, while itdecreased the gene expression of the venous EC
marker EphB4, suggesting that shear stress affects
arterial-venous differentiation of EPCs.
Embryonic stem (ES) cells have the potential todifferentiate into every cell type in the body, andattracting interest as a promising source of cells foruse in regenerative medicine. Embryonic cells are
exposed to fluid-mechanical forces, including shear
stress and the cyclic strain generated by beating heart
during the process of embryonic development. We
found that shear stress induces the differentiation ofmurine ES cells into vascular EC lineage in vitro;
cyclic strain induces the differentiation into vascularsmooth muscle cell (SMC) lineage. Differentiation
into the EC lineage and differentiation into SMC
lineage are mediated by ligand-independent
phosphorylation of vascular endothelial growth factor
receptor 2 (VEGFR2) and platelet derived growth
factor receptor (PDGFR), respectively. Moreover, ourstudy has shown that shear stress increases expressionof ephrinB2 in murine ES cells via the VEGF-Notch
signaling pathways, suggesting that shear stress canalso affect the arterial-venous differentiation of ES
cells. Based on these findings, in a collaborative study,
a new hybrid type of artificial blood vessel, in which
ES cells were cultured on the surface of polymer tubes
and exposed to pulsatile shear stress and cyclic strain,
was developed.

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4. Mechanosensing and mechanotransduction
We were the first to show that Ca2+ signaling plays
an important role in the mechanism by which ECs
recognize the shear stress signal and transmit it into
the cell interior. Strong shearing forces induced by
dragging ECs with a balloon causes an increase incytoplasmic Ca2+ concentrations. A relatively weak
shearing force like shear stress generated by fluid flowneeds the presence of extracellular ATP to induce Ca2+
response, and at several hundred nanomolar of ATP,intracellular Ca2+ concentrations increase in a shear
stress-dependent manner. Generally, flow-induced
Ca2+ responses are initiated at a locus at the cell edge
and propagate throughout the entire cell in the form ofa Ca2+ wave. The initiation locus corresponded
precisely to caveolae rich cell edges. We found that a
subtype of ATP-gated cation channel, the P2X4
receptor, is expressed in human vascular ECs and that
P2X4 receptors play a crucial role in the shear stressdependent Ca2+ response. Endogenously released ATP
by shear stress is involved in the P2X4-mediated Ca2+
responses. We produced P2X4-deficient mice andobserved that the P2X4-deficent mice have impaired
flow-dependent control of vascular tone and remodeling, indicating that shear stress signal transduction via
P2X4 plays a critical role in the regulation of circulatory functions.
Our study revealed that cell surface ATP synthase
localized in caveolae/lipid rafts are involved in theshear-stress-induced ATP release by ECs. Recently, wedemonstrate that the cellular mitochondria play a
critical role in this process. Cultured humanpulmonary artery ECs were exposed to controlledlevels of shear stress in a flow-loading device and thechanges in the mitochondrial ATP levels were
examined by real-time imaging using a fluorescenceresonance energy transfer-based ATP biosensor.
Immediately upon the exposure of the cells to flow,
the mitochondrial ATP levels increased, which wasboth reversible and dependent on the shear stressintensity. Inhibitors of the mitochondrial electrontransport chain and ATP synthase, as well as
knockdown of caveolin-1, a major structural protein of
the caveolae, abolished the shear-stress-induced
mitochondrial ATP generation, resulting in the loss of
the ATP release and influx of Ca2+ into the cells. These

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

References
1. Kamiya A, and Yamamoto K. A biomechanicallyderived minimum work model of the fish gilllamellarsystemexhibits
its
exquisite
morphological arrangement and perfusate

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regulation for oxygen uptake from water. J.
Biomech. 88:155-163, 2019.
2. Yoshida K, Tajima M, Nagano T, Obayashi K, Ito
M, Yamamoto K, Matsuoka I. Co-stimulation ofpurinergic P2X4 and prostanoid EP3 receptors
triggers synergistic degranulation in mouse bonemarrow-derived mast cells. Int. J. Mol. Sci.
20:5157-5171, 2019.
3. Yamamoto K and Ando J. Vascular mechanosensing.
The Cell. 51:644-648, 2019.

70

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

Associate Professor
Mako Kamiya, Ph.D.

Assistant Professor
Ryosuke Kojima, Ph.D.

Webpage

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

Introduction and Organization
The Laboratory of Chemical Biology and Molecular
Imaging is one of the laboratories in the department ofRadiology and Biomedical Engineering. Ourlaboratory is located in the annex of the medicalbuilding 3. Our lab members consist of 1 postdoctoral
researcher, 7 PhD students, 2 master course students,
one undergraduate student and one technical staff, as
of FY2019.

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

Research activities
Our lab aims at developing novel fluorescenceprobes and applying these molecules to biology andmedicine. So far, we have succeeded in establishingrational design strategies of fluorescence probes basedon several mechanisms including intramolecularspirocyclization. In FY2019, we have developed a red
fluorescent probe for esophageal cancer detection, afluorescent probe for prostate-specific membrane

antigen (PSMA) detection, a conjugate ofavidin-protease probe for sensitive cancer detection, aphotosensitizer for target cell ablation in a single-cellresolution, and a highly sensitive and stable fluorescence probe for a sialidase. The details are described
below.
Regarding the red fluorescent probe for esophageal
cancer detection, we developed a red fluorescentprobe, EP-2OMe SiR600 by conjugating a
dipeptidylpeptidase-IV (DPP-IV) substrate to SiR600,
which is a red fluorescent dye developed in ourlaboratory. By precisely controlling the fluorescencequantum yield of the dye before and after the reaction
with the enzyme by means of Photoinduced electronTransfer (PeT), it was possible to achieve a large
activation ratio before and after the reaction with the
enzyme, which made it possible to detect cancer withhigh sensitivity using clinical specimens fromesophageal cancer patients. (Ref 1)
To develop a fluorescent probe for detecting
prostate-specific membrane antigen (PSMA, which
has carboxidase activity), we first conjugated aryl
glutamate, a substrate of PSMA, to a benzene ring in
the vicinity of the fluorophore via an azoformyl linker,
and found that LUMO (lowest unoccupied molecularorbital) energy level was sufficiently reduced toquench the fluorescence by PeT. In addition, reactionof the probe with PMSA led to the desorption of aryl

71

glutamate followed by denitrogenation, which yieldeda large fluorescence increase due to the liberationfrom PeT quenching. This probe is a first-in-classfluorescence probe for detecting PSMA activity, and it
was possible to detect cancer using clinical specimensfrom prostate cancer patients, paving the way for the
fluorescence detection of prostate cancer during
surgery. In addition, the design principle of the probe
may be useful for the detection of various
carboxypeptidases as well. (Ref 2)
As for the probe based on avidin-small-molecule
probe conjugate, a fluorescent probe that recognizes
leucine aminopeptidase (LAP), a peptidase highly
expressed in certain types of cancer cells, wasconjugated to avidin, a protein that binds to lectins
expressed on cancer cells. By using a mouse model ofperitoneal dissemination of ovarian cancer, we showedthat a high signal to noise ratio (S/N ratio) can beobtained. (Ref 3)
Regarding the photosensitizer for killing target cells
at the single-cell level, we developed SPiDER-killer-gal, which is converted to active photosensitizing
form after the rection with -galactosidase and at thesame time trapped by intracellular protein by the
nucleophilic attack. This probe may be a particularly
useful tool in cell ablation experiments to analyze therole of specific cells in complex biological processes,
such as the developmental stage of animals.
(Publication 4)
Regarding the sialidase probe, a highly sensitive
probe was developed by conjugating a substrate
recognition site to HMRef, a fluorophore developed in
our laboratory, by precisely controlling the spirocyclization equilibrium before and after the reaction. A
self-immolative linker was inserted between thesubstrate and the fluorophore to stabilize the probe
and to detect the target enzyme with high sensitivity.
Sialidase is highly expressed in a variety of cancers
and bacteria that induce infections, so the prove
developed in this study may be useful for the sensitive
detection of these diseases. (Ref 5)
We also performed several collaboration works(Reference 6-7).

References
1. A. Ogasawara, M. Kamiya, K. Sakamoto, Y.
Kuriki, K. Fujita, T. Komatsu, T. Ueno, K.
Hanaoka, H. Onoyama, H. Abe, Y. Tsuji, M.
Fujishiro, K. Koike, M. Fukayama, Y. Seto, Y.
Urano, Red Fluorescence Probe Targeted to
Dipeptidylpeptidase-IV for Highly Sensitive
Detection of Esophageal Cancer, Bioconjugate
Chem. 30 (2019) 1055-1060..
2. M. Kawatani, K. Yamamoto, D. Yamada, M.
Kamiya, J. Miyakawa, Y. Miyama, R. Kojima, T.
Morikawa, H. Kume, Y. Urano, Fluorescence
Detection of Prostate Cancer by an Activatable
Fluorescence Probe for PSMA Carboxypeptidase
Activity, J. Am. Chem. Soc. 141 (2019) 1040910416.
3. K. Yamamoto, M. Kamiya, Y. Urano, Highly
sensitive fluorescence imaging of cancer withavidin-protease probe conjugate, Bioorg. Med.
Chem. Lett. 29 (2019) 126663.
4. M. Chiba, M. Kamiya, K. Tsuda-Sakurai, Y.
Fujisawa, H. Kosakamoto, R. Kojima, M. Miura,
Y. Urano, Activatable Photosensitizer for Targeted
Ablation of lacZ-Positive Cells with Single-Cell
Resolution, ACS Cent. Sci. 5 (2019) 1676-1681.
5. C. Rivas, M. Kamiya, Y. Urano, A novel
sialidase-activatable fluorescence probe withimproved stability for the sensitive detection of
sialidase, Bioorg. Med. Chem. Lett. 30 (2020)126860.
6. T. Akashi, H. Isomoto, K. Matsushima, M.
Kamiya, T. Kanda, M. Nakano, T. Onoyama, M.
Fujii, J. Akada, Y. Akazawa, K. Ohnita, F.
Takeshima, K. Nakao, Y. Urano, A novel method
for rapid detection of a Helicobacter pylori
infection using a gamma-glutamyltranspeptidaseactivatable fluorescent probe, Sci. Rep. 9 (2019)
9467.
7. K. Yamamoto, S. Ohnishi, T. Mizushima, J.
Kodaira, M. Ono, Y. Hatanaka, K.C. Hatanaka, Y.
Kuriki, M. Kamiya, N. Ehira, K. Shinada, H.
Takahashi, Y. Shimizu, Y. Urano, N. Sakamoto,Detection of early adenocarcinoma of theesophagogastric junction by spraying an enzymeactivatable fluorescent probe targeting Dipeptidyl
peptidase-IV, BMC Cancer 20 (2020) 64.

72

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

Homepage

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

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

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

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

73

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

ideal TAH that surpass the outcome of the hearttransplantation with combination of the technologiesof the physiological control and hybrid materials
described later.
How to control the output of a TAH is primary interest.
We have developed our original physiological control
method of the TAH, named 1/R control. The 1/R
control was developed with a conductance (1/R:
reciprocal of a resistance) parallel circuit model. Withthe 1/R control, the particular problems of a TAH suchas venous hypertension, slight anemia, low thyroid
hormone level and so on, were not observed and theoutput changed in accordance with a metabolic
demand of the animal.
The problem of the 1/R control was a mismatching of
the time constants between the control systems of thedevice and the body. As a consequence, the 1/R
control occasionally diverged in the animal experiment of the UPTAH and HFTAH. To improve theproblem of instability in the 1/R control, a new control
method based on the fluctuation of arterial and venous
pressures (named P control) was developed byreforming the 1/R control function. At present, P
control is tested with the animal experiment.
On the other hand, the 1/R control was applied to the
UPTAH and HFTAH to perform a physiological study
with a nonpulsatile TAH by changing the drive mode
from pulsatile to nonpulsatile in a single goat. The
result showed that, for a period of several weeks, the
1/R control could be promising not only with apulsatile flow, but also with a nonpulsatile flow. The
general conditions and organ functions were notchanged by the application of the nonpulsatile flow.
The cardiac output and the arterial pressure changed
with the condition of the goat in the pulsatile and also
nonpulsatile flow, which seemed almost identical.
However, under the physiological atrial pressure, thesucking effect of atria was more significant in the
nonpulsatile flow than the pulsatile flow. Therefore,
the nonpulsatile TAH with the 1/R control was
considered to be inadequate, unless some pulsatility
would be introduced to avoid the sucking effect for
ensuring sufficient inflow condition.
Concerning the materials, we have been developing a
new method to develop hybrid materials. In general, it
is not easy to develop mechanical parts for complex
artificial organs such as artificial hearts from the74

components 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 started. The
device consists of a blood pump, an oxygenator, adrive and control unit, and a battery unit. To realize
several-months support, the left side blood pump ofhelical flow TAH has been employed. This system is
expected to offer more opportunities and safer surgicalinterventions to those who are waiting for lungtransplants. In case of high afterload, the sequential
flow pump (SFP) would be applied. The SFP in which
fluid is given centrifugal force sequentially twice in apump was invented in our laboratory in 2013. Thissequential pressurization mechanism enables highpressure output without high impeller speed, which
can reduce the sheer stress of the blood. To realize
integration of the pump with the artificial lung, inlet
and outlet ports are located at lateral side and center ofthe pump, respectively, which is the reverse
configuration of conventional centrifugal pumps.

References
1.

Osamu Fukayama, Naoki Sudo, and Takashi
Isoyama, Leading a Rat along a Moving Virtual
Reward Circle with “Rattractor”, a Closed-loop
Deep-Brain Stimulator. 9th International IEEE
EMBS Conference on Neural Engineering San
Francisco, CA, USA, 2019; 1195-1198.

75

Division of Integrative Genomics
Professor
Katsutoshi Oda, 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. The division of Integrative
Genomics is organized by Professor Katsutoshi Oda,
and will include one Associate Professor Aya Ushiku
from June 2020. We focus on both basic research andtranslational research in the field of genomics(especially genomic medicine in cancer).

Activities
Basic Research(1) Genome-wide analysis of cancer
a. Whole-genome sequencing, whole-exome
sequencing, Comprehensive Genomic Profilingb. Multi-omics (Copy Number Variation Analysis,RNA-sequencing, Methylation Array, etc)
c. Liquid biopsy (with circulating tumor cells,
cell-free tumor DNA, DNA from ascites, etc)
d. Analysis of hereditary cancer syndromes(Genetic testing and NGS-based comprehensive
analysis)(2) Analysis of molecular-targeted therapies in cancer
cells
a. PI3K/mTOR inhibitors
b. PARP inhibitors, ATM inhibitors, ATR
inhibitors (all of which target DNA repair
pathway)c. MDM2 inhibitors in TP53 wild-type cancers
d. Histone methyltransferase inhibitors(3) Exploration of biomarkers for molecular-targeteddrugs
a. Evaluation of homologous recombination
deficiency by using mutational signatures
b. CDK4/6 enzymatic activities and prognosis forrecurrencec. Classification by expression signature to predict
sensitivity to immune checkpoint inhibitors
Translational Research(1) Todai OncoPanel and Genomic Medicine inCancerTrial of a multiplex genomic testing by "Todai
OncoPanel" for Geneprofiling of malignant solid
tumors as Advanced Medical Care Category B was
performed in 200 cancer patients (from 2018 to 2020).
UMIN000033647
Todai OncoPanel (TOP) has been originallyestablished at the University of Tokyo (by Professor
Hiroyuki Mano (currently Director of National Cancer
Center Research Institute) and Professor Hiroyuki
Aburatani et al), which is composed of DNA panel(version 3: 464 genes) and RNA panel (version 4: 463
genes). We reported the usefulness of TOP panel,
especially in detecting gene fusions, including ALK,
ROS1, and NTRK.
(2) Investigator-Initiated Clinical Trial using a PARP
inhibitor, entitled “A multi-center, phase II study of
Olaparib maintenance therapy in patients with highgrade ovarian cancer, combined with translational
research by integrated genome-wide analysis”
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 by

76

whole-exome sequencing of fresh-frozen tumor
samples.
Clinical activities are described in the section of“Department of Clinical Genomics”.

Publications
1.

2.

3.

4.

5.

Kawata Y, Nagasaka K, Matsumoto Y, Oda K,
Tanikawa M, Sone K, Mori-Uchino M, Tsuruga T,
Arimoto T, Osuga Y, Fujii T. Usefulness of cell-freeand concentrated ascites reinfusion therapy in thetherapeutic management of advanced ovarian cancer
patients with massive ascites. Int J Clin Oncol
2019;24(4):420-7.
Akino N, Wada-Hiraike O, Isono W, Terao H, Honjo
H, Miyamoto Y, Tanikawa M, Sone K, Hirano M,
Harada M, Hirata T, Hirota Y, Koga K, Oda K, Fujii
T, Osuga Y. Activation of Nrf2/Keap1 pathway byoral Dimethylfumarate administration alleviates
oxidative stress and age-associated infertility might
be delayed in the mouse ovary. Reprod Biol
Endocrinol 2019;17(1):23.
Bagnoli M, Shi TY, Gourley C, Speiser P, Reuss A,
Nijman HW, Creutzberg CL, Scholl S, Negrouk A,
Brady MF, Hasegawa K, Oda K, McNeish IA, Kohn
EC, Oza AM, MacKay H, Millan D, Bennett K,
Scott C, Mezzanzanica D. Gynecological Cancers
Translational, Research Implementation, andHarmonization: Gynecologic Cancer InterGroup
Consensus and Still Open Questions. Cells 2019;8(3).
Kohsaka S, Tatsuno K, Ueno T, Nagano M,
Shinozaki-Ushiku A, Ushiku T, Takai D, Ikegami M,
Kobayashi H, Kage H, Ando M, Hata K, Ueda H,
Yamamoto S, Kojima S, Oseto K, Akaike K, Suehara
Y, Hayashi T, Saito T, Takahashi F, Takahashi K,
Takamochi K, Suzuki K, Nagayama S, Oda Y,
Mimori K, Ishihara S, Yatomi Y, Nagase T,
Nakajima J, Tanaka S, Fukayama M, Oda K,
Nangaku M, Miyazono K, Miyagawa K, Aburatani
H, Mano H. Comprehensive assay for the molecularprofiling of cancer by target enrichment fromformalin-fixedparaffin-embedded
specimens.
Cancer Sci 2019;110(4):1464-79.
Kukita A, Sone K, Oda K, Hamamoto R, Kaneko S,
Komatsu M, Wada M, Honjoh H, Kawata Y, Kojima

M, Oki S, Sato M, Asada K, Taguchi A, Miyasaka A,
Tanikawa M, Nagasaka K, Matsumoto Y, WadaHiraike O, Osuga Y, Fujii T. Histone methyltransferase SMYD2 selective inhibitor LLY-507 in
combination with poly ADP ribose polymerase
inhibitor has therapeutic potential against highgrade serous ovarian carcinomas. Biochem Biophys
Res Commun 2019;513(2):340-6.
6. Kojima M, Sone K, Oda K, Hamamoto R, Kaneko S,
Oki S, Kukita A, Machino H, Honjoh H, Kawata Y,
Kashiyama T, Asada K, Tanikawa M, Mori-Uchino
M, Tsuruga T, Nagasaka K, Matsumoto Y, WadaHiraike O, Osuga Y, Fujii T. The histone methyltransferase WHSC1 is regulated by EZH2 and isimportant for ovarian clear cell carcinoma cellproliferation. BMC Cancer 2019;19(1):455.
7. Tsuruga T, Hirata T, Akiyama I, Matsumoto Y, Oda
K, Fujii T, Osuga Y. Mixed endometrioid and clear
cell carcinoma arising from laparoscopic trocar site
endometriosis. J Obstet Gynaecol Res 2019;45(8):1613-8.
8. Takeuchi M, Nagasaka K, Yoshida M, Kawata Y,
Miyagawa Y, Tago S, Hiraike H, Wada-Hiraike O,
Oda K, Osuga Y, Fujii T, Ayabe T, Kim SH, Fujii T.
On-chip immunofluorescence analysis of single
cervical cells using an electroactive microwell arraywith barrier for cervical screening. Biomicrofluidics
2019;13(4):044107.
9. Makii C, Ikeda Y, Oda K, Uehara Y, Nishijima A,
Koso T, Kawata Y, Kashiyama T, Miyasaka A, Sone
K, Tanikawa M, Tsuruga T, Mori-Uchino M,
Nagasaka K, Matsumoto Y, Wada-Hiraike O,
Kawana K, Hasegawa K, Fujiwara K, Aburatani H,
Osuga Y, Fujii T. Anti-tumor activity of dual
inhibition of phosphatidylinositol 3-kinase andMDM2 against clear cell ovarian carcinoma.
Gynecol Oncol 2019;155(2):331-9.
10. Aotsuka A, Matsumoto Y, Arimoto T, Kawata A,
Ogishima J, Taguchi A, Tanikawa M, Sone K, MoriUchino M, Tsuruga T, Oda K, Kawana K, Osuga Y,
Fujii T. Interleukin-17 is associated with expressionof programmed cell death 1 ligand 1 in ovariancarcinoma. Cancer Sci 2019;110(10):3068-78.
11. Takeuchi M, Tanikawa M, Nagasaka K, Oda K,
Kawata Y, Oki S, Agapiti C, Sone K, Miyagawa Y,
Hiraike H, Wada-Hiraike O, Kuramoto H, Ayabe T,
Osuga Y, Fujii T. Anti-Tumor Effect of Inhibition of

77

DNA Damage Response Proteins, ATM and ATR, in
Endometrial Cancer Cells. Cancers 2019;11(12).
12. Inoue S, Hirota Y, Ueno T, Fukui Y, Yoshida E,
Hayashi T, Kojima S, Takeyama R, Hashimoto T,
Kiyono T, Ikemura M, Taguchi A, Tanaka T, Tanaka
Y, Sakata S, Takeuchi K, Muraoka A, Osuka S, Saito
T, Oda K, Osuga Y, Terao Y, Kawazu M, Mano H.
Uterine adenomyosis is an oligoclonal disorderassociated with KRAS mutations. Nat Commun
2019;10(1):5785.
13. Ando M, Kobayashi H, Shinozaki-Ushiku A,
Chikuda H, Matsubayashi Y, Yoshida M, Saito Y,
Kohsaka S, Oda K, Miyagawa K, Aburatani H,
Mano H, Yamasoba T. Spinal solitary fibrous tumorof the neck: Next-generation sequencing-based
analysis of genomic aberrations. Auris Nasus
Larynx 2019;S0385-8146(19)30932-0

Neuroscience
1. Basic Neuroscience

79

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

Associate
Kaoru Yamada, Ph.D.
Ryoko Ihara, M.D.

Homepage

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

Dr. Iwatsubo’s research group has been pursuing
the pathogenesis of Alzheimer’s disease (AD) andrelated neurodegenerative conditions (especially,
dementia with Lewy bodies; DLB) by multidisciplinary approaches, based on histopathology andprotein biochemistry of postmortem human brains.
They then extended the knowledge derived from thehuman studies in a way to establish cellular models
and to elucidate the key steps in the pathologicalcascade of neurodegeneration. Thus, Dr. Iwatsubo’sgroup has been addressing the pathogenesis ofneurodegenerative disorders from the downstream (i.e.,analysis of aggregated proteins) as well as from the
upstream (i.e., pathogenic effects of pathogenic genes),
covering a number of crucial proteins/genes related to
AD and DLB, i.e., β-amyloid (including its binding
protein CLAC), presenilin/γ-secretase and α-synuclein.
In this way Dr. Iwatsubo’s group has contributed
much to the widely accepted notion that abnormal
misfolding of brain proteins is the common cause of avariety of neurodegenerative disorders including AD.
Furthermore, Dr. Iwatsubo’s group is currently
working hard to translate the basic findings into theclinical application of mechanism-based, diseasemodifying therapies for AD through the world-wide
ADNI project, in which Dr. Iwatsubo serves as the PI
of Japanese ADNI.
1. Research on β-amyloid and presenilins
Using C-terminal specific monoclonal antibodies
that discriminate amyloid β peptides (Aβ) ending at
40th or 42nd residues (Aβ40 and Aβ42, respectively),

Dr. Iwatsubo has performed a systematic immunohistochemical studies on autopsied brain tissues frompatients with AD, Down syndrome and familial AD,
and demonstrated that Aβ42, that most readily form
amyloid fibrils in vitro, is the initially andpredominantly deposited species in human cerebral
β-amyloidosis (Iwatsubo et al. Neuron 1994, Ann
Neurol 1995). Dr. Iwatsubo’s group then establishedcelllar models expressing mutant forms of presenilin(PS) genes linked to familial AD (FAD), and using
their original highly-sensitive ELISA quantitation
system, his group has clearly shown that an increasein the production of Aβ42 is the pathogenic
mechanism leading to FAD (Tomita et al. Proc Natl
Acad Sci USA, 1997). These findings have provided afirm basis for the currently prevailing β-amyloid
hypothesis. They then focused on the mechanisms ofγ-secretase complex that cleaves the C terminus of Aβ,
and set out to cell biological studies using RNAinterference on the formation and function of theγ-secretase complex harboring PS as the catalytic
center, associated with three additional membraneproteins. They demonstrated that APH-1 and Nicastrin
serve as the “stabilizing” co-factor of PS, whereas
PEN-2 is the component that confers proteolytic
activity to this complex. They also showed that PS,
APH-1, nicastrin and PEN-2 are the essential set ofproteins that comprise the γ-secretase complex(Takasugi et al. Nature, 2003). This study ishighlighted as a milestone work that elucidated themechanistic roles of protein cofactors in the formationand function of γ-secretase (see reviews; Iwatsubo

80

Mol Psychiatr, 2004; Curr Opin Neurobiol, 2004). His
group has also shown by establishing in vitro
γ-secretase assays that sulindac sulfide, a major
non-steroidal anti-inflammatory drugs, directly acts on
γ-secretase and selectively reduce Aβ42-generating
activities (Takahashi et al., J Biol Chem, 2003),
providing important implications to the therapeuticstrategies of AD by γ-secretase modulation. Recently,
he has established a novel method for an efficient invitro reconstituion of γ-secretase complex, paving theway towards the structural analysis of active
γ-secretase (Hayashi et al. J Biol Chem, 2004), andusing thus highly purified γ-secretase particles, they
have partially unveiled the submolecular structure ofthis complex by single-particle EM analysis (Ogura etal. BBRC, 2006). Very recently, his group has
established an elegant strategy to analyze thestructure-function relationship within the catalytic
structure of γ-secretase complex by cystein chemistry,and demonstrated that γ-secretase harbors a waterpermeable catalytic pore (Sato et al. J Neurosci, 2006),
and that substrate proteins enter the catalytic porethrough the lateral gate located at the C terminal sideof PS (Sato et al. J Neurosci, 2008). Thus, Dr.
Iwatsubo’s group started from an elegant immunohistochemical analysis of Aβ deposits in AD brains
and extended it to a contemporary molecular/cellularbiology of PS, that proved to play a key role in“intramembrane proteolysis”.
2. Identification and characterization of α-synuclein
as a major component of Lewy bodies.
Using cortical Lewy bodies purified frompostmortem brains of patients with dementia with
Lewy bodies (DLB) by his original method (Iwatsubo
et al. Am J Pathol 1996) as immunogens, Dr.
Iwatsubo’s group, in collaboration with Drs. Virginia
Lee and John Trojanowski at Univ. Penn, performed
an extensive immunochemical search for componentsof Lewy bodies. They have demonstrated by raising a
specific monoclonal antibody that α-synuclein, thatproved to be a product of pathogenic gene for familial
form of Parkinson’s disease, is one of the major
constituent of Lewy bodies in sporadic Parkinson’s
disease and DLB (Baba et al. Am J Pathol 1998). His
group then purified aggregated α-synuclein from DLB
cortices using fine biochemical techniques, purified it

to near homogeneity, and demonstrated using mass
spectrometry and specific antibodies that α-synuclein
deposited in synucleinopathy lesions is highly
phosphorylated at a specific serine residue (Fujiwara
et al. Nature Cell Biol 2002). This finding led to arange of studies focusing on the role of synuclein
phosphorylation in neurodegeneration. Also, thephospho-specific α-synuclein antibody is widely usedas the most sensitive marker for α-synucleinopathy
lesions, and has characterized a wide spectrum of
α-synuclein
pathologies
inneurodegenerative
disorders.
3. Identification of a non-Aβ Alzheimer amyloid plaquecomponent CLAC, and its precursor CLAC-P
The major component of Alzheimer’s amyloid
plaques is Aβ, although there are a number of non-Aβ
components that potentially affect fibrillization anddegradation of amyloid deposits. Among these, there
has been an enigmatic “missing piece” protein ofmolecular masses of 50/100 kDa. Dr. Iwatsubo’sgroup raised a monoclonal antibody against amyloid
fraction that recognizes this protein, and using thisantibody as a probe, they conducted a thoroughbiochemical purification of these antigens and finallycloned a cDNA coding for the precursor of this protein.
This protein turned out to be a novel class ofmembrane-bound collagen, which was named CLAC
(collagen-like Alzheimer amyloid plaque component)
and its precursor CLAC-P (Hashimoto et al. EMBO J
2002). This finding had an immense impact both on
fields of AD research as well as on general biology as
a first discovery of neuron-specific collagen harboringa unique membrane-spanning structure. CLAC has
been highlighted as a protein that may affectfibrillization of Aβ and contribute to amyloid plaqueformation. Indeed, he has recently shown that CLACpositive senile plaques constitute a unique subset ofplaques distinct from the classical, β-sheet-richamyloid deposits, underscoring the pathobiologicalrole of CLAC in amyloid formation, and that CLAC
inhibits fibrillization of Aβ in vitro. Knockout micestudies have confirmed the role of CLAC inneuromuscular development (Tanaka et al. J Neurosci,2014).
4. Japanese ADNI: clinical studies for the identification of surrogate imaging and biomarkers of AD

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Basic studies on the pathomechanism of AD haveboosted the development of mechanism-based drugs
for AD, whereas the bottleneck has been the lack ofsurrogate biomarkers that represent the progression of
AD pathology and are useful in the clinical trial of
disease-modifying drugs. In close collaboration with
Drs. Mike Weiner and Ron Petersen of US-ADNI, Dr.
Iwatsubo has initiated the Japanese ADNI as theprincipal investigator on 2006, recruiting 38 clinicalsites nationwide, and preparing all the infrastructures
required for the large-scale clinical study. The J-ADNI
group recruit 537 individuals in total, and all the data
derived from the J-ADNI study have been made inpublic from the National Bioscience Database Center
for research use. Recently, the J-ADNI group has
demonstrated the similarity between MCI due to AD
in Asian and Caucasian populations by comparing theclinical and biomarker features of J-ADNI and ADNI
participants, supporting the feasibility of global
clinical trials of disease-modifying therapies for AD.
Recently, his group is leading the “Japanese
Trial-Ready cohort for prevention of AD (J-TRC).

References
1) Ishida T, Tokuda K, Hisaka A, Honma M, Iwatsubo
T, Moritoyo T, Suzuki H, Alzheimer’s Disease
Neuroimaging Initiative. Development of a novel
method to estimate chronological changes indisease progression. Clin Pharmacol Therapeut
105: 436-447, 20192) Bannai T, Mano T, Chen X, Ohtomo G, Ohtomo R,
Tsuchida T, Koshi-Mano K, Hashimoto T, Okazawa
H, Iwatsubo T, Tsuji S, Toda T, Iwata A: Chronic
cerebral hypoperfusion shifts the equilibrium ofamyloid  oligomers to aggregation-prone species
with higher molecular weight. Sci Rep 9:2827, 20193) Sato K, Mano T, Ihara R, Suzuki K, Tomita N, Arai
H, Ishii K, Senda M, Ito K, Ikeuchi T, Kuwano R,
Matsuda H, Iwatsubo T, Toda T, Iwata A: Lower
serum calcium as a potential risk factor for mild
cognitive impairment conversion to early
Alzheimer’s disease in Japanese Alzheimer’s
Disease Neuroimaging Initiative. J Alz Dis
68:777-788, 20194) Goncalves TJM, Boutillon F, Lefebvre S, Goffin V,
Chanoine C, Iwatsubo T, Wakabayashi T, Oury F,

Armand AS: Collagen XXV promotes myoblast
fusion during myogenic differentiation and muscle
formation. Sci Rep 9:5878, 20195) Wakabayashi T, Yamaguchi K, Matsui K, Sano T,
Kubota T, Hashimoto T, Mano A, Yamada K,
Matsuo Y, Kubota N, Kadowaki T, Iwatsubo T:
Differential effects of diet- and genetically-induced
brain insulin resistance on amyloid pathology in amouse model of Alzheimer’s disease. Mol
Neurodegener 14:15, 20196) Eto M, Hashimoto T, Shimizu T, Iwatsubo T:
Characterization of the unique in vitro effects of
unsaturated fatty acids on the formation of amyloid fibrils. PLOS One 14:e0219465, 20197) Yagi T, Kanekiyo M, Ito J, Ihara R, Suzuki K, Iwata
A, Iwatsubo T, Aoshima K: Identification of
prognostic factors to predict cognitive decline ofearly Alzheimer’s disease patients in the Japanese
Alzheimer’s Disease Neuroimaging Initiative study.
Alzheimers Dementia: Translational Research &Clinical Interventions 5:364-373, 20198) Park S, Park S-K, Watanabe N, Hashimoto T,
Iwatsubo T, Shelkovnikova TA, Liebman SW:
Calcium-responsive
transactivator(CREST)
toxicity is rescued by loss of PBP1/ATXN2 function
in a novel yeast proteinopathy model and intransgenic flies. PLOS Genetics 15:e1008308, 20199) Sato K, Mano T, Matsuda H, Senda M, Ihara R,
Suzuki K, Arai H, Ishii K, Ito K, Ikeuchi T, Kuwano
R, Toda T, Iwatsubo T, Iwata A: Visualizing
modules of coordinated structural brain atrophyduring the course of Alzheimer's disease conversion
by applying methodology from gene co-expression
analysis. Neuroimage Clinical 24:101957, 201910) Tanaka Y, Yamada K, Satake K, Nishida I,
Heuberger M, Kuwahara T, Iwatsubo T: Seeding
activity-based detection uncovers the different
release mechanisms of seed-competent tau versus
inert tau via lysosomal exocytosis. Front Neurosci
13:1258, 201911) Munezane H, Oizumi H, Wakabayashi T, Nishio S,
Hirasawa T, Sato T, Harada A, Yoshida T, Eguchi T,
Yamanashi Y, Hashimoto T, Iwatsubo T：Roles ofcollagen XXV and its putative receptors PTPσ/δ inintramuscular motor innervation and congenital
cranial dysinnervation disorder. Cell Rep 29:
4362-4376, 2019

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

Assistant Professor
Hajime Fujii, Ph.D., Masayuki Sakamoto, Ph.D., Ryang Kim, 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 Westwing of the third building of the Medical School. The
Department currently enrolls one professor, threeassistant professors, two postdoctoral scholar, one
technical staff member, seven Ph.D. graduate students,
one rotating medical student, one technical assistantand three administrative assistants.

83

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-KO
and
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 in

84

fact 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
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

85

imaging with optical manipulation) to simultaneously
measure activities of two distinct signaling moleculesin living neurons. Applying originally developed
FRET probes to dFOMA method enabled us tomeasure activities of CaMKII, calcineurin and Ca2+,
when a neuron received various frequencies ofsynaptic inputs. These experiments provided evidence
that CaMKIIα and calcineurin are fine-tuned to uniquebandwidths and compute input variables in an
asymmetric manner (Fujii et al., Cell Reports 2013).
In line with the visualization of neuronal activity
and Ca2+ signaling, we have developed R-CaMP2, a
red genetically-encoded Ca2+ indicator that has singleaction-potential sensitivity based on rational designthat takes advantage of our long-standing effort andknowledge about CaMKK-CaMKIV signaling. By
combining R-CaMP2 with green Ca2+ indicator
G-CaMP, distinct activity patterns between excitatory
and inhibitory neurons in somatosensory cortex was
revealed (Inoue et al., Nat. Methods 2015).
Furthermore, we have advanced our visualization
probe technology to developed ultra-fast, ultrasensitive Ca2+ indicators XCaMP-B/G/Y/R, whichallowed imaging in blue, green, yellow, and red, andsimultaneously tracked activities of high-frequency
firing parvalbumin (PV)-positive cells, as well asactivities of three different neuronal cell types(excitatory pyramidal cells, PV-positive andsomatostatin (SST)-positive cells) (Inoue et al., Cell,2019).
One further important topic that we have been
focusing for a number of years is the role of gene
expression in prolongation / consolidation of synapsespecific local changes. Neurons undergoing various
stimulus patterns have been followed up in time andthe amount of newly synthesized proteins and the
local distribution of induced gene products have beenmonitored. Using state-of-the-art multi-wavelength
fluorescence imaging techniques, we are now quantitatively assessing how local distribution of these
newly synthesized gene products affect synaptic
protein complexes (Okuno and Bito, AfCS/Nature
Mol. Pages 2006).
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon

terminals.
Both synaptic maturation and synaptic plasticity
have been shown to include a morphological component that is directed by the dynamics of actin
cytoskeleton, a major cytoskeletal component both in
the dendritic spines and at the very proximity ofboutons in the axon terminals. Few studies in the past,
however, had directly addressed what moleculardeterminants regulate actin dynamics in living central
neurons undergoing synaptic activity. This was in part
because actin filament assembly and disassembly wereclassically studied mostly at the moving edges oflamellipodia of large growth cones in large-size
neurons from either mollusc or peripheral nerve cells.
Such visualization turned out to be much moredifficult in seemingly far less mobile spine structures
tightly apposed to presynaptic active zones.
We (and others) used GFP-actin imaging to try tounderstand how neuronal actin cytoskeleton in
hippocampal neurons was organized and reorganizedby exposure to synaptic activity. In our dissociatedculture system, virtually all spines contained a highamount of GFP-actin and most of them with few
exceptions were apposed to FM4-64-positive active
presynaptic termini. In these cultures, increases insynaptic glutamatergic transmission by repeated burstsof high-frequency synaptic activity clearly induced
several distinct kinds of activity-dependent actin
mobilization, including a slow but sustained synaptic
delivery of GFP-actin in a non-negligible number ofactivated spines and a massive but transientenhancement in cortical actin at the somatic periphery.
The former was entirely dependent on NMDAdependent Ca2+-influx while the latter was likely to be
mediated at least in part by L-type voltage-gated Ca2+
channel activity. Thus, distinct patterns and sources of
Ca2+ influx were likely to trigger a complex spatiallysegregated patterns of actin cytoskeletal reorganization, with variable impact on either neuronalmorphology and/or synaptic protein assembly(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

86

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 2019- December 2019)
1. Zhang T, Hernandez O, Chrapkiewicz R, Shai A,
Wagner MJ, Zhang Y, Wu CH, Li JZ, Inoue M,
Gong Y, Ahanonu B, Zeng H, Bito H, Schnitzer
MJ. Kilohertz two-photon brain imaging in awake
mice. Nat Methods. 2019 Nov;16(11):1119-1122.
2. Chowdhury S, Hung CJ, Izawa S, Inutsuka A,
Kawamura M, Kawashima T, Bito H, Imayoshi I,
Abe M, Sakimura K, Yamanaka A. Dissociating
orexin-dependent and -independent functions oforexin neurons using novel Orexin-Flp knock-in
mice. eLife. 2019 Jun 4;8. pii: e44927.
3. Inoue M, Takeuchi A, Manita S, Horigane SI,
Sakamoto M, Kawakami R, Yamaguchi K, Otomo
K, Yokoyama H, Kim R, Yokoyama T,
Takemoto-Kimura S, Abe M, Okamura M, Kondo
Y, Quirin S, Ramakrishnan C, Imamura T,
Sakimura K, Nemoto T, Kano M, Fujii H,

87

4.

5.

6.

7.

Deisseroth K, Kitamura K, Bito H. Rational
Engineering of XCaMPs, a Multicolor GECI Suite
for In Vivo Imaging of Complex Brain Circuit
Dynamics. Cell. 2019 May 16;177(5): 1346-1360.
e24.
Murata K, Kinoshita T, Fukazawa Y, Kobayashi K,
Kobayashi K, Miyamichi K, Okuno H, Bito H,
Sakurai Y, Yamaguchi M, Mori K, Manabe H.
GABAergic neurons in the olfactory cortex
projecting to the lateral hypothalamus in mice. Sci
Rep. 2019 May 9;9(1):7132.
Moda-Sava RN, Murdock MH, Parekh PK, Fetcho
RN, Huang BS, Huynh TN, Witztum J, Shaver
DC, Rosenthal DL, Alway EJ, Lopez K, Meng Y,
Nellissen L, Grosenick L, Milner TA, Deisseroth
K, Bito H, Kasai H, Liston C. Sustained rescue ofprefrontal circuit dysfunction by antidepressantinduced spine formation Science. 2019 Apr 12;364(6436):eaat8078.
Kikuchi K, Ihara D, Fukuchi M, Tanabe H,
Ishibashi Y, Tsujii J, Tsuda M, Kaneda M,
Sakagami H, Okuno H, Bito H, Yamazaki Y,
Ishikawa M, Tabuchi A. Involvement of SRF
coactivator MKL2 in BDNF-mediated activationof the synaptic activity-responsive element in the
Arc gene J Neurochem. 2019 Jan;148(2):204-218.
Koizumi K, Inoue M, Chowdhury S, Bito H,
Yamanaka A, Ishizuka T, Yawo H. Functional
emergence of a column-like architecture in layer 5of mouse somatosensory cortex in vivo J Physiol
Sci. 2019 Jan;69(1):65-77.

Neuroscience
2. Integrative Medical Neuroscience89

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

Assistant professor
Yosuke Eriguchi, M.D., Ph.D., Ayaka Ishii-Takahashi, M.D., Ph.D.

Homepage

http://childpsy.umin.jp/

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

Teaching activities
In the year of 2019, we had 7 graduate students. In
addition to research training, educational program
including full-year lectures of child psychiatry, caseconference and journal club was implemented withfurther improvement.

Research activities
Main subjects of our research are Autism Spectrum
Disorder (ASD), Attention-Deficit/Hyperactivity
Disorder (ADHD), Tourette syndrome which is asevere and chronic tic disorder, and child & adolescentobsessive-compulsive disorder (OCD). We are trying
to combine scientific analysis of objective mental andbehavioral indicators with neuropsychological, brainimaging, and genetic studies into comprehensive andmultidimensional approach to problems in development of brain and mind. We are applying this comprehensive approach to intervention studies including
pharmacotherapy.
Major research projects with full or preliminary
performance in 2019 are as follows:・Epidemiological, behavior phenotype, neuropsychological, genetic and treatment study of Tourette
syndrome and child & adolescent OCD
・Brain-imaging study of ASD, ADHD and Tourette
syndrome by structural-MRI, functional-MRI andnear-infrared spectroscopy (NIRS)
・Genomic and epigenomic analysis of ASD
・Development of predictor of parent training for
ADHD
・Effectiveness study of early intervention for autisticpreschoolers and group cognitive behavior therapy
for adults with high-functioning ASD
・Investigation on clinical evaluation and psychological education for adults with developmental
disorders90

References
1. Kimura Y, Ikegaya N, Iijima K, Takayama Y,
Kaneko Y, Omori M, Kaido T, Kano Y, Iwasaki
M: Withdrawal of deep brain stimulation inpatients with gilles de la tourette syndrome. Mov
Disord.2019; 34(12):1925-1926.
2. Goto R, Fujio M, Matsuda N, Fujiwara M,
Nobuyoshi M, Nonaka M , Kono T, Kojima M,
Skokauskas N & Kano Y: The effects of comorbid
Tourette symptoms on distress caused bycompulsive-like behavior in very young children:a cross-sectional study, Child and Adolescent
Psychiatry and Mental Health 2019; 13: 28.
3. Murakami J, Tachibana Y, Akiyama S, Kato T,
Taniguchi A, Nakajima Y, Shimoda M, Wake H,
Kano Y, Takada M, Nambu A, Yoshida A: Oral
splint ameliorates tic symptoms in patients withtourette syndrome. Mov Disord.2019; 34(10):1577-1578.
4. Owada K, Okada T, Munesue T, Kuroda M,
Fujioka T, Uno Y, Matsumoto K, Kuwabara H,
Mori D, Okamoto Y, Yoshimura Y, Kawakubo Y,
Arioka Y, Kojima M, Yuhi T, Yassin W, Kushima I,
Benner S, Ogawa N, Kawano N, Eriguchi Y,
Uemura Y, Yamamoto M, Kano Y, Kasai K,
Higashida H, Ozaki N, Kosaka H, Yamasue H:
Quantitative facial expression analysis revealed
the efficacy and time course of oxytocin in autism.
Brain 2019; 142(7): 2127-2136.
5. Yassin W, Kojima M, Owada K, Kuwabara H,
Gonoi W, Aoki Y, Takao H, Natsubori T, Iwashiro
N, Kasai K, Kano Y, Abe O, Yamasue H. Paternal
age contribution to brain white matter aberrationsin autism spectrum disorder. Psychiatry Clin
Neurosci. 2019; 73(10): 649-659.
6. Ochi K, Ono N, Owada K, Kojima M, Kuroda M,
Sagayama S, Yamasue H. Quantification of
speech and synchrony in the conversation of
adults with autism spectrum disorder. PLoS One
2019; 14(12): e0225377.

Neuroscience
3. Clinical Neuroscience92

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

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

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

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

Research Associate
Shinsuke Kondo, M.D.

Kayo Ichihashi, M.D.

Taiki Johse, M.D.

Go Taniguchi, M.D., Ph.D.

Kenji Kirihara, M.D., Ph.D.

Oji Tomoatsu, MD.

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

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

Mizuo Hoshino, 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 20
staff psychiatrists, 5 clinical psychologists and 2 psy-

chiatric social workers. In 2019, approximately 800
new patients visited our outpatient clinic, and the total
visits per day were about 140.
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 400 patientswith various psychiatric disorders were admitted in
2019. Recently, the number of inpatients who werereferred from the emergency unit is increasing. Mean
hospitalization is 30 day long, and the age of patientsis from teenager to senior. The majority of the patientsare schizophrenia, mood disorder and the psychosis
based on the somatic diseases. Modified electroconvulsive therapy was performed for over 400
patients per year.
We established the day care unit for outpatientswith schizophrenia in 1974, and the patients areengaged in rehabilitation and re-work programs.

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

93

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.

Research2.

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).

Publications
1. Yamasaki M, Makino T, Khor SS, Toyoda H,
Miyagawa T, Liu X, Kuwabara H, Kano Y,
Shimada T, Sugiyama T, Nishida H, Sugaya N,

3.

4.

5.

6.

Tochigi M, Otowa T, Okazaki Y, Kaiya H,
Kawamura Y, Miyashita A, Kuwano R, Kasai K,
Tanii H, Sasaki T, Honda M, Tokunaga K.
Sensitivity to gene dosage and gene expression
affects genes with copy number variants observed
among neuropsychiatric diseases. BMC Med
Genomics. 2020 Mar 29;13(1):55. doi: 10.1186/
s12920-020-0699-9. PMID: 32223758
Koshiyama D, Kirihara K, Usui K, Tada M,
Fujioka M, Morita S, Kawakami S, Yamagishi M,
Sakurada H, Sakakibara E, Satomura Y, Okada N,
Kondo S, Araki T, Jinde S, Kasai K. Resting-state
EEG beta band power predicts quality of life
outcomes in patients with depressive disorders: A
longitudinal investigation. J Affect Disord. 2020
Mar 15; 265:416-422. doi: 10.1016/j.jad.2020.01.
030. PMID: 32090768
Yasuda Y, Okada N, Nemoto K, Fukunaga M,
Yamamori H, Ohi K, Koshiyama D, Kudo N,
Shiino T, Morita S, Morita K, Azechi H, Fujimoto
M, Miura K, Watanabe Y, Kasai K, Hashimoto R:
Brain morphological and functional features incognitive subgroups of schizophrenia. Psychiatry
Clin Neurosci. 2020 Mar;74(3):191-203. doi:
10.1111/pcn.12963. Epub 2019 Dec 27. PMID:
31793131
Iijima Y, Okumura Y, Yamasaki S, Ando S, Okada
K, Koike S, Endo K, Morimoto Y, Williams A,
Murai T, Tanaka SC, Hiraiwa-Hasegawa M, Kasai
K, Nishida A. Assessing the hierarchy of personalvalues among adolescents: A comparison of rating
scale and paired comparison methods. J Adolesc.
2020 Feb 13;80:53-59. doi: 10.1016/j.adolescence.
2020.02.003. PMID: 32062170
Kotake R, Kanehara A, Miyamoto Y, Kumakura Y,
Sawada U, Takano A, Chiba R, Ogawa M, Kondo
S, Kasai K, Kawakami N. Reliability and validityof the Japanese version of the INSPIRE measureof staff support for personal recovery incommunity mental health service users in Japan.
BMC Psychiatry. 2020 Feb 7;20(1):51. doi:
10.1186/s12888-020-2467-y. PMID: 32028913
Sugimoto N, Nishida A, Ando S, Usami S,
Toriyama R, Morimoto Y, Koike S, Yamasaki S,
Kanata S, Fujikawa S, Furukawa TA, Sasaki T,
Hiraiwa-Hasegawa M, Kasai K. Use of social
networking sites and desire for slimness among

94

10-year-old girls and boys: A population-based
birth cohort study. Int J Eat Disord. 2020 Feb;
53(2):288-295. doi: 10.1002/eat.23202. PMID:
31743492
7. Ichikawa N, Lisi G, Yahata N, Okada G,
Takamura M, Hashimoto RI, Yamada T, YamadaM, Suhara T, Moriguchi S, Mimura M, Yoshihara
Y, Takahashi H, Kasai K, Kato N, Yamawaki S,
Seymour B, Kawato M, Morimoto J, Okamoto Y.
Primary functional brain connections associatedwith melancholic major depressive disorder andmodulation by antidepressants. Sci Rep. 2020 Feb
26;10(1):3542. doi: 10.1038/s41598-020-60527-z.
PMID: 32103088
8. Endo K, Yamasaki S, Ando S, Kikusui T, Mogi K,
Nagasawa M, Kamimura I, Ishihara J, Nakanishi
M, Usami S, Hiraiwa-Hasegawa M, Kasai K,
Nishida A. Dog and Cat Ownership Predicts
Adolescents' Mental Well-Being: A PopulationBased Longitudinal Study. Int J Environ Res
Public Health. 2020 Jan 31;17(3). pii: E884. doi:
10.3390/ijerph17030884. PMID: 32023841
9. Nakamura Y, Okada N, Koshiyama D, Kamiya K,
Abe O, Kunimatsu A, Okanoya K, Kasai K, Koike
S. Differences in functional connectivity networks
related to the midbrain dopaminergic systemrelated area in various psychiatric disorders.
Schizophr Bull. 2020 Jan 5;46(5):1239-1248. doi:
10.1093/schbul/sbz121.
10. Nemoto K, Shimokawa T, Fukunaga M,
Yamashita F, Tamura M, Yamamori H, Yasuda Y,
Azechi H, Kudo N, Watanabe Y, Kido M,
Takahashi T, Koike S, Okada N, Hirano Y,
Onitsuka T, Yamasue H, Suzuki M, Kasai K,
Hashimoto R, Arai T: Differentiation of schizophrenia using structural MRI with considerationof scanner differences: A real-world multi-site
study. Psychiatry Clin Neurosci. 2020 Jan;74(1):56-63. doi: 10.1111/pcn.12934. PMID: 31587444
11. Sawada K et al. Is Utena’s Brief Objective
Measures (UBOM) useful in real-world
behavioral assessment of functioning? Validity
and utility testing in patients with schizophrenia.
Psychiatry Clin Neurosci. 2020 Jan;74(1):40-48.
doi: 10.1111/pcn.12929. PMID: 31482653
12. Murata Y, Fujii A, Kanata S, Fujikawa S, Ikegame
T, Nakachi Y, Zhao Z, Jinde S, Kasai K, Bundo M,

Iwamoto K: Evaluation of the usefulness of saliva
for DNA methylation analysis in cohort studies.
Neuropsychopharmacol Rep. 2019 Dec; 39(4):301-305. doi: 10.1002/npr2.12075. PMID:
31393092
13. Zhao Z, Jinde S, Koike S, Tada M, Satomura Y,
Yoshikawa A, Nishimura Y, Takizawa R,
Kinoshita A, Sakakibara E, Sakurada H,
Yamagishi M, Nishimura F, Inai A, Nishioka M,
Eriguchi Y, Araki T, Takaya A, Kan C, Umeda M,
Shimazu A, Hashimoto H, Bundo M, Iwamoto K,
Kakiuchi C, Kasai K. Altered expression of
microRNA-223 in the plasma of patients with
first-episode schizophrenia and its possible
relation to neuronal migration-related genes.
Transl Psychiatry. 2019 Nov 11;9(1):289. doi:
10.1038/s41398-019-0609-0. PMID: 31712567
14. Akechi T, Kato T, Fujise N, Yonemoto N, Tajika A,
Furukawa TA; SUN☺D Investigators. Why somedepressive patients perform suicidal acts andothers do not. Psychiatry Clin Neurosci. 2019 Oct;73(10):660-661. doi: 10.1111/pcn.12918. PMID:
31355505
15. Ando S, Nishida A, Yamasaki S, Koike S,
Morimoto Y, Hoshino A, Kanata S, Fujikawa S,
Endo K, Usami S, Furukawa TA, HiraiwaHasegawa M, Kasai K; TTC Scientific and Data
Collection Team: Cohort Profile: The Tokyo Teen
Cohort study (TTC). Int J Epidemiol. 48(5):1414-1414g, 2019. doi: 10.1093/ije/dyz033.
PMID: 30879075 (October 1, 2019)16. Yassin W, Kojima M, Owada K, Kuwabara H,
Gonoi W, Aoki Y, Takao H, Natsubori T, Iwashiro
N, Kasai K, Kano Y, Abe O, Yamasue H: Paternal
age contribution to brain white matter aberrationsin autism spectrum disorder. Psychiatry Clin
Neurosci. 2019 Oct;73(10):649-659. doi: 10.1111/
pcn.12909. PMID: 31271249
17. Nakanishi M, Yamasaki S, Endo K, Ando S,
Morimoto Y, Fujikawa S, Kanata S, Takahashi Y,
Furukawa TA, Richards M, Hiraiwa-Hasegawa M,
Kasai K, Nishida A: The association between rolemodel presence and self-regulation in earlyadolescence: A cross-sectional study. PLoS One.
2019 Sep 19;14(9):e0222752. doi: 10.1371/
journal.pone.0222752. eCollection 2019. PMID:
31536579

95

18. 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. 2019 Aug;73:508-509. doi: 10.
1111/pcn.12865. PMID: 31102322
19. Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Kudo N, Azechi H, Okada N,
Koshiyama D, Ikeda M, Kasai K, Hashimoto R:
Eye movement abnormalities and their association
with cognitive impairments in schizophrenia.
Schizophr Res. 2019 Jul; 209:255-262. doi:
10.1016/j.schres.2018.12.051. PMID: 30661730
20. Owada K, Okada T, Munesue T, Kuroda M,
Fujioka T, Uno Y, Matsumoto K, Kuwabara H,
Mori D, Okamoto Y, Yoshimura Y, Kawakubo Y,
Arioka Y, Kojima M, Yuhi T, Yassin W, Kushima I,
Benner S, Ogawa N, Kawano N, Eriguchi Y,
Uemura Y, Yamamoto M, Kano Y, Kasai K,
Higashida H, Ozaki N, Kosaka H, Yamasue:
Quantitative facial expression analysis revealed
the efficacy and time course of oxytocin in autism.
Brain. 2019 Jul 1;142(7):2127-2136. doi: 10.
1093/brain/awz126. PMID: 31096266
21. Kozono N, Honda S, Tada M, Kirihara K, Zhao Z,
Jinde S, Uka T, Yamada H, Matsumoto M, Kasai
K, Mihara T: Auditory Steady State Response;
nature and utility as a translational science tool.
Sci Rep. 2019 Jun 11;9(1):8454. doi: 10.1038/
s41598-019-44936-3.
22. Nakamura M, Takahashi T, Takayanagi Y,
Sasabayashi D, Katagiri N, Sakuma A, Obara C,
Koike S, Yamasue H, Furuichi A, Kido M,
Nishikawa Y, Noguchi K, Matsumoto K, Mizuno
M, Kasai K, Suzuki M: Surface morphology ofthe orbitofrontal cortex in individuals at risk ofpsychosis: a multicenter study. Eur Arch
Psychiatry Clin Neurosci. 2019 Jun;269(4):397406. doi: 10.1007/s00406-018-0890-6. Epub 2018
Mar 23. PMID: 29572660
23. Kojima M, Yassin W, Owada K, Aoki Y,
Kuwabara H, Natsubori T, Iwashiro N, Gonoi W,
Takao H, Kasai K, Abe O, Kano Y, Yamasue H.
Neuroanatomical correlates of advanced paternal
and maternal age at birth in autism spectrum

disorder. Cereb Cortex. Cereb Cortex. 2019 Jun
1;29(6):2524-2532. doi: 10.1093/cercor/bhy122.
PMID: 29800092
24. Koshiyama D, Kirihara K, Tada M, Nagai T,
Fujioka M, Usui K, Koike S, Suga M, Araki T,
Hashimoto K, Kasai K: Gamma-band auditory
steady-state response is associated with plasma
levels of d-serine in schizophrenia: An exploratory study. Schizophr Res 208: 467-469, 2019. pii:
S0920-9964(19)30072-6. doi: 10.1016/j.schres.
2019.02.012. PMID: 30819595 (Jun 2019)25. Malda A, Boonstra N, Barf H, de Jong S, Aleman
A, Addington J, Pruessner M, Nieman D, de Haan
L, Morrison A, Riecher-Rössler A, Studerus E,
Ruhrmann S, Schultze-Lutter F, An SK, Koike S,
Kasai K, Nelson B, McGorry P, Wood S, Lin A,
Yung AY, Kotlicka-Antczak M, Armando M,
Vicari S, Katsura M, Matsumoto K, Durston S,
Ziermans T, Wunderink L, Ising H, van der Gaag
M, Fusar-Poli P, Pijnenborg GHM: Individualized
prediction of transition to psychosis in 1,676
individuals at clinical high risk: development andvalidation of a multivariable prediction model
based on individual patient data meta-analysis.
Front Psychiatry. 2019 May 21;10:345. doi:
10.3389/fpsyt.2019.0034. PMID: 31178767
26. Okada N, Ando S, Sanada M, Hirata-Mogi S,
Iijima Y, Sugiyama H, Shirakawa T, Yamagishi M,
Kanehara A, Morita M, Yagi T, Hayashi N,
Koshiyama D, Morita K, Sawada K, Ikegame T,
Sugimoto N, Toriyama R, Masaoka M, Fujikawa
S, Kanata S, Tada M, Kirihara K, Yahata N, Araki
T, Jinde S, Kano Y, Koike S, Endo K, Yamasaki S,
Nishida A, Hiraiwa-Hasegawa M, Bundo M,
Iwamoto K, Tanaka SC, Kasai K. Populationneuroscience study of the Tokyo TEEN Cohort(pn-TTC): Cohort longitudinal study to explore
the neurobiological substrates of adolescent
psychological and behavioral development.
Psychiatry Clin Neurosci. 2019 May;73(5):231242. doi: 10.1111/pcn.12814. PMID: 30588712
27. Yamasaki S, Ando S, Richards M, Hatch SL,
Koike S, Fujikawa S, Kanata S, Endo K,
Morimoto Y, Arai M, Okado H, Usami S,
Furukawa TA, Hiraiwa-Hasegawa M, Kasai K,
Nishida A: Maternal diabetes in early pregnancy,and psychotic experiences and depressive

96

symptoms in 10-year-old offspring: A populationbased birth cohort study. Schizophr Res. 2019
Apr;206:52-57. doi: 10.1016/j.schres.2018.12.016.
PMID: 30594455
28. Yamashita A, Yahata N, Itahashi T, Lisi G,
Yamada T, Ichikawa N, Takamura M, Yoshihara Y,
Kunimatsu A, Okada N, Yamagata H, Matsuo K,
Hashimoto R, Okada G, Sakai Y, Morimoto J,
Narumoto J, Shimada Y, Kasai K, Kato N,
Takahashi H, Okamoto Y, Tanaka SC, Kawato M,
Yamashita O, Imamizu H: Harmonization ofresting-state functional MRI data across multiple
imaging sites via the separation of site differences
into sampling bias and measurement bias. PLoS
Biol. 2019 Apr 18;17(4):e3000042.

97

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

Associate Professor
Atsushi Iwata, M.D., Ph.D.

Lecturer
Kaori Sakuishi, M.D., Ph.D.
Wataru Satake, M.D., Ph.D.

Associate
Masashi Hamada, M.D., Ph.D., Hiroyuki Ishiura, M.D., PhD.,
Akatsuki Kubota, M.D., Ph.D., Yuichiro Shirota, M.D., PhD.,Yu Nagashima, M.D., Ph.D., Tatsuo Mano, M.D., PhD.

Homepage

http://www.utokyo-neurology.org

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

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

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

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

98

consultation for Neurology, rotation at ER and supervising of junior trainees. This program is integrated
with clinical practice at the affiliated hospitals whererich experience is obtained for numerous cases inClinical Neurology.
In Graduate School, we offer highly advanced
research activities based on the interest of graduate
students.

Research activities
Our research field covers broad fields related toneurological diseases, with the goals to elucidate themechanisms of neurological diseases, and to eventuallydevelop new therapeutic strategies. Our research
activities include molecular genetics, developmental
biology, cell biology, pharmacology, pathology, andphysiology. We aim to integrate these broad research
fields to better contribute to clinical neurology.
In the development of molecular therapeutics thatameliorate α-dystroglycan (α-DG)-associated diseases,
we identified the glycan unit ribitol 5-phosphate(Rbo5P) in α-DG and showed that enzyme activities ofα-DG-associated diseases are involved in the synthesisof tandem Rbo5P. We also found that FKTN and FKRP
can transfer GroP to O-mannosyl glycans by using
CDP-glycerol (CDP-Gro) as a donor substrate. The
analysis of mouse models of α-DG-associated diseases
indicated that spatiotemporal persistence of functionally glycosylated α-DG may be crucial for brain
development. These findings provide insight into
pathogenesis and therapeutic strategies in α-DGassociated diseases. (Toda, T., Kanagawa, M.,
Kobayashi, K., Sudo, A.)
We perform case-control association studies in
Parkinson disease (PD) employing whole-exome
sequence analysis to discover rare PD susceptibility
variants. Employing a novel bioinformatics approach
using GWAS loci in PD along with in vitro functional
studies and MPTP mouse model analysis, we identified
a novel drug candidate for the prevention of neurodegeneration in PD. We also identified genetic factors
responsible for the individual difference of the effectsof zonisamide by using GWAS. (Toda, T., Satake, W.,
Uenaka, T., Cha, P.C., Fujino, G.)
In the field of molecular genetics, we havedeveloped the Genomic Medicine Research Support

Center, and introduced next-generation sequencers to
conduct comprehensive genome analyses to elucidate
molecular bases of various neurological diseases.
Regarding monogenic neurologic diseases, we conduct
pedigree analyses in various neurological diseases
including epilepsy, multiple system atrophy, amyotrophic lateral sclerosis, hereditary spastic paraplegia,
spinocerebellar atrophy, and adrenoleukodystrophy. As
for sporadic neurologic diseases, we perform casecontrol association studies in multiple system atrophy
and amyotrophic lateral sclerosis to identify genetic
factors underlying these diseases. On the basis of thefindings that mutations in COQ2 are associated withfamilial as well as sporadic multiple system atrophy, weare conducting an investigator-initiated clinical trial
using coenzyme Q10 for patients with multiple system
atrophy. After identifying expanded intronic TTTCA
and TTTTA repeats in three independent genes inpatients with benign adult familial myoclonic epilepsy,
which postulated a new disease mechanism in epilepsy,
we also identified expanded CGG repeats in three
genes are causes of neuronal intranuclear inclusion
disease, oculopharyngeal myopathy with leukoencephalopathy, and oculopharyngodistal myopathy.
We reported safety and efficacy of hematopoietic stem
cell transplantation for adolescent-/adulthood-onset
cerebral form/cerebello-brainstem form of adrenoleukodystrophy. (Toda, T., Tsuji, S., Mitsui, J., Ishiura,
H., Matsukawa, T., Sato, N., Naruse, FH., Matsukawa,
M., Kikuchi, J., Shibata, S., Chikada, A., Nagasako, Y.,
Hao, A., Shinmi, J, Mitsue, A., Almansour, M. A., Porto,
K. J. L.)The human neurophysiology section specializes instudying the physiology of the human motor andsensory systems in awake healthy volunteers and thepathophysiology of neurological disorders using
several non-invasive physiological methods, such as
TMS, EEG, MEG, fMRI, NIRS and EOG. Our final
goal is to devise new therapeutic techniques for
intractable neurological disorders. To this end, the work
extends from the study of spinal systems to basal
ganglia and cerebral cortex. We are especiallyinterested in plasticity induction by non-invasive brain
stimulation (NIBS) techniques, offering potential forclinical application. Our lab has a long experience inthe use of transcranial magnetic stimulation (TMS)
which is able to stimulate neurons in intact human brain

99

and has devised a highly effective repetitive TMS
method to induce long-term effects (quadripulse
stimulation, QPS). We have recently started a clinical
trial of repetitive TMS to treat patients with Parkinson’s
disease. (Hamada, M., Shirota, Y., Kodama, S.,
Sugiyama., Y., Sato, K., and Otsuka, J.)
In the field of neuromuscular diseases, we provide
pathological diagnosis of biopsied materials frompatients with myopathy or neuropathy. We also provide
autoantibody testing for anti-ganglioside antibodies,muscle specific antibodies and paraneoplastic
neurological antibodies. In research field, using
biopsied muscles and collected serum samples, wehave been studying the mechanisms of inflammatory
myopathies from the view points of pathologicalchanges, myositis specific autoantibodies, serum
cytokines, and expression profiling of muscle samples.
Our aim is to increase understanding of the etiology andpathogenesis of neuromuscular diseases. (Shimizu, J.,
Kubota A., Maeda M., Kadoya M., Unuma, A).
In the biochemistry laboratory, autopsy brain
analysis of Alzheimer's disease and Lewy body disease
was performed, and a new gene involvement was
discovered. Chronic cerebral hypoperfusion model
mouse was created and its characteristics wereanalyzed, the technology was applied to analyze
amyloid β metabolism under chromic hypoperfusion.
On the other hand, we analyzed J-ADNI cohort data.
Comparison
with
US-ADNIdata
revealed
compatibility between the two cohorts. The influenceof sex difference and education level, and the influenceof serum calcium level was discovered.
Other
activities include development of new imaging
techniques using Raman microspectroscopy. We
recently invented a novel high-sensitivity lipid imaging
methodology using delipidation technique for sample
preconditioning before Raman observation, which
successfully determined spatial distribution of minor
lipid species in porcine nerve and muscle tissues. We
also developed a new optical sensor chip detecting
biomarkers for Alzheimer’s disease using nanoimprint
lithography (NIL)-based two-dimensional photonic
crystal (2D-PhC), which achieved the sensitivity
surpassing ELISA. We newly developed a detection
device for our sensor chip, realizing automated, highthroughput measurement. We also developed a novel
preanalytical sample handling protocol for highsensitivity measurement. We are also participating inobservational studies of preclinical Alzheimer's disease(AMED Preclinical research) and DIAN-J studies.
（Atsushi Iwata, Yu Nagashima, Toji Miyagawa, Ryo
Ohtomo, Tatsuo Mano, Taro Bannai, Takeyuki
Tsuchida, Kensuke Hamada, Kagari Mano, Gaku
Ohtomo, Kenichiro Sato, Masanori Kurihara）
Neuroimmunology section is focused onunderstanding inflammatory disease of the CNS:
namely multiple Sclerosis and neuromyelitis optica.
Through application of both conventional and more
contemporary immunological methods (FACS, ELISA,
cell culture and NGS analysis), we aim to reveal
disease-specific patho-mechanisms for better diagnosis
and treatment of immune-mediated CNS inflammation.
(Sakuishi, K, Koguchi, A)

Publication
1: Ishiura H, Shibata S, Yoshimura J, Suzuki Y, Qu W,
Doi K, Almansour MA,Kikuchi JK, Taira M,
Mitsui J, Takahashi Y, Ichikawa Y, Mano T, Iwata
A, Harigaya Y, Matsukawa MK, Matsukawa T,
Tanaka M, Shirota Y, Ohtomo R, Kowa H, Date H,
Mitsue A, Hatsuta H, Morimoto S, Murayama S,
Shiio Y, Saito Y, Mitsutake A, Kawai M, Sasaki T,
Sugiyama Y, Hamada M, Ohtomo G, Terao Y,
Nakazato Y, Takeda A, Sakiyama Y, UmedaKameyama Y, Shinmi J, Ogata K, Kohno Y, Lim
SY, Tan AH, Shimizu J, Goto J, Nishino I, Toda T,
Morishita S, Tsuji S. Noncoding CGG repeat
expansions in neuronal intranuclear inclusion
disease, oculopharyngodistal myopathy and an
overlapping disease. Nat Genet. 2019 Aug; 51(8):1222-1232. doi: 10.1038/s41588-019-0458-z.
Epub 2019 Jul 22. PMID:31332380.
2: Sato K, Mano T, Iwata A, Toda T. Neurological andrelated adverse events in immune checkpoint
inhibitors: a pharmacovigilance study from theJapanese Adverse Drug Event Report database. J
Neurooncol. 2019 Oct;145(1):1-9. doi: 10.1007/
s11060-019-03273-1. Epub 2019 Aug 26. PMID:
31452071.
3: Nagayama H, Kano O, Murakami H, Ono K,
Hamada M, Toda T, Sengoku R, Shimo Y, Hattori
N. Effect of istradefylline on mood disorders in
Parkinson's disease. J Neurol Sci. 2019 Jan 15;

100

4:

5:

6:

7:

8:

9:

396:78-83. doi: 10.1016/j.jns.2018.11.005. Epub
2018 Nov 5. PMID: 30423541.
Otsuka I, Akiyama M, Shirakawa O, Okazaki S,
Momozawa Y, Kamatani Y, Izumi T, Numata S,
Takahashi M, Boku S, Sora I, Yamamoto K, Ueno
Y, Toda T, Kubo M, Hishimoto A. Genome-wide
association studies identify polygenic effects forcompleted suicide in the Japanese population.
Neuropsychopharmacology. 2019 Nov;44(12):2119-2124. doi: 10.1038/s41386-019-0506-5.
Epub 2019 Sep 2. PMID: 31476763; PMCID:
PMC6887868.
Kurihara M, Mano T, Saito Y, Murayama S, Toda
T, Iwata A. Colocalization of BRCA1 with Tau
Aggregates in Human Tauopathies. Brain Sci. 2019
Dec 20;10(1):7. doi: 10.3390/brainsci10010007.
PMID: 31861888; PMCID: PMC7016802.
Endo H, Shimada H, Sahara N, Ono M, Koga S,
Kitamura S, Niwa F, Hirano S, Kimura Y, Ichise M,
Shinotoh H, Zhang MR, Kuwabara S, Dickson DW,
Toda T, Suhara T, Higuchi M. In vivo binding of atau imaging probe, [<sup>11</sup> C]PBB3, in
patients with progressive supranuclear palsy. Mov
Disord. 2019 May;34(5):744-754. doi: 10.1002/
mds.27643. Epub 2019 Mar 20. PMID: 30892739;
PMCID: PMC6593859.
Ujihara Y, Kanagawa M, Mohri S, Takatsu S,
Kobayashi K, Toda T, Naruse K, Katanosaka Y.
Elimination of fukutin reveals cellular andmolecular
pathomechanisms
inmusculardystrophy-associated heart failure. Nat Commun.
2019 Dec 17; 10(1):5754. doi: 10.1038/s41467019-13623-2.
PMID:
31848331;
PMCID:
PMC6917736.
Kurihara M, Ishiura H, Bannai T, Mitsui J,
Yoshimura J, Morishita S, Hayashi T, Shimizu J,
Toda T, Tsuji S. A Novel de novo KIF1A Mutation
in a Patient with Autism, Hyperactivity, Epilepsy,
Sensory Disturbance, and Spastic Paraplegia.
Intern Med. 2020 Mar 15;59(6):839-842. doi:
10.2169/internalmedicine.3661-19. Epub 2019
Dec 6. PMID: 31813911; PMCID: PMC7118386.
Katsuse K, Kurihara M, Sugiyama Y, Kodama S,
Takahashi M, Momose T, Yumoto M, Kaneko K,
Takahashi T, Kubota A, Hayashi T, Toda T. Aphasic
status epilepticus preceding tumefactive left
hemisphere lesion in anti-MOG antibody

associated disease. Mult Scler Relat Disord. 2019
Jan;27:91-94. doi: 10.1016/j.msard.2018.10.012.
Epub 2018 Oct 15. PMID: 30347340.
10: Sato K, Mano T, Matsuda H, Senda M, Ihara R,
Suzuki K, Arai H, Ishii K, Ito K, Ikeuchi T,
Kuwano R, Toda T, Iwatsubo T, Iwata A; Japanese
Alzheimer's Disease Neuroimaging Initiative.
Visualizing modules of coordinated structuralbrain atrophy during the course of conversion to
Alzheimer's disease by applying methodology
from gene co-expression analysis. Neuroimage
Clin. 2019;24:101957. doi: 10.1016/j.nicl.2019.
101957. Epub 2019 Jul 25. PMID: 31400633;
PMCID:PMC6700430.
11: Bujo S, Amiya E, Kojima T, Yamada S, Maki H,
Ishizuka M, Uehara M, Hosoya Y, Hatano M,
Kubota A, Toda T, Komuro I. Variable Cardiac
Responses to Immunosuppressive Therapy in AntiMitochondrial Antibody-Positive Myositis. Can J
Cardiol. 2019 Nov;35(11):1604.e9-1604.e12. doi:
10.1016/j.cjca.2019.07.002. Epub 2019 Jul 11.
PMID: 31587935.
12: Sekiya H, Kowa H, Koga H, Takata M, Satake W,
Futamura N, Funakawa I, Jinnai K, Takahashi M,
Kondo T, Ueno Y, Kanagawa M, Kobayashi K,
Toda T. Wide distribution of alpha-synuclein
oligomers in multiple system atrophy brain
detected by proximity ligation. Acta Neuropathol.
2019 Mar;137(3):455-466. doi: 10.1007/s00401019-01961-w. Epub 2019 Feb 5. PMID: 30721406.
13: Kodama S, Tokushige SI, Sugiyama Y, Sato K,
Otsuka J, Shirota Y, Hamada M, Iwata A, Toda T,
Tsuji S, Terao Y. Rituximab improves not only
back stiffness but also "stiff eyes" in stiff person
syndrome: Implications for immune-mediatedtreatment. J Neurol Sci. 2020 Jan 15; 408:116506.
doi: 10.1016/j.jns.2019.116506. Epub 2019 Nov 2.
PMID: 31734550.
14: Akatani R, Chihara N, Tachibana H, Koto S, Kowa
H, Kanda F, Matsumoto R, Toda T. Validation of
the Guy's Neurological Disability Scale as ascreening tool for cognitive impairment in multiple
sclerosis. Mult Scler Relat Disord. 2019 Oct; 35:
272-275. doi: 10.1016/j.msard.2019.08.012. Epub
2019 Aug 12. PMID: 31442905.
15: Sato K, Mano T, Iwata A, Toda T. SubtypeDependent Reporting of Stroke With SGLT2

101

Inhibitors: Implications From a Japanese Pharmacovigilance Study. J Clin Pharmacol. 2019 Dec 2.
doi: 10.1002/jcph.1561. Epub ahead of print.
PMID: 31792991.
16: Sugawara Y, Hamada K, Yamada Y, Kumai J,
Kanagawa M, Kobayashi K, Toda T, Negishi Y,
Katagiri F, Hozumi K, Nomizu M, Kikkawa Y.
Characterization of dystroglycan binding inadhesion of human induced pluripotent stem cells
to laminin-511 E8 fragment. Sci Rep. 2019 Sep 10;
9(1):13037. doi: 10.1038/s41598-019-49669-x.
PMID: 31506597; PMCID: PMC6737067.
17: Naruse H, Matsukawa T, Ishiura H, Mitsui J,
Takahashi Y, Takano H, Goto J, Toda T, Tsuji S.
Association of ATXN2 intermediate-length CAG
repeats with amyotrophic lateral sclerosis
correlates with the distributions of normal CAG
repeat alleles among individual ethnic populations.
Neurogenetics. 2019 May; 20(2): 65-71. doi:
10.1007/s10048-019-00570-9. Epub 2019 Mar 7.
PMID: 30847648.
18: Kodama S, Shirota Y, Hagiwara A, Otsuka J, SatoK, Sugiyama Y, Mori H, Watanabe M, Hamada M,
Toda T. Multinodular and vacuolating neuronaltumor (MVNT): A presumably incidental andasymptomatic case in an intractable epilepsy
patient. Clin Neurophysiol Pract. 2019 Jul 16;
4:164-167.
doi:
10.1016/j.cnp.2019.05.003.
PMID: 31886439; PMCID: PMC6921157.
19: Niimi Y, Ito S, Mizutani Y, Murate K, Shima S,
Ueda A, Satake W, Hattori N, Toda T, Mutoh T.
Altered regulation of serum lysosomal acidhydrolase activities in Parkinson's disease: A
potential peripheral biomarker? Parkinsonism
Relat Disord. 2019 Apr; 61: 132-137. doi:
10.1016/j.parkreldis.2018.10.032. Epub 2018 Nov
2. PMID: 30415794.
20: Ando J, Fujisawa KK, Hiraishi K, Shikishima C,
Kawamoto T, Nozaki M, Yamagata S, Takahashi Y,
Suzuki K, Someya Y, Ozaki K, Deno M, Tanaka M,
Sasaki S, Toda T, Kobayashi K, Sakagami M,
Okada M, Kijima N, Takizawa R, Murayama K.
Psychosocial Twin Cohort Studies in Japan: The
Keio Twin Research Center (KoTReC). Twin Res
Hum Genet. 2019 Dec; 22(6): 591-596. doi:
10.1017/thg.2019.109. Epub 2020 Jan 15. PMID:
31937382.

21: Sato K, Toda T, Iwata A. Fragility Index inRandomized Controlled Trials of Ischemic Stroke.
J Stroke Cerebrovasc Dis. 2019 May;28(5):12901294. doi: 10.1016/j.jstrokecerebrovasdis.2019.
01.015. Epub 2019 Feb 12. PMID: 30765294.
22: Naruse H, Ishiura H, Mitsui J, Takahashi Y,
Matsukawa T, Tanaka M, Doi K, Yoshimura J,
Morishita S, Goto J, Toda T, Tsuji S. Burden of rarevariants in causative genes for amyotrophic lateralsclerosis (ALS) accelerates age at onset of ALS. J
Neurol Neurosurg Psychiatry. 2019 May;90(5):537-542. doi: 10.1136/jnnp-2018-318568. Epub
2018 Oct 24. PMID: 30355605.
23: Sato K, Nagashima Y, Mano T, Iwata A, Toda T.
Quantifying normal and parkinsonian gait featuresfrom home movies: Practical application of a deeplearning-based 2D pose estimator. PLoS One. 2019
Nov 14;14(11):e0223549. doi: 10.1371/journal.
pone.0223549. PMID: 31725754; PMCID: PMC
6855634.
24: Sato K, Iwata A, Kurihara M, Nagashima Y, Mano
T, Toda T. Estimating acceleration time point of
respiratory decline in ALS patients: A novel metric.
J Neurol Sci. 2019 Aug 15; 403:7-12. doi:
10.1016/j.jns.2019.05.031. Epub 2019 May 30.
PMID: 31170513.
25: Naruse H, Takahashi Y, Ishiura H, Matsukawa T,
Mitsui J, Ichikawa Y, Hamada M, Shimizu J, GotoJ, Toda T, Tsuji S. Prominent Spasticity andHyperreflexia of the Legs in a Nepalese Patientwith Friedreich Ataxia. Intern Med. 2019 Oct 1;
58(19):2865-2869. doi: 10.2169/internalmedicine.
2953-19. Epub 2019 Jun 7. PMID: 31178521;
PMCID: PMC6815894.
26: Bannai T, Mano T, Chen X, Ohtomo G, Ohtomo R,
Tsuchida T, Koshi-Mano K, Hashimoto T,
Okazawa H, Iwatsubo T, Tsuji S, Toda T, Iwata A.
Chronic cerebral hypoperfusion shifts theequilibrium of amyloid β oligomers toaggregation-prone species with higher molecularweight. Sci Rep. 2019 Feb 26;9(1):2827. doi:
10.1038/s41598-019-39494-7. PMID: 30808940;
PMCID: PMC6391466.
27: Sato K, Mano T, Ihara R, Suzuki K, Tomita N, Arai
H, Ishii K, Senda M, Ito K, Ikeuchi T, Kuwano R,
Matsuda H, Iwatsubo T, Toda T, Iwata A;
Alzheimer’s Disease Neuroimaging Initiative, and102Japanese Alzheimer’s Disease Neuroimaging
Initiative. Lower Serum Calcium as a Potentially
Associated Factor for Conversion of Mild
Cognitive Impairment to Early Alzheimer's
Disease in the Japanese Alzheimer's Disease
Neuroimaging Initiative. J Alzheimers Dis. 2019;
68(2):777-788. doi: 10.3233/JAD-181115. PMID:
30814351.
28: Koh K, Ishiura H, Shimazaki H, Tsutsumiuchi M,
Ichinose Y, Nan H, Hamada S, Ohtsuka T, Tsuji S,
Takiyama Y. VPS13D-related disorders presenting
as a pure and complicated form of hereditary
spastic paraplegia. Mol Genet Genomic Med. 2020
Mar;8(3):e1108. doi: 10.1002/mgg3.1108. Epub
2019 Dec 26. PMID: 31876103; PMCID: PMC
7057107.
29: Hashiguchi S, Doi H, Kunii M, Nakamura Y,
Shimuta M, Suzuki E, Koyano S, Okubo M,
Kishida H, Shiina M, Ogata K, Hirashima F, Inoue
Y, Kubota S, Hayashi N, Nakamura H, Takahashi
K, Katsumoto A, Tada M, Tanaka K, Sasaoka T,
Miyatake S, Miyake N, Saitsu H, Sato N, Ozaki K,
Ohta K, Yokota T, Mizusawa H, Mitsui J, Ishiura
H, Yoshimura J, Morishita S, Tsuji S, Takeuchi H,
Ishikawa K, Matsumoto N, Ishikawa T, Tanaka F.
Ataxic phenotype with altered Ca<sub>V</sub>3.1 channel property in a mouse model forspinocerebellar ataxia 42. Neurobiol Dis. 2019
Oct;130:104516. doi: 10.1016/j.nbd.2019.104516.
Epub 2019 Jun 20. PMID: 31229688.
30: Togawa J, Ohi T, Yuan JH, Takashima H, Furuya H,
Takechi S, Fujitake J, Hayashi S, Ishiura H, Naruse
H, Mitsui J, Tsuji S. Atypical Familial
Amyotrophic Lateral Sclerosis with Slowly
Progressing Lower Extremities-predominant Lateonset Muscular Weakness and Atrophy. Intern Med.
2019;
58(13):1851-1858.
doi:
10.2169/
internalmedicine.2222-18. Epub 2019 Jul 1.
PMID: 31257275; PMCID: PMC6663526.
31: Sekine SI, Kaneko M, Tanaka M, Ninomiya Y,
Kurita H, Inden M, Yamada M, Hayashi Y, Inuzuka
T, Mitsui J, Ishiura H, Iwata A, Fujigasaki H,
Tamaki H, Tamaki R, Kito S, Taguchi Y, Tanaka K,
Atsuta N, Sobue G, Kondo T, Inoue H, Tsuji S,
Hozumi I. Functional evaluation of PDGFBvariants in idiopathic basal ganglia calcification,using patient-derived iPS cells. Sci Rep. 2019 Apr

5;9(1):5698. doi: 10.1038/s41598-019-42115-y.
PMID: 30952898; PMCID: PMC6450963.
32: Ichinose Y, Ishiura H, Tanaka M, Yoshimura J, Doi
K, Umeda T, Yamauchi H, Tsuchiya M, Koh K,
Yamashiro N, Mitsui J, Goto J, Onishi H, Ohtsuka
T, Shindo K, Morishita S, Tsuji S, Takiyama Y.
Neuroimaging, genetic, and enzymatic study in a
Japanese family with a GBA gross deletion.
Parkinsonism Relat Disord. 2019 Apr;61:57-63.
doi: 10.1016/j.parkreldis.2018.11.028. Epub 2018
Dec 2. PMID: 30528172.
33: Shirota Y, Ohminami S, Tsutsumi R, Terao Y,
Ugawa Y, Tsuji S, Hanajima R. Increased
facilitation of the primary motor cortex in de novo
Parkinson's disease. Parkinsonism Relat Disord.
2019 Sep; 66:125-129. doi: 10.1016/j.parkreldis.
2019.07.022. Epub 2019 Jul 18. PMID: 31327628.
34: Nan H, Ichinose Y, Tanaka M, Koh K, Ishiura H,
Mitsui J, Mizukami H, Morimoto M, Hamada S,
Ohtsuka T, Tsuji S, Takiyama Y. UBAP1 mutations
cause juvenile-onset hereditary spastic paraplegias(SPG80) and impair UBAP1 targeting toendosomes. J Hum Genet. 2019 Nov;64(11):10551065. doi: 10.1038/s10038-019-0670-9. Epub
2019 Sep 12. PMID: 31515522.
35: Tanaka N, Tsutsumi R, Shirota Y, Shimizu T,
Ohminami S, Terao Y, Ugawa Y, Tsuji S, Hanajima
R. Effects of L-DOPA on quadripulse magnetic
stimulation-induced long-term potentiation inolder adults. Neurobiol Aging. 2019 Dec;84:217224. doi: 10.1016/j.neurobiolaging.2019.08.005.
Epub 2019 Aug 9. PMID: 31570179.
36: Yasuda T, Matsukawa T, Mitsui J, Tsuji S. Oxygen
consumption rate for evaluation of COQ2 variants
associated with multiple system atrophy. Neurogenetics. 2019 Mar;20(1):51-52. doi: 10.1007/
s10048-018-0563-7. Epub 2019 Jan 7. PMID:
30613928.
37: Sasaki R, Ohta Y, Sato K, Tadokoro K, Takahashi
Y, Shang J, Takemoto M, Hishikawa N, Yamashita
T, Ishiura H, Tsuji S, Abe K. Spastic Paraplegia
Accompanied by Extrapyramidal Sign and Frontal
Cognitive Dysfunction. Intern Med. 2019 Nov 1;
58(21):3163-3165. doi: 10.2169/internalmedicine.
2765-19. Epub 2019 Jul 10. PMID: 31292381;
PMCID: PMC6875453.
38: Koh K, Ichinose Y, Ishiura H, Nan H, Mitsui J,103Takahashi J, Sato W, Itoh Y, Hoshino K, Tsuji S,
Takiyama Y; Japan Spastic Paraplegia ResearchConsotium.
Correction:
PLA2G6-associatedneurodegeneration presenting as a complicatedform of hereditary spastic paraplegia. J Hum Genet.
2019 Jan;64(1):61-63. doi: 10.1038/s10038-0180533-9. Erratum for: J Hum Genet. 2019 Jan;64(1):55-59. PMID: 30410098.
39: Miyabayashi T, Ochiai T, Suzuki N, Aoki M, Inui
T, Okubo Y, Sato R, Togashi N, Takashima H,
Ishiura H, Tsuji S, Koh K, Takiyama Y, Haginoya
K. A novel homozygous mutation of the TFG genein a patient with early onset spastic paraplegia andlater onset sensorimotor polyneuropathy. J Hum
Genet. 2019 Feb;64(2):171-176. doi: 10.1038/
s10038-018-0538-4. Epub 2018 Nov 22. PMID:
30467354.
40: Matsukawa T, Yamamoto T, Honda A, Toya T,
Ishiura H, Mitsui J, Tanaka M, Hao A, Shinohara
A, Ogura M, Kataoka K, Seo S, Kumano K, Hosoi
M, Narukawa K, Yasunaga M, Maki H, Ichikawa
M, Nannya Y, Imai Y, Takahashi T, Takahashi Y,
Nagasako Y, Yasaka K, Mano KK, Matsukawa MK,
Miyagawa T, Hamada M, Sakuishi K, Hayashi T,
Iwata A, Terao Y, Shimizu J, Goto J, Mori H,
Kunimatsu A, Aoki S, Hayashi S, Nakamura F,
Arai S, Momma K, Ogata K, Yoshida T, Abe O,
Inazawa J, Toda T, Kurokawa M, Tsuji S. Clinicalefficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy. Brain
Commun 2020; 2: fcz048.
41: Uchigami H, Sato K, Kubota A, Hayashi T,
Shimizu J, Ikemura M, Toda T. Localized’ chronic
invasive fungal rhinosinusitis without serologicalabnormalities. Neurology and Clinical Neuroscience. 2019 Mar.7(2):96-97.doi: 10.1111/ncn3.
12252
42: Miyano R, Kurihara M, Orimo K, Mano T,
Kaburaki T, Tanaka R, Nisijima H, Ikemura M,
Takahashi M, Mori H, Muroh T, Hamada M,
Hayashi T, Toda T. Severe visual impairment andsubclinical encephalitis preceding clinical signs ofchondritis in relapsing polychondritis. Neurology
and Clinical Neuroscience 2019 Mar.7（2）:75-77.
doi:10.1111/ncn3.12243
43: Matsuda KM, Koguchi A, Toyama T, Sakuishi K,
Kobayashi M, Miura S, Miyazaki M, Suga H,

Asano Y, Toda T, Sato S. Concurrence ofpolyarteritis nodosa and multiple sclerosis. J Eur
Acad Dermatol Venereol.
44: Aoh Y, Hsiao HJ, Lu MK, Macerollo A, Huang HC,
Hamada M, Tsai CH, Chen JC. Event-Related
Desynchronization/Synchronization in Spinocerebellar Ataxia Type 3. Front Neurol. 2019 Jul
31;10:822. doi: 10.3389/fneur.2019.00822.
45: Sinjab F, Hashimoto K, Zhao X, Nagashima Y,
Ideguchi T. “Enhanced spectral resolution forbroadbandcoherent
anti-Stokes
Raman
spectroscopy.” Opt Lett. 2020 Mar 1;45(5). doi:
10.1364/OL.388624.
46: Toda K, Tamamitsu M, Nagashima Y, Horisaki R,
Ideguchi T. "Molecular contrast on phase-contrast
microscope." Sci Rep. 2019 Jul 18;9(1):9957. doi:
10.1038/s41598-019-46383-6.

104

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

Associate Professor
Hirofumi Nakatomi, M.D., Ph.D.

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

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

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

Associate
Osamu Ishikawa, M.D., Ph.D.

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

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

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

Mariko Kawashima, M.D.

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

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

Yuki Shinya, M.D.

Homepage

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

Introduction and Organization

Clinical activities

The Department of Neurosurgery at the Universityof Tokyo Hospital consists of 14 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research, and education. The staffs include
a professor/chairman, an associate professor, 2lecturers, 2 project lectures,and 8 associates.
Clinical ward for neurosurgery in our university
hospital was founded in 1951 as the first neurosurgicalclinic in Japan. Dr. Keiji Sano, as the founding
professor, established the Department of Neurosurgery
in 1962. Dr. Kintomo Takakura and Dr. Takaaki Kirino
served as the second and the third professor,
respectively. The incumbent professor, Dr. Nobuhito
Saito, has been serving as the fourth professor since
2006.
Our department provides expertise for patients withbrain tumor, cerebrovascular disease, spinal disease,functional disorder, head trauma, etc.

General outpatient clinic including new patient clinic
is open every weekday and subspecialty clinic is open
three days a week (Monday, Wednesday and Friday).
The latter is open for patients with brain tumor,
pituitary disease, spinal disease, cerebrovasculardisease, endovascular intervention, epilepsy, andgamma knife treatment. From April 2019 to March
2019, 18,723 patients were treated at the outpatient
clinics.
The neurosurgery ward has approximately 40 beds on
the seventh floor of the new hospital building opened
in September 2001. In 2019, 940 patients wereadmitted to the neurosurgery ward. 462 surgicalprocedures and 171 gamma knife procedures were
performed in 2019. Our practice covers a wide varietyof neurosurgical diseases including malignant andbenign brain tumors, hemorrhagic and thromboembolic

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cerebrovascular diseases, spinal disorders, epilepsy,
pain and movement disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional mapping in epilepsy surgery are frequently used to preserve
brain function as much as possible. State-of-the-art
techniques including intraoperative computer-aided
navigation and intravascular procedures help ourcontinuous effort to increase the safety of surgicaltreatment. Some endovascular procedures are
performed in our hybrid operating room with thecooperation of the operation department and theanesthesiology doctors.
Our department is affiliated with 35 neurosurgicalinstitutions in and around the city of Tokyo including
10 university medical centers, where our residents andstudents are exposed to various clinical experiences.
Surgical case volume in all hospitals exceeds 11,500
cases.

Teaching activities
Medical students take lectures of clinicalneurosurgery in their second year. Clinical case studies
and bedside teaching are scheduled in the third andfourth years. The lecturers introduce general
neurosurgery as well as the state-of-art neurosurgicalpractice to the students. At the bedside teaching andclinical clerkship, they are offered opportunities tolearn clinical management of neurosurgical patients in
the hands-on style, and also are exposed to practice invarious subspecialties in neurosurgery through special
seminars given by experts in the fields.
We accepted 14 residents in 2015, 4 in 2016, 16 in2017, 5 in 2018, 7 in 2019 in our neurosurgicalresidency program. These residents are trained in theuniversity hospital and affiliated hospitals toexperience every aspect of neurosurgical practice forfive years on average. Our residency training is
finalized after the sixth year, when the finishingresidents serve as senior residents at the university
hospital for 6 months. Academic training is provided
through numerous intramural clinical and research
conferences, journal clubs, seminars as well as
quarterly regional meetings of the Japan NeurosurgicalSociety. After or during residency training, ourresidents can choose to be admitted into the Ph.D.

course at the Graduate School of Medicine, theUniversity of Tokyo, to be involved in advanced basic
research activities for 4 years. Upon completion oftraining, our graduates stay in the department to be
associates in our university hospital or become clinicalstaffs in our affiliated hospitals.

Research activities
Clinical research in the last few years have mainly
focused on treatments of acoustic neurinoma, techniques of skull base surgery, treatments of malignant
brain tumors, epilepsy surgery, and stereotactic
radiosurgery. The results were presented at domestic aswell as international meetings including Annual
Meetings of the Japan Neurosurgical Society andAnnual Meetings of American Association of
Neurological Surgeons.
Our department has maintained prominent basic
research activities as well. The fields of our current
research are as follows:
1) Pathogenesis of cerebral ischemia and neuronal
regeneration after ischemic brain damage
One of the major topics in recent basic science is toregenerate the brain with endogenous neuralprogenitors. Our laboratory has started basic research
to regenerate neurons in vivo following ischemic insult.
We have demonstrated that the 40% of the lost neurons
could be regenerated by administration of growth
factors. We also succeeded in regeneration of striatal
neurons. Molecular mechanisms of adult neurogenesis
are currently investigated using various models toenhance post-ischemic regeneration. By extending the
research into primate model, we are pursuing clinicalapplication in the future.
2) Genetic analyses of cerebrovascular diseases andbenign brain tumors
Genetic analyses were conducted to identify
clinically relevant molecular markers of cerebrovascular diseases and benign brain tumors and to
elucidate the pathogenic mechanisms of these diseases.
Specifically, genes such as RNF213 in moyamoya
disease, NF2 in meningioma and schwannoma, andCCM in cerebral cavernous malformation wereanalyzed. In addition, comprehensive genetic analyses,

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including analysis of whole exome sequences, were
performed to identify novel disease-related genes.
Results showed that the RNF213 mutation is associatedwith not only moyamoya disease but also various
intracranial artery stenoses. For NF2 analysis inneurofibromatosis type 2, the diagnostic rate of somatic
mosaicism was improved by analyzing DNA fromvarious tissues; this revealed the phenotype characteristics of the somatic mosaic NF2.
3) Development of new therapeutic modalities formalignant brain tumors
Genotyping is now widely accepted as an essential
component of pathological diagnosis in glioma. We
have been routinely analysisng surgically resected
tumor specimens in a semi-prospective fashion. The
genetic analyses includes sequencing of IDH1/2, TP53,
and histone gene mutations, 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 approches with whole exome
sequencing, RNA sequencing, expression profiling,
and methylation analysis. Our particular interest lies intumor heterogeneity and malignant progression.
To develop a novel strategy for the treatment ofmalignant glioma, we have isolated brain tumor
initiating cells, which are supposed to be responsible
for resistance to conventional therapies, from surgical
specimens, and we are studying specific targetingtherapy against these cells.
We have been collaborating with a basic research lab
in our university and developing new fluorescenceprobes specifically detecting glioma with a hope thatfluorescence-guided surgery may result in greater
extent of resection.
4) Development and evaluation of function-preserving
and less invasive treatment of intractable epilepsy
We have been promoting the research on development,
evaluation and standardization of the novel treatment
for intractable epilepsy. Particularly, in order toimprove the outcome of epilepsy surgery for MRInegative cases, we are seeking to increase the accuracyof localizing epileptic focus using intracranialelectrodes. In addition to the state-of-art technologies
such as time-frequency analysis and cortico-corticalevoked potentials, we are developing next-generation
intracranial electrodes and accelerating research toidentify epileptogenic network. At the same time, we
aim to evaluate the effectiveness of function-preserving
procedures such as multiple hippocampal transection,
which has been originally developed in Japan. Also, as
the first facility to introduce vagus nerve stimulation(VNS) therapy in Japan, we are participating in aninternational collaborative research on the verificationof the effectiveness of VNS in the real world.
5) Research on brain function using non-invasive andinvasive techniques
We have been studying human brain function using
not only non-invasive techniques such as fMRI, MEG,NIRS but also electrocorticography (ECoG) obtainedby intracranial electrodes implanted in epilepsy
patients. The latter is our markedly advantageous
feature that enables us to extract brain information withmuch higher spatial resolution and SN ratio. We aim tounderstand brain mechanisms as complicated network
systems and to improve the reliability of non-invasive
techniques. Since ECoG is a strong candidate for a
decoding source of brain-computer interface (BCI), weare planning to expand the research on this field toclinical implementation of BCI for communication andmotor control in cooperation with other brain researchlaboratories and engineering laboratories.
6) Clinical applications of the functional brain
imaging and operative simulation using 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 three-107

dimensional 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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Kawashima M., Takahashi W., Iwasaki S., Kashio
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Social Medicine
1. Occupational, Environmental
and Preventive Medicine

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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.
Shuto Hayashi, Ph.D.

Homepage https://plaza.umin.ac.jp/prm/
Introduction and Organization
Department of Preventive Medicine is the oldest
laboratory in the University of Tokyo, established by
Masanori Ogata in 1885. Ever since, for more than 130
years, the laboratory has been a hub to importantresearch leading to disease prevention and developed
and produced core human resources in public healthadministration. The philosophy of the Department toPreventive Medicine has not changed throughout its
history, but its focus of research has changed from time
to time, like infectious diseases and occupational healthto name a few, to meet the expectations of the society.
Eventually, in response to the completion of the Human
Genome Project and the recent advancement inmolecular biology, the laboratory had changed its nameto the Department of Molecular Preventive Medicine.
Under Professor Koji Matsushima, the 8th director of
the laboratory, research was actively conducted toclarify inflammation/immune phenomenon with focus
on cytokines in disease background, and its clinicalapplication for secondary/tertiary prevention. In
December 2018, Professor Shumpei Ishikawa became
the 9th director, and in April 2019, he changed the nameof the department back to Preventive Medicine.
Currently, our lab includes (besides the professor, theassociate professor, and the assistant professors) 9
students (3 are from outside of UTokyo), 2 technicalstaffs, 8 technical assistants, 1 collaboration researcher,1 academic support staff, and 1 assistant clerk. 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 fourth-year undergraduate students, and “Introduction to Preventive
Medicine” in medical science master’s program.
Specific emphases are on alteration of the disease
pattern associated 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. Through our lectures and practicalcourses in “Preventive Medicine”, students learn theconcept of preventive medicine.

Research activities
In Department of Preventive Medicine, we conduct
research based on genome science and information
science to explore the appropriate points of intervention for various health issues, in particular, cancer
prevention and treatment. Cancer and inflammation/
immune diseases are complex systems comprised ofnumerous types of cells. We aim to elucidate thedynamics of such complex systems by collecting
extensive data at genome-level, as well as to explore

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specific phenomena which may serve as intervenablepreventive/therapeutic targets, and to evaluate theirsignificance in the related diseases. In addition, we aredeveloping bioinformatics technology to extractessential information from massive and multidimensional biological data, e.g., genome sequence andimages, for human interpretation by techniques such as
dimensionality reduction and visualization.
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 inlymphocyte population is called immune repertoire,
and its profiling in individuals has now become
possible thanks to the advancement in genome analysis
technology such as next-generation sequencing (NGS).
Immune repertoires are considered to reflect immune
history affected by external factors, e.g., pathogens andfoods that the individual has encountered, and byinternal factors, e.g., self-antigens and cancer antigens.
In the department of Preventive Medicine, we aretrying to develop a method to extract not only current
disease conditions but also other relevant healthinformation, such as past disease history and lifestyles,
by analyzing immune repertoires. In particular, in
immune repertoire analysis using gastric cancer andgastric mucosa tissues, we combine the results withcancer genome and microbiome analyses to decipher
immune history with regard to cancer antigens and H.
pylori in its entirety, and revealed that the sulfatedglycosaminoglycans are major and functional B cell
antigens in human cancers. We also use information
analysis technique such as deep learning to analyze
information related to cancer prevention and treatment.
Also, we are applying the obtained immune repertoire
data to design antibodies and use them in cancer
treatment and prevention.
2. Cancer Genome Analysis 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
and showed that its mutation signature differs from theintestinal-type gastric adenocarcinoma, suggesting thatcarcinogenic factors are different in these two types ofcancer. We are looking at cancer tissues as a whole, byapplying genomics point of view, i.e., single-cell
analysis, to cancer cells, immune cells, and vascularstroma cells that comprise cancer tissue, to elucidate
carcinogenic and progression factors and points ofintervention from higher dimensions.
3. Contribution to Elimination of Medical Care
Disparities by Histopathological Image Analysis
As the volume of available biomedical information
is growing rapidly, technology to extract essential
abstract information by compressing dimensions of anenormous amount of biological data is extremely
important in our society. In the department ofPreventive Medicine, deep neural network is applied to
extract essential information (deep texture) of cancerfrom cancer histopathological images. Our goal is todevelop tools to achieve a uniform pathologicaldiagnosis and to help eliminate regional medical caredisparities. We developed Luigi, a content-based image
retrieval system for cancer histopathological images,
and made it available to pathologists and researchers in
Web (https://luigi-pathology.com/) and smartphone
application. The database in Luigi contains
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. Our current
focus is on the development of contents which would
seamlessly connect routine lab tests performed in small

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clinics and cancer genome medicine given in large core
hospitals by integrated analysis of histopathologicalinformation and cancer genome information.

Publications
1. Nakayama A, Abe H, Kunita A, …, Ishikawa S, etal. Viral loads correlate with upregulation of PDL1 and worse patient prognosis in Epstein-Barr
Virus-associated gastric carcinoma. PLoS One.
2019 Jan;14(1):e0211358.
2. Bandi P, Geessink O, Manson Q, …, Komura D, etal. From Detection of Individual Metastases toClassification of Lymph Node Status at the Patient
Level: The CAMELYON17 Challenge. IEEE
Trans Med Imaging. 2019 Feb;38(2):550-560.
3. Okamoto H, Yoshimatsu Y, Tomizawa T, …,
Komura D, …, Ishikawa S, et al. Interleukin-13
receptor α2 is a novel marker and potential
therapeutic target for human melanoma. Sci Rep.
2019 Feb;9(1):1281.
4. Krishnan NM, Katoh H, Palve V, …, Ishikawa S,
Panda B. Functional genomics screen with pooled
shRNA library and gene expression profiling withextracts of Azadirachta indica identify potential
pathways for therapeutic targets in head and necksquamous cell carcinoma. PeerJ. 2019 Mar; 7:
e6464.
5. Konishi H, Komura D, Katoh H, Atsumi S, Koda
H, Yamamoto A, …, Ishikawa S. Capturing thedifferences between humoral immunity in thenormal and tumor environments from repertoireseq of B-cell receptors using supervised machinelearning. BMC Bioinformatics. 2019 May;20(1):267.
6. Komura D, Ishikawa S. Machine learning
approaches for pathologic diagnosis. VirchowsArch. 2019 Aug;475(2):131–8.
7. Akiyama Y, Maeda D, Katoh H, …, Ishikawa S, etal. Molecular Taxonomy of Interstitial Cystitis/
Bladder Pain Syndrome Based on Whole
Transcriptome Profiling by Next-Generation RNA
Sequencing of Bladder Mucosal Biopsies. J Urol.
2019 Aug;202(2):290-300.
8. Suga H, Oka T, Sugaya M, Sato Y, Ishii T, Nishida
H, …, Ishikawa S. et al. Keratinocyte Proline-RichProtein Deficiency in Atopic Dermatitis Leads toBarrier Disruption. Journal of Investigative
Dermatology. 2019 Sep;139(9):1867-1875.e7.
9. Nishizawa T, Nakano K, Fujii E, Komura D,
Kuroiwa Y, Ishimaru C, …, Ishikawa S. et al. In
vivo effects of mutant RHOA on tumor formationin an orthotopic inoculation model. Oncology
Reports. 2019 Nov;42(5):1745–54.

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

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

Project Associate Professor
Jung Su Lee, Ph.D.

Lecturer
Jun Tomio, M.D., M.Sc., Ph.D.

Research Associate
Masayoshi Zaitsu, M.D., Ph.D.

Project Research Associate
Taeko Oguma, M.D., Ph.D. (until July 2019)

Homepage

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

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

Health was established in the University of Tokyo, andthe Department became a part of School of Public
Health (Department of Health Policy) and remained
being a part of Division of Social Medicine(Department of Public Health).
The objectives of the Department are botheducation and research of public health. The
Department trains graduate and undergraduate
students through lectures, seminars, field practice, andlaboratory work in public health and occupational
medicine, for the degrees of Medical Doctor (MD),Master of Public Health (MPH), and Doctor of
Medical Sciences (equivalent to PhD). The
Department has conducted research on a wide variety
for public health issues, including health policy andeconomics, occupational medicine, clinical epidemiology, health services research, and so on. In addition,
the staff members of the Department have offeredpublic and occupational health services to the governments, industries, and local communities.

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In the academic year of 2019, the Department
consists of 6 faculty members above listed, 4 project
researchers (part-time), 2 supporting staff members,
11 graduate students (6 in PhD program, 1 in
temporary supervised program, 4 in professional
degree course), 15 part-time lecturers, and 37 visiting
fellows.

Teaching activities
1) Undergraduate Program (Medical School)
In the winter term of the fourth grade in School of
Medicine (M2), students are provided with thefollowing lectures; current issues of public health,preventive services, epidemiology, evidence based
medicine (EBM), health economics, quality of care,
community medicine, infection and tuberculosis
control, mental health, human ecology, global health,current health policy and administration in Japan, andso on. Similarly, in the sixth grade (M4), an intensive
course of public health (e.g., health care systems,
current health policy, occupational and environmental
health, nutritional epidemiology, and health services
research) is provided. All the above lectures are given
by faculty members and part-time lectures including
governmental officials and health practitioners.
Field practice and laboratory work in public healthis due in the summer term of the fifth grade (M3),which is jointly provided by the other departments
related to public health fields. Averagely four to five
students (small group) are assigned to one special
topic group with a tutor (faculty member or part-time
lecturer). Each group conducts field practice, review
work, or laboratory work, and writes a report in thestyle of original or review paper. The reports
submitted are bound and made available to thosestudents in subsequent years.
The Department also provides those lectures related
to public health and occupational medicine forundergraduate students in the School of Integrated
Health Sciences, Faculty of Arts and Sciences, andFaculty of Engineering.
2) MPH Program
Various courses (more than 40 courses) are given by
those departments affiliated with School of Public
Health. Among them, our Department offers threecourses; “Health Policy”, “Public Health Preparedness”, and “Public Health Practice”.
3) PhD Program
The Department offers special lectures, seminars,
field practice, and laboratory work on public healthand occupational medicine to graduate students. In
these training, special emphasis has been placed on
the following points: (1) how to conduct epidemiological studies, (2) how to use epidemiological andstatistical methods, (3) how to use economic concepts
and methods in the health fields, (4) how to establish
the collaboration with health professionals in thevarious fields, and (5) how to read and write original
papers.

Research activities
1) Health policy and economics
Our research activities focus on the topics of healthcare system and economics in general. We have
performed and published those studies related tosupply and demand sides of health services in Japan;such as supply and distribution of physicians, accessto health care, cost studies of outpatient and inpatient
services, and the efficiency and equity issues of theJapan's health insurance system as well as universal
health coverage system. We also conduct research on
quality of care (cancer, diabetes, and osteoporosis)
and social determinants of health. These studies havebeen published in health policy and health services
research journals. We have continued a collaborative
study on a system of HIV/AIDS care with theintroduction of highly active anti-retroviral therapy(HAART) in developing countries, since such asystem involves medical, behavioral, social, andeconomic factors, and would inevitably become 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

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Other research activities include, (1) evaluation ofdisaster preparedness in local communities and healthcare facilities, (2) study on risk communication in
public health emergencies, and (3) epidemiologicalstudy on incidence and survival rate of children withcerebral palsy.

References
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study from Japan. Social Science & Medicine
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10. Zaitsu M, Toyokawa S, Takeuchi T, Kobayashi Y,
Kawachi I. Sex-specific analysis of renal cell
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11. Zaitsu M, Kim Y, Lee HE, Takeuchi T, Kobayashi
Y, Kawachi I. Occupational class differences inpancreatic cancer survival: a population-based
cancer registry-based study in Japan. Cancer
Medicine 8(6): 3261-3268, 2019. doi.org/10.1002/
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13. Kuboyama I, Sagisaka R, Saito E, Ito S,
Toyokawa S. Selection of regional factors related
to cerebral function after out-of-hospital cardiac
arrest in Japan. EC Neurology 11(4):279-287,
2019.
14. Hasegawa J, Ikeda T, Toyokawa S, Jojima E,
Satoh S, Ichizuka K, Tamiya N, Nakai A, Fujimori
K, Maeda T, Takeda S, Suzuki H, Ueda S,
Iwashita M, Ikenoue T. Obstetric factors
associated with uterine rupture in mothers who
deliver infants with cerebral palsy.Journal of
Maternal-Fetal & Neonatal Medicine 23:1-7, 2019.
doi: 10.1080/14767058.2019.1611775.
15. Tanaka H, Ihana-Sugiyama N, Sugiyama T,
Ohsugi M. Contribution of diabetes to theincidence and prevalence of comorbid conditions(cancer, periodontal disease, fracture, impaired
cognitive function, and depression): a systematic
review of epidemiological studies in Japanese
populations. Journal of Epidemiology 29(1):1-10,
2019. https://doi.org/10.2188/jea.JE20170155.
16. Zaitsu M, Kaneko R, Takeuchi T, Sato Y,
Kobayashi Y, Kawachi I. Occupational class andmale cancer incidence: nationwide, multicenter,
hospital-based case-control study in Japan. Cancer
Medicine 8(2):795-813, 2019. doi.org/10.1002/
cam4.1945.
17. Yoshihara T, Zaitsu M, Shiraishi F, Arima H,
Takahashi-Yanaga F, Arioka M, Kajioka S,
Sasaguri T. Influence of genetic polymorphisms
and habitual caffeine intake on the changes inblood pressure, pulse rate, and calculation speed
after caffeine intake: A prospective, double blind,randomized trial in healthy volunteers. Journalof Pharmacological Sciences, 2019. doi.org/10.
1016/j.jphs.2019.01.006.
18. Kuno T, Sugiyama T, Imaeda S, Hashimoto K,
Ryuzaki T, Yokokura S, Saito T, Yamazaki H,
Tabei R, Kodaira M, Numasawa Y. Novel insights
of jailed balloon and jailed Corsair technique for
percutaneous coronary intervention of bifurcation
lesions. Cardiovascular Revascularization Medicine 20:1065-1072, 2019. doi.org/10.1016/j.carrev.
2019.01.033
19. Akamatsu T, Sugiyama T, Aoki Y, Kawabata K,

Shimizu M, Okazaki K, Kondo M, Takahashi K,
Yokoyama Y, Takahashi N, Goto YI, Oka A, Itoh
M. A pilot study of soluble form of LOX-1 as anovel biomarker for neonatal hypoxic-ischemic
encephalopathy. The Journal of Pediatrics 206 (1):49-55, 2019. doi.org/10.1016/j.jpeds.2018.10.036.
20. Zaitsu M, Kato S, Kim Y, Takeuchi T, Sato Y,
Kobayashi Y, Kawachi I. Occupational class andrisk of cardiovascular disease incidence in Japan:
nationwide, multicenter, hospital-based casecontrol study. Journal of the American Heart
Association 8(6): e011350, 2019. doi.org/10.1161/
JAHA.118.011350.
21. Kubota S, Zaitsu M, and Yoshihara T. Growth
patterns of neonates treated with thermal control
in neutral environment and nutrition regulation tomeet. Basal Metabolism. Nutrients 11(3):592,
2019. doi.org/10.3390/nu11030592.
22. Takeuchi T, Toyokawa S, Okuno Y, Ishida N,
Yamagoe M, Zaitsu M, Mikami K. Prospective
randomized controlled study directly comparing
tadalafil and tamsulosin for male patients withlower urinary tract symptoms. Japanese Journal of
Urological Surgery 32:269-276, 2019. https://doi.
org/10.1101/404566.
23. Okamoto M, Shipley MJ, Wilkinson IB,
McEniery CM, Valencia-Hernàndez CA, SinghManoux A, Kivimaki M, Brunner EJ. Does poorer
pulmonary function accelerate arterial stiffening?:
A cohort study with repeated measurements ofcarotid-femoral pulse wave velocity. Hypertension
74(4):929-935, 2019. doi: 10.1161/HYPERTENSIONAHA.119.13183.
24. Ogata S, Nishimura K, Guzman-Castillo M,
Sumita Y, Nakai M, Nakao YM, Nishi N, Noguchi
T, Sekikawa A, Saito Y, Watanabe T, Kobayashi Y,
Okamura T, Ogawa H, Yasuda S, Miyamoto Y,
Capewell S, O'Flaherty M. Explaining the decline
in coronary heart disease mortality rates in Japan:
contributions of changes in risk factors andevidence-based treatments between 1980 and2012. International Journal of Cardiology 291:
183-188, 2019. doi: 10.1016/j.ijcard.2019.02.022.
25. Kaneko R, Zaitsu M, Sato Y, Kobayashi Y Risk ofcancer and longest-held occupations in Japanese
workers: a multicenter hospital-based case-control
study. Cancer Medicine 8(13): 6139-6150, 2019.

118

doi: 10.1002/cam4.2499.
26. Ito Y, Hara K, Yoo BK, Tomio J, Kobayashi Y.
Can income-based co-payment rates improvedisparity? The case of the choice between brandname and generic drugs. BMC Health Services
Research 19:780, 2019. doi: 10.1186/s12913-0194598-8.
27. Miyawaki A, Lee JS, Kobayashi Y. Impact of theschool lunch program on overweight and obesity
among junior high school students: a nationwide
study in Japan. Journal of Public Health 41(2):362-370, 2019. doi:10.1093/pubmed/fdy095.
28. Ideno Y, Hayashi K, Lee JS, Miyazaki Y, Suzuki S.
A proper reference metabolic equivalent value toassess physical activity intensity in Japanese
female nurses. Women’s Midlife Health 5:4, 2019.
https://doi.org/10.1186/s40695-019-0048-3.
29. Katanoda K, Noda M, Goto A, Mizunuma H, Lee
JS, Hayashi K. Being underweight in adolescenceis independently associated with adult-onset
diabetes among women: The Japan Nurses’ HealthStudy. Journal of Diabetes Investigation 10(3):827-836, 2019. https://doi.org/10.1111/jdi.12947.
30. InterLACE Study Team (Mishra GD, Hsin-Fang
Chung HF, Pandeya N, Schoenaker DAJM, Kuh D,
Hayashi K, Lee JS, Mizunuma H, Crawford SL,
Avis NE, Gold EB, Mitchell ES, Woods NF,
Anderson D, Brown D, Sievert LL, Brunner EJ,
Demakakos P, Cade JE, Greenwood DC, Giles
GG, Bruinsma F, Cooper R, Hardy R, Tillin T,
Obermeyer CM, Simonsen MK, Weiderpass E,
Sandin S, Adami HO, Dobson AJ). Variations in
reproductive events across life: a pooled analysisof data from 505,147 women across ten countries.
Human Reproduction 34(5):881-893, 2019.
https://doi.org/10.1093/humrep/dez015.
31. Zhu D, Chung HF, Pandeya N, Dobson AJ, Hardy
R, Kuh D, Brunner EJ, Bruinsma F, Giles GG,
Demakakos P, Lee JS, Mizunuma H, Hayashi K,
Adami HO, Weiderpass E, Mishra GD.
Premenopausal cardiovascular disease and age atnatural menopause: a pooled analysis of over
170,000 women. European Journal of Epidemiology 34:235-246, 2019. https://doi.org/10.1007/
s10654-019-00490-w.
32. Yasui T, Ideno Y, Onizuka Y, Nakajima-Shimada J,
Lee JS, Shinozaki H, Kishi M, Suzuki R, Hayashi

K. The association of urinary estrogen levels withurinary isoflavone levels: Difference between
premenopausal women and postmenopausal
women. Maturitas 121:41-47, 2019. https://doi.
org/10.1016/j.maturitas.2018.12.010.
33. Hino K, Asami Y, Lee JS. Step counts ofmiddle-aged and elderly adults for term months
before and after the release of Pokémon GO in
Yokohama, Japan. Journal of Medical Internet
Research 21(2): e10724, 2019. doi: 10.2196/
10724.
34. Kato D, Ryu H, Matsumoto T, Abe K, Kaneko M,
Ko M, Irving G, Ramsay R, Kondo M. Building
primary care in Japan: literature review. Journal of
General and Family Medicine 20(5):170-179,
2019. doi.org/10.1002/jgf2.252.
35. Shinya Y, Hasegawa H, Shin M, Sugiyama T,
Kawashima M, Takahashi W, Iwasaki S, Kashio A,
Nakatomi H, Saito N. Long-Term Outcomes of
Stereotactic
Radiosurgery
for
Vestibular
Schwannoma Associated with Neurofibromatosis
Type 2 in Comparison to Sporadic Schwannoma.
Cancers 2019, 11(10), 2019. https://doi.org/10.
3390/cancers11101498.
36. Iwagami M, Kobayashi Y, Tsukazaki E, WatanabeT, Sugiyama T, Wada T, Hara A, Tamiya N.
Associations between self-reported hearing loss
and outdoor activity limitations, psychologicaldistress and self-reported memory loss amongolderpeople:Analysis
of
the
2016
Comprehensive Survey of Living Conditions inJapan. Geriatrics and Gerontology International
19(8):747-754, 2019. doi: 10.1111/ggi.13708.
37. Miyawaki A, Kobayashi Y, Kawachi I.
Self-reported hearing/visual loss and mortality in
middle-aged and older adults: Findings from the
Komo-Ise cohort, Japan.Journal of Epidemiology,
2019 [Epub ahead of print]. https://doi.org/10.
2188/jea.JE20180198.
38. Abe T, Aoki M, Deshpande G, Sugiyama T,
Iwagami M, Uchida M, Nagata I, Saitoh D,
Tamiya N. Is whole-body CT associated with
reduced in-hospital mortality in children withtrauma? A nationwide study. Pediatric Critical
Care Medicine, 2019 [Epub ahead of print].
doi.org/10.1097/PCC.0000000000001898.
39. Cuevas AG, Trudel-Fitzgerald C, Cofie L, Zaitsu

119M, Allen J, Williams DR. Placing prostate cancer
disparities within a psychosocial context:
challenges and opportunities for future research.
Cancer Causes Control, 2019 [Epub ahead ofprint]. doi.org/10.1007/s10552-019-01159-1.
40. Zaitsu M, Lee HE, Lee S, Takeuchi T, Kobayashi
Y, Kawachi I. Occupational disparities in bladdercancer survival: a population-based cancer
registry study in Japan. Cancer Medicine, 2019
[Epub ahead of print]. doi:10.1002/cam4.2768.
41. Shibahashi K, Sugiyama K, Tomio J, Hoda H,
Morita A. In-hospital mortality and length of
hospital stay with craniotomy versus craniectomy
for acute subdural hemorrhage: a multicenter,
propensity score-matched analysis. Journal of
Neurosurgery, 2019 [Epub ahead of print]. doi:
10.3171/2019.4.JNS182660.
42. Inada H, Tomio J, Nakahara S, Ichikawa M.
Area-wide traffic-calming zone 30 policy of Japanand incidence of road traffic injuries among
cyclists and pedestrians. American Journal of
Public Health, 2019 [Epub ahead of print].
doi:10.2105/AJPH.2019.305404.
43. Morioka N, Moriwaki M, Tomio J, Kashiwagi M,
Fushimi K, Ogata Y. Structure and process ofdementia care and patient outcomes after hip
surgery in elderly people with dementia: A
retrospective observational study in Japan.
International Journal of Nursing Studies, 2019
[Epub ahead of print]. doi: 10.1016/j.ijnurstu.
2019.103470.
44. Ihana-Sugiyama N, Sugiyama T, Tanaka H, Ueki
K, Kobayashi Y, Ohsugi M. Comparison ofeffectiveness and drug cost between dipeptidyl
peptidase-4 inhibitor and biguanide as thefirst-line anti-hyperglycaemic medication among
Japanese working generation with type 2 diabetes.
Journal of Evaluation in Clinical Practice, 2019
[Epub ahead of print]. doi:10.1111/jep.13171.
45. Miyawaki A, Tsugawa Y. Association between
Newsweek’s Global Hospital Ranking and patient
outcomes in the USA. Journal of General Internal
Medicine, 2019 [Epub ahead of print].
https://doi.org/10.1007/s11606-019-05212-2.
46. Kuno T, Takagi H, Sugiyama T, Ando T,
Miyashita S, Valentin N, Shimada YJ, Kodaira M,
Numasawa Y, Kanei Y, Hayashida K, Bangalore S.

Antithrombotic strategies after transcatheter aortic
valve implantation: Insights from a network
meta-analysis. Catheterization and CardiovascularInterventions, 2019 [Epub ahead of print]. doi:
10.1002/ccd.28498.

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

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

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

Assistant Professor
Suguru Torimitsu, M.D., Ph.D., Rutsuko Yamaguchi, M.P.H., M.D., Ph.D.

Project Assistant Professor
Go Inokuchi, M.D., Ph.D., Ayumi Motomura, M.D., Ph.D., Fumiko Chiba, M.D., Ph.D.

Homepage

http://ut-forensic.jp/

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

The 6th Professor Ikuo Ishiyama encouraged
forensic pathology. He also introduced DNA fingerprinting and PCR technique in the forensic practices.
The 7th Professor Takehiko Takatori studied thebiochemical changes of the lipid in cadavers. He
dissected five victims of sarin subway attacks inTokyo and identified sarin in tissue by a sophisticatedmethod.
The 8th Professor Ken-ichi Yoshida studied themolecular mechanism of ischemic heart disease andsudden cardiac death.
Hirotaro Iwase has been directing our department
since 2014 as the 9th Professor. In order to reconstruct
the field of forensic medicine as the attractive one, six
sections (forensic pathology, clinical forensic
medicine, forensic toxicology, forensic radiology,
forensic odontology, forensic genetics) have started incooperation with Chiba University. We are preparing
to teach practice and research for the future forensic
pathologists.

Postmortem examination
The determination of precise cause of death is oneof the most important practices at our department. We
perform medico-legal autopsies for around 120
criminal cases in eastern part of Tokyo every year. We
also perform post-mortem CT at the request of police.

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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.

Education
As for under-graduate education, our department
provides lectures for the 4th year medical students,
Free Quarter training course for the 3-4th year medical
students, and Elective Clerkship learning for the 5thyear medical students.
The lectures consist of forensic pathology, clinicalforensic medicine, forensic toxicology, forensic
radiology, forensic odontology and forensic genetics.
In the Free Quarter training course, students
experience laboratory practices (toxicology, DNA
typing, histology) or experiments. In the Elective
Clerkship learning, each student experiences theprocess from autopsy to presentation of expert
opinion.
In addition, students of school of public health and(undergraduate & graduate) law school are provided
with somewhat practical lectures with exercises. We
have provided opportunity for PhD students of Schoolof Hearth Science, and master course of Medical
Science.

Research
In cooperation with other universities including
Chiba University and Tokyo Medical and Dental
University, researches in 6 sections (forensic
pathology, clinical forensic medicine, forensic
toxicology, forensic radiology, forensic odontology
and forensic genetics) have proceeded.
1. Forensic Pathology
In autopsy, it is difficult to examine a vertebral
artery. We therefore conduct study on a method of
the artery using angioscopy. We also conduct
research about the usefulness of coronary
angiography using 3D-CT. As to pathologicalresearch, we investigate about the lipid peroxidationin the cases of stimulant intoxication and crash
syndrome.

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

Publications
1. Torimitsu S, Fujii Y, Saka K, Abe H, Makino Y,
Chiba F, Iwase H. Fatal intoxication with
1,1-difluoroethane (DFE) due to inhalation of aspray cleaner: analysis by GC–MS. Forensic
Toxicol. 2019; 37: 245-249.

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2. Torimitsu S, Makino Y, Saitoh H, Ishii N,
Inokuchi G, Motomura A, Chiba F, Yamaguchi R,
Hoshioka Y, Urabe S, Iwase H. Age estimation
based on maturation of the medial clavicularepiphysis in a Japanese population using
multidetector computed tomography. Leg Med(Tokyo). 2019; 37: 28-32.
3. Torimitsu S, Makino Y, Yamaguchi R, Chiba F,
Tsuneya S, Iwase H. Fatal Spontaneous Retropharyngeal Hematoma with Airway Obstructionin the Setting of Treatment with Dipyridamole. J
Forensic Sci. [Epub ahead of print]
4. Saitoh H, Moriya T, Takeyama M, Yusa K,
Sakuma A, Chiba F, Torimitsu S, Ishii N,
Sakurada K, Iino M, Iwase H, Tokanai F.
Estimation of birth year by radiocarbon dating of
tooth enamel: Approach to obtaining enamel
powder. J Forensic Leg Med. 2019; 62: 97-102.
5. Unuma K, Makino Y, Sasaki Y, Iwase H, Uemura
K. Presepsin: A potential superior diagnostic
biomarker for the postmortem differentiation ofsepsis based on the Sepsis-3 criteria. Forensic Sci
Int. 2019; 299:17–20.
6. Hofman P, Alminyah A, Apostol M, Boel LWT,
Brough A, Bouwer H, O'Donnell C, Fujimoto H,
Iino M, Kroll J, Lee CT, Levey DS, Makino Y,
Oesterhelweg L, Ong B, Ranson D, Robinson C,
Rutty G, Singh MKC, Villa C, Viner MD,
Woodford N, Watkins T, Wozniak K. Use of
post-mortem computed tomography in disastervictim identification. Updated positional statement of the members of the disaster victim
identification working group of the International
Society of Forensic Radiology and Imaging; July
2019. Journal of Forensic Radiology and Imaging,2019; 19:3
7. Yamaguchi R, Makino Y, Inokuchi G, Hattori S,
Chiba F, Torimitsu S, Saito N, Kishimoto T, Iwase
H. Fatal atlantoaxial dislocation due to an
odontoid synchondrosis fracture in a child withchromosome 9 abnormality: A case report. J
Forensic Leg Med. 2019; 61: 92-96.
8. Inokuchi G, Yoshida M, Makino Y, Iwase H.
Utility of Contrast-Enhanced Computed Tomography in Forensic Examination of a Stab Woundin Living Individuals. ForensicSciMe Pathol.
2019;15(3):463-469.

9. Makino Y, Yoshida M, Yajima D, Iwase H: Brain
Imaging in Postmortem Forensic Radiology. Lo
Re G, Argo A, Midiri M, Cattaneo C, editors.
Radiology in Forensic Medicine. Cham: Springer;
2019; p. 279-296.

124

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., Ken Imai, Ph.D.

Assistant Professor
Yusuke Ida, D.D., Ph.D.

Homepage

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

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

University of Tokyo Hospital by using information
systems as well as the planning, design, development,
and operation of information systems for the whole
hospital. The DPIM was newly established on April 1,
2003, after integration of the Hospital Computer
Center and the project team for hospital development,
which separately existed until the end of March, 2003.
Since the professor runs the Department of Medical
Informatics and Economics with staffs of DPIM, they
are practically the same organization. Therefore,
educations and researches in the graduate course arepromoted together with DPIM activities. The origin of
the Department of Medical Informatics andEconomics dates back to 1983 when the hospitalcomputer center was officially approved as one of thecentral clinical service facilities in the hospital. At thesame time, the doctor’s course for medical informatics
was established. The first professor was Dr. Shigekoto
Kaihara, who is the founder of medical informatics inJapan. In accordance with the reform to the university
with graduate school curriculum in the university ofTokyo, the Department of Medical Informatics andeconomics was established in present division ofsocial medicine in 1997. Then, one professor and one
associate professor belonging to the hospital computer
center moved to the department. In 2000, medical
informatics field was set up in the Interfaculty
Initiative in Information Studies, Graduate School of125Interdisciplinary Information Studies. The department
is located on the fourth floor in Administration andResearch Building in the University of Tokyo
Hospital.

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

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

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

126

References
1. Yamaguchi M, Inomata S, Harada S, Matsuzaki Y,
Kawaguchi M, Ujibe M, Kishiba M, Fujimura Y,
Kimura M, Murata K, Nakashima N, Nakayama
M, Ohe K, Orii T, Sueoka E, Suzuki T, Yokoi H,
Takahashi F, Uyama Y. Establishment of the
MID-NET® medical information database network as a reliable and valuable database for drug
safety assessments in Japan. Pharmacoepidemiol
Drug Saf. 2019 Oct;28(10):1395-1404.
2. Sakurai R, Ohe K. Effects of Computerized
Guideline-Oriented Clinical Decision Support
System on Antithrombotic Therapy in Patientswith Atrial Fibrillation: A Systematic Review andMeta-Analysis. Stud Health Technol Inform. 2019
Aug 21;264:768-772.
3. Fukuma N, Hasumi E, Fujiu K, Waki K, Toyooka
T, Komuro I, Ohe K. Feasibility of a T-Shirt-Type
Wearable Electrocardiography Monitor for
Detection of Covert Atrial Fibrillation in Young
Healthy Adults. Sci Rep. 2019 Aug 13;9(1):11768.
4. Imatoh T, Sai K, Takeyama M, Segawa K,
Yamashita T, Nakashima N, Kataoka Y, Yokoi H,
Hiramatsu T, Ohe K, Kimura M, Hori K,
Kawakami J, Saito Y. Evaluating the impact ofregulatory action on denosumab-induced hypocalcaemia in Japan. J Clin Pharm Ther. 2019 Oct;44(5):788-795.
5. Kawaguchi H, Koike S, Ohe K. Facility andRegional Factors Associated With the New
Adoption of Electronic Medical Records in Japan:
Nationwide Longitudinal Observational Study.
JMIR Med Inform. 2019 Jun 14;7(2):e14026.
6. Nakashima N, Noda M, Ueki K, Koga T, Hayashi
M, Yamazaki K, Nakagami T, Ohara M, Gochi A,
Matsumura Y, Kimura M, Ohe K, Kang D, Toya Y,
Yamagata K, Yokote K, Ikeda S, Mitsutake N,
Yamamoto R, Tanizawa Y. Recommended
configuration for personal health records bystandardized data item sets for diabetes mellitus
and associated chronic diseases: a report from acollaborative initiative by six Japanese
associations. Diabetol Int. 2019 Apr 25;10(2):85-92.
7. Kaori Yamada Maori Itoh Yoshiaki Fujimura

Michio Kimura Koichiro Murata Naoki
Nakashima Masaharu Nakayama Kazuhiko Ohe
Takao Orii Eizaburo Sueoka Takahiro Suzuki
Hideto Yokoi Chieko Ishiguro Yoshiaki Uyama on
behalf of MID ‐ NET project group: Theutilization and challenges of Japan’s MID ‐NET® medical information database network inpostmarketing drug safety assessments: A
summary of pilot pharmacoepidemiologicalstudies. Pharmacoepidemiology and Drug Safety
28(5),601-608,May 2019.
8. Hayakawa M, Imai T, Kawazoe Y, Kozaki K, Ohe
K. Auto-Generated Physiological Chain Data for
an Ontological Framework for Pharmacology andMechanism of Action to Determine Suspected
Drugs in Cases of Dysuria. Drug Safety. 2019,42.
9. Kagawa R, Shinohara E, Imai T, Kawazoe Y, Ohe
K. Bias of Inaccurate Disease Mentions inElectronic Health Record-based Phenotyping.
International journal of medical informatics.
2019;124: 90-96.
10. Nakashima N, Noda M, Ueki K, Koga T, Hayashi
M, Yamazaki K, Nakagami T, Ohara M, Gochi A,
Matsumura Y, Kimura M, Ohe K, Kang D, Toya Y,
Yamagata K, Yokote K, Ikeda S, Mitsutake N,
Yamamoto R, Tanizawa Y.: Recommended
configuration for personal health records bystandardized data item sets for diabetes mellitus
and associated chronic diseases: A report fromCollaborative Initiative by six Japanese
Associations. J Diabetes Investig. 2019 May;10(3):868-875.
11. Yamaguchi S, Waki K, Nannya Y, Nangaku M,
Kadowaki T, Ohe K.: Usage Patterns of
GlucoNote, a Self-Management Smartphone App,
Based on ResearchKit for Patients With Type 2
Diabetes and Prediabetes. JMIR Mhealth Uhealth.
2019 Apr 24;7(4):e13204.
12. Matoba T, Kohro T, Fujita H, Nakayama M,
Kiyosue A, Miyamoto Y, Nishimura K,
Hashimoto H, Antoku Y, Nakashima N, Ohe K,
Ogawa H, Tsutsui H, Nagai R.: Architecture of theJapan Ischemic Heart Disease Multimodal
Prospective Data Acquisition for Precision
Treatment (J-IMPACT) System. Int Heart J. 2019
Mar 20;60(2):264-270.
13. Seki T, Tamura T, Suzuki M, SOS-KANTO, Study

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cardiac arrest with presumed cardiac aetiology
using an advanced machine learning technique.,
Resuscitation 2019.
14. Marina Okada, Yoshitaka Tada, Tomohisa Seki,
Shugo Tohyama, Jun Fujita, Toshihiro Suzuki,
Manami Shimomura, Kazuya Ofuji, Yoshikazu
Kishino, Kazuaki Nakajima, Sho Tanosaki, Shota
Someya, Hideaki Kanazawa, Satoru Senju,
Tetsuya Nakatsura, Keiichi Fukuda, Selective
elimination of undifferentiated human pluripotent
stem cells using pluripotent state-specificimmunogenic antigen Glypican-3. Biochemicaland biophysical research communications 511(3)711- 717,2019.
15. Tabei R, Kawaguchi S, Kanazawa H, Tohyama S,
Hirano A, Handa N, Hishikawa S, Teratani T,
Kunita S, Fukuda J, Mugishima Y, Suzuki T,
Nakajima K, Seki T, Kishino Y, Okada M,
Yamazaki M, Okamoto K, Shimizu H, Kobayashi
E, Tabata Y, Fujita J, Fukuda K. Development of atransplant injection device for optimal distribution
and retention of human induced pluripotent stem
cell‒derived cardiomyocytes. The Journal of heart
and lung transplantation : the official publicationof the International Society for Heart Transplantation 38(2) 203-214,2019.

Internal Medicine
1. Medicine Ⅰ

129

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

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

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

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

Jiro Andoh, M.D.

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

Homepage

Norifumi Takeda, M.D., Ph.D.

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

Introduction and Organization
The Department of Cardiovascular Medicine wasestablished in 1998 by regrouping cardiologists of fiveprevious internal medical departments. After Yoshio
Yazaki, the first professor, and Ryozo Nagai, the second
professor, the present professor Issei Komuro waselected in August, 2012. Our department comprises one
professor, 4 lecturers, 2 hospital lecturers, 15 research
assistants, 9 staff members, and 40 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 2019, a total of 1,803 patients were newly
admitted to our hospital ward of 61 beds. The average
duration of hospitalization was 10.4 days.

Because we are an authorized facility for heart transplantation, the use of left ventricular assist device incases of severe heart failure has been increasing. In
2006, the first patient with heart failure from ourdepartment underwent a heart transplant procedure atthe Department of Cardiovascular Surgery. In 2019, 27
patients underwent heart transplant (total 138 cases). In
March 2014, our facility was also authorized to perform
lung transplantation. Coronary angiography was
performed in 738 patients, of which 349 patients
underwent interventional procedures. CT coronary
angiography and cardiovascular MRI were performed
in 440 and 135 patients, respectively. With regard toarrhythmias, there were 319 cases of catheter ablation,
112 cases of implantation or replacement of pacemakers and other specialized pacemaker devices,
including 20 cases of implantation or replacement of
implantable cardioverter-defibrillator and 25 cases of
implantation or replacement of a cardiac resynchronization device.
Out-patient clinics are available as a specialized
department and as part of the Department of Medicine.
Out-patient clinics are open in the mornings andafternoons from Monday to Friday, and approximately
189.1 patients visit each day. The disease profile
includes ischemic heart disease, heart failure,arrhythmia. hypertension and peripheral artery disease,
There are special outpatient clinics for pulmonary

130

hypertension, congenital heart disease, valvular heartdisease, cardiomyopathy, arrhythmia, Marfan’s
syndrome, cardiac amyloidosis, cardiac sarcoidosis,
chronic myocarditis The department is also focusedon acute cases of coronary heart disease and aortic
disease, as emergent catheterization is available on a
24-hour basis.

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

Research activities
From a research perspective, our interests include all
fields of cardiovascular medicine, ranging frommolecular biology to clinical research, including
genomics. Importantly, our research interests are aimed
at facilitating new diagnostic and treatment methods
for cardiovascular diseases. Our areas of interest
include the following:
1. Cardiac hypertrophy and heart failure: analyses ofpathogenic mechanisms and development of novel
therapies (e.g., gene therapy)
2. Nitric oxide and endothelial function
3. Interplay between organs, cells, and molecules inchronic inflammation
4. Mechanisms underlying cardiorenal association
5. Role of hypoxia signaling in cardiovascular diseases
6. Genetic analysis of inherited cardiomyopathy
7. Experiments on pathophysiology ofcardiomyopathy using human iPS cells
8. Investigation of disease pathophysiology anddevelopment of novel therapies (severe heart
failure, cardiac transplantation, congenital heartdisease, etc.)
9. New treatments for structural heart disease

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

Publications (2019)
1. Abe H, Takeda N, Isagawa T, Semba H, Nishimura
S, Morioka MS, Nakagama Y, Sato T, Soma K,
Koyama K, Wake M, Katoh M, Asagiri M, Neugent
ML, Kim JW, Stockmann C, Yonezawa T, Inuzuka
R, Hirota Y, Maemura K, Yamashita T, Otsu K,
Manabe I, Nagai R, Komuro I. Macrophage
hypoxia signaling regulates cardiac fibrosis via
Oncostatin M. Nat Commun. 2019;10:2824.
2. Akazawa H, Toko H, Harada M, Ueda K, Kodera
S, Kiyosue A, Fujiu K, Hatano M, Daimon M,
Ando J, Takimoto E, Morita H, Komuro I.
Overview of the 83rd annual scientific meeting of
the Japanese circulation society- renaissance of
cardiology for the creation of future medicine. Circ
J. 2019;83(9):1829-1835.
3. Fukuma N, Hasumi E, Fujiu K, Kayo W, Toyooka
T, Komuro I, Ohe K. Feasibility of a t-shirt-typewearable electrocardiography monitor for
detection of covert atrial fibrillation in young
healthy adults. Sci Rep. 2019;9(1):11768.
4. Hasumi E, Fujiu K, Nakanishi K, Komuro I.
Impacts of left bundle/peri-left bundle pacing onleft ventricular contraction. Circ J. 2019;83(9):1965-1967.
5. Hayakawa N, Kodera S, Ohki N, Kanda J. Efficacy
and safety of endovascular therapy by diluted
contrast digital subtraction angiography in patientswith chronic kidney disease. Heart Vessels. 2019;34(11):1740-1747.
6. Ito M, Hara H, Takeda N, Naito AT, Nomura S,
Kondo M, Hata Y, Uchiyama M, Morita H,
Komuro I. Characterization of a small moleculethat promotes cell cycle activation of human

131

induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol. 2019;128:90-95.
7. Itoh H, Kaneko H, Kiriyama H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Komuro I. Relationship between the
updated blood pressure classification according to
the american college of cardiology/american heart
assiciation guidelines and carotid intima-media
thickness. Am J Cardiol. 2019;124(3):396-401.
8. Kaneko H, Komuro I. C-reactive protein andchronic inflammation - is it a novel therapeutictarget for subsequent cancer death in patients withcoronary artery disease?. Circ J. 2019;83(3):513514.
9. Kiriyama H, Ishida J, Kadowaki H, Iwasa T,
Kiyosue A, Kodera S, Ando J, Akazawa H,
Komuro I. OCT-based management of nilotinibassociated cad in a patient with chronic myeloid
leukemia. JACC CardioOncology. 2019;1(2):318321.
10. Kiriyama H, Kaneko H, Itoh H, Uehara M, Kodera
S, Kiyosue A, Yamauchi H, Daimon M, Ando J,
Morita H, Ono M, Komuro I. Left main coronary
artery obstruction by huge noncoronary cusp
calcification after transcatheter aortic valve
replacement. JACC Cardiovasc Interv. 2019;12:1285-1287.
11. Kiriyama H, Kaneko H, Itoh H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Komuro I. Role of anemia andproteinuria in the development of subsequent renal
function deterioration in a general population withpreserved glomerular filtration rate: a communitybased cohort study. J Nephrol. 2019;32(5):775-781.
12. Ko T, Fujita K, Nomura S, Uemura Y, Yamada S,
Tobita T, Katoh M, Satoh M, Ito M, Domoto Y,
Hosoya Y, Amiya E, Hatano M, Morita H,
Fukayama M, Aburatani H, Komuro I.
Quantification of DNA damage in heart tissue as anovel prediction tool for therapeutic prognosis ofpatients with dilated cardiomyopathy. JACC BasicTransl Sci. 2019;4(6):670-680.
13. Kodera S, Morita H, Kiyosue A, Ando J, Komuro
I. Cost-effectiveness of percutaneous coronary
intervention compared with medical therapy forischemic heart disease in Japan. Circ J. 2019;
83(7):1498-1505.

14. Nakanishi K, Jin Z, Homma S, Elkind MS, Rundek
T, Schwartz J, Lee S, Tugcu A, Yoshita M, DeCarli
C, Wright C, Sacco RL, Di Tullio MR. Nighttime
systolic blood pressure and subclinicalcerebrovascular disease: the cardiovascularabnormalities and brain lesions (cabl) study. Eur
Heart J Cardiovasc Imaging. 2019;20:765-771.
15. Nakayama A, Amiya E, Morita H, Hyodo K,
Takayama N, Konishi Y, Taya M, Fujiwara T,
Hosoya Y, Hoshina K, Komuro I. The potential of
cardiac rehabilitation as a method of suppressing
abdominal arotic aneurysm expansion: a pilot study.
Heart Vessels. 2019;34(12):2031-2039.
16. Nakayama A, Morita H, Fujiwara T, Komuro I.
Effects of treatment by female cardiologists on
short-term readmission rates of patients
hospitalized with cardiovascular diseases. Circ J.
2019;83(9):1937-1943.
17. Nakayama A, Morita H, Hoshina K, Komuro I.
Quantification of abdominal aortic aneurysm
calcification using the agatston method can predict
accelerated expansion rate. Circ J. 2019;83(3):689.
18. Okada J, Fujiu K, Washio T, Sugiura S, Hisada T,
Hasumi E, Komuro I. Longitudinal dissociationand transition in thickness of the His–Purkinje
system cause various QRS waveforms of surface
ECG under His bundle pacing:a simulation study
based on clinical observations. J Cardiovasc
Electrophysiol. 2019;30(11):2582-2590.
19. Sato T, Ishida J, Kojima T, Komuro I. Successfultransvenous pacemaker implantation via redirected persistent left superior vena cava. Circ J.
2019;83(10):2082.
20. Satoh M, Nomura S, Harada M, Yamaguchi T, Ko
T, Sumida T, Toko H, Naito AT, Takeda N, Tobita
T, Fujita T, Ito M, Fujita K, Ishizuka M, Kariya T,
Akazawa H, Kobayashi Y, Morita H, Takimoto E,
Aburatani H, Komuro I. High-throughput singlemolecule RNA imaging analysis reveals
heterogeneous responses of cardiomyocytes tohemodynamic overload. J Mol Cell Cardiol. 2019;
128:77-89.
21. Sawada N, Daimon M, Kawata T, Nakao T, Kimura
K, Nakanishi K, Kurano M, Hirokawa M, Xu B,
Yamanaka Y, Kato TS, Watanabe M, Yatomi Y,
Komuro I. The significance of the effect of visceral

132

adiposity on left ventricular diastolic function in
the general population. Sci Rep. 2019;9(1):4435.
22. Sawada N, Nakanishi K, Daimon M, Yoshida Y,
Ishiwata J, Hirokawa M, Nakao T, Morita H, Di
Tullio MR, Homma S, Komuro I. Influence ofvisceral adiposity accumulation on adverse left andright ventricular mechanics in the community. Eur
J Prev Cardiol. 2019;2047487319891286.
23. Takano N, Amiya E, Oguri G, Nakayama A, Taya
M, Nakajima T, Morita H, Komuro I. Influence ofatrial fibrillation on oxygen uptake and exercise
tolerance in cardiovascular patients; close
association with heart rate response. Int J Cardiol
Heart Vasc. 2019;22:84-91.
24. Tsuji M, Amiya E, Hatano M, Nitta D, Maki H,
Bujo C, Saito A, Hosoya Y, Minatsuki S, Hara T,
Nemoto M, Kagami Y, Endo M, Kimura M,
Kinoshita O, Nawata K, Morita H, Ono M,
Komuro I. Abdominal skeletal muscle mass as apredictor of mortality in Japanese patients
undergoing left ventricular assist device
implantation. ESC Heart Fail. 2019;6(3):526-535.
25. Tsuji M, Hatano M, Yamauchi H, Ono M, Komuro
I. Multiple arteriovenous fistulas after laser leadextraction in heart transplant patient. Eur Heart J
Cardiovasc Imaging. 2019;20(5):511.
26. Tsuji M, Nitta D, Minatsuki S, Maki H, Hosoya Y,
Amiya E, Hatano M, Takimoto E, Kinoshita O,
Nawata K, Ono M, Komuro I. Emergency
percutaneous coronary intervention for left main
trunk thrombus following orthotopic hearttransplantation. ESC Heart Fail. 2019;6(3):575578.
27. Ueda K, Toko H, Komuro I. Endothelial cellderived angiocrines elicit physiological cardiomyocyte hypertrophy. Circulation. 2019;139(22):2585-2587.
28. Yoshida Y, Nakanishi K, Daimon M, Ishiwata J,
Sawada N, Hirokawa M, Kaneko H, Nakao T,
Mizuno Y, Morita H, Di Tullio MR, Homma S,
Komuro I. Alteration of cardiac performance andserum B-type natriuretic peptide level in healthy
aging. J Am Coll Cardiol. 2019;74(14):1789-1800.

133

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

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

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

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

Hirokazu Urushiyama, M.D.,Ph.D., Yosuke Amano, M.D.,Ph.D.
Satoshi Noguchi, M.D.,Ph.D.,

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

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

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

Homepage

http://kokyuki.umin.jp/

Introduction and Organization
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, 17 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.

Clinical activities
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 clinicalconference for respiratory disease has been held oncea week since the late 1990s, where staff from ourdepartment, Department of Thoracic Surgery, andDepartment of Radiology join and discuss together todetermine the best diagnostic and therapeutic
approach to individual patients. This conference has
been highly appreciated as a prototype of Cancer
Board of the University of Tokyo Hospital, and, is134

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 2019
1. Primary lung cancer
464
2. Interstitial pneumonia
87
3. Respiratory infections
18
4. Pneumothorax
10
5. COPD
9
6. Non-tuberculous
mycobacterial infections
8
6. Malignant mesothelioma
7
7. Pulmonary aspergillosis
6
A weekly chart round and professor’s round arescheduled every Tuesday afternoon.
A specialized clinical conference for patients withrespiratory diseases is held as Respiratory Cancer
Board every Thursday evening, together with thoracic
surgeons and radiologists. At this conference,
radiological diagnosis, indication of CT-guided biopsy
and thoracoscopic biopsy, and treatment strategies not
only about thoracic malignancies but also otherrespiratory diseases are discussed, making it possible
to give the best care to every patient.

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

135

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.



chemotherapy in malignancy including lungcancerEpidemiological study of respiratory diseases,
using
Diagnosis
Procedure
Combination
database.

Takahide Nagase is a GOLD Assembly member.

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










Search for diseases-susceptibility genes andelucidation of their pathophysiological roles in
respiratory diseases
Analysis of disease-models using geneticallyengineered mice
Analysis of DNA methylation, histone modification and miRNA in lung cancer
Search for previously unidentified oncogenic
driver mutations in lung cancer and elucidation ofresistant mechanisms to molecular-targeted dugs
Analysis of functional alterations of airway
epithelial cells and fibroblasts in relation to tissue
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 to

1. Watanabe K, Kage H, Nagoshi S, Toyama K,
Ohno Y, Shinozaki-Ushiku A, NakazakiK, Suzuki
H, Kurokawa M, Nagase T. Dual EGFR and ABL
Tyrosine Kinase Inhibitor Treatment in a Patientwith Concomitant EGFR-Mutated Lung Adenocarcinoma and BCR-ABL1-Positive CML. Case
Rep Oncol Med. 2020 Mar 19;2020:4201727
2. Jo T, Yasunaga H, Yamauchi Y, Mitani A, Hiraishi
Y, Hasegawa W, Sakamoto Y, Matsui H, Fushimi
K, Nagase T. Inhaled corticosteroid withdrawal
may improve outcomes in elderly patients with
COPD exacerbation: a nationwide database study.
ERJ Open Res. 2020 Feb 3;6(1). pii: 00246-2019
3. Ando T, Kage H, Matsumoto Y, Zokumasu K,
Yotsumoto T, Maemura K, Amano Y, Watanabe K,
Nakajima J, Nagase T, Takai D. Integrin α11 in
non-small cell lung cancer is associated withtumor progression and postoperative recurrence.
Cancer Sci. 2020 Jan;111(1):200-208
4. Mikami Y, Jo T, Matsuzaki H, Ishimori T, Saito M,
Sakamoto Y, Yamauchi Y, Takai D, Yatomi Y,
Nagase T. Preoperative intervention withlong-acting bronchodilators for the reduction of
postoperative pulmonary complications in
untreated patients with obstructive lung disease.
Clin Respir J. 2020 Feb;14(2):92-101
5. Ishii T, Muroi M, Horiguchi K, Tanamoto KI,
Nagase T, Yamashita N. Activation throughtoll-like receptor 2 on group 2 innate lymphoidcells can induceasthmatic characteristics. Clin
Exp Allergy. 2019 Dec;49(12):1624-1632
6. Isago H, Mitani A, Mikami Y, Horie M,
Urushiyama H, Hamamoto R, Terasaki Y, Nagase
T. Epithelial Expression of YAP and TAZ Is
Sequentially Required in Lung Development. Am
J Respir Cell Mol Biol. 2020 Feb;62(2):256-266
7. Sakatani T, Kage H, Takayanagi S, Watanabe K,

136

Hiraishi Y, Shinozaki-Ushiku A, Tanaka S, Ushiku
T, Saito N, Nagase T. Brain Metastasis Mimicking
Brain Abscess in ALK-Positive Non-Small-Cell
Lung Cancer. Case Rep Oncol Med. 2019 Jun 17;
2019:9141870
8. Saito A, Hakamata Y, Yamada Y, Sunohara M,
Tarui M, Murano Y, Mitani A, Tanaka K, Nagase
T, Yanagimoto S. Pleural thickening on screening
chest X-rays: a single institutional study. Respir
Res. 2019 Jul 5;20(1):138
9. Sawai Y, Katsuya Y, Shinozaki-Ushiku A, Iwasaki
A, Fukayama M, Watanabe K, Nagase T. Rapid
temporal improvement of pembrolizumab-induced
pneumonitis using the anti-TNF-α antibody
infliximab. Drug Discov Therc. 2019 Jul 22;
13(3):164-167
10. Kage H, Kohsaka S, Shinozaki-Ushiku A, Hiraishi
Y, Sato J, Nagayama K, Ushiku T, Takai D,
Nakajima J, Miyagawa K, Aburatani H, Mano H,
Nagase T. Small lung tumor biopsy samples arefeasible for high quality targeted next generation
sequencing. Cancer Sci. 2019 Aug;110(8):26522657
11. Watanabe K, Suzukawa M, Arakawa S, Kobayashi
K, Igarashi S, Tashimo H, Nagai H, Tohma S,
Nagase T, Ohta K. Leptin enhances cytokine/
chemokine production by normal lung fibroblasts
by binding to leptin receptor. Allergol Int. 2019
Sep;68S:S3-S8
12. Urushiyama H, Terasaki Y, Nagasaka S, Kokuho
N, Endo Y, Terasaki M, Kunugi S, Makita K,
Isago H, Hosoki K, Souma K, Ishii T, Matsuzaki
H, Hiraishi Y, Mikami Y, Noguchi S, Tamiya H,
Mitani A, Yamauchi Y, Shimizu A, Nagase T.
Naftopidil reduced the proliferation of lungfibroblasts and bleomycin-induced lung fibrosis inmice. J Cell Mol Med. 2019 May;23(5):35633571

137

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

Lecturer
Minoru Tada, M.D., Ph.D.
Keisuke Tateishi, M.D., Ph.D.
Motoyuki Otsuka, M.D., Ph.D.

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

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

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

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

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

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

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

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

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

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

Koji Uchino, M.D., Ph.D.

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

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

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

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

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

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

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

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

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

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

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

Homepage

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

Introduction and Organization
The Department of Gastroenterology wasestablished through a reorganization of the Graduate
School of Medicine and that of the Division ofInternal Medicine of The University of Tokyo
Hospital in 1998. The department is responsible forclinical services, education and research activities in
the field of liver, pancreato-biliary and digestive canal.
It is comprised of a professor, 3 lecturers, 21
associates, 9 fellows, 72 graduates and other visiting
researchers including students from abroad. A numberof others are under a temporary transfer in- andoutside the country. The North and South wings on the
11th floor of Ward A have provided core hospitalrooms for the department. At present, 9th floors of
Ward B also take important part for providing rooms
for inpatients. Laboratories of the department are
scattered in each floor, mainly of Clinical ResearchCenter.

Clinical Activities
The Department of Gastroenterology is in chargeof about 80 inpatients on average, which are about
2,900 in total per year. We receive about 110 new
patients in and out of the hospital each week, with anaverage hospital stay of 9.4 days. Resident, junior andsenior staff members bear the responsibility for a
medical management of each inpatient, in collabora-

138tion with subspecialty groups concerned. The staff
members examine about 5,300 outpatients withvarious digestive diseases in a month. Professor’s
ward round is performed on Monday and Wednesday
mornings. Specialty and subspecialty clinical conferences are held on Monday evening.
Hepatocellular carcinoma is the most common
disease in patients who are admitted to the department(～600 cases in 2019). Number of treatments forhepatocellular carcinoma treatments, represented by
percutaneous radiofrequency ablation, nearly 250
cases per year, showing one of the greatest achievements in the field. Number of cases undergoingradiofrequency ablation for metastatic liver tumors is
also increasing recent years. In addition, we aremaking efforts to develop an innovation for dailyclinical activities. For example, fibrosis progression inchronic liver disease is conventionally assessed byliver biopsy. Recently we can evaluate the stage ofliver fibrosis by FibroScan®, newly developed
equipment that measures liver stiffness by ultrasound,which is useful for the evaluation of increasing
non-alcoholic steatohepatitis patients. In addition,nearly 100% cure for the HCV hepatitis can beachieved now by the use of oral anti-viral agents
instead of IFN therapy. This will be especiallybeneficial for the elderly patients and advanced
fibrotic patients.
In the pancreato-biliary field, about 1000 ERCPs
are performed annually. The cumulative number ofendoscopic treatments of bile duct stones using endoscopic papillary balloon dilation (EPBD) andendoscopic sphincterotomy (EST) exceeds 1,000 cases.
Endoscopic placement of a metal stent is the standardof care for malignant obstructive jaundice and ourgroup has led the development of covered metal stents.
Pancreatic interventions such as pancreatic stenting,cystic drainage and stone extraction are also
performed, which are often technically challenging. In
addition to these conventional ERCPs, we have
performed a number of advanced endoscopic
procedures such as 1,000 balloon-assisted ERCPs for
surgically altered anatomy cases, 1,000 EUS-FNAs
and 300 EUS-guided interventions. In combination
with these interventions, we have conducted clinical
trials of chemotherapy for advanced pancreatobiliary
cancer.

In the gastrointestinal field, ESD (endoscopic
submucosal dissection) is performed as a curativeendoscopic treatment for neoplasms in esophagus,
stomach or colon (approximately 450 patients a year).
Collaborative endoscopic surgery with other departments is actively performed: 1) ESD for superficial
pharyngeal cancer is often performed in cooperation
with the department of otorhinolaryngology; 2) ESD
for duodenal epithelial tumor with the support of the
Department of Gastrointestinal surgery, 3) as for
Non-exposed endoscopic wall-inversion surgery(NEWS), which was developed with the Department
of Gastrointestinal Surgery, its clinical indication has
been now expanded from the resection of GIST to thetreatment of gastric cancer. Double-balloon endoscopy
and capsule endoscopy enabled the examination ofwhole small intestines (approximately 320 cases in2017). All those interventions are performed by themembers of our department, who are specially trainedfor each technique. In addition, for the management of
inoperative malignancies, we effectively combine theinterventional treatments with various chemotherapy
regimens including new molecular-targeting drugs.
On outpatient basis, the number of performed
ultrasonography, gastroduodenal endoscopy, andcolonoscopy is 12,500 patients, 12,000 patients, and
6,000 patients per year respectively. In the endoscopy
examinations, we diagnose approximately 370 casesof esophageal cancer, 760 cases of gastric cancer and1300 cases of colorectal tumor annually, and half ofthem are treated endoscopically. Using these resected
tissues, we perform various basic studies in order tofeed the new finding back to actual clinical activities.

Educational Activities
The undergraduate medical students regularly
take the clinical lectures of the staffs in our
department. Several courses of practical teaching arealso provided for the students. Particularly, in theClinical Clerkship program during the fourth grade,each student joins in the medical treatment of inward
patients as a member of the clinical team in our
hospital. At the end of period, the students make thesummary presentation of the patients and also outline
the articles from world’s leading medical journals.
The residents of internal medicine participate in the

139

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
subspecialty take the expert training of gastroenterology in the affiliated hospitals for several years.
The students of Department of Gastroenterology
in the Graduate School of Medicine perform highstandard of medical research in the basic or clinicalfield for 4 years. Currently, 72 students are in our
department.

Research Activities
Both basic and clinical researchers are equallyencouraged, on condition that the results may
eventually contribute to the cure of gastroenterological disorders. The themes of our recent basic
researches include the study on carcinogenesis in
gastroenterological neoplasms, mechanism of viral
hepatitis infection, pathogenesis of metabolic liverdiseases, liver regeneration, liver fibrosis, pathogenesis of Helicobacter pylori infection, molecularcharacterization of gastrointestinal morphology,
establishing new animal models, tracing celldifferentiation, and stem cell biology for various
diseases in our area. Using new concepts such astransparent organs, genomic and epigenomic
profiling of clinical samples, organoids, or liquidbiopsy, we perform various experiments, in order toeventually translate the basic results into clinics.
Various clinical activities are recorded in database and analyzed. Studies oriented for evidencebased medicine are highly appreciated. Recent studies
include radiofrequency ablation for liver metastasis ofcolorectal cancer, impact of metabolic factors inhepatocarcinogenesis. We have also designed many
clinical trials as follows; molecular target drugs foradvanced hepatocellular carcinoma, SNPs analyses foranti-viral treatment for hepatitis C, new chemotherapeutic regimens for advanced pancreatobiliary
cancer, duration of antibiotics after endoscopic biliary
drainagefor
acutecholangitis,
balloonendoscope-assisted ERCP for surgically alteredanatomy, new chemotherapeutic regimens foradvanced pancreatic cancer or biliary tract cancer,
efficacy of polyglycolic acid sheets for artificial
endoscopic ulcers, personalized salvage therapy of
Helicobacter infection.
Our department always tries to show the newest
and highest-level clinical activities, based on thevarious data of many patients especially sufferingfrom malignant diseases. Furthermore, we aim to findthe new aspects of diseases and create a new strategy
against it, which are based on clinical, basic, andepidemiological studies in our area.

Selected References
1. Aoki T, Nagata N, Yamada A, Shimbo T,
Matsushita Y, Shimomura A, Kobayashi S,
Moriyasu S, Niikura R, Sakurai T, Hirata Y,
Akiyama J, Uemura N, Koike K. Next endoscopic
approach for acute lower gastrointestinal bleeding
without an identified source on colonoscopy:
upper or capsule endoscopy? Endosc Int Open
2019;7(3):E337-E346
2. Aoki T, Yamada A, Aoyama K, Saito H, Tsuboi A,
Nakada A, Niikura R, Fujishiro M, Oka S,
Ishihara S, Matsuda T, Tanaka S, Koike K, Tada T.
Automatic detection of erosions and ulcerations inwireless capsule endoscopy images based on a
deep convolutional neural network. Gastrointest
Endosc 2019;89(2):357-363.e2
3. Enooku K, Nakagawa H, Fujiwara N, Kondo M,
Minami T, Hoshida Y, Shibahara J, Tateishi R,
Koike K. Altered serum acylcarnitine profile isassociated with the status of nonalcoholic fatty
liver disease (NAFLD) and NAFLD-related
hepatocellular carcinoma. Sci Rep 2019;9(1):10663
4. Fujiwara H, Tateishi K, Misumi K, Hayashi A,
Igarashi K, Kato H, Nakatsuka T, Suzuki N,
Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H,
Tanaka Y, Ijichi H, Kogure H, Nakai Y, Isayama H,
Hasegawa K, Fukayama M, Soga T, Koike K.
Mutant IDH1 confers resistance to energy stressin normal biliary cells through PFKP-induced
aerobic glycolysis and AMPK activation. Sci Rep
2019;9(1):18859

140

5. Hakuta R, Hamada T, Nakai Y, Isayama H,
Kogure H, Takahara N, Mizuno S, Yagioka H,
Togawa O, Matsubara S, Ito Y, Yamamoto N, Tada
M, Koike K. Early pancreatic stent placement inwire-guided biliary cannulation: A multicenter
retrospective study. J Gastroenterol Hepatol 2019;34(6):1116-1122
6. Hamada T, Isayama H, Nakai Y, Iwashita T, Ito Y,
Mukai T, Yagioka H, Saito T, Togawa O, Ryozawa
S, Hirano K, Mizuno S, Yamamoto N, Kogure H,
Yasuda I, Koike K. Antireflux covered metal stentfor nonresectable distal malignant biliary
obstruction: Multicenter randomized controlled
trial. Dig Endosc 2019;31(5):566-574
7. Hayakawa Y, Tsuboi M, Asfaha S, Kinoshita H,
Niikura R, Konishi M, Hata M, Oya Y, Kim W,
Middelhoff M, Hikiba Y, Higashijima N, Ihara S,
Ushiku T, Fukayama M, Tailor Y, Hirata Y, Guha
C, Yan KS, Koike K, Wang TC. BHLHA15Positive Secretory Precursor Cells Can Give Riseto Tumors in Intestine and Colon in Mice.
Gastroenterology. 2019 Mar;156(4):1066-1081.
e16
8. Kado A, Tsutsumi T, Enooku K, Fujinaga H,
Ikeuchi K, Okushin K, Moriya K, Yotsuyanagi H,
Koike K. Noninvasive diagnostic criteria fornonalcoholic steatohepatitis based on gene
expression levels in peripheral blood mononuclear
cells. J Gastroenterol 2019;54(8):730-741
9. Kageyama-Yahara N, Yamamichi N, Takahashi Y,
Takeuchi C, Matsumoto Y, Sakaguchi Y, Koike K.
Tandem repeats of the 5' flanking region of human
MUC5AC have a role as a novel enhancer in
MUC5AC gene expression. Biochem Biophys
Rep 2019;18:100632
10. Kataoka Y, Tsuji Y, Hirasawa K, Takimoto K,
Wada T, Mochizuki S, Ohata K, Sakaguchi Y,
Niimi K, Ono S, Kodashima S, Yamamichi N,
Fujishiro M, Koike K. Endoscopic tissue
shielding to prevent bleeding after endoscopic
submucosal dissection: a prospective multicenter
randomized controlled trial. Endoscopy 2019;
51(7):619-627
11. Mizuno S, Isayama H, Nakai Y, Ishigaki K, Saito
K, Sato T, Takeda T, Hakuta R, Saito T, Takahara
N, Kogure H, Ijichi H, Tateishi K, Tada M,
Shikata N, Tagami T, Kikuchi S, Yamamoto H,

Yamakado M, Koike K. Diagnostic yield of theplasma free amino acid index for pancreaticcancer in patients with diabetes mellitus.
Pancreatology 2019;19(5):695-698
12. Nakagomi R, Tateishi R, Masuzaki R, Soroida Y,
Iwai T, Kondo M, Fujiwara N, Sato M, Minami T,
Uchino K, Enooku K, Nakagawa H, Asaoka Y,
Kondo Y, Tanaka Y, Otsuka M, Kato N, Moriya K,
Ikeda H, Koike K. Liver stiffness measurementsin chronic hepatitis C: Treatment evaluation andrisk assessment. J Gastroenterol Hepatol 2019;34(5):921-928
13. Nakatsuka T, Soroida Y, Nakagawa H, Shindo T,
Sato M, Soma K, Nakagomi R, Kobayashi T,
Endo M, Hikita H, Sato M, Gotoh H, Iwai T,
Yasui M, Shinozaki-Ushiku A, Shiraga K, Asakai
H, Hirata Y, Fukayama M, Ikeda H, Yatomi Y,
Tateishi R, Inuzuka R, Koike K. Identification ofliver fibrosis using the hepatic vein waveform inpatients with Fontan circulation. Hepatol Res
2019;49(3):304-313
14. Niikura R, Hayakawa Y, Hirata Y, Ogura K,
Fujishiro M, Yamada A, Ushiku T, Konishi M,
Fukayama M, Koike K. The Reduction in GastricAtrophy after Helicobacter pylori Eradication Is
Reduced by Treatment with Inhibitors of Gastric
Acid Secretion. Int J Mol Sci 2019;20(8):1913
15. Niikura R, Yamada A, Fujishiro M, Tanaka K,
Matsuda K, Saito Y, Ohtsuka K, Oda I, Katada C,
Kato M, Kida M, Kobayashi K, Hoteya S,
Horimatsu T, Kodashima S, Matsuda T, Muto M,
Yamamoto H, Ryozawa S, Iwakiri R, Kutsumi H,
Miyata H, Kato M, Haruma K, Fujimoto K,
Uemura N, Kaminishi M, Shinozaki T, Tajiri H,
Koike K. The Effects of Direct Oral Anticoagulants, Warfarin, Aspirin and Thienopyridineon the Performance of Immunochemical, Faecal,
Occult Blood Tests. Digestion 2019;100(2):117126
16. Nishibatake Kinoshita M, Minami T, Tateishi R,
Wake T, Nakagomi R, Fujiwara N, Sato M,
Uchino K, Enooku K, Nakagawa H, Asaoka Y,
Shiina S, Koike K. Impact of direct-acting
antivirals on early recurrence of HCV-related
HCC: Comparison with interferon-based therapy.
J Hepatol 2019;70(1):78-86
17. Saito K, Isayama H, Nakai Y, Takahara N,

141

Ishigaki K, Takeda T, Hakuta R, Saito T, Uchino
R, Kishikawa T, Hamada T, Mizuno S, Sasaki T,
Kogure H, Matsubara S, Yamamoto N, Ijichi H,
Tateishi K, Tada M, Koike K. A phase II trial of
gemcitabine, S-1 and LV combination (GSL)
therapy in patients with advanced pancreaticcancer. Invest New Drugs 2019;37(2):338-344
18. Saito T, Nakai Y, Mizuno S, Isayama H, SasahiraN, Watanabe T, Matsubara S, Arizumi T, Togawa
O, Hirano K, Tsujino T, Ishigaki K, Hakuta R,
Saito K, Takahara N, Hamada T, Kogure H, Tada
M, Koike K. A randomized-controlled trial ofearly endotherapy versus wait-and-see policy for
mild symptomatic pancreatic stones in chronicpancreatitis. Eur J Gastroenterol Hepatol 2019;31(8):979-984
19. Sakaguchi Y, Yamamichi N, Tomida S, Takeuchi
C, Kageyama-Yahara N, Takahashi Y, Shiogama
K, Inada KI, Ichinose M, Fujishiro M, Koike K.
Identification of marker genes and pathways
specific to precancerous duodenal adenomas andearly stage adenocarcinomas. J Gastroenterol
2019;54(2):131-140
20. Sato T, Kogure H, Nakai Y, Hamada T, Takahara
N, Mizuno S, Kawaguchi Y, Akamatsu N, Kaneko
J, Hasegawa K, Tada M, Tsujino T, Isayama H,
Koike K. Long-term outcomes of endoscopic
treatment for duct-to-duct anastomotic strictures
after living donor liver transplantation. Liver Int
2019;39(10):1954-1963
21. Sekiba K, Otsuka M, Ohno M, Yamagami M,
Kishikawa T, Seimiya T, Suzuki T, Tanaka E,
Ishibashi R, Funato K, Koike K. Pevonedistat, a
Neuronal Precursor Cell-Expressed Developmentally Down-Regulated Protein 8-Activating
Enzyme Inhibitor, Is a Potent Inhibitor of
Hepatitis B Virus. Hepatology 2019;69(5):19031915
22. Sekiba K, Otsuka M, Ohno M, Yamagami M,
Kishikawa T, Suzuki T, Ishibashi R, Seimiya T,
Tanaka E, Koike K. Inhibition of HBVTranscription From cccDNA With Nitazoxanide
by Targeting the HBx-DDB1 Interaction. Cell Mol
Gastroenterol Hepatol 2019;7(2):297-312
23. Takahara N, Isayama H, Nakai Y, Sasaki T, Saito
K, Sato T, Hakuta R, Ishigaki K, Saito T, Hamada
T, Mizuno S, Kogure H, Tada M, Koike K. A

feasibility study of gemcitabine, S-1 andleucovorin combination therapy (GSL) foradvanced biliary tract cancer. J Chemother 2019;31(5):284-289
24. Tanaka E, Miyakawa Y, Kishikawa T, Seimiya T,
Iwata T, Funato K, Odawara N, Sekiba K,
Yamagami M, Suzuki T, Ishibashi R, Otsuka M,
Koike K. Expression of circular RNA CDR1-AS
in colon cancer cells increases cell surface PD-L1
protein levels. Oncol Rep 2019;42(4):1459-1466
25. Tateishi R, Uchino K, Fujiwara N, Takehara T,
Okanoue T, Seike M, Yoshiji H, Yatsuhashi H,
Shimizu M, Torimura T, Moriyama M, Sakaida I,
Okada H, Chiba T, Chuma M, Nakao K, Isomoto
H, Sasaki Y, Kaneko S, Masaki T, Chayama K,
Koike K. A nationwide survey on non-B, non-C
hepatocellular carcinoma in Japan: 2011-2015
update. J Gastroenterol 2019;54(4):367-376
26. Tsuji Y, Saito I, Koike K. Traction-assisted
esophageal endoscopic submucosal dissection fortreatment of squamous cell carcinoma involving adiverticulum. Dig Endosc 2019;31(1):e7-e8
27. Wake T, Tateishi R, Nakagomi R, Fujiwara N,
Kinoshita MN, Nakatsuka T, Sato M, Minami T,
Uchino K, Enooku K, Nakagawa H, Asaoka Y,
Tanaka Y, Shiina S, Koike K. Ischemic
complications after percutaneous radiofrequency
ablation of liver tumors: Liver volume loss andrecovery. Hepatol Res 2019;49(4):453-461
28. Yamada A, Kogure H, Nakai Y, Takahara N,
Mizuno S, Tada M, Koike K. Performance of a
new short-type double-balloon endoscope withadvanced force transmission and adaptive bending
for pancreaticobiliary intervention in patients withsurgically altered anatomy: A propensity-matchedanalysis. Dig Endosc 2019;31(1):86-93

Internal Medicine
2. Medicine Ⅱ143

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

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

Lecturer

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

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

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

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

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

Kenjiro Honda, M.D., Ph.D.,

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

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

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

Tomoko Usui, M.D., Ph.D.

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

Official website

http://www.todai-jinnai.com

Introduction and Organization

Clinical activities

The Department of Nephrology and Endocrinology
is one of the major divisions in the Department ofInternal Medicine of the University of Tokyo, which
covers nephrology, hypertension, and endocrinology,
and also renal diseases associated with diabetes
mellitus, cardiovascular diseases, collagen diseases
and so on. Usually we have up to 30 inpatients in thehospital. The Professor and each member of the staff
have an active responsibility for all clinical activities.
Each member has an office and a research laboratory.
In our department, almost all members support theclinical works of our residents. We are intimately
working together in all clinical activities under thesupervision of the professor, the associate professors,
and the lecturers.

The residents are in charge of up to 30 patients ofour department and supervised by associates andfaculty staffs. We have clinical conferences to discuss
the diagnosis and treatment of our patients with all
members of the staff. Particularly difficult cases arefurther discussed with guest specialists from outside.
Nephritis should be morphologically diagnosed byrenal biopsy and the optimal treatment should bechosen for each patient. In our department, renal
biopsy is actively performed to give the real benefitsof treatment to the patients. We also treat diabetic
patients with proteinuria and end-stage renal failure.
Each staff of our department also works at the
hemodialysis unit, thus we can manage patients inevery stage of renal diseases. In collaboration with

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Department of Urology, we are conducting renaltransplantation and promoting peritoneal dialysis.
In the endocrine unit there is a variety of patients
having disorders in thyroid, parathyroid, pituitary,adrenal and gonadal glands. It is also our specialty todiagnose and treat secondary hypertension caused byprimary aldosteronism, Cushing’s syndrome, pheochromocytoma, renal artery stenosis and so on. We
often have consultation from other departments concerning disorders of water and mineral metabolism.

Education
We have responsibility for educating undergraduates, graduate students and residents. Our staffs
take part in several lectures for undergraduate andgraduate students. In addition, our members areactively involved in clinical clerkship for undergraduate students, and other clinical practice. Particularly, we have put emphasis on participation of thestudents in clinical practice including medical investigations, diagnosis, and treatment. In the wards, we arealso educating residents during daily clinical works
and periodical lectures concerning kidney andendocrine diseases. Our department also participatesin Metabolism Research Course for educating young
clinical researchers and fellows in collaboration with
Department of Diabetes and Metabolic Diseases,
Department of Cardiology, and Department ofGeriatric Medicine.

Research
In our department there are more than 30 studentsof the graduate school. We have research conferences
to discuss the results of the research with the Professor
and faculty members. As you see in the references
below, our research topics are various and cover every
field of nephrology, hypertension and endocrinology.
We are also actively collaborating with scientists
outside the department and outside the University
including foreign countries. Achievements of ourresearches are published in the world’s leading
journals of nephrology, hypertension and endocrinology.
1. Investigation of mechanism and development oftreatment of chronic kidney diseases: from theviewpoints of hypoxia, oxidative stress, epigen-etics, carbonyl stress and endoplasmic reticulum
stress.
2. Investigation of causes of atypical hemolyticuremic syndrome.
3. Roles of renal proximal tubule transport in theregulation of plasma volume and blood pressure.
4. Physiological and pathological significance of
Na-HCO3 cotransporter NBCe1.
5. Molecular mechanism of G protein-coupled
receptor (GPCR)-mediated signal transduction, anddevelopment of a new drug and strategy targeting
GPCR.
6. Investigation on pathogenesis of disorders andtreatments of mineral and bone metabolism

Department of Hemodialysis &Apheresis
Introduction and Organization
Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for Hemodialysis in 2000 at the University Hospital. The Centerfor Hemodialysis was further renovated and started
operations in Fall of 2006.
This new Center for Hemodialysis is equipped with
one pressure control unit in addition to 12 hemodialysis machines under a state-of-the-art hemodialysis control system. Our concept of a hemodialysis
controlling system is a hub to transfer all digital andanalog data from patients and to monitor machines,
including blood purification machines, to the hostcomputer in our hospital, centralizing all data andadministering medical coding and billing robustly.
Blood purification machines in the ICU can bemonitored seamlessly under the cloud system of our
hospital. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.
Clinical activities
1. Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
2. Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does

145

3.
4.

5.
6.
7.
8.
9.

not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.
DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
LDL apheresis for nephrotic syndrome and ASO
patients.
White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.
Cell-free and concentrated ascites reinfusion
therapy (CART) for refractory ascites.
Induction and maintenance of peritoneal dialysis
for ESRD.

Education
1. A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acuteand chronic renal failure including diabetic
nephropathy.
2. Technical development course for medical
engineers and nurses.
3. Tutorial course for clinical fellows applying to thespeciality of blood purification therapy.
4. Exposure in hemodialysis & apheresis course to
second year residents on request.
5. Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. “Apheresis Pocket Manual” hasbeen translated into Chinese and English, andthose translated versions have helped a number of
non-Japanese-speaking people to learn how to
perform apheresis.
6. Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.
Research
1. Prognostic analysis for post-liver transplantpatients who received plasma exchange therapy.
2. Development and application of a non-invasive
pulse hemoglobin meter.
3. Genome wide association study for Nephrotic

4.
5.
6.
7.
8.

syndrome and those functional analyses.
Association between factors at the initiation ofrenal replacement therapy and prognosis.
Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
AKI biomarkers and their clinical significance in
ICU/CCU.
Renal biomarker to determine clinical action
ability in CKD and type-2 DN.

Publications(1) Mitochondrial Damage Causes Inflammation via
cGAS-STING Signaling in Acute Kidney Injury.
Maekawa H, Inoue T, Ouchi H, Jao TM, Inoue R,
Nishi H, Fujii R, Ishidate F, Tanaka T, Tanaka Y,
Hirokawa N, Nangaku M, Inagi R.Cell Rep. 201929(5):1261-1273.e6.
(2) The role of oxidative stress and hypoxia in renal
disease. Honda T, Hirakawa Y, Nangaku M.
Kidney Res Clin Pract. 2019 38(4):414-426.
(3) Pathogenesis of Atypical Hemolytic Uremic
Syndrome. Yoshida Y, Kato H, Ikeda Y,
Nangaku M.J Atheroscler Thromb. 2019 26(2):99-110.
(4) Hypoxia-Inducible Factor-Prolyl Hydroxylase
Domain Inhibitors to Treat Anemia in Chronic
Kidney Disease. Sakashita M, Tanaka T,
Nangaku M. Contrib Nephrol. 2019;198:112-123.
(5) Safety and effectiveness of long-term use ofdarbepoetin alfa in non-dialysis patients withchronic kidney disease: a post-marketingsurveillance study in Japan. Tanaka T, Nangaku
M, Imai E, Tsubakihara Y, Kamai M, Wada M,
Asada S, Akizawa T. Clin Exp Nephrol. 201923(2):231-243.
(6) Recent advances in renal regeneration. Hasegawa
S, Tanaka T, Nangaku M. F1000Res. 2019 8:
F1000 Faculty Rev-216. doi: 10.12688/f1000
research.17127.1. eCollection 2019. PMID:
30828435(7) Association between intravenous contrast media
exposure and non-recovery from dialysis-requiring septic acute kidney injury: anationwide observational study. Miyamoto Y,

146

Iwagami M, Aso S, Yasunaga H, Matsui H,
Fushimi K, Hamasaki Y, Nangaku M, Doi K.
Intensive Care Med. 2019 45(11):1570-1579.
(8) JTZ-951 (enarodustat), a hypoxia-inducibe factor
prolyl hydroxylase inhibitor, stabilizes HIF-α
protein and induces erythropoiesis without effects
on the function of vascular endothelial growth
factor. Fukui K, Shinozaki Y, Kobayashi H, Deai
K, Yoshiuchi H, Matsui T, Matsuo A, Matsushita
M, Tanaka T, Nangaku M. Eur J Pharmacol.
2019;859:172532.
(9) Podocyte lipotoxicity in diabetic kidney disease.
Nishi H, Nangaku M. Kidney Int. 2019;96(4):809-812.
(10) Profiles of Coagulation and Fibrinolysis
Activation-Associated Molecular Markers ofAtypical Hemolytic Uremic Syndrome in the
Acute Phase. Sakurai S, Kato H, Yoshida Y,
Sugawara Y, Fujisawa M, Yasumoto A,
Matsumoto M, Fujimura Y, Yatomi Y, Nangaku
M. J Atheroscler Thromb. Epub 2019 Sep 4.
PMID: 31484852(11) Effectiveness and safety of cinacalcet for primary
hyperparathyroidism: a single center experience.
Manaka K, Sato J, Kinoshita Y, Ito N, Fujita M,
Iiri T, Nangaku M, Makita N. Endocr J. 2019;
66(8):683-689.
(12) ATF6α downregulation of PPARα promotes
lipotoxicity-induced tubulointerstitial fibrosis.
Jao TM, Nangaku M, Wu CH, Sugahara M, Saito H,
Maekawa H, Ishimoto Y, Aoe M, Inoue T,
Tanaka T, Staels B, Mori K, Inagi R. Kidney Int.
2019;95(3):577-589.
(13) Linagliptin and cardiorenal outcomes in Asians
with type 2 diabetes mellitus and establishedcardiovascular and/or kidney disease: subgroup
analysis of the randomized CARMELINA® trial.
Inagaki N, Yang W, Watada H, Ji L, Schnaidt S,
Pfarr E, Okamura T, Johansen OE, George JT,
von Eynatten M, Rosenstock J, Perkovic V,
Wanner C, Cooper ME, Alexander JH, Komuro I,
Nangaku M. Diabetol Int. 2019;11(2):129-141(14) Non-canonical cholinergic anti-inflammatory
pathway-mediated activation of peritoneal
macrophages induces Hes1 and blocks
ischemia/reperfusion injury in the kidney. Inoue
T, Abe C, Kohro T, Tanaka S, Huang L, Yao J,

Zheng S, Ye H, Inagi R, Stornetta RL, Rosin DL,
Nangaku M, Wada Y, Okusa MD. Kidney Int.
2019;95(3):563-576.
(15) Regional variance in patterns of prescriptions forchronic kidney disease in Japan. Inoue R, Nishi H,
Tanaka T, Nangaku M. Clin Exp Nephrol. 2019;23(6):859-864.
(16) Bexarotene-induced hypothyroidism: Characteristics and therapeutic strategies. Makita N,
Manaka K, Sato J, Mitani K, Nangaku M, Iiri T.
Clin Endocrinol (Oxf). 2019;91(1):195-200.
(17) Insulin promotes sodium transport but suppresses
gluconeogenesis via distinct cellular pathways inhuman and rat renal proximal tubules. Nakamura
M, Tsukada H, Seki G, Satoh N, Mizuno T, Fujii
W, Horita S, Moriya K, Sato Y, Kume H,
Nangaku M, Suzuki M. Kidney Int. 2020;97(2):316-326.
(18) Urinary chloride concentration as a prognostic
marker in critically ill patients. Komaru Y, Doi K,
Matsuura R, Yoshida T, Miyamoto Y, Yoshimoto
K, Nangaku M. Nephrology (Carlton). 2020;25(5):384-389.
(19) JTZ-951, an HIF prolyl hydroxylase inhibitor,
suppresses
renalinterstitial
fibroblast
transformation and expression of fibrosis-related
factors. Wakashima T, Tanaka T, Fukui K,
Komoda Y, Shinozaki Y, Kobayashi H, Matsuo A,
Nangaku M. Am J Physiol Renal Physiol. Epub
2019 Oct 21.PMID: 31630548(20) Prolyl hydroxylase inhibition protects the kidneys
from ischemia via upregulation of glycogenstorage. Ito M, Tanaka T, Ishii T, Wakashima T,
Fukui K, Nangaku M. doi: 10.1016/j.kint.2019.
10.020. Epub 2019 Nov 9.PMID: 32033782(21) Renal Effects after Pembrolizumab Treatment for
Non-small Cell Lung Carcinoma. Oki R,
Hirakawa Y, Kimura H, Honda K, Hinata M, Abe
H, Domoto Y, Tanaka G, Nagase T, Nangaku
M.Intern Med. doi: 10.2169/internalmedicine.
3928-19. Epub 2019 Dec 6.PMID: 31813918(22) Effects of a prolyl hydroxylase inhibitor on
kidney and cardiovascular complications in a rat
model of chronic kidney disease. Uchida L,
Tanaka T, Saito H, Sugahara M, Wakashima T,
Fukui K, Nangaku M.Am J Physiol Renal Physiol.

147

doi: 10.1152/ajprenal.00419.2019. Epub 2019
Dec 16. PMID: 31841388(23) Temporal change in characteristics and outcomesof acute kidney injury on renal replacement
therapy in intensive care units: analysis of anationwide administrative database in Japan,
2007-2016. Miyamoto Y, Iwagami M, Aso S,
Yasunaga H, Matsui H, Fushimi K, Hamasaki Y,
Nangaku M, Doi K. Crit Care. 2019;23(1):172.
The oral hypoxia-inducible factor prolyl hydroxylase
inhibitor enarodustat counteracts alterations inrenal energy metabolism in the early stages ofdiabetic kidney disease. Hasegawa S, Tanaka T,
Saito T, Fukui K, Wakashima T, Susaki EA,
Ueda HR, Nangaku M.Kidney Int. doi:
10.1016/j.kint.2019.12.007. Epub 2019 Dec 25.
PMID: 32171449(26) Increased albuminuria in bardoxolone methyltreated type 2 diabetes patients: mere reflection ofeGFR improvement? Ito M, Nangaku M. KidneyInt. 2019;96(4):823-825.
(27) Are SGLT2 inhibitors a targeted treatment fordiabetic kidney disease? Kanda E, Nangaku M.
Kidney Int. 2019;96(1):8-10.
(28) Inhibition of prolyl hydroxylase domain (PHD)
by JTZ-951 reduces obesity-related diseases in
the liver, white adipose tissue, and kidney in micewith a high-fat diet. Saito H, Tanaka T, Sugahara
M, Tanaka S, Fukui K, Wakashima T, Nangaku
M. Lab Invest. 2019;99(8):1217-1232.
(29) Vascular Ehlers-Danlos Syndrome Diagnosed ina Patient Initiating Hemodialysis. Ouchi H, Nishi
H, Nakamura M, Hirakawa Y, Tanaka T, Takeda
N, Akai T, Ohashi Y, Hoshina K, Takayama T,
Nangaku M.Kidney Int Rep. 2019; 4(11):16461648.
(30) Comprehensive
three-dimensional
analysis(CUBIC-kidney) visualizes abnormal renal
sympathetic nerves after ischemia/reperfusion
injury. Hasegawa S, Susaki EA, Tanaka T,
Komaba H, Wada T, Fukagawa M, Ueda HR,
Nangaku M. Kidney Int. 2019;96(1):129-138.
(31) Association of dialysis with in-hospital disability
progression and mortality in community-onset
stroke. Usui T, Hanafusa N, Yasunaga H,
Nangaku M. Nephrology (Carlton). 2019;24(7):737-743.

(32) Longitudinal change in blood pressure and risk ofend-stage renal disease in a community-based
cohort in Okinawa. Usui T, Iseki C, Iseki K,
Kawakami K, Nangaku M. Clin Exp Nephrol.
2019;23(11):1280-1287.
(33) The role of anti-complement factor H antibodies
in the development of atypical haemolytic uremic
syndrome: a possible contribution to abnormalityof platelet function. Fujisawa M, Yasumoto A,
Kato H, Sugawara Y, Yoshida Y, Yatomi Y,
Nangaku M. Br J Haematol. doi: 10.1111/
bjh.16297. Epub 2019 Dec 26.PMID: 31879952(34) Cinacalcet corrects biased allosteric modulationof CaSR by AHH autoantibody. Makita N, Ando
T, Sato J, Manaka K, Mitani K, Kikuchi Y, Niwa
T, Ootaki M, Takeba Y, Matsumoto N,
Kawakami A, Ogawa T, Nangaku M, Iiri T. JCIInsight. 2019;4(8):e126449.
(35) Extraperitoneal Placement of a Peritoneal
Dialysis Catheter. Nakamura Y, Kurata Y,
Hamasaki Y, Nangaku M.Intern Med. 2019;
58(1):147-148.
(36) Diagnostic accuracy of urine dipstick forproteinuria category in Japanese workers. Usui T,
Yoshida Y, Nishi H, Yanagimoto S, Matsuyama
Y, Nangaku M.Clin Exp Nephrol. doi: 10.1007/
s10157-019-01809-3. Epub 2019 Nov 16.PMID:
31734818(37) Prolyl hydroxylase domain inhibitors: a new erain the management of renal anemia. Kurata Y,
Tanaka T, Nangaku M.Ann Transl Med. 2019
Dec;7 (Suppl 8): S334. doi: 10.21037/atm.2019.
09.118.PMID: 32016052(38) Nutcracker Syndrome with the Superimpositionof Thin Basement Membrane Syndrome.
Hirakawa Y, Miura R, Sasaki Y, Yoshida Y,
Mimura I, Katsura M, Shintani-Domoto Y,
Ogawa M, Hayashi A, Nangaku M. Intern Med.
2019;58(3):411-414.
(39) Strategies for the Super-Aged Dialysis
Population: Survival Benefits or Alternative
Goals? Sakurai S, Hanafusa N, Nomura T,
Tsuchiya K, Nitta K, Nangaku M.Blood Purif.
2019;47 Suppl 2:95-105.
(40) Predicting 3-year mortality based on the tumor
necrosis factor alpha concentration in low-flux
hemodialysis patients. Thang LV, Loc ND, Dung

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NH, Kien NT, Quyen DBQ, Tuan NM, Ha DM,
Kien TQ, Dung NTT, Van DT, Van Duc N, Ha
NTT, Toan PQ, Usui T, Nangaku M. Ther Apher
Dial. 2019 Dec 19. doi: 10.1111/1744-9987.
13463. PMID: 31856402(41) Endogenous
Erythropoietin
andHepatic
Dysfunction in Acute Kidney Injury Requiring
Renal Replacement Therapy. Matsuura R, Doi K,
Komaru Y, Miyamoto Y, Yoshida T, Isegawa T,
Yoshimoto K, Yamashita T, Noiri E, Nangaku M.
Nephron. 2019;142(1):10-16.
(42) Regulatory roles of hypoxia-inducible, noncoding
RNAs on mitochondrial dynamics during AKI.
Tanaka T, Nangaku M. Kidney Int. 2019; 95(2):252-253.
(43) Modulating the immune system to delay theclinical onset of type 1 diabetes. Sugahara M,
Tanaka T, Nangaku M. Kidney Int. doi: 10.1016/j.
kint.2019.10.010. Epub 2019 Oct 25. PMID:
31980070(44) Novel
CFHR2-CFHR1
Hybridin
C3Glomerulopathy Identified by Genomic Structural
Variation Analysis. Sugawara Y, Kato H,
Yoshida Y, Fujisawa M, Kokame K, Miyata T,
Akioka Y, Miura K, Hattori M, Nangaku M.
Kidney Int Rep. 2019;4(12):1759-1762.
(45) Molecularanalysisandliterature-based
hypothesis of an immunonegative prostate small
cell carcinoma causing ectopic ACTH syndrome.
Takeuchi M, Sato J, Manaka K, Tanaka M,
Matsui H, Sato Y, Kume H, Fukayama M, Iiri T,
Nangaku M, Makita N. Endocr J. 2019;66(6):547-554.
(46) Kinetic estimated glomerular filtration rate as apredictor of successful continuous renal
replacement therapy discontinuation. Yoshida T,
Matsuura R, Komaru Y, Miyamoto Y, Yoshimoto
K, Hamasaki Y, Noiri E, Morimura N, Nangaku
M, Doi K. Nephrology (Carlton). 2019;24(3):287-293.

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Department of Diabetes andMetabolic Diseases
Professor
Toshimasa Yamauchi, M.D., Ph.D.

Associate Professor
Hironori Waki, M.D., Ph.D. (since Sep 2019)

Lecturer
Masato Iwabu, M.D., Ph.D. (since Jan 2020),

Project Lecturer
Yoko Iizuka, M.D., Ph.D.,

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

Yukiko Okazaki, M.D., Ph.D. (until Nov 2019)

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

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

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

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

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

Takayoshi Sasako, M.D., Ph.D. (since Apr 2019)Jun Hosoe, M.D., Ph.D. (since Dec 2019)

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

clinical, teaching and research activities. Currently,
we hold 28 beds mainly on the 12th floor of the North
Wing Ward A of the University of Tokyo Hospital, andtook care of 611 new inpatients per year. Besides thestaffs listed above, our division holds faculties inbranches, for example, Department of Prevention of
Diabetes and Lifestyle-Related Diseases (Project
Professor: Dr. Takashi Kadowaki), 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, Project
Associate Professor: Dr. Masato Iwabu [until Jan
2020]), Genomic Research Support Center (Project
Associate Professor: Dr. Nobuhiro Shojima),
Ubiquitous Health Informatics (Project Associate
Professor: Dr. Kayo Waki [until Aug 2019]),

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Department of Healthcare Information Management(Associate Professor: Dr. Kayo Waki [since Sep
2019]), Department of Clinical Laboratory (Lecturer:
Dr. Makoto Kurano), Division for Health Service
Promotion, The University of Tokyo (AssistantProfessor: Dr. Sachiko Okazaki) and Center for
Epidemiology and Preventive Medicine (Project
Assistant Professor: Dr. Yukari Masuda). With allthese staffs, we actively instruct and teach theresidents and medical school students; annual
evaluation of the teaching skill by the students always
rates our department within the three places of the top.
In addition, there are 12 students of Graduate Schoolin our division. With all these 52 members, we
enthusiastically work on the research activities, whichlead to the outstanding contributions in the field of
metabolism.

Clinical activities
Based on the update clinical evidences and with theexperienced skills, we provide patient-centered
medical services in the highest quality. We haveoutpatient clinics from Monday through Friday, andhave been following approximately 164 patients perday (total 39,802 patients per year). On the inpatientward, we not only take care of around 28 patients inour division as mentioned above, but also provide a
sophisticated management to all patients sufferingfrom metabolic diseases, especially diabetes mellitus.
Diabetes mellitus, metabolic syndrome, dyslipidemia
and obesity disease are becoming more prevalent inJapan, and lead to complications including nephropathy, retinopathy, neuropathy and cardiovasculardiseases. Thus, in collaboration with other departments, we optimize the treatment of each patient.
We provide the educational classes to the patients
every weekday in the inpatient ward, and also givelectures twice a week in the outpatient unit. In
addition, in collaboration with ancillary staffs of our
hospital, we provide patients well-reasoned
instructions regarding nutritional management, excise
therapy and medical therapy.
The weekly official activities of our department
consist of the pre-round case conference and the Ward
Round by the Professor on Monday. We also hold aweekly case conference by the consultation group

staffs.

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

Research activities
There are several laboratories in our departments;
collaborating with each other or with other departments, we focus on the molecular mechanisms of themetabolic diseases and the establishment of the novel
therapeutics.
1) Molecular mechanisms of type 2 diabetes
We have been attempting to elucidate the mechanisms

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underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, in
collaboration with RIKEN and several cohorts, we
explored the comprehensive catalog of genomic
variations to identify variations conferring susceptibility to type 2 diabetes in the Japanese population.
We are also exploring the signal transduction
pathways and physiological roles of insulin andadipokines in various tissues and the mechanisms 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)", systematic reviews and metaanalyses with a focus on important issues such as
metabolic syndrome, and investigator initiated clinical
trials targeting for a new class of anti-diabetic agents.

References
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574:353-358. doi: 10.1038/s41586-019-1545-0,
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2. Caterson ID, Alfadda AA, Auerbach P, Coutinho
W, Cuevas A, Dicker D, Hughes C, Iwabu M,
Kang JH, Nawar R, Reynoso R, Rhee N, Rigas G,
Salvador J, Sbraccia P, Vázquez-Velázquez V,
Halford JCG: Gaps to bridge: Misalignment
between perception, reality and actions in obesity.
Diabetes Obes. Metab. 21:1914-1924, 2019
3. Eguchi J, Miyashita K, Fukamachi I, Nakajima K,
Murakami M, Kawahara Y, Yamashita T, Ohta Y,
Abe K, Nakatsuka A, Mino M, Takase S, Okazaki
H, Hegele RA, Ploug M, Hu X, Wada J, Young
SG, Beigneux AP: GPIHBP1 autoantibody
syndrome during interferon β1a treatment. J Clin
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4. Fukuma N, Hasumi E, Fujiu K, Waki K, Toyooka
T, Komuro I, Ohe K: Feasibility of a T-Shirt-Type
Wearable Electrocardiography Monitor for
Detection of Covert Atrial Fibrillation in Young
Healthy Adults. ： Sci Rep. 13;9:1:11768. doi:
10.1038/s41598-019-48267-1, 2019
5. Igarashi M, Miura M, Williams E, Jaksch F,
Kadowaki T, Yamauchi T, Guarente L: NAD+supplementation rejuvenates aged gut adult stem
cells. Aging Cell. 18:e12935, 2019
6. Igarashi M, Watanabe K, Tsuduki T, Kimura I,
Kubota N: NAPE-PLD controls OEA synthesis

152

and fat absorption by regulating lipoprotein
synthesis in an in vitro model of intestinal
epithelial cells. FASEB Journal 33:3167-3179,
2019.
7. Iwabu M, Okada-Iwabu M, Yamauchi T,
Kadowaki T: Adiponectin/AdipoR Research and
Its Implications for Lifestyle-Related Diseases.
Front. Cardiovasc. Med. 6:116, 2019.
8. Kadowaki T, Nangaku M, Hantel S, Okamura T,
von Eynatten M, Wanner C, Koitka-Weber A:
Empagliflozin and kidney outcomes in Asianpatients with type 2 diabetes and establishedcardiovascular disease: Results from the EMPAREG OUTCOME® trial. J. Diabetes Investig. 10:
760-769, 2019
9. Kurano M, Tsuneyama K, Morimoto Y, Nishikawa
M, Yatomi Y: Apolipoprotein M suppresses thephenotypes of IgA nephropathy in hyper-IgA mice.
FASEB J. 33:4:5181-5195. doi: 10.1096/fj.20180
1748R, 2019
10. Kurano M, Yatomi Y: Use of gas chromatography
mass spectrometry to elucidate metabolites
predicting the phenotypes of IgA nephropathy in
hyper IgA mice. PLoS One. 10;14:7:e0219403.
doi: 10.1371/journal.pone.0219403, 2019
11. Kurano M, Yasukawa K, Ikeda H, Aoki J, Yatomi
Y: Redox state of albumin affects its lipid
mediator binding characteristics. Free Radic Res.
30:1-9. doi: 10.1080/10715762.2019.1641603,
2019
12. Morita Y, Kurano M, Sakai E, Nishikawa M,
Sawabe M, Aoki J, Yatomi Y: Evaluation of
Lysophospholipid Measurement in Cerebrospinal
Fluid Samples using Liquid ChromatographyTandem Mass Spectrometry. Lipids. 54:8:487-500.
doi: 10.1002/lipd.12175, 201913. Murayama Y, Yahagi N, Takeuchi Y, Aita Y,
Mehrazad Saber Z, Wada N, Li E, Piao X, Sawada
Y, Shikama A, Masuda Y, Nishi-Tatsumi M,
Kubota M, Izumida Y, Miyamoto T, Sekiya M,
Matsuzaka T, Nakagawa Y, Sugano Y, Iwasaki H,
Kobayashi K, Yatoh S, Suzuki H, Yagyu H,
Kawakami Y, Shimano H: Glucocorticoid receptor
suppresses gene expression of Rev-erbα (Nr1d1)
through interaction with the CLOCK complex.
FEBS Lett. 593:4:423-432, 201914. Nojiri T, Kurano M, Araki O, Nakawatari K,
Nishikawa M, Shimamoto S, Igarashi K, Kano K,
Aoki J, Kihara S, Murakami M, Yatomi Y: Endocr
J. 28;66:5:409-422. doi: 10.1507/endocrj.EJ180451, 201915. Okada-Iwabu M, Iwabu M, Yamauchi T,
Kadowaki T: Drug development research fornovel adiponectin receptor-targeted antidiabetic
drugs contributing to healthy longevity. Diabetol.
Int. 10:237-244, 201916. Okumura T, Horie Y, Lai CY, Lin HT, Shoda H,
Natsumoto B, Fujio K, Kumaki E, Okano T, Ono
S, Tanita K, Morio T, Kanegane H, Hasegawa H,
Mizoguchi F, Kawahata K, Kohsaka H, Moritake
H, Nunoi H, Waki H, Tamaru SI, Sasako T,
Yamauchi T, Kadowaki T, Tanaka H, Kitanaka S,
Nishimura K, Ohtaka M, Nakanishi M, Otsu M:
Robust and highly efficient hiPSC generationfrom patient non-mobilized peripheral bloodderived CD34+ cells using the auto-erasable
Sendai virus vector.Stem Cell Res. Ther. 10:185,
2019
17. Pratley R, Amod A, Hoff ST, Kadowaki T,
Lingvay I, Nauck M, Pedersen KB, Saugstrup T,
Meier JJ; PIONEER 4 investigators: Oral
semaglutide versus subcutaneous liraglutide andplacebo in type 2 diabetes (PIONEER 4): a
randomised, double-blind, phase 3a trial. Lance.
394:39-50, 201918. Rose L, Kadowaki T, Pieber TR, Buchholtz K,
Ekelund M, Gorst-Rasmussen A, Philis-Tsimikas
A: Efficacy and Safety of Fast-Acting Insulin
Aspart in People with Type 1 Diabetes Using
Carbohydrate Counting: A Post Hoc Analysis of
Two Randomised Controlled Trials.Diabetes Ther.
10:1029-1041, 201919. Saheki T, Moriyama M, Kuroda E, Funahashi A,
Yasuda I, Setogawa Y, Gao Q, Ushikai M, Furuie
S, Yamamura KI, Takano K, Nakamura Y, Eto K,
Kadowaki T, Sinasac DS, Furukawa T, Horiuchi
M, Tai YH: Pivotal role of inter-organ aspartate
metabolism for treatment of mitochondrial
aspartate-glutamate carrier 2 (citrin) deficiency,
based on the mouse model. Sci. Rep. 9:4179,
2019

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20. Sasako T, Kadowaki T, Ueki K. ADDITIONEurope: the first decade and beyond. Lancet
Diabetes Endocrinol 7: 891-893, 2019.
21. Satoh J, Yokono K, Ando R, Asakura T, Hanzawa
K, Ishigaki Y, Kadowaki T, Kasuga M, Katagiri H,
Kato Y, Kurosawa K, Miura M, Nakamura J,
Nishitsuka K, Ogawa S, Okamoto T, Sakuma S,
Sakurai S, Satoh H, Shimauchi H, Shimokawa H,
Shoji W, Sugiyama T, Suwabe A, Tachi M,
Takahashi K, Takahashi S, Terayama Y, Tomita H,
Tsuchiya Y, Waki H, Watanabe T, Yahata K,
Yamashita H: Diabetes care providers' manual fordisaster diabetes care.Diabetol. Int. 10:153-179,
2019
22. Satoh J, Yokono K, Ando R, Asakura T, Hanzawa
K, Ishigaki Y, Kadowaki T, Kasuga M, Katagiri H,
Kato Y, Kurosawa K, Miura M, Nakamura J,
Nishitsuka K, Ogawa S, Okamoto T, Sakuma S,
Sakurai S, Satoh H, Shimauchi H, Shimokawa H,
Shoji W, Sugiyama T, Suwabe A, Tachi M,
Takahashi K, Takahashi S, Terayama Y, Tomita H,
Tsuchiya Y, Waki H, Watanabe T, Yahata K,
Yamashita H: Diabetes Care Providers' Manual
for Disaster Diabetes Care.J. Diabetes Investig.
10:1118-1142, 201923. Sugiyama T, Imai K, Ihana-Sugiyama N, Tanaka
H, Yanagisawa-Sugita A, Sasako T, Higashi T,
Okamura T, Yamauchi T, Ueki K, Ohsugi M,
Kadowaki T: Variation in process quality
measures of diabetes care by region andinstitution in Japan during 2015-2016: An
observational study of nationwide claims data.
Diabetes Res. Clin. Pract. Jun 20:107750, 201924. Suzuki K, Akiyama M, Ishigaki K, Kanai M,
Hosoe J, Shojima N, Hozawa A, KadotaA, Kuriki
K, Naito M, Tanno K, Ishigaki Y, Hirata M,
Matsuda K, Iwata N, Ikeda M, Sawada N, Yamaji
T, Iwasaki M, Ikegawa S, Maeda S, Murakami Y,
Wakai K, Tsugane S, Sasaki M, Yamamoto M,
Okada Y, Kubo M, Kamatani Y, Horikoshi M,
Yamauchi T, Kadowaki T: Identification of 28
new susceptibility loci for type 2 diabetes in theJapanese population. Nat Genet. 51:3, 379-386,
2019
25. Takanashi M, Kimura T, Li C, Tanaka M,
Matsuhashi A, Yoshida H, Noda A, Xu P, Takase
S, Okazaki S, Iizuka Y, Kumagai H, Ikeda Y,

Gotoda T, Takahashi M, Yagyu H, Ishibashi S,
Yamauchi T, Kadowaki T, Liang G, Okazaki H:
Critical Role of SREBP-1c Large-VLDL Pathway
in Environment-Induced Hypertriglyceridemia of
Apo AV Deficiency. Arterioscler Thromb Vasc
Biol. Mar;39:3:373-386, 201926. Takehara K, Oe M, Ohashi Y, Tsunemi Y,
Kadowaki T, Sanada H: Differences Between
Patient-Reported
VersusClinician-Observed
Nonulcerative Signs and Symptoms of the Foot in
Patients With Diabetes Mellitus. J. Wound
Ostomy Continence Nurs, 201927. Tamura K, Waki K, Kawai Y, Ueda E, Ishii T,
Wakui H: Possible interesting link between
dipping status and morning surge for subclinicaltarget organ damage in hypertension. ： J Clin
Hypertens (Greenwich). 21:9:1295-1297. doi:
10.1111/jch.13637, 201928. Ueno H, Ishikawa H, Suzuki R, Izumida Y,
Ohashi Y, Yamauchi T, Kadowaki Kiuchi T: The
association between health literacy levels andpatient-reported outcomes in Japanese type 2
diabetic patients. SAGE Open Med. 7:2050312119865647, 2019
29. Wakabayashi T, Yamaguchi K, Matsui K, Sano T,
Kubota T, Hashimoto T, Mano A, Yamada K,
Matsuo Y, Kubota N, Kadowaki T, Iwatsubo T:
Differential effects of diet- and geneticallyinduced brain insulin resistance on amyloid
pathology in a mouse model of Alzheimer's
disease. Mol. Neurodegener. 14:15, 2019.
30. Wiviott SD, Raz I, Bonaca MP, Mosenzon O,
Kato ET, Cahn A, Silverman MG, Zelniker TA,
Kuder JF, Murphy SA, Bhatt DL, Leiter LA,
McGuire DK, Wilding JPH, Ruff CT,
Gause-Nilsson IAM, Fredriksson M, Johansson
PA, Langkilde AM, Sabatine MS; DECLARE–
TIMI 58 Investigators: Dapagliflozin andCardiovascular Outcomes in Type 2 Diabetes.N.
Engl. J. Med. 380:347-357, 2019
31. GBD 2016 Neurology Collaborators (incl.
Yamada T). Global, regional, and national burdenof neurological disorders, 1990-2016: asystematic analysis for the Global Burden of
Disease Study 2016. Lancet Neurol. 18:5:459-480,
2019

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32. GBD 2016 Stroke Collaborators (incl. Yamada t).
Global, regional, and national burden of stroke,
1990-2016: a systematic analysis for the Global
Burden of Disease Study 2016. Lancet Neurol.
185:439-458, 201933. Yamada S, Yamada Y, Irie J, Hara K, Kadowaki T,
Atsumi Y: Societal Marketing in the Treatment ofType 2 Diabetes Mellitus: A Longitudinal
Questionnaire Survey for Michelin-Starred
Restaurants in Japan. Int. J. Environ. Res. Public
Health 16: E636, 201934. Yamada T, Kondo Y, Momosaki R: PICO andRisk Of bias Navigator for Evidence Based
Medicine (PICORON). PeerJ Preprints. 7:e27684
v1, 2019
35. Yamada T, Kondo Y, Momosaki R: Automateddata extraction software for medical summary
using text mining (T-Library). PeerJ Preprints. 7:
e27685v1, 201936. Yamada T, Lee C, Liu W, Shojima N: Slow weightloss during comprehensive treatment and worse
metabolic control with higher weight regain: A
trajectory analysis. Obesity (Silver Spring),
Accepted, 201937. Yamada T, Tanikawa Y, Mori R, Hosoe J, Shojima
N, Kamata R, Ishinohachi K, Kadowaki T,
Yamauchi T: Glucagon-like peptide (GLP)-1
analogues as an add-on to insulin for adults with
type 1 diabetes mellitus (Protocol paper).
Cochrane Database of Systematic Reviews 2019:
CD013164, 201938. Yamaguchi S, Waki K, Nannya Y, Nangaku M,
Kadowaki T, Ohe K: Usage Patterns of GlucoNote,a Self-Management Smartphone App, Based on
ResearchKit for Patients With Type 2 Diabetes
and Prediabetes. JMIR Mhealth Uhealth. 7:
e13204, 2019.
39. Yuki Matsushima, Hisashi Noma, Tomohide
Yamada, Toshi A: Furukawa. Bayesian influencediagnostics and outlier detection for meta-analysis
of diagnostic test accuracy. arXiv2019:1906.
10445, 201940. Yuta Hamaguchi, Hisashi Noma, Kengo
Nagashima, Tomohide Yamada, Toshi A.
Furukawa: Frequentist performances of Bayesianprediction intervals for random-effects metaanalysis. arXiv 2019:1907.00345, 2019

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

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

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

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

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

Kazuhiro Toyama, M.D., Ph.D.,

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

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

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

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

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

Homepage

http://www.u-tokyo-hemat.com/

Introduction and Organization
The Department of Hematology and Oncology is
responsible for clinical activities in outpatient as wellas inpatient clinics of hematological disorders,
research activities for hematology/oncology, and education of undergraduate as well as graduate students.
We are also engaged in continuous education of
post-graduate doctors who develop into sophisticatedhematologists of eminent distinction. These activities
are performed by the united efforts of all members
who belong to the department. Dr. Mineo Kurokawa
was assigned as Professor of the Department of
Hematology and Oncology in 2005. Other staff of ourdepartment consists of 2 lecturers and 8 assistantprofessors.

Clinical activities
On the average, 60-70 patients with hematologicaldiseases are treated in the ward. Clinical facilities
include patient rooms with high-efficiency particulate
air filtration and filtrated water supply. Patients whoare eligible for the treatment with high-grade infection
prophylaxis are admitted to the facilities. Patient careis provided by team management. That is, three
doctors (a junior resident, a senior resident, and an
assistant professor) are assigned to a single patient.
Since clinical issues are highly related to hematopoietic stem cell transplantation especially for patientswith hematological diseases, a substantial portion of
our clinical conferences are shared with staff membersof the Department of Cell Therapy and Transplantation Medicine and the Department of Pediatrics(Hematology/Oncology). Many problems arising indaily clinical practice are discussed in the morning
clinical conference held thrice a week. Diagnostic andtherapeutic issues as well as pathological aspects ofindicative and/or educational cases are discussed inclinical conferences held twice a month.
Outpatient clinical services are provided from
Monday to Friday in the morning and afternoon using
three booths. Approximately 60-65 patients visit our
outpatient clinic every weekday. One of our ultimate
goals in the clinical activities is to cure patients withhematological malignancies.
We perform various kinds of genetic or molecular
tests to detect, characterize, and monitor neoplastic
cells and their results are used in the diagnosis and156

treatment.
Here we introduce technical aspects on the treatment strategy:
1. High dose chemotherapy with autologous stem
cell transplant: High-dose chemotherapy isadministered for the treatment of hematologicalneoplasms and solid tumors. For the autologous
stem cell support, peripheral blood stem cell isusually selected as a source of stem cells.
2. Allogeneic hematopoietic stem cell transplant:
Bone marrow cells are harvested from healthy
donors by operation under general anesthesia andimmediately infused to a recipient. Peripheral
blood stem cells (PBSCs) are harvested fromhealthy donors by leukapheresis using an
automated continuous flow blood cell separator.
PBSCs are immediately infused to a recipient orpreserved in liquid nitrogen in cooperation with
the Department of Transfusion Medicine.
Allogeneic transplant with non-myeloablative
conditioning (also referred to as reduced-intensity
stem cell transplant (RIST)) is commonly
performed for elderly patients and patients with
impaired organ function. HLA-haploidentical
hematopoietic stem cell transplantation is also
ready to be performed to patients if necessary.
Allogeneic hematopoietic stem cell transplant for
the elderly are performed under the admission ofPatient Relations and Clinical Ethics Center. Cord
blood cells are also used as a source ofhematopoietic stem cells.

Teaching activities
A lecture course on etiology, pathogenesis, clinicaland laboratory features, differential diagnosis, therapy
and prognosis for all hematological diseases isprovided for the second grade medical students. The
course contents include:
1. Mechanisms of hematopoiesis, transplantation
medicine and cell therapy
2. Acute leukemia and myeloproliferative disorders
3. Bone marrow failure syndrome (aplastic anemia
and myelodysplastic syndrome)
4. Lymphoma and myeloma
5. Hemostasis and thrombosis
6. Hemolytic anemia and anemia of various causes

Clinical clerkships on diagnostic and therapeutic
issues and arts are given for the third grade medical
students on a man-to-man basis with a senior faculty
member who is erudite both in general internal
medicine and in hematology and oncology. During thecourse, students are required to learn the basic techniques of medical interview and physical examination,interpretation of laboratory tests, and practical
medical procedures.
Undergraduate students are educated to become
independent researchers both in basic and clinicalresearch.
Education of clinical fellows to train hematologists
is also provided. They are trained to achieve knowledge and techniques necessary for hematologists in
our hospital and encouraged to present clinical studies
at academic meetings.

Research activities
The major research projects are as follow: (1)molecular mechanisms of hematopoietic neoplasms,(2) hematopoietic transcription factors, (3) signaltransduction in hematopoietic cells, (4) chromosomal
and genomic approaches to leukemogenesis, (5)generation of murine models for leukemias, (6)reprogramming of leukemic cells into iPS cells, andfunctional analysis using iPS cells, (7) regulation ofhematopoiesis. (8) genetic and pathologicalmechanism of Erdheim-Chester disease. Translational
research to develop novel methods for diagnosis andtreatment based on basic research is also performed.
Every effort has been made to achieve the highest
quality in both clinical and basic medical research.
The ultimate aims of our research are the applicationof epoch-making discoveries in research fields to theclinical hematology and oncology. Representative
publications from our departments published in thepast year are listed in the reference.

References
1. Uni M, Masamoto Y, Sato T, Kamikubo Y, Arai S,
Hara E, and Kurokawa M. Modeling ASXL1
mutation revealed impaired hematopoiesis caused
by derepression of p16Ink4a through aberrant
PRC1-mediated histone modification. Leukemia

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2.

3.

4.

5.

6.

7.

8.

9.

33(1): 191-204, 2019.
Matsuda K, Koya J, Arai S, Nakazaki K,
Nakamura F, and Kurokawa M. Cyclosporine
therapy in patients with transfusion-independent
non-severe aplastic anemia; retrospective analysis.
Internal Medicine 58(3): 355-360, 2019.
Ito Y, Miyauchi M, Nakamura T, Takahara N,
Nakai Y, Taoka K, Toyama K, Shinozaki-Ushiku
A, Koike K, Kurokawa M. Significance of biopsy
with ERCP for diagnosis of bile duct invasion of
DLBCL. Int J Hematol 110(3): 381-384, 2019.
Matsumura T, Nakamura-Ishizu A, Takaoka K,
Maki H, Muddineni SSNA, Wang CQ, Suzushima
H, Kawakita M, Asou N, Matsuoka M, Kurokawa
M, Osato M, Suda T. TUBB1 dysfunction in
inherited thrombocytopenia causes genome
instability. Br J Haematol 185(5): 888-902, 2019.
Takaoka K*, Kawazu M*, Koya J, Yoshimi A,
Masamoto Y, Maki H, Toya T, Kobayashi T,
Nannya Y, Arai S, Ueno T, Ueno H, Suzuki K,
Harada H, Manabe A, Hayashi Y, Mano H,
Kurokawa M. A germline HLTF mutation infamilial MDS induces DNA damage accumulation
through impaired PCNA polyubiquitination.
Leukemia 33(7): 1773-1782, 2019.
Sasaki K, Miyauchi M, Ogura M, ShimuraNukina A, Toyama K, Nakazaki K, Watadani T,
Abe O, Kurokawa M. Arteritis after administration of granulocyte colony-stimulating factor: acase series. Int J Hematol 110(3): 370-374, 2019.
Matsuda K, Honda A, Arai S, Maki H, Nakazaki
K, Kurokawa M. Retrospective Analysis on
Transient Recurrence of Steroid-Sensitive AcuteGraft-Versus-Host Disease.
Bone Marrow
Transplant 54(2): 316-319, 2019.
Tateishi R, Seike M, Kudo M, Tamai H, Kawazoe
S, Katsube T, Ochiai T, Fukuhara T, Kano T,
Tanaka K, Kurokawa M, Yamamoto K, Osaki Y,
Izumi N, and Imawari M.
Randomized
controlled trial of lusutrombopag in Japanesepatients with chronic liver disease undergoingradiofrequency ablation. Journal of Gasteroenterology 54(2): 171-181, 2019.
Aoki T, Yamada A, Takahashi M, Niikura R,
Toyama K, Ushiku T, Momose T, Fukayama M,
and Koike K.
Development and internal
validation of a risk scoring system for gastro-

intestinal events required surgery among gastrointestinal lymphoma patients. Journal of Gasteroenterology and Hepatology 34(4): 693-699, 2019.
10. Senda N, Miyagaki T, Oka T, Itoigawa A, Kikuchi
K, Kobayashi T, Nakamura F, Kurokawa M,
Sugaya M, and Sato S. A Case of Epstein-Barr
Virus-Positive Extranodal Natural Killer/T Cell
Lymphoma, Nasal Type accompanied by EpsteinBarr Virus-Positive Nasopharyngeal Carcinoma.
The Journal of Dermatology 46(5): e161-e163,
2019.
11. Hidaka H, Kurosaki M, Tanaka H, Kudo M, Abiru
S, Igura T, Ishikawa T, Seike M, Katsube T,
Ochiai T, Kimura K, Fukuhara T, Kano T, Nagata
T, Tanaka K, Kurokawa M, Yamamoto K, c, Osaki
Y, Izumi N, and Imawari M. Lusutrombopag
reduces the need for platelet transfusion inthrombocytopenic patients undergoing invasive
procedures.
Clinical Gastroenterology andHepatology 17(6): 1192-1200, 2019.
12. Ebisawa K, Masamoto Y, Tokushige J, Nishi H,
Honda K, Hinata M, Toyama K, Nangaku M, andKurokawa M. Tocilizumab for focal segmental
glomerulosclerosis secondary to multicentric
Castleman’s disease. Annals of Hematology
98(8): 1995-1997, 2019.
13. Yokomizo T, Watanabe N, Umemoto T, Matsuo J,
Harai R, Kihara Y, Nakamura E, Tada N, Sato T,
Takaku T, Shimono A, Takizawa H, Nakagata N,
Mori S, Kurokawa M, Tenen D, Osato M, Suda T,
and Komatsu N. Hlf marks the developmental
pathway for hematopoietic stem cells but not forerythro-myeloid progenitors. The Journal of
Experimental Medicine 216(7): 1599-1614, 2019.
14. Kizaki M, Takahashi N, Iriyama N, Okamoto S,
Ono T, Usui N, Inokuchi K, Nakaseko C,
Kurokawa M, Sumi M, Nakamura F, Kawaguchi
T, Suzuki R, Yamamoto K, Ohnishi K,
Matsumura I, and Naoe T. Efficacy and Safety of
Tyrosine Kinase Inhibitors for Newly Diagnosed
Chronic-Phase Chronic Myeloid Leukemia Over a
5-year Period: Results From the Japanese Registry
Obtained by the New TARGET System
International Journal of Hematology 109(4): 426439, 2019.
15. Ebisawa K, Masamoto Y, Koya J, Shimura A,
Shinozaki-Ushiku A, Toyama K, Nakazaki K, and158

Kurokawa M.
Long-term remission bybrentuximab vedotin for non-mediastinal grayzone lymphoma refractory to autologous stem celltransplantation. Clinical Lymphoma, Myeloma
and Leukemia 19(11): e602-e604, 2019.
16. Shull LC, Sen R, Menzel J, Goyama S, Kurokawa
M, and Artinger KB.
The conserved anddivergent roles of Prdm3 and Prdm16 in zebrafish
and mouse craniofacial development. Developmental Biology 461(2): 132-144, 2020. Ito Y,
Toyama K, Honda A, Nakazaki K, Arai S,
Kurokawa M. Posterior reversible encephalopathy
syndrome concurrent with human herpesvirus-6B
encephalitis after allogeneic hematopoietic stem
cell transplantation. J Infect Chemother 26(2):265-268, 2020.
17. Takaoka K, Koya J, Yoshimi A, Toya T,
Kobayashi T, Nannya Y, Nakazaki K, Arai S,
Ueno H, Usuki K, Yamashita T, Imanishi D, SatoS, Suzuki K, Harada H, Manabe A, Hayashi Y,
Miyazaki Y, Kurokawa M. Nationwide epidemiological survey of familial myelodysplastic
syndromes/acute myeloid leukemia in Japan: amulticenter
retrospective
study.
Leuk
Lymphoma 61(7): 1688-1694, 2020.
18. Hirano Y, Miyawaki S, Satou M, Taoka K,
Toyama K, Ikemura M, Tanaka R, Takayanagi S,
Tanaka S, Nakatomi H, Kurokawa K, and Saito N.
Small cell variant of anaplastic lymphoma
kinase-positive anaplastic large cell lymphoma of
the dura mimicking tentorial meningioma.
World Neurosurgery 138: 169-173, 2020.
19. Iida T, Nozawa H, Sonoda H, Toyama K, Kawai
K, Hata K, Tanaka T, Nishikawa T, Sasaki K,
Shuno Y, Kaneko M, Murono K, Emoto S, Ishii H,
Kurokawa M, and Ishihara S. Upfront surgery
for small intestinal Non-Hodgkin’s Lymphoma.
Anticancer Research 40(4): 2373-2377, 2020.
20. Goyal G, Heaney M, Collin M, Aubart FC, VaglioA,
DurhamB,
Hershkovitz-RokahO,
Girschikofsky M, Jacobsen E, Toyama K,
Goodman A, Hendrie P, Cao X, Estrada-Veras J,
Shpilberg O, Abdo A, Kurokawa M, Dagna L,
McClain K, Mazor R, Picarsic J, Janku F, Go R,
Haroche J, and Diamond E. Erdheim-Chester
disease: Consensus recommendations for theevaluation, diagnosis, and treatment in themolecular era.

Blood 135(22): 1929-1945, 2020.

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

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

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

Research Associate
Yukiko Iwasaki, M.D., Ph.D. (Rheumatology)
Haruka Tsuchiya, M.D., Ph.D. (Rheumatology)
Yumi Tsuchida，M.D., Ph.D. (Rheumatology)
Toshihiko Komai, M.D., Ph.D. (Rheumatology)
Norio Hanada, M.D., Ph.D. (Rheumatology)
Toshiaki Shimizu, M.D., Ph.D. (Rheumatology)
Bunki Natsumoto, M.D., Ph.D. (Rheumatology)

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

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

Homepage

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

Introduction and Organization
The Department of Allergy and Rheumatology
presently consists of 13 staffs mentioned above, who
preside over 3 medical staff, 14 graduate students for"Doctor of Medical Science". The outpatient facilities
are situated on the 2nd floor of the Outpatient Clinic.
The inpatient facility is mainly located on the 14th
floor of the Hospital Ward A. The physician's office issituated in the East Hospital Ward and the researchrooms are located in the East Hospital Ward, theCentral Ward and the Clinical Research Center A.

Education
In regard to undergraduate education, the Department is in charge of internal medicine diagnosis andsystemic lectures for M2 students and clinical lecturesand bedside education for M3 and M4 students incooperation with other departments of internal
medicine. The systemic lectures and clinical lectures
cover clinical immunology, connective tissue diseases

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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.

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.

Research
The Department consists of some laboratories inwhich clinical and basic studies are carried out
concerning mainly rheumatology and allergology.
Recently the mainstream of research has employedvarious techniques of molecular biology and cellularimmunology. The principal research topics are listed
below.
1. Functional genomics in autoimmune diseases
2. Analysis of newly-identified regulatory T cellsubset and inhibitory cytokines, and its roles in
autoimmune diseases.
3. Analysis of T cell and B cell repertoires in
autoimmune diseases.
4. Analysis of autoimmune associated gene functions in mice and human models.
5. Analysis of signal transduction mechanisms in
autoimmune diseases.
6. Analysis of autoimmune disease-specific iPS cells

7. Exploration of the roles of protein prenylation in
the animal models of lung disease.
8. Analysis of bone strength in glucocorticoidinduced osteoporosis.
9. Investigation of biomarkers in autoimmune
disease.

Publications
1. Early Growth Response Gene 2-Expressing
CD4+LAG3+ Regulatory T Cells: The Therapeutic
Potential for Treating Autoimmune Diseases.
Okamura T, Yamamoto K, Fujio K. Front
Immunol. 2018;9:340.
2. Integrated bulk and single-cell RNA-sequencing
identified disease-relevant monocytes and a gene
network module underlying systemic sclerosis.
Kobayashi S, Nagafuchi Y, Okubo M, Sugimori Y,
Shirai H, Hatano H, Junko M, Yanaoka H,
Takeshima Y, Ota M, Iwasaki Y, Sumitomo S,
Okamura T, Yamamoto K, Shoda H, Fujio K. J
Autoimmun. 2020 Oct 7:102547.
3. Deteriorating anemia in an 86-year-old man was
improved by prednisolone. Kitago M, Kase Y,
Iwata Y, Suwa Y, Tsuchiya H, Hanata N, Kojima
T, Ogawa S, Fujio K, Akishita M. Geriatr
Gerontol Int. 2020 Sep 20.
4. Peptidylarginine Deiminase 4 Promotes the Renal
Infiltration of Neutrophils and Exacerbates the
TLR7 Agonist-Induced Lupus Mice. Hanata N,
Shoda H, Hatano H, Nagafuchi Y, Komai T,
Okamura T, Suzuki A, Gunarta IK, Yoshioka K,
Yamamoto K, Fujio K. Front Immunol. 2020;11:1095.
5. Reduction of Myeloperoxidase-Antineutrophil
Cytoplasmic Antibody by Mepolizumab in
Eosinophilic Granulomatosis With Polyangiitis.
Komai T, Harada H, Takahashi H, Shoda H, Fujio
K. J Clin Rheumatol. 2020 Jun 18.
6. High incidence of malignancy in SAPHO
syndrome. Yamada S, Nagafuchi Y, Kono M,
Hatano H, Tateishi S, Harada H, Sumitomo S,
Kubo K, Shoda H, Kanda H, Fujio K.Clin Exp
Rheumatol. 2020 Jul-Aug;38(4):805-806
7. Decreased peripheral blood memory B cells areassociated with the presence of interstitial lungdisease in rheumatoid arthritis: a case-control

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study. Shimizu T, Nagafuchi Y, Harada H,
Tsuchida Y, Tsuchiya H, Hanata N, Tateishi S,
Kanda H, Sumitomo S, Shoda H, Yamamoto K,
Fujio K. Mod Rheumatol. 2020 Feb 5:1-6.
8. 2019 Diagnostic criteria for mixed connective
tissue disease (MCTD): From the Japan researchcommittee of the ministry of health, labor, andwelfare for systemic autoimmune diseases.
Tanaka Y, Kuwana M, Fujii T, Kameda H, Muro
Y, Fujio K, Itoh Y, Yasuoka H, Fukaya S,
Ashihara K, Hirano D, Ohmura K, Tabuchi Y,
Hasegawa H, Matsumiya R, Shirai Y, Ogura T,
Tsuchida Y, Ogawa-Momohara M, Narazaki H,
Inoue Y, Miyagawa I, Nakano K, Hirata S, Mori
M. Mod Rheumatol. 2020 Jan 7:1-5
9. Response to tocilizumab and work productivity inpatients with rheumatoid arthritis: 2-year
follow-up of FIRST ACT-SC study. Tanaka Y,
Kameda H, Saito K, Kaneko Y, Tanaka E, Yasuda
S, Tamura N, Fujio K, Fujii T, Kojima T, Anzai T,
Hamada C, Fujino Y, Matsuda S, Kohsaka H.
Mod Rheumatol. 2020 Jan 20:1-11.
10. Extremely high levels of multiple cytokines in thecord blood of neonates born to mothers withsystemic autoimmune diseases. Takahashi N,
Nagamatsu T, Fujii T, Takahashi K, Tsuchida Y,
Fujio K, Fujii T. Cytokine. 2020 Mar;127:154926.
11. Identification of U11snRNA as an endogenous
agonist of TLR7-mediated immune pathogenesis.
Negishi H, Endo N, Nakajima Y, Nishiyama T,
Tabunoki Y, Nishio J, Koshiba R, Matsuda A,
Matsuki K, Okamura T, Negishi-Koga T,
Ichinohe T, Takemura S, Ishiwata H, Iemura SI,
Natsume T, Abe T, Kiyonari H, Doi T, Hangai S,
Yanai H, Fujio K, Yamamoto K, Taniguchi T.
Proc Natl Acad Sci U S A. 2019;116(47):2365323661.
12. The RNA-binding protein Mex-3B plays criticalroles in the development of steroid-resistantneutrophilic airway inflammation. Yamazumi Y,
Sasaki O, Suyama-Fuchino S, Kohu K,
Kamoshida Y, Harada H, Fujio K, Oda T,
Akiyama T. Biochem Biophys Res Commun.
2019;519(2):220-226.
13. Eosinophilic cholangitis with eosinophilic
granulomatosis with polyangiitis: A case reportand review of the literature. Yoshihara R, Komai

T, Nagafuchi Y, Tsuchida Y, Shoda H, Tanaka M,
Ushiku T, Fujio K. Allergol Int. 2020;69:154156.
14. Serum phosphatidylserine-specific phospholipase
A1 as a novel biomarker for monitoring systemic
lupus erythematosus disease activity. Sawada T,
Kurano M, Shirai H, Iwasaki Y, Tahara K,
Hayashi H, Igarashi K, Fujio K, Aoki J, Yatomi Y.
Int J Rheum Dis. 2019 Nov;22(11):2059-2066.
15. CD4+CD25+LAG3+ T Cells With a Feature of
Th17 Cells Associated With Systemic Lupus
Erythematosus Disease Activity. Kato R,
Sumitomo S, Tsuchida Y, Tsuchiya H, Nakachi S,
Sakurai K, Hanata N, Nagafuchi Y, Kubo K,
Tateishi S, Kanda H, Okamura T, Yamamoto K,
Fujio K. Front Immunol. 2019;10:1619.
16. Robust and highly efficient hiPSC generationfrompatient
non-mobilized
peripheral+
blood-derived CD34 cells using the auto-erasable
Sendai virus vector. Okumura T, Horie Y, Lai CY,
Lin HT, Shoda H, Natsumoto B, Fujio K, Kumaki
E, Okano T, Ono S, Tanita K, Morio T, Kanegane
H, Hasegawa H, Mizoguchi F, Kawahata K,
Kohsaka H, Moritake H, Nunoi H, Waki H,
Tamaru SI, Sasako T, Yamauchi T, Kadowaki T,
Tanaka H, Kitanaka S, Nishimura K, Ohtaka M,
Nakanishi M, Otsu M. Stem Cell Res Ther. 2019;10(1):185.
17. Evaluation of Response Criteria in Rheumatoid
Arthritis
TreatedWith
Biologic
Disease-Modifying Antirheumatic Drugs. Inoue
M, Kanda H, Tateishi S, Fujio K. Arthritis Care
Res (Hoboken). 2020;72:942-949.
18. Metabolism as a key regulator in the pathogenesisof systemic lupus erythematosus. Takeshima Y,
Iwasaki Y, Fujio K, Yamamoto K. Semin
Arthritis Rheum. 2019;48:1142-1145.

162

Department of Infectious
Diseases (Internal Medicine)
Professor
Kyoji Moriya, M.D., Ph.D.

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

Assistant Professor
Koh Okamoto, M.D.

Homepage

Daisuke Jyubbishi, M.D, Ph.D

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

Introduction and Organization
The Department of Infectious Diseases has been
one of the leading academic organizations specialized
for internal medicine, in particular, infectious disease
medicine in Japan since 1998, when the Departmentsof Internal Medicine, established in 1890, wererearranged into new ones according to subspecialty ofinternal medicine. Our department has been chiefly
engaged in clinical, educational and research activities
for infectious diseases including bacterial, fungal andviral infections of all organs including HIV infection,
tuberculosis and viral hepatitis. Our department islocated on 11th floor of the University of Tokyo
Hospital Building and has well-furnished researchlaboratories including P-2 class laboratory, andcomputer rooms as own properties. In clinical andresearch activities, we are collaborating with the
Department of Infection Control and Prevention. One
professor, one associate professor, three assistantprofessors, some residents and full-time staff members
are all performing their own duties in clinical,
educational and research activities.

Clinical activities
We have hospital beds on the 13th floor of the Ward
A of University of Tokyo Hospital. Diseases include
HIV infection, viral hepatitis, pneumonia, drug-

resistant bacteria infections or tuberculosis, EBV
infection, CMV infection, parasite infection, etc.
Every effort is made to give patients the best care andbest quality of life. Assistant associates and residents
take care of inpatients. The case presentation by
residents is held every day. Weekly clinical conferenceis held to discuss all cases, in particular, those withclinical problems difficult to be solved. Consultations
are very frequent from other departments on the
management of infectious diseases. The generaldiagnostic, therapeutic plans and decisions for eachpatient are given at the Professor’s round.
Our department offers out-patient care everyday on
infectious diseases and general medicine. We are also
engaged in infection control and prevention of
emerging infectious diseases with the department of
infection control and prevention.

Teaching activities
Our department takes a part in clinical lectures andbed-side learning of the internal medicine for undergraduate medical students according to the educational programs of the University of Tokyo. For the fourthyear medical students, six lectures of infectious
diseases are given. In addition, principles of medical
diagnosis are taught at the bedside. During the
bed-side teaching for fifth and sixth year students, ourassociates teach them on man-to man basis the basic

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way of thinking for correct diagnosis and therapy, thetechniques of interrogation and physical examination,
the way for interpretations of laboratory tests andother medical examinations, and the basic medical
procedures on each case. The education of juniorresidents and fellows is performed as described in“Clinical Activities”.

(6) Establishment of the effective infection control
method and therapy of MRSA and other MDRO
infection.
(7) Elucidating the mechanism and signal transduction of bacterial infection through toll-likereceptors.
(8) Establishment of effective diagnosis methods andtherapy for CDI infection

Research activities
Both clinical and basic researches are necessary to
improve the diagnosis and treatment to infectious
diseases. The members of our department are doing
best to obtain new findings using highly sophisticatedmethodologies. A intramural research conference isheld, in which some members present their annual
research progresses to be discussed by all the
department staff. In addition, each laboratory holds its
own conference and/or journal club on a weekly or
bi-weekly basis.
The research field covers wide areas of infectious
diseases including HIV infection, viral hepatitis andhepatocarcinogenesis, and bacterial infection, such as
Clostridioides difficile infection. Also, various
emerging and re-emerging infectious diseases arecovered. Following themes are currently being
investigated in the department.
(1) Establishment of effective therapy for HIV
infection: we have made a great contribution in
the establishment of the guideline for treatment of
HIV infection in Japan.
(2) Elucidation of the mechanism of hepatocarcinogenesis in hepatitis viral infection: the direct
involvement of both HBV and HCV in hepatocarcinogenesis has been demonstrated using ourtransgenic mouse systems.
(3) Establishment of effective therapy for HCV and
HBV infection: we have made a great contribution
in the establishment of the guideline for treatmentof hepatitis viral infection in Japan.
(4) Establishment of effective therapy for HCV/HIV
co-infection: we have made a great contribution in
the establishment of the guideline for treatment of
HCV/HIV co-infection in Japan.
(5) Innovation of new methods to control viral
hepatitis or prevent the development of hepatocellular carcinoma in chronic viral hepatitis.

References
1. Wakabayashi Y, Jubishi D, Okamoto K, Ikeda M,
Tatsuno K, Mizoguchi M, et al. A rare case of a
prostatic abscess, bacteremia and chronic granulomatous disease associated with Klebsiella pneumoniae. J Infect Chemother. 2019;25(5):365-7.
2. Tatsuno K, Ikeda M, Wakabayashi Y, Yanagimoto
S, Okugawa S, Moriya K. Clinical Features ofBloodstream
Infections
Associatedwith
Peripheral Versus Central Venous Catheters.
Infect Dis Ther. 2019;8(3):343-52.
3. Shimasaki T, Seekatz A, Bassis C, Rhee Y, Yelin
RD, Fogg L, et al. Increased Relative Abundanceof Klebsiella pneumoniae Carbapenemaseproducing Klebsiella pneumoniae Within the Gut
Microbiota Is Associated With Risk of Bloodstream Infection in Long-term Acute Care Hospital
Patients. Clinical Infectious Diseases. 2019;
68(12):2053-9.
4. Sato S, Aoyama T, Uejima Y, Furuichi M,
Suganuma E, Takano T, et al. Pyogenic liverabscess due to hypervirulent Klebsiella pneumoniae in a 14-year-old boy. J Infect Chemother.
2019;25(2):137-40.
5. Ruchlemer R, Ben-Ami R, Bar-Meir M, Brown
JR, Malphettes M, Mous R, et al.
Ibrutinib-associated invasive fungal diseases inpatients with chronic lymphocytic leukaemia andnon-Hodgkin lymphoma: An observational study.
Mycoses. 2019;62(12):1140-7.
6. Okamoto K, Rhee Y, Schoeny M, Lolans K,
Cheng J, Reddy S, et al. Impact of doffing errors
on healthcare worker self-contamination whencaring for patients on contact precautions. InfectCont Hosp Ep. 2019;40(5):559-65.
7. Okamoto K, Asano S, Yamamoto T, Toyono T,
Yamaguchi R, Okada Y, et al. Poor penetration of

164

cefcapene into aqueous humor after oral
administration of cefcapene pivoxil to patients
undergoing cataract surgery. J Infect Chemother.
2019.
8. Nakagomi R, Tateishi R, Masuzaki R, Soroida Y,
Iwai T, Kondo M, et al. Liver stiffness
measurements in chronic hepatitis C: Treatment
evaluation and risk assessment. J Gastroen
Hepatol. 2019;34(5):921-8.
9. Muto Y, Moroishi T, Ichihara K, Nishiyama M,
Shimizu H, Eguchi H, et al. Disruption of
FBXL5-mediated cellular iron homeostasis
promotes liver carcinogenesis. J Exp Med. 2019;
216(4):950-65.
10. Miyashita H, Okamoto K, Kobayashi T,
Wakabayashi Y, Kitaura S, Ikeuchi K, et al.
Bacterial peritonitis in a patient with malignant
ascites caused by pancreatic carcinoma: Case
report and review of literature. J Infect Chemother.
2019;25(6):473-6.
11. Midorikawa Y, Takayama T, Nakayama H, Higaki
T, Moriguchi M, Moriya K, et al. Prior hepatitis B
virus infection as a co-factor of chronic hepatitis
C patient survival after resection of hepatocellular
carcinoma. Bmc Gastroenterology. 2019;19(1).
12. Kado A, Tsutsumi T, Enooku K, Fujinaga H,
Ikeuchi K, Okushin K, et al. Noninvasive
diagnostic criteria for nonalcoholic steatohepatitis
based on gene expression levels in peripheral
blood mononuclear cells. Journal of Gastroenterology. 2019;54(8):730-41.
13. Hau TTT, Nakamura-Hoshi M, Kanno Y, Nomura
T, Nishizawa M, Seki S, et al. CD8(+) T
cell-based strong selective pressure on multiple
simian immunodeficiency virus targets in
macaques possessing a protective MHC class I
haplotype. Biochem Bioph Res Co. 2019;512(2):213-7.
14. Hatakeyama S, Okamoto K, Ogura K, Sugita C,
Nagi M. Histoplasmosis among HIV-Infected
Patients in Japan: a Case Report and Literature
Review. Japanese Journal of Infectious Diseases.
2019;72(5):330-3.
15. Harada S, Aoki K, Okamoto K, Kinoshita O,
Nawata K, Ishii Y, et al. Left ventricular assist
device-associated endocarditis involving multiple
clones of Staphylococcus aureus with distinct

antimicrobial susceptibility patterns. Int J InfectDis. 2019;84:44-7.
16. Chlipala GE, Lei ZA, Maienschein-Cline M,
Kunstman K, Okamoto K, Green SJ, et al.
Complete Genome Sequence of a USA100
Methicillin-Resistant Staphylococcus aureus
Strain. Microbiol Resour Ann. 2019;8(11).

165

Department of Stress Science andPsychosomatic Medicine
Associate Professor
Kazuhiro Yoshiuchi, M.D., Ph.D.

Associate
Makoto Otani, M.D., Ph.D.

Homepage

http://psmut.umin.ac.jp/

Introduction and Organization

Teaching activities

The Department of Stress Science andPsychosomatic Medicine is one of 11 divisions of the
Department of Internal Medicine, the University ofTokyo. It covers eating disorder, panic disorder, andvarious psychosomatic diseases such as chronicheadache, irritable bowel syndrome, functional
dyspepsia, hypertension, diabetes mellitus, andhyperthyroidism. Our teaching staff consists of one
associate professor, one associates, and 5 adjunctprofessors, and other members are 4 senior residents,
13 graduate students, and 5 researchers.

We are giving 6 methodical lectures on
psychosomatic medicine for fourth grade medical
students, ‘clinical clerkship’ for fifth grade students
lasting two weeks, ‘advanced clinical clerkship’ for 3
to 4 fifth grade students lasting 4 weeks each, andclinical lectures on psychosomatic diseases in
cardiology for fifth grade students and on eating
disorders for sixth grade students. We are trying toteach them not only basic knowledge of specificdiseases, ways of physical examination, or interpretation of laboratory data, but also relevant ways ofclinical interview, doctor-patient relationship building,and behavior modification.
As for education for junior residents, our seniorresidents and an associate provide man-to-man
instruction. In addition, they can learn how to present
the history of newly-admitted patients at the weekly
professor’s round from our teaching staff.

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 2019 April to 2020 March, overall 2,061
patients (71 individuals) were admitted to the ward,
many of whom were eating disorder patients.
Outpatient clinic is attended on every morning andafternoon in three consultation rooms by approximately fifteen physicians. During 2019 April to 2020
March, the numbers of the new outpatients and of theoverall outpatients in our department were 196 and
4,876, respectively.

Research activities
Targeting stress-related diseases such as not only
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.

166

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.
Seven graduate students and 5 researchers actively
conducted their researches along with our teaching
staff. We have been also collaborating with many
scientists belonging to other departments either inJapan or abroad. Research conferences are held once amonth, where one of the graduate students presents
his/her research for open discussion by all themembers of our department.

References
1. Yamazaki T, Inada S, Yoshiuchi K. Body mass index
cut-off
point
associatedwithrefeedinghypophosphatemia in adults with eating disorders.
Int J Eat Disord 52:1322-1325, 20192. Kawanishi H, Sekiguchi A, Funaba M, Fujii Y,
Yoshiuchi K, Kikuchi H, Kawai K, Maruo K,
Sugawara N, Hatano K, Shoji T, Yamazaki T, Toda
K, Murakami M, Shoji M, Ohara C, Tomita Y,
Fukudo S, Ando T. Cognitive behavioral therapy
with interoceptive exposure and complementary
video materials for Irritable bowel syndrome (IBS):
protocol for a multicenter randomized controlled
trial in Japan. BioPsychoSocial Medicine 13:14,
2019

3. Okuyama T, Yoshiuchi K, Ogawa A, Iwase S,
Yokomichi N, Sakashita A, Tagami K, Uemura K,
Nakahara R, Akechi T. Current pharmacotherapy
does not improve severity of hypoactive delirium inpatients with advanced cancer: PharmacologicalAudit study of Safety and Efficacy in Real World(Phase-R). The Oncologist 24:e574-e582, 2019
4. Choa S, Park S, Takahashia S, Yoshiuchi K,
Shephardc RJ, Aoyagia Y. Changes in andInteractions between Physical and Mental Health inOlder Japanese: the Nakanojo Study. Gerontology
65:340-352, 2019
5. Kurisu K, Yoshiuchi K, Ogino K, Oda T. Machinelearning analysis to identify the association between
risk factors and onset of nosocomial diarrhea: aretrospective cohort study. Peer J 7:e7969, 2019
6. Harashima S, Fujimori M, Akechi T, Matsuda T,
Saika K, Hasegawa T, Inoue K, Yoshiuchi K,
Miyashiro I, Uchitomi Y, Matsuoka YJ. Suicide,other externally caused injuries and cardiovasculardeath following a cancer diagnosis: study protocol
for a nationwide population-based study in Japan(J-SUPPORT 1902). BMJ Open 9:e030681, 2019
7. Harashima S, Yoneda R, Horie T, Fujioka Y,
Nakamura F, Kurokawa M, Yoshiuchi K.
Psychosocial Assessment of Candidates forTransplantation scale (PACT) and survival after
allogeneic hematopoietic stem cell transplantation.
Bone Marrow Transplant 54:1013-1021, 2019
8. Inada S, Iizuka Y, Ohashi K, Kikuchi H, Yamamoto
Y, Kadowaki T, Yoshiuchi K. Preceding
psychological factors and calorie intake in patientswith type 2 diabetes: Investigation by ecologicalmomentary assessment. BioPsychoSoc Med 13:20,
2019
9. Kim J, Marcusson-Clavertz D, Yoshiuchi K, Smyth
JM. Potential benefits of integrating ecologicalmomentary assessment data into mHealth caresystems. BioPsychoSocial Med 13:19, 2019
10. Koishizawa M, Kurihara K, Kita S, Takagi S, Omori
M, Nakamoto C, Yoshiuchi K, Kamibeppu K. Peer
support and hope in mothers of children with eating
disorders. Asian J Fam Ther 3:63-79, 2019

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

168

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

Associate
Toshiyuki Ikeda, M.D., Sho Yamazaki, M.D., Ph.D., Kazuhiko Ishii, M.D.

Homepage

http://square.umin.ac.jp/traf-tky/

Introduction and Organization
The Transfusion Medicine service was established in1949, as an internal provisional measure, andofficially established in 1966. In 1984, Professor
Hiroshi Toyama assumed as the first Professor of thedepartment. Professor Toyama greatly contributed to
the field of transfusion medicine, especially by
publishing “Transfusion Medicine” (actually in its 3rd.
edition), which is the bible of transfusion medicine inJapan. Other great contributions from the department
are as follows. Dr. Kazuo Okochi, ex-lecturer of thedepartment, is the pioneer in the field of transfusionassociated hepatitis research, ex-Professor Takeo Jujiclarified the mechanisms of transfusion-associatedgraft-versus-host disease (TA-GVHD), a serious posttransfusion complication, and ex-Professor Yoichi
Shibata contributed enormously to the field of platelet
immunology. In 1997, the Department of Transfusion
Medicine was established as a chair of the Division ofInternal Medicine of the Graduate School of Medical
Sciences, the University of Tokyo.
Actually, the department is composed of 6 medical
doctors (4 full-time, and 2 partial-time), 10 laboratory
technicians, 2-3 nurses and 1 office assistant.

Clinical activities
The main activity of the department of Transfusion
Medicine is the control, preservation, and provision ofsafe blood products and their derivatives (including
albumin). The control of all blood products in thehospital is centralized to the department, which, in
addition, provides information and orientation related
to blood transfusion. Transfusion-related laboratory
tests and tests for transfusion-transmitted infectious
diseases are routine practices of the department, which
also actively takes part in the diagnosis, prevention
and treatment of adverse reactions and posttransfusion complications. Collection, preservationand provision of autologous blood are also importantfunctions of the department, where the outpatient
clinic for autologous blood was established by
ex-Professor Koki Takahashi in January 2006. At theoutpatient clinic, the first established in Japan, thetransfusionist gives consultation to the patients,
prepares the adequate blood collection schedule, takes
the informed consent, and performs the bloodcollection, according to the surgeons’ needs.
Additionally, collection and preservation of peripheral
blood stem cells are also performed.
The main activities are as follows:
I Control and preservation of blood products and its
derivatives;
II. Laboratory tests
1) Blood typing and histocompatibility testing;2) Detection of anti-erythrocyte, anti-leukocyte
and anti-platelet antibodies;3) Detection of HBV antigens and antibodies, HCV,
HAV, HTLV and HIV antibodies;
4) HLA typing for hematopoietic stem cell transplantation and organ transplantation;
III. Clinical work

1691) Pre-operative autologous blood collection andpreservation;2) Collection and preservation of peripheral blood
stem cells for transplantation;

Teaching activities
Sixth-grade medical students are provided withpractical courses focusing on clinical practice of bloodtransfusion and laboratory tests. Courses are given insmall groups of 6 students each, in a total of 18 groups
per year. The course lasts 5 days/week, including thefollowing subjects;
1) Visit to the laboratories of the department tounderstand the routine of a laboratory;
2) Introduction to the blood group types (red cells,
platelets, leukocytes) and their importance intransfusion medicine and in transplantation (bonemarrow and organ);3) Methodology of blood typing and compatibility
testing for transfusion;4) Methodology for screening of irregular antibodies,and their importance in transfusion practice;5) Introduction to the post-transfusional complications, their etiology, prevention and treatment.
6) Introduction to the preventive measures of bloodborne viral transmission, especially focusing on
the NAT test and the look-back survey.
7) Acquisition of informed consents related to bloodtransfusion, using the role playing method.
8) The indications and techniques of autologous
blood collection and preservation;9) The techniques for peripheral blood stem cells(PBSCs) collection and preservation, as well as
their clinical application;10) The recent advances in the field of bloodtransfusion, including the “Blood Law”, and therecently revised “Indications of blood products”
and “The principles of transfusion practice”.
11) One-day visit to the Japanese Red Cross Blood
Center, to learn the general process of blood
donation and transfusion, including the types ofblood products, and their indications.

Research activities
Research on red cells, leukocytes, and platelets, thepost-tranfusional complications, transplantation im-

munology, immunotherapy, and stem cell biology are
the main themes of the department. Typing of blood
cells is performed by serological and DNA-based
methods. The HLA typing, which was introduced by
ex-Professor Takeo Juji, one of the pioneers of thisfield, is an essential test for hematopoietic stem celland organ transplantations, and still continues as oneof the most important research fields of the department. The mixed-passive hemagglutination (MPHA)
method, the most popular methodology for platelet
serology in Japan, was developed by ex-Professor
Yoichi Shibata and its applicability is now extended
for granulocyte as well as endothelial cell serology.
Transplantation immunology, including stem cellbiology is also an important subject. Also, development of new materials for medical use is also being
researched. Recently, the risk factors of the
detrimental effects of autologous blood donation,
especially focusing on the noninvasive measurementof circulating blood volume, are being investigated.
Following are the main themes.
1. Detection of platelet alloantigens and antibodies
and their role in the transfusion practice.
2. Diagnosis and prevention of post-transfusional
complications and thrombocytopenic purpura of
the newborn.
3. Clinical application of refrigerated and frozenstored blood for autologous transfusion in surgicalpatients, and the improvement of the preservation
methods.
4. Study on the effect of pre-storage leukoreductionof autologous blood for the prevention of possible
adverse effects.
5. Development of a new methodology for plateletcross-match.
6. HLA and HPA genotyping.
7. Development of a new methodology for evaluationof platelet function.
8. Ex-vivo expansion of hematopoietic stem cells andtheir clinical application.
9. Pathophysiology of TRALI and TACO.
10. Study on the risk factors of autologous blood
donation.
11. Study on the correlation between the results
obtained by conventional coagulation tests and themeasurement results of thromboelastograms.

170

References
1. Ikebe E, Matsuoka S, Tanaka A, Yonemura Y,
Fujii Y, Ohsaka A, Okazaki H, Kitazawa J,
Ohtani S, Nakayama T, Momose SY, Miwa I,
Taira R, Toyota K, Kino S, Kato H, Hamaguchi I:
Reduction in adverse transfusion reactions withincreased use of washed platelet concentrates inJapan—A retrospective multicenter study.
Transfus Apher Sci 58;162-168, 2019
2. Bruun MT, Yazer MH, Spinella PC, Titlestad K,
Lozano M, Delaney M, Lejdarová H, Pavlova D,
Trakhtman P, Starostin N, Zhiburt E, van Kraaij
MGJ, Huisman E, Kutner JM, Sakashita AM,
Yokoyama APH, Zubicaray J, Sevilla J, Okazaki
H, Hiwatari M, Nagura Y, Manzini PM, Facco G,
Pecoraro C, Singh L, Hans R, Sharma RR, Kumar
P, Wikman A, Deschmann E, Kaur H, Mei Lam JC,
Ying Ho SK, Koh PL, Moss R, New HV,
Kinmonth A, Comande M, Savoia H, Crighton G,
Yacobovich J, Yahalom V, Lau W.: Vox SanguinisInternational Forum on paediatric indications forblood component transfusion: Summary Vox
Sanguinis 114:523-530, 2019
3. Terada R, Ikeda T, Mori Y, Yamazaki S,
Kashiwabara K, Yamauchi H, Ono M, Yamada Y,
Okazaki H.: Comparison of two point of carewhole blood coagulation analysis devices andconventional coagulation tests as a predicting toolof perioperative bleeding in adult cardiac surgery- A pilot prospective observational study in Japan– Transfusion 59:3525-3535, 2019

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

172

Department of
Reproductive Endocrinology
Professors
Tomoyuki Fujii

Associate Professors
Takeshi Nagamatsu

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika02/index.html#reproduction
Organization
The Department of Reproductive Endocrinology isorganized by Professor Tomoyuki Fujii. All the staff
members are taking part in both clinical and research
activities. For the clinical aspect, we are engaged within-patient and out-patient care including the activities
in the delivery units.

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases, genetic
counseling and assisted reproductive technologies(ART).
We have a highly organized infertility clinic, where
every patient is systemically examined and after diagnosis of underlying infertility factor (s) appropriate
treatment is performed following our protocol. Once itturns out that higher level of treatment is necessary,
ART is applied to such cases. We have been engaged
in in vitro fertilization and embryo transfer (IVF-ET)
as a main axis of ART for twenty years. Conventional
IVF-ET is mainly indicated to cases with tubal factor,
mild male factor, immunological factor or of
unexplained infertility factor. In case of severe male
factor or other fertilization disorder intracytoplasmic
sperm injection (ICSI is performed. Now we haveabout 200 OPU cycles of IVF-ET every year, whichconventional IVF-ET and ICSI share almost equally.
The clinical pregnancy rate of conventional IVF-ET isaround 30% per embryo transfer cycle, which iscomparable with that of ICSI. Other ART techniquessuch as embryo cryopreservation and assisted hatching
are also performed.
In basic research section, a couple of projects asfollows are under way, some of which have alreadyyielded interesting findings; 1) the mechanism offolliculogenesis and follicular apoptosis in the ovary,2) the functions of gynecologic hormones such as
gonadotropins and ovarian steroids, 3) the analysis /etiology of endometriosis, adenomyosis and fibroma
and so on.

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

173

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

13. Takahashi N, Yoshino O, Hayashida E, Nakamura
M, Hori M, Iwahata S, et al. Quantitative analysisof ovarian cysts and tumors by using T2 star
mapping.
J
ObstetGynaecolRes.
2020;46(1):140-6.
14. Takamura M, Koga K, Harada M, Hirota Y, Fujii
T, Osuga Y. A case of hemorrhagic shock occurred
during dienogest therapy for uterine adenomyosis.
J Obstet Gynaecol Res. 2020.
15. Takeuchi A, Koga K, Tokita Y, Matsumoto T,
Satake E, Taguchi A, et al. The effects oftokishakuyakusan, a traditional Japanese medicine(kampo), ferulic acid and paeoniflorin, on humanendometriotic stromal cells and peritoneal
macrophages.
J
ReprodImmunol.
2020;139:103104.
16. Kunitomi C, Harada M, Takahashi N, Azhary
JMK, Kusamoto A, Nose E, et al. Activation of
endoplasmic reticulum stress mediates oxidative
stress-induced apoptosis of granulosa cells in
ovaries affected by endometrioma. Mol Hum
Reprod. 2020;26(1):40-52.
17. Hirata T, Koga K, Osuga Y. Extra-pelvic
endometriosis: A review. Reprod Med Biol.
2020;19(4):323-33.
18. Arakawa T, Fukuda S, Hirata T, Neriishi K, Wang
Y, Takeuchi A, et al. PAX8: A Highly Sensitive
Marker for the Glands in Extragenital
Endometriosis. Reprod Sci. 2020;27(8):1580-6.
19. Ma S, Hirata T, Arakawa T, Sun H, Neriishi K,
Fukuda S, et al. Expression of ALDH1A Isozymes
in Human Endometrium with and without
Endometriosis and in Ovarian Endometrioma.
Reprod Sci. 2020;27(1):443-52.
20. Sun H, Fukuda S, Hirata T, Arakawa T, Ma S,
Neriishi K, et al. IFITM1 is a Novel, Highly
Sensitive Marker for Endometriotic Stromal Cells
in Ovarian and Extragenital Endometriosis.
Reprod Sci. 2020;27(8):1595-601.
21. Nose-Ogura S, Yoshino O, Kanatani M, Dohi M,
Tabei K, Harada M, et al. Effect of transdermal
estradiol therapy on bone mineral density of
amenorrheic female athletes. Scand J Med Sci
Sports. 2020;30(8):1379-86.
22. Hiraoka T, Hirota Y, Fukui Y, Gebril M, Kaku T,
Aikawa S, et al. Differential roles of uterine
epithelial and stromal STAT3 coordinate uterine

174

receptivity and embryo attachment. Sci Rep.
2020;10(1):15523.
23. Inaba K, Wada-Hiraike O, Harada M, Hirota Y,
Koga K, Fujii T, et al. Dienogest suppresses
cellular proliferation status of endometrial polyps
and acts differently depending on themorphological type. Womens Health (Lond).
2020;16:1745506520952003.
24. Takahashi N, Harada M, Oi N, Izumi G,
Momozawa K, Matsuzawa A, et al. Preclinicalvalidation of the new vitrification device
possessing a feature of absorbing excess
vitrification solution for the cryopreservation ofhuman embryos. J Obstet Gynaecol Res. 2020;
46(2):302-9.
25. Gebril M, Hirota Y, Aikawa S, Fukui Y, Kaku T,
Matsuo M, et al. Uterine Epithelial Progesterone
Receptor Governs Uterine Receptivity ThroughEpithelial Cell Differentiation. Endocrinology.
2020;161(12).

175

Department of
Gynecologic Oncology
Professor
Yutaka Osuga

Associate Professor
Yasushi Hirota

Homepage https://www.h.u-tokyo.ac.jp/patient/depts/jyoseigeka/
Organization
The Department of Gynecologic Oncology isorganized by one professor and one associate
professors, being directed practically by Professor
Yutaka Osuga, the Department of Obstetrics andGynecology. The staff members are taking part inclinical and research activities as well as teachingactivities.

Activities
In the clinical activities, more than 150 patients withgynecological cancer and more than one thousand
patients with benign gynecological diseases are treatedin our department every year. Appropriate combinations of surgical treatment, chemotherapy andradiotherapy have been chosen according to thepatients’ conditions, and favorable clinical outcomes
have been achieved. Minimally-invasive surgery isfrequently employed in the treatment of benign andgynecological tumors and genital organ malformation.
We take charge of more than 400 cases of endoscopic
gynecological surgery including robotically-assisted
laparoscopic surgery annually. We also employ theclinical trials of JCOG (Japan Clinical Oncology
Group) and JGOG (Japanese Gynecologic Oncology
Group) as well as the single-institution clinical trials.
Advanced treatment performed in our department is asfollows:(1) Cancer genomic medicine (Genetic tests of thehereditary gynecologic cancers)(2) Radical trachelectomy for women of childbearing
age with early cervical cancer(3) Laparoscopic sacralcolpopexy for pelvic organ
prolapse(4) Adenomyomectomy
Based on our knowledge and experience in this field,
we also perform clinical, translational and basic
research energetically. Our department focuses on thepathogenesis and the pathophysiology of malignant
gynecological diseases such as cervical, endometrial
and ovarian cancers, and benign diseases such as
endometriosis and adenomyosis. Our ongoing projects
are as follows:(1) Establishment of new therapeutic approachtargeting histone modification enzymes ingynecological malignancies(2) Search for epigenomic biomarkers using deeplearning in gynecological malignancies(3) Development of an automated hysteroscopic
diagnosis system for gynecological diseases using
deep learning(4) Control mechanism of genome stability ingynecological malignancies(5) Search for novel biomarkers using germline andsomatic variants in gynecological cancers(6) Genomic approach to elucidate the pathogenesis
and pathophysiology of endometriosis andadenomyosis(7) Immunological aspects in the pathophysiology ofendometriosis

176

References published in 2020
(1) Maru Y, Kawata A, Taguchi A, Ishii Y, Baba S,
Mori M, Nagamatsu T, Oda K, Kukimoto I, Osuga
Y, Fujii T, Hippo Y. Establishment and Molecular
Phenotypingof
Organoids
fromtheSquamocolumnar Junction Region of the Uterine
Cervix. Cancers (Basel). 2020 Mar 15;12(3):694.
(2) Kawata Y, Nagasaka K, Oda K, Makii C, Takeuchi
M, Oki S, Honjo H, Kojima M, Miyagawa Y,
Taguchi A, Tanikawa M, Sone K, Hiraike H,
Matsumoto Y, Wada-Hiraike O, Ayabe T, Osuga
Y, Fujii T. Effect of murine double-minute 2
inhibitors in preclinical models of advanced clear
cell carcinomas originating from ovaries andkidneys. Cancer Sci. 2020 Jul 25;111(10):3824-34.
(3) Sone K, Eguchi S, Asada K, Inoue F, Miyamoto Y,
Tanikawa M, Tsuruga T, Mori-Uchino M,
Matsumoto Y, Hiraike-Wada O, Oda K, Osuga Y,
Fujii T. Usefulness of biopsy by officehysteroscopy for endometrial cancer: A case report.
Mol Clin Oncol. 2020 Aug;13(2):141-145.
(4) Toyohara Y, Sone K, Nishida H, Taguchi A,
Miyamoto Y, Tanikawa M, Mori M, Tsuruga T,
Matsumoto Y, Oda K, Osuga Y, Fujii T.
Desensitization strategy for hypersensitivity
reactions to carboplatin in five patients withgynecological cancer. J Obstet Gynaecol Res.
2020 Nov;46(11):2298-2304.
(5) The histone methyltransferase SMYD2 is a novel
therapeutic target for the induction of apoptosis in
ovarian clear cell carcinoma cells.Kojima M, Sone
K, Oda K, Hamamoto R, Kaneko S, Oki S, Kukita
A, Kawata A, Honjoh H, Kawata Y, Kashiyama T,
Sato M, Taguchi A, Miyamoto Y, Tanikawa M,
Tsuruga T, Nagasaka K, Wada-Hiraike O, Osuga
Y, Fujii T. Oncol Lett. 2020 Nov;20(5):153.

177

Department of Perinatal Medicine
Professor
Tomoyuki Fujii

Associate Professor
Kaori Koga

Homepage https://www.obstetrics-htu.jp/
Organization
The Department of Perinatal Medicine is organized
by one professor and one associate professor, being
directed practically by Professor Tomoyuki Fujii, thechairman of the Department of Obstetrics andGynecology. All the staff members take part in bothclinical and research activities, as well as teachingactivities, with 19 associates of the University ofTokyo 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 200 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.

178

References published in 2020
1

2

3

4

5

6

7

8.

Kumasawa K, Iriyama T, Nagamatsu T, Osuga Y,
Fujii T. Pravastatin for preeclampsia: Fromanimal to human. J Obstet Gynaecol Res. 2020
Aug;46(8):1255-1262.
Yoshikawa M, Iriyama T, Suzuki K, Sayama S,
Tsuruga T, Kumasawa K, Nagamatsu T, Homma
K, Naguro I, Osuga Y, Ichijo H, Fujii T. ASK1
promotes uterine inflammation leading topathological preterm birth. Sci Rep. 2020 Feb 5;10(1):1887.
Samejima T, Nagamatsu T, Akiba N, Fujii T,
Sayama S, Kawana K, Taguchi A, Kumasawa K,
Iriyama T, Osuga Y, Fujii T. Secretory leukocyte
protease inhibitor and progranulin as possible
regulators of cervical remodeling in pregnancy. J
Reprod Immunol. 2020 Nov 1;143:103241.
Kumasawa K, Kubota K, Takahashi Y, Nakayama
T, Iriyama T, Nagamatsu T, Osuga Y, Fujii T.
Abdominal compartment syndrome complicatedby preeclampsia and partial HELLP syndrome ina 45-year-old woman: A case report. Clin Case
Rep. 2020 Apr 28;8(7):1251-1254.
Samejima T, Nagamatsu T, Iriyama T, Nakayama
T, Seyama T, Sayama S, Kumasawa K, Komatsu
A, Kawana K, Osuga Y, Fujii T. Impact ofadditional risk factors on the incidence of preterm
delivery among pregnant women diagnosed withshort cervix. Taiwan J Obstet Gynecol. 2020 Mar;59(2):195-199.
Takahashi Y, Nagamatsu T, Fujii T, Hashimoto A,
Sayama S, Seyama T, Iriyama T, Kumasawa K,
Osuga Y, Fujii T. Congenital extracardiac venous
system anomaly in two siblings with normal
karyotype and increased nuchal translucency
thickness: a case report. Oxf Med Case Reports.
2020 Jun 13;2020(6)Nabeshima T, Fujii T, Nagamatsu T, Hashimoto
A, Seyama T, Kubota K, Sayama S, Nakayama T,
Kumasawa K, Iriyama T, Osuga Y, Fujii T.
Polyhydramnios is associated with postnatal
dysphagia determining short-term prognosis of thenewborn with 22q11.2 deletion syndrome - A caseseries analysis. Taiwan J Obstet Gynecol. 2020
Sep;59(5):744-747.
Sayama S, Song A, Brown BC, Couturier J, Cai X,

Xu P, Chen C, Zheng Y, Iriyama T, Sibai B,
Longo M, Kellems RE, D'Alessandro A, Xia Y.
Maternal erythrocyte ENT1-mediated AMPK
activation counteracts placental hypoxia andsupports fetal growth. JCI Insight. 2020 May 21;
5(10):e130205.

179

Department of Molecular andCellular Reproductive Medicine
Professor
Yutaka Osuga

Associate Professor
Osamu Hiraike

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika02/index.html#reproduction
Organization
The Department of Molecular and Cellular
Reproductive Medicine is organized by one professor
and one associate professor.

Activities
Our department mainly aims to investigate thereproductive endocrinology, and molecular biologicalmethods are utilized to accomplish this purpose. Basic
researches are currently performed and we reportmany interesting findings annualy. We specificallyfocus on the role of inflammation and transcription
machinery in these issues. Senescence and aging
process are also extensively investigated.
1) The mechanism of folliculogenesis, follicularatresia and intrafollicular microenvironment in theovary.
2) The physiological functions of sex steroid
hormones and gonadotoropins.
3) The molecular mechanisms of endometriosis.
4) The molecular mechanisms of uterine fibroid andadenomyosis.
5) The effects of aging and cellular senescence on the
reproductive system.
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine disorders andgenetic counseling. We also perform minimallyinvasive surgery for benign gynecological diseases

including endometriosis, uterine fibroid, adenomyosis,
infertility, and pelvic organ prolapse. More than 90%of surgery cases for benign gynecological disorders
are operated using endoscope, and we deal with morethan 400 cases annually.
In accordance with the notion of life stage specificapproches, we also manage patients complaining
primary/secondary amenorrhea, infertility, dysmenorrhea, heavy menstrual bleeding, and climactirium.
Osteoporosis in their 10’s to 20’s and perimenopausal
age could be a heavy burden for patinets and we havealready established the primary care system for these
women. Numerous number of female athletes refer toour clinic as well.

References published in 2019
1. A survey of public attitudes toward uterustransplantation, surrogacy, and adoption in Japan.
Nakazawa A, Hirata T, Arakawa T, Nagashima N,
Fukuda S, Neriishi K, Harada M, Hirota Y, Koga
K, Wada-Hiraike O, Koizumi Y, Fujii T, Irahara M,
Osuga Y. PLoS One. 2019 Oct 30;14(10):e0223571. doi: 10.1371/journal.pone.0223571.
2. Accumulation of advanced glycation end products
in follicles is associated with poor oocyte
developmental competence. Takahashi N, Harada
M, Azhary JMK, Kunitomi C, Nose E, Terao H,
Koike H, Wada-Hiraike O, Hirata T, Hirota Y,
Koga K, Fujii T, Osuga Y. Mol Hum Reprod. 2019
Nov 30; 25(11): 684-694. doi: 10.1093/molehr/

180

3.

4.

5.

6.

7.

8.

gaz050.
Clinical aspects and management of inguinal
endometriosis: A case series of 20 patients.
Arakawa T, Hirata T, Koga K, Neriishi K, Fukuda
S, Ma S, Sun H, Nagashima N, Harada M, Hirota
Y, Wada-Hiraike O, Fujii T, Osuga Y. J Obstet
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Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

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Department of Pediatrics,
Department of Developmental
Pediatrics
Professor
Akira Oka, M.D., Ph.D.
Naoto Takahashi, M.D., Ph.D. (Department of Pediatric and Neonatal Intensive Care)

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

Lecturer
Ryo Inuzuka, M.D., PhD., Satsuki Kakiuchi, M.D.,Ph.D.(Department of Maternal, Fetal andNeonatal Medicine), Youichirou Hirata, M.D., Ph.D., Mitsuteru Hiwatari, M.D., Ph.D.
(Department of Cell Therapy and Transplantation Medicine), Hikoro Matsui M.D., Ph. D.

Associate
Riki Nishimura, M.D.,Ph.D., Shoichiro Kanda, M.D.,Ph.D., Atsushi Sato, M.D.,Ph.D.,
Kohei Kashima, M.D.,Ph.D., Yuko Kajiho, M.D.,Ph.D., Ryo Nakagawa, M.D.,Ph.D., Hiroko
Asakai, M.D.,Ph.D., Konomi Shimoda, M.D., Keihou Owada, M.D.,Ph.D., Satoshi
Takenaka, M.D., Susumu Urata, M.D., Yoshihiko Shitara, M.D., Miki Sugimoto, M.D.,
Kenichiro Hayashi, M.D., Yu Kakimoto, M.D., Katsutoshi Nakano, M.D., Takayuki Mori,
M.D., Yumiko Terada, M.D., Hidetoshi Ohta, M.D., Mamiko Unuma, M.D., Kaname Uchida,
M.D., Moe Hidaka, M.D., Go Kimoto, M.D., Nao Takasugi, M.D., Keita Hogetsu, M.D.
Chie Takahashi, M.D., Mami Kobayashi, M.D., Shota Kato, M.D.
(As of March 31, 2020)

Homepage

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

Introduction and Organization
The former Department of Pediatrics developed
into Department of Pediatrics and Department ofDevelopmental Pediatrics, which comprise subgroupsof the Group of Reproductive, Developmental andAging Medicines, Graduate School of Medicine, The
University of Tokyo.
Our staff consists of 2 professors, 1 associate

professor, 4 lecturers, 2 project lecturers, 23 associate
professors, 3 project research associates, 5 seniorresidents, and graduate students on March 31, 2020.
The outpatient clinic of our department is on thesecond floor of the outpatient clinic building. We treat
patients at the Pediatric Medical Center in the inpatient building. Offices are on the second and third
floors of the East Research Building.

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Our laboratories are located on the seventh floor of
the Clinical Research Building Center and on thesecond and third floors of the East Research Building.

Clinical activities
We have specialized clinics covering all fields ofpediatric disorders. Children or neonates stay in thePediatric Medical Center and receive appropriate
treatments. Since June, 2019, we have increased
activity of intensive care and developed the section of
Pediatric and Perinatal Intensive Care including
neonatal intensive care unit (NICU) and the pediatricintensive care unit (PICU). There are 21 beds in the
NICU and 36 beds in the growing care unit (GCU).
There are 12 beds in the PICU and our institution isgoing to fulfill the designation as children’s hospital
affiliated to the university hospital. In the NICU, we
are taking care of small premature babies weighingfrom 400g to 4,000g often associated with congenital
disorders requiring invasive interventions. PICU is
one of tertiary centers of pediatric emergency
covering the east part of Tokyo. In general ward of thePediatric Medical Center, we treat variety of patientswith diseases, such as hematological/oncologicaldisorders(acuteleukemia,
neuroblastoma,
rhabdomyosarcoma, hepatoblastoma, brain tumors,etc.), cardiac disorders (congenital heart diseases andKawasakidisease),neuromusculardisorders,immunological/allergic disorders (common variable
immunodeficiency, chronic granulomatous disease
and bronchial asthma), renal and urinary tract diseases(nephrotic syndrome, chronic glomerulonephritis,
purpura nephritis and renal and/or urinary tract
anomalies), endocrinological disorders, metabolic
disorders and psychosomatic diseases are admitted in
the wards.
Cardiology; We use the most comprehensive hearttests and treatments to deliver the highest quality carefrom admission, to discharge, to follow-up, and ourservices range from fetal cardiology to cardiac disease
prevention to pediatric interventional cardiology toheart transplantation.
Neurology; We are part of several multidisciplinary
teams, including those that treat: childhood stroke,
hypoxic ischemic encephalopathy and other neurological disease.

Hematology/Oncology; A multidisciplinary team ofexperienced healthcare providers will care for children.
Approximately 10 patients received hematopoietic
stem cell transplantation every year. There are patientswith severe combined immunodeficiency, aplastic
anemia-syndrome, relapse/refractory acute lymphoblastic leukemia, acute myeloid leukemia andhigh-risk neuroblastoma. Our team includes: Pediatrichematologist/oncologists, Stem cell transplant
physicians, Nurse specialists, Nurses, Social workers
Kidney disease, Endocrinology; Our team has many
years of experience and a great depth of knowledge
about kidney diseases affecting children andadolescents. Furthermore, the Division of Endocrinology at The University of Tokyo Hospital treats
more children with hormone (endocrine) disorders
At Department of Pediatrics, we pay for all treatment;
McDonald House housing for families with options
for bigger accommodations with low price staying.
Our onsite school allows patients to keep up with theirschool program back home. We offer numerous otherservices for our families, including psychosocial help
for caregivers and siblings coping with a child’s
diseases diagnosis; child life specialists, translation
help for those who do not speak Japanese as a first
language, Niko-niko Volunteer and much more.
Many patients need to stay long in the hospital. We
provide an official in-hospital school ”Kodama
Gakkyu” where patients receive education and havechances to communicate with other patients as well as
their family members. “Niko-niko Volunteer”
members, an official volunteer group in the hospital,
visit the pediatric ward every weekday to play withpatients and help their mothers, providing enormous
comfort to both patients and their mothers. Various
activities are scheduled for patients in the hospitalsuch as a Tanabata festival, a Christmas party andmusic concerts. All the residents, fellows and nurses
participate in these activities. We have two child carespecialists in the pediatric ward.

Teaching activities
The staff members and the visiting lecturers givelectures of general pediatrics to the second year
students. The third year students have clinicalclerkship in the inpatient ward for 2 weeks. During

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bedside learning, teaching sessions on variety ofpediatric fields are held every day. We also offer anelective clinical clerkship course for selected students
in their fourth year. In the outpatient learning of the
fourth year students, students take histories andperform physical examinations of patients under thesupervision of the teaching staff. On the last day ofclinical learning, the Professor and an Associate
Professor evaluate the students’ achievements. We
also provide variety of online contents for students.

Research activities
Our departments have the following researchgroups: nephrology, hematology/oncology, neurology,
cardiology, endocrinology/metabolism, immunology/
allergy, and neonatology. We also have multidisciplinary research groups and laboratories such ascell biology, genetic molecular biology andepidemiology. The main subjects of research during
the last year are listed as follows.
Hematology/Oncology group:
Our division has performed whole-genome
sequencing (WGS), whole-exome sequencing (WES)
and RNA-Sequencing with more than 500 pediatriccancer patients to reveal novel mechanism of pediatrictumors such as leukemia, rhabdomyosarcoma andneuroblastoma.
Nephrology group:
Our aim is to reveal the molecular mechanism ofpediatric kidney diseases. We identified novel
causative mutations on several proteinuric diseases
including pediatric nephrotic syndrome and congenital
anomalies of the kidney and urinary tract. We also
analyzed pathogenic mechanism of nail-patella
syndrome.
Endocrinology and Metabolism group:
We are analyzing genes and mechanisms involvedin endocrinology and bone diseases. We analyzed thefunction of the novel gene identified in a rarecongenital disease using model animals and iPS cells.
We also analyzed the responsible gene for hereditary
rickets and found novel mutations and etiology.
Cardiology group:
To reveal the molecular mechanism of cardiomyopathy, we perform genome-wide association
studies and generating animal model for cardio-

myopathy. Also we perform hemodynamic analysis
for patients with congenital heart disease using
clinical imaging modalities.
Neurology Group:
The pathogenetic mechanism of acute encephalopathy is investigated. Using mouse models of tuberous
sclerosis, the pathogenetic mechanism of neurodevelopmental disorders is investigated. Based onearlier research, a clinical trial of valganciclovir, anantiviral drug for cytomegalovirus infection has been
conducted for infants with congenital cytomegalovirus
infection.
Neonatology group:
Epigenetic changes in cord blood and postnatal
peripheral blood of preterm and SGA infants areinvestigated using epigenome-wide methylation
analysis. Influence of microbiome on neonatal
immune function is also investigated. Neonatal brain
function has been investigated using near infra-red
spectro-scopy (NIRS) with researchers of Departmentof Education. Cytokine profiles have been
investigated in order to elucidate pathophysiology ofseveral diseases in perinatal period.

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Matsumoto H, Yamanaka G, Kikuchi K, Kuki I,
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Ohta M, Yamagata T, Takanashi JI, Kubota M,
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36. Shibata Y, Maruyama H, Hayashi T, Ono H,
Wada Y, Fujinaga H, Fujino S, Nagasawa J,
Amari S, Tsukamoto K, Ito Y: Effect andComplications of Everolimus Use for Giant
Cardiac Rhabdomyomas with Neonatal Tuberous
Sclerosis. AJP Rep 2019; 9: e213-e217.
37. Shiraga K, Ono K, Inuzuka R, Asakai H, Ookubo
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38. Takamori A, Izawa K, Kaitani A, Ando T, Okamoto
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Watanabe D, Ando T, Ide T, Matsuzawa M, Maeda
K, Nakano N, Tamura N, Ikeda K, Ebihara N,
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Identification of inhibitory mechanisms in
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Immunol 2019; 143: 1231-1235.
39. Takano T, Akagi M, Takaki H, Inuzuka R,
Nogimori Y, Ono H, Kaneko M, Hagiwara N: Sex
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Psychiatry Clin Neurosci 2019; 73: 649-659.

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Department of Pediatric Surgery
Professor
Jun Fujishiro, M.D., Ph.D.

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

Research Associate
Chizue Ichijo, M.D.,Ph.D.

Eiichiro Watanabe, M.D., Ph.D.

Tomohiro Sunouchi, M.D.

Homepage

Kotaro Tomonaga, M.D.

Yasuo Watanabe, 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, one
lecturer, five research associates and nine graduate
students. More than 20 members of our department
shoulder the clinical work as pediatric surgeons.

191

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 400 patients a year are
hospitalized within it. Most operation cases are
inguinal hernia, but we manage other cases such as
respiratory surgery disease, neonatal digestive organ
obstructions, infant malignant tumors such as Wilms'
tumor and neuroblastoma, biliary tract diseases suchas biliary tract dilatation and biliary atresia,
respiratory anomalies such as tracheal stenosis andlung cysts, gastrointestinal anomalies, and urologicaldisorders including hydronephrosis and vesicoureteral
reflux.
We work with other pediatric surgery teams at otherinstitutions who perform endoscopic surgery (laparoscopic surgery/thoracoscopic surgery). We havedeveloped an endoscopic surgery technique forpediatric diseases not covered by insurance, for cases
requiring advanced medical care. Furthermore, we
surgically manage seriously ill, mentally andphysically handicapped infants, as well as patientswith intractable nervous system diseases, to improvetheir quality of life, and we cooperate withpediatricians (neonatologists) to treat patients withprenatal diagnoses.

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

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192

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K, Mushiake S, Ida S, Fujishiro J, Yamashita Y,
Taguchi T, Yamamoto K. Clinical Features,
Molecular Genetics, and Long-Term Outcome inCongenital Chloride Diarrhea: A Nationwide
Study in Japan. J Pediatr. 214 2019. PMID:
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Ishimaru T, Fujiogi M, Michihata N, Matsui H,
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H. Impact of congenital heart disease on
outcomes after primary repair of esophageal
atresia: a retrospective observational study usinga nationwide database in Japan. Pediatr Surg Int.
35(10) 2019. PMID: 31396739
Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Early Outcomes of
Laparoscopic Versus Open Surgery for Urachal
Remnant Resection in Children: A Retrospective
Analysis Using a Nationwide Inpatient Databasein Japan. J Laparoendosc Adv Surg Tech A. 29(8)2019. PMID: 31313966
Fujiogi M, Goto T, Yasunaga H, Fujishiro J,
Mansbach JM, Camargo CA Jr., Hasegawa K.
Trends in bronchiolitis hospitalizations in the
United States, 2000-2016. Pediatrics. 144(6)2019. PMID: 31699829
Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Ishimaru T, Fujishiro J. Factors
affecting successful atropine therapy for infantile
hypertrophic pyloric stenosis: a retrospective
analysis using a Nationwide Database in Japan.
Ann Clin Epidemiol. 1 2019.
Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Outcomes Following
Laparoscopic Versus Open Surgery for PediatricInguinal Hernia Repair: Analysis using a National
Inpatient Database in Japan. J Pediatr Surg. 54(3)2019. PMID:29661573
Kawashima Y, Watanabe E, Umeyama T,
Nakajima D, Hattori M, Honda K, Ohara O.
Optimization of Data-Independent Acquisition
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20(23) 2019. PMID: 31779068
Sakamoto T, Fujiogi M, Matsi H, Fushimi K,
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Esophageal Cancer: A Nationwide Retrospective
Analysis. Ann Surg. 2019. PMID: 31356263(9) Sakamoto T, Fujiogi M, Matsui H, Fushimi K,
Yasunaga H. Clinical Features and Outcomes ofNonocclusive Mesenteric Ischemia After Cardiac
Surgery: A Retrospective Cohort Study. Heart
Vessels. 35(5) 2019. PMID: 31679059(10) Komura M, Komura H, Satake R, Suzuki K,
Yonekawa H, Ikebukuro K, Komuro H, Hoshi K,
Takato T, Moriwaki T, Nakayama Y. Fabricationof an anatomymimicking BIO-AIR-TUBE withengineered cartilage. Regen Ther. 11 2019.
PMID: 31453272(11) Hayashi K, Ishimaru T, Kawashima H.
Reoperation After Laparoscopic Inguinal Hernia
Repair in Children: A Retrospective Review. J
Laparoendosc Adv Surg Tech A. 29(10) 2019.
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Shimojima N, Sasaki H, Nio M, Tahara K,
Kanamori Y, Shinkai M, Yamamoto H, Sugawara
Y, Hibi T, Ishimaru T, Kawashima H, Koga H,
Yamataka A, Uchida H. Multicenter, retrospective, comparative study of laparoscopic andopen Kasai portoenterostomy in children withbiliary atresia from Japanese high-volume
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PMID: 30488647(13) Hosokawa T, Yamada Y, Takahashi H, Tanami Y,
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Tanami Y, Sato Y, Ishimaru T, Kawashima H,
Hosokawa M, Oguma E, Yamada Y. Ultrasound
Evaluation of Dermal Sinuses/Fistulas in
Pediatric Patients. J Ultrasound Med. 38(12)2019. PMID: 31063247(15) Ishimaru T, Deie K, Kawashima H, Sumida W,
Kakihara T, Katoh R, Aoyama T, Hayashi K.
Comparison of Three- and Two-Dimensional
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PMID: 31483194

Reproductive, Developmental andAging Sciences
3. Aging Sciences

194

Department of Geriatric Medicine
Department of Aging Research
Professor
Masahiro Akishita, MD, PhD.

Associate Professor
Sumito Ogawa, MD, PhD.

Lecturer
Taro Kojima, MD, PhD.

Masaki Ishii, MD, PhD.

Research Associate
Yumi Kameyama, MD, PhD.

Mitsutaka Yakabe, MD, PhD.

Michiko Nanao, MD, PhD.

Yoshitaka Kase, MD, PhD.

Homepage http://www.h.u-tokyo.ac.jp/geriatrics/
Introduction and Organization
The Department of Geriatric Medicine wasestablished in 1962, as the first geriatric department
in Japan.
Since elderly patients tend to have multiple organ
disorders, these patients should be taken cared as awhole from multiple points of view. In addition,
symptoms, signs and responses to the treatment in theelderly patients could be quite different from theyounger counterparts. Specific knowledge on thephysiological and metabolic changes with aging isnecessary when these elderly patients are treated.
Quality of life of the patients is another point of viewwhich should be emphasized. The department belongs
to the division of Internal Medicine. The staff includes
one professor, one associate professor, two lecturers,
and 6 assistant professors.
Our sub-specialty includes pneumology, cardiology,
neurology, hematology, endocrinology, and bonemetabolism, besides geriatrics.The main objective ofour research is to elucidate the pathophysiology of
aging process and to understand elderly patients fromviewpoints of basic aging science using molecularbiology technique and clinical aspects using the recent
advancement of technology and geriatric assessment.

Clinical activities
In the clinical ward, there are approximately 20
patients who are taken care of by junior, senior andchief residents of our staff. Because senior and chief
residents are very experienced, they team up with ajunior resident, give instructions as to the assessmentof the patient's problem, making of future plans, andhelp the residents with various procedures. Very
important issues are discussed and decisions are madein weekly professor's round.

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 through195

lectures in a case-oriented manner with an emphasis
placed on the multidisciplinary basis of geriatricpatients.

Research
Various studies have been done over a wide rangeof field, such as clinical observational studies or basic
molecular studies.
1) Research on the molecular mechanism ofvascular calcification
2) Regulation of vascular function by sex hormone
3) Molecular biology for the control of aging:
Association of vascular and neuronal senescence and the role of Sirt1
4) Molecular biology and treatment of sarcopenia5) Multicenter-investigation of the optimal treatment strategy for hypertension or lipid disorderin the elderly
6) Clinical study on metabolic syndrome in theelderly7) Biomarkers of dementia, caregiver’s stress andgeriatric syndromes8) Research on appropriate healthcare for theelderly including pharmacotherapy9) Expression and regulation of nuclear receptors
in osteoblast and osteoclast10) Molecular mechanism under the treatment of
osteoporosis11) Genetic analysis of osteoporosis and osteoarthritis
12) Identification and functional analysis of thetarget gene networks associated with hormone
responsiveness in prostate and breast cancers13) Role of nuclear receptors in senescence andcarcinogenesis14) Molecular mechanism of vitamin K function
and its roles in aging
15) Diagnosis and prevention of aspiration pneumonia
16) Novel roles of antimicrobial peptide, defensin17) Adrenomedullin and airway hyperresponsiveness18) Klotho protein and vitamin D in lung19) Clinical investigation of sleep-related breathing
disorderPublications
Original Article
1. Adomi M, Iwagami M, Kawahara T, Hamada S,
Iijima K, Yoshie S., Ishizaki T, Tamiya N. Factors
associated with long-term urinary catheterisationand its impact on urinary tract infection amongolder people in the community: A populationbased observational study in a city of Japan. BMJ
Open. 2019 Jun 19; 9(6): e028371. doi: 10.1136/
bmjopen-2018-028371.
2. Chen LK, Woo J, Assantachai P, Auyeung TW,
Chou MY, Iijima K, Jang HC, Kang L, Kim M,
Kim S, Kojima T, Kuzuya M, Lee JSW, Lee SY,
Lee WJ, Lee Y, Liang CK, Lim JY, Lim WS, Peng
LN, Sugimoto K, Tanaka T, Won CW, Yamada M,
Zhang T, Akishita M, Arai H. Asian Working
Group for Sarcopenia: 2019 Consensus Update on
Sarcopenia Diagnosis and Treatment. Journal of
the American Medical Directors Association.
2020;21(3):300-307.
3. Hamada S, Kojima T, Maruoka H, Ishii S, Hattori
Y, Okochi J, Akishita M. Utilization of drugs forthe management of cardiovascular diseases atintermediate care facilities for older adults inJapan. Arch Gerontol Geriatr. 2020;88:104016.
doi: 10.1016/j.archger.2020.104016.
4. Hamada S, Kojima T, Sakata N, Ishii S, Tamiya
N, Okochi J, Akishita M. Drug costs in long-termcare facilities under a per diem bundled payment
scheme in Japan. Geriatr Gerontol Int. 2019
Jul;19(7):667-672. doi: 10.1111/ggi.13663. Epub
2019 Apr 9. PubMed PMID: 30968552.
5. Hamada S, Ohno Y, Kojima T, Ishii S, Okochi J,
Akishita M. Prevalence of cytochrome P450mediated potential drug-drug interactions inresidents of intermediate care facilities for older
adults in Japan. Geriatr Gerontol Int. 2019
Jun;19(6):513-517. doi: 10.1111/ggi.13652. Epub
2019 Mar 25. PubMed PMID:30912281.
6. Hamada S, Takahashi H, Sakata N, Jeon B, MoriT, Iijima K, Yoshie S, Ishizaki T, Tamiya N.
Associations of household income with healthservices utilization and health care expendituresin people aged 75 years or older in Japan: apopulation-based study using medical and longterm care insurance claims data. Journal of

196

Epidemiology. 2019 Oct 5; 29(10): 377-383. doi:
10.2188/jea.JE20180055
7. Hashimoto R, Fujii K, Shimoji S, Utsumi A,
Hosokawa K, Tochino H, Sanehisa S, Akishita M,
Onda M. Study of pharmacist intervention inpolypharmacy among older patients: Nonrandomized, controlled trial. Geriatr Gerontol Int.
2020;20:229-237. doi: 10.1111/ggi.13850.
8. Hashizume T, Son BK, Taniguchi S, Ito K, Noda
Y, Endo T, Nanao-Hamai M, Ogawa S, Akishita
M. Establishment of Novel Murine Modelshowing
Vascular
Inflammation-derived
Cognitive Dysfunction. Sci Rep. 2019; 9(1):4023.
9. Hattori Y, Kojima T, Komura H, Ura N, Akishita
M. Percutaneous Endoscopic Gastrostomy Tube
Removal for Patients With Advanced Dementia:
Case Series Study. Ann Geriatr Med Res. 2019
Mar;23(1):27-30.
10. Ishii M, Yamaguchi Y, Hamaya H, Ogawa S,
Imura M, Akishita M. Characteristics of factors
for decreased lung function in elderly patientswith type 2 diabetes. Sci Rep. 2019 Dec
27;9(1):20206. doi: 10.1038/s41598-019-56759-3.
11. Ishiura H, Shibata S, Yoshimura J, Suzuki Y, Qu
W, Doi K, Almansour MA, Kikuchi JK, Taira M,
Mitsui J, Takahashi Y, Ichikawa Y, Mano T,
Iwata A, Harigaya Y, Matsukawa MK,
Matsukawa T, Tanaka M, Shirota Y, Ohtomo R,
Kowa H, Date H, Mitsue A, Hatsuta H, Morimoto
S, Murayama S, Shiio Y, Saito Y, Mitsutake A,
Kawai M, Sasaki T, Sugiyama Y, Hamada M,
Ohtomo G, Terao Y, Nakazato Y, Takeda A,
Sakiyama Y, Umeda-Kameyama Y, Shinmi J,
Ogata K, Kohno Y, Lim SY, Tan AH, Shimizu J,
Goto J, Nishino I, Toda T, Morishita S, Tsuji S.
Noncoding CGG repeat expansions in neuronal
intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat
Genet. 2019 ;51 (8):1222-1232.
12. Ishizaki T, Mitsutake S, Hamada S, Teramoto C,
Shimizu S, Akishita M, Ito H. Drug prescription
patterns and factors associated with polypharmacy in >1 million older adults in Tokyo.
Geriatr Gerontol Int. 2020 Feb 12. [Epub ahead ofprint] doi: 10.1111/ggi.13880.
13. Iwagami, M., Taniguchi, Y., Jin, X., Adomi, M.,
Mori, T., Hamada, S., Shinozaki, T., Suzuki, M.,

Uda, K., Ueshima, H., Iijima, K., Yoshie, S.,
Ishizaki, T., Ito, T., & Tamiya, N. Association
between recorded medical diagnoses andincidence of long-term care needs certification: A
case control study using linked medical and longterm care data in two Japanese cities. Annals ofClinical Epidemiology. 2019; 1(2): 56-68.
14. Kameyama M, Umeda-Kameyama Y, Ogawa S.
Model for age-dependent decline in dopaminetransporter. Ann Nucl Med. 2019;33(10):783-784.
15. Kase Y, Otsu K, Shimazaki T, Okano H.
Involvement of p38 in Age-Related Decline in
Adult Neurogenesis via Modulation of Wnt
Signaling. Stem Cell Reports. 2019;12(6):1313–
1328. doi:10.1016/j.stemcr.2019.04.010
16. Kojima T, Matsui T, Suzuki Y, Takeya Y, Tomita
N, Kozaki K, Kuzuya M, Rakugi H, Arai H,
Akishita M. Risk factors for adverse drug
reactions in older inpatients of geriatric wards at
admission: Multicenter study. Geriatr Gerontol
Int. 2020 Feb;20(2):144-149. doi: 10.1111/ggi.
13844.
17. Kunieda K, Fujishima I, Wakabayashi H, Ohno T,
Shigematsu T, Itoda M, Mori T, Machida N,
Ogawa S. Relationship between tongue pressure
and pharyngeal function using high resolution
manometry in older dysphagia patients withsarcopenia. Dysphargia 2020 Mar 5. doi: 10.1007/
s00455-020-10095-1.
18. Kuroda N, Hamada S, Sakata N, Jeon B, Iijima K,
Yoshie S, Ishizaki T, Jin X, Watanabe T, Tamiya
N. Antipsychotic use and related factors amongpeople with dementia aged 75 years or older inJapan: a comprehensive population-based estimation using medical and long-term care data. Int J
Geriatr Psychiatry. doi: 10.1002/gps.5041. 2019;34(3): 472-479.
19. Mori T, Hamada S, Yoshie S, Jeon B, Jin X,
Takahashi H, Iijima K, Ishizaki T, Tamiya N. The
Associations of multimorbidity with the sum ofannual medical and long-term care expendituresin Japan. BMC Geriatrics. 2019. doi: 10.1186/
s12877-019-1057-7.
20. Nakatoh S, Fujimori K, Tamaki J, Okimoto N,
Ogawa S, Iki M. Insufficient increase in bonemineral density testing rates and pharmacotherapy after hip fracture in Japan. J Bone

197

Miner Metab. 2020 Mar 7. doi: 10.1007/s00774020-01093-2.
21. Nanao-Hamai M, Son BK, Komuro A, Asari Y,
Hashizume T, Takayama K, Ogawa S, Akishita M.
Ginsenoside Rb1 inhibits vascular calcification asa selective androgen receptor modulator. Eur J
Pharmacol. 2019; 859:172546. doi: 10.1016/j.
ejphar.2019.172546.
22. Noguchi-Watanabe M, Maruyama-Sakurai K,
Yamamoto-Mitani N, Matsumoto Y, Yoshie S,
Iijima K, Yamanaka T, Akishita M. Communitybased program promotes interprofessional
collaboration among home healthcare professionals: A non-randomized controlled study. Geriatr
Gerontol Int. 2019;19:660-666. doi: 10.1111/ggi.
13681.
23. Ogawa S, Hosoi T, Akishita M, Igarashi A.
Malnutrition-related healthcare cost in Japan: An
analysis of health insurance claims data. Asia Pac
J Public Health. 2019; 31(7): 594-602.
24. Shibasaki K, Kin SK, Yamada S, Akishita M,
Ogawa S. Sex-related differences in theassociation between frailty and dietary consumption in Japanese older people: a crosssectional study. BMC Geriatr. 2019;19:211. doi:
10.1186/s12877-019-1229-5.
25. Son BK, Eto M, Oura M, Ishida Y, Taniguchi S,
Ito K, Umeda-Kameyama Y, Kojima T, Akishita
M. Low-intensity exercise suppresses C/EBPδ/
myostatin pathway through androgen receptor inmuscle cells. Gerontology. 2019;16:1-10. doi:
10.1159/000499826.
26. Son BK, Kojima T, Ogawa S, Akishita M.
Testosterone inhibits aortic abdominal aneurysm
formation and vascular inflammation in malemice. J Endocrinol. 2019;241:307-317. doi: 10.
1530/JOE-18-0646.
27. Suthutvoravut U, Takahashi K, Murayama H,
Tanaka T, Akishita M, Iijima K. Association
Between Traditional Japanese Diet Washoku andSarcopenia in Community-Dwelling Older
Adults: Findings from the Kashiwa Study. J Nutr
Health Aging. 2020;24(3):282-289. doi: 10.1007/
s12603-020-1318-3.
28. Suthutvoravut U, Tanaka T, Takahashi K,
Akishita M, Iijima K. Living with Family yet
Eating Alone is Associated with Frailty in

Community-Dwelling Older Adults: The Kashiwa
Study. J Frailty Aging. 2019;8(4):198-204. doi:
10.14283/jfa.2019.22.
29. Takase M, Murayama H, Hirukawa S, Sugimoto
M, Ono S, Tanaka T, Kimata M. Which Aspects
of Dining Style are Associated with Depressive
Mood? A Study at an Assisted Living Facility inJapan. Journal of nutrition in gerontology andgeriatrics. 2019;38(4):377-386.
30. Tamaki J, Fujimori K, Ikehara S, Kamiya K,
Nakato S, Okimoto N, Ogawa S, Ishii S, Iki M.
Estimates of hip fracture incidence in Japan using
the National Health Insurance Claim Database in2012-2015. Osteoporos Int. 2019; 30:975-983.
31. Wada-Isoe K, Kikuchi T, Umeda-Kameyama Y,
Mori T, Akishita M, Nakamura Y; ABC Dementia
Scale Research Group. ABC Dementia ScaleClassifies Alzheimer's Disease Patients into
Subgroups Characterized by Activities of Daily
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Alzheimers Dis. 2020;73(1):383-392. doi: 10.
3233/JAD-190767.
32. Wada-Isoe K, Kikuchi T, Umeda-Kameyama Y,
Mori T, Akishita M, Nakamura Y; ABC Dementia
Scale Research Group. Global Clinical Dementia
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2019; 10;3(1):233-239. doi: 10.3233/ADR190126.
33. Yamaguchi Y, Shiota S, Kusunoki Y, Hamaya H,
Ishii M, Kodama Y, Akishita M, Kida K,
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Polysomnographic features of low arousal
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23(4):1095-1100. doi: 10.1007/s11325-01901786-7. Epub 2019 Jan 26.

Surgical Sciences
1. Surgery

199

Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Sato, Masaaki
Nagayama, Kazuhiro
Kitano, Kentaro
Konoeda, Chihiro
Shiiya, HaruhikoHomepage

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
researches of the thoracic surgery have been
performed since the prewar era at the Second
department of Surgery in this university. Professor
Tsuduki, Masao adopted the modified Coryllos’s
thoracoplasty for the treatment of the pulmonary
tuberculosis in 1934. In 1942, they initiatedthoracoscopy for the treatment of the tuberculosis in
our country. Before the World War II, thoracic surgery
had been performed under spontaneous breathing.
Since 1950 safer anesthesia with endotracheal
intubation has been started in this university.
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 in December 15,
1964 as the first department of this field along withthe cardiovascular surgery in the Japanese national
universities. Since then it has played an internationallyleading role and contributed to development of the
field in our country.
Professors and Chairs in the history of thedepartment are as follows: Kimoto, Seiji (1964.12.15~ 1968.3.31), Saigusa, Masahiro (1968.4.1 ~ 1981.
3.31), Asano, Ken-ichi (1981.4.1 ~ 1986.3.31), Furuse,
Akira (1986.4.1 ~ 1997.3.31) and Takamoto, Shinichi(1997.6.1 ~ 2009.3.31). Nakajima, Jun has taken overthe mission of the department since April 2011.
The Department of Cardiothoracic Surgery has been
divided into two departments, Department of
Cardiovascular Surgery and Department of Thoracic
Surgery in 1997.
The mission of the Department of Thoracic Surgery
is to cure the patients with diseases of the thoracic
organs through clinical works, basic and clinicalresearches, and education of the medical students,
postgraduates, and the surgical residents in our
university.

Clinical activities

Five of six staffs (Nakajima J, Sato M, Nagayama K,
and Kitano K, and Konoeda C), who are certificated200

as members of the Japanese Board of General
Thoracic Surgery, are in charge of the Department ofThoracic Surgery, University of Tokyo Hospital. They
specialize in surgical treatment for diseases of therespiratory and the mediastinal organs and the chest
wall, except for diseases of the esophagus andmammary glands.
Lung cancer is the leading cause of cancer death inour country: In 2018, Ministry of Health, Labour andWelfare documented that number of deaths frommalignant neoplasms was approximately 386 thousandout of 1.36 million total deaths in Japan. Of them, 74
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), i.e. lobectomy and lymphadenectomy through thoracoscopy: Since 2015, morethan 90% of patients with NSCLC has undergone
thoracoscopic surgery in our department. Researches
on less-invasiveness, oncological advantage of thethoracoscopic surgery are thus actively done.
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 41 lung transplants(including 7 living related donor lung transplantations) to date.

Academic education
Medical students in the fifth grade have three-weekprogram on the clinical training of the thoracic and the
cardiovascular surgery. They are also able toparticipate the clinical clerkship of the thoracic
surgery, an elective course for 4 weeks. We also
conduct a further research training for medical
students who like to study thoracic surgery. The
Department of Thoracic Surgery also offers the 4-year
postgraduate program for qualified surgeons who arewilling to specialize in the thoracic surgery. We have a
training program for surgeons who wish to be a boardcertified thoracic surgeon after 4-year residency.

Current researches
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

201(4) Global analysis of oncogenes and suppressor
genes associated with lung cancer.
(5) Application of new fluorescent agents fordiagnosis of lung cancer.
(6) Immunotherapy for lung cancer.
(7) Analysis on mechanisms of acute or chronic
rejection of the allogeneic lung and trachea after
allogeneic transplantation.
(8) Regeneration of the de-cellularized allogeneic
lung with autologous cell seeding(9) Research on extracorporeal membranous oxygenation for bridge use to lung transplantation

Selected publications (2019)
1. Yanagiya M, Kitano K, Yotsumoto T, Takai D,
Asahina H, Nagayama K, Nakajima J. Effect of
normal saline flush injection into a bronchus onlung decellularization. J Thorac Dis. 2019 Dec;
11(12):5321-5327
2. Tian D, Shiiya H, Sato M, Sun CB, Anraku M,
Nakajima J. Tumor location may affect theclinicopathological features and prognosis ofthymomas. Thorac Cancer. 2019 Nov;10(11):2096-2105
3. Nakao K, Anraku M, Karasaki T, Kitano K,
Nagayama K, Sato M, Nakajima J. Impact ofPrevious Malignancy on Outcome in Surgically
Resected Non-Small Cell Lung Cancer. Ann
Thorac Surg. 2019 Dec;108(6):1671-1677
4. Shiiya H, Tian D, Sato M, Karasaki T, Kitano K,
Nagayama K, Anraku M, Kaga K, Matsui Y,
Nakajima J. Differences Between Patients With
Idiopathic Pleuroparenchymal Fibroelastosis andThose With Other Types of Idiopathic Interstitial
Pneumonia in Candidates for Lung Transplants.
Transplant Proc. 2019 Jul-Aug;51(6):2014-2021
5. Kage H, Kohsaka S, Shinozaki-Ushiku A, Hiraishi
Y, Sato J, Nagayama K, Ushiku T, Takai D,
Nakajima J, Miyagawa K, Aburatani H, Mano H,
Nagase T. Small lung tumor biopsy samples arefeasible for high quality targeted next generation
sequencing. Cancer Sci. 2019 Aug;110(8):26522657
6. Matsumura M, Yamashita S, Ishizawa T,
Akamatsu N, Kaneko J, Arita J, Nakajima J,
Kokudo N, Hasegawa K. Oncological benefit ofcomplete metastasectomy for simultaneouscolorectal liver and lung metastases. Am J Surg.
2020 Jan;219(1):80-87
7. Terada Y, Takahashi T, Morita S, Kashiwabara K,
Nagayama K, Nitadori JI, Anraku M, Sato M,
Shinozaki-Ushiku A, Nakajima J. Spread throughair spaces is an independent predictor ofrecurrence in stage III (N2) lung adenocarcinoma.
Interact Cardiovasc Thorac Surg. 2019 Sep 1;
29(3):442-448
8. Sato M, Shinohara Y, Yanagiya M, Karasaki T,
Kitano K, Nagayama K, Nakajima J. Use ofelectromagnetic navigation bronchoscopy invirtual-assisted lung mapping: the effect of on-site
adjustment. Gen Thorac Cardiovasc Surg. 2019
Dec;67(12):1062-1069
9. Ito T, Nakamura A, Tanaka I, Tsuboi Y, Morikawa
T, Nakajima J, Takai D, Fukayama M, Sekido Y,
Niki T, Matsubara D, Murakami Y. CADM1
associates with Hippo pathway core kinases;
membranous co-expression of CADM1 andLATS2 in lung tumors predicts good prognosis.
Cancer Sci. 2019 Jul;110(7):2284-2295
10. Sato M, Murayama T, Nakajima J. Concepts andtechniques: how to determine and identify theappropriate target segment in anatomical
pulmonary segmentectomy? J Thorac Dis. 2019
Mar;11(3):972-986
11. Nozawa H, Takiyama H, Hasegawa K, Kawai K,
Hata K, Tanaka T, Nishikawa T, Sasaki K, Kaneko
M, Murono K, Emoto S, Sonoda H, Nakajima J.
Adjuvant chemotherapy improves prognosis ofresectable stage IV colorectal cancer: acomparative study using inverse probability oftreatment weighting. Ther Adv Med Oncol. 2019
Apr 16; 11:1758835919838960. doi: 10.1177/
1758835919838960. eCollection 2019.
12. Yoshida Y, Manaka T, Nitadori JI, ShinozakiUshiku A, Doke T, Saito T, Sato J, Miyaji T,
Yamaguchi T, Oyama H, Fukayama M, Nakajima
Y, Nakajima J A comparison between 2- and3-dimensional approaches to solid component
measurement as radiological criteria for sublobar
resection in lung adenocarcinoma ≤ 2 cm in size.
Surg Today. 2019 Oct;49(10):828-835
13. Hino H, Karasaki T, Yoshida Y, Fukami T, Sano
A, Tanaka M, Furuhata Y, Kashiwabara K,

202

Ichinose J, Kawashima M, Nakajima J.
Competing Risk Analysis in Lung Cancer Patients
Over 80 Years Old Undergoing Surgery. World J
Surg. 2019 Jul;43(7):1857-1866
14. Sato M, Murayama T, Nakajima J. The
AMAGAMI technique: an easy technique toachieve precise stapling in thoracoscopic
segmentectomy. J Thorac Dis. 2019 Jan; 11(1):276-279
15. Yanagiya M, Matsumoto J, Yamaguchi H,
Nakajima J, Sato M. Effect of patient position
during virtual-assisted lung mapping. J Thorac
Dis. 2019 Jan;11(1):162-170
16. Sato M, Nagayama K, Kobayashi M, Nakajima J.
Virtual-Assisted Lung Mapping 2.0: Preoperative
Bronchoscopic Three-Dimensional Lung Mapping.
Ann Thorac Surg. 2019 Jul;108(1):269-273
17. Yoshida Y, Sakane T, Isogai J, Suzuki Y, Miki S,
Nomura Y, Nakajima J. Computer-assisted
detection of metastatic lung tumors on computed
tomography. Asian Cardiovasc Thorac Ann. 2019
Mar; 27(3):199-207.
18. Okumura M, Yoshino I, Yano M, Watanabe SI,
Tsuboi M, Yoshida K, Date H, Yokoi K, NakajimaJ, Toyooka SI, Asamura H, Miyaoka E. Tumour
size determines both recurrence-free survival anddisease-specific survival after surgical treatment
for thymoma. Eur J Cardiothorac Surg. 2019 Jul
1; 56(1):174-181
19. Watanabe K, Kage H, Shinozaki-Ushiku A,
Kohsaka S, Takai D, Nakajima J, Miyagawa K,
Aburatani H, Mano H, Nagase T. SpontaneousTransdifferentiation from Small Cell Lung
Carcinoma to Squamous Cell Carcinoma. J
Thorac Oncol. 2019 Feb;14(2):e31-e34
20. Yanagiya M, Matsumoto J, Kawahara T,
Yamaguchi H, Nagayama K, Anraku M, Sato M,
Nakajima J. Influence of Smoking and Histologic
Subtype on Developing Extrathymic Malignancy
in Thymoma Patients. Ann Thorac Surg. 2019
May;107(5):1532-1539
21. Nakajima J. Advances in techniques for
identifying small pulmonary nodules. Surg Today.
2019 Apr;49(4):311-315
22. Endo S, Ikeda N, Kondo T, Nakajima J, Kondo H,
Shimada Y, Sato M, Toyooka S, Okada Y, Sato Y,
Yoshino I, Okada M, Okumura M, Chida M,

Fukuchi E, Miyata H. Risk assessments forbroncho-pleural fistula and respiratory failure
after lung cancer surgery by National Clinical
Database Japan. Gen Thorac Cardiovasc Surg.
2019 Mar; 67(3):297-305
23. Kitano K, Sato M. Latest update about virtualassisted lung mapping in thoracic surgery. Ann
Transl Med. 2019 Jan;7(2):36.

203

Department of
Cardiac Surgery
Professor
Minoru Ono, M.D.

Associate Professor
Yasutaka Hirata, M.D.

Lecturer
Haruo Yamauchi, M.D., Osamu Kinoshita, M.D., Mitsutoshi Kimura, M.D.

Associate
Akihiro Masuzawa, M.D., Shogo Shimada, M.D., Ando Masahiko, M.D.,
Itoda Yoshifumi, M.D., Hyoe Komae, M.D., Miyuki Shibata, M.D., Yasuhiro Hoshino, M.D.
Lee Yangsin, M.D., Inoue Takafumi, M.D.

Homepage

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

Introduction and Organization
Cardiac surgery in the Department was initiated by
Dr. Seiji Kimoto, who performed ligation of patentductus arteriosus in June, aortic arch aneurysm
resection in July and first-in-Japan Blalock-Taussig
operation for Tetralogy of Fallot in October in 1951. Healso started implantation of alcohol-preserved aortic
homograft for abdominal aortic aneurysm in 1952, andclosed commissurotomy for mitral valve stenosis in
1954. The first open heart surgery (atrial septal defectclosure) was performed in 1955, using selective brain
perfusion cooling method that was developed in the
Department.
Establishment of Department of Thoracic Surgery in
the University of Tokyo Hospital was approved by thegovernment first in Japan December 15, 1964. Under
the leadership of Professor Kimoto excellent researchworks were created especially on pacemaker andartificial heart, and many opinion leaders were
produced. Dr. Masahiro Saigusa, the second Professor,
endeavored to make open heart surgery safer byintroducing new- generation heart-lung machines to the

Department. Dr. Kenichi Asano, the third Professor,
started posterior-leaflet preserving mitral valve
replacement first in Japan. He also dramatically
improved surgical results of Tetralogy of Fallot. Dr.
Akira Furuse, the fourth Professor, modernizedmanagement of extremely busy clinical works. During
this time, the Department was divided into two
Divisions, Cardiovascular and General thoracic, due tothe University policy of Graduate-school.
Dr. Shinichi Takamoto assumed the fifth Professor in
June 1997. He rearranged clinical teams into threegroups (adult cardiac disease, thoracic aortic diseaseand congenital heart disease) to adapt the rapid
progress of cardiovascular surgery.
Dr. Minoru Ono was elected as the sixth Professor in
November 2009. Advanced Heart Failure Center was
open on the 5th Floor of Hospital Building B, January
2018 to cope with an increasing number of patients who
require ventricular assist device and hearttransplantation treatment. Present staffs are one Chief
Professor, one Associate Professor and three Lecturer
and seven Associates.

204

Clinical Activities
Clinical conference starts at 7:15 am in weekdays.
Regular surgery is scheduled on Monday, Wednesday
and Friday. Patient round is on Tuesday. Adult patientsare hospitalized in the South Wing of 5th floor, andpediatric patients in the South Wing of 2nd floor. Clinics
are open Monday through Friday for the follow-up visit
as well as for patient referral.
Case volume in recent years has been over 380,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There are
13 Board-certified surgeons, each of whom has his own
subspecialty among adult cardiac, thoracic aortic orcongenital heart disease. We are famous for off- pumpcoronary artery bypass surgery, mitral valve plasty,
heart transplantation, ventricular assist device
implantation, aortic valve sparing root replacement,arch replacement, treatment of extended thoracic aortic
aneurysm and repair of complex congenital heartdiseases, such as Jatene, Fontan and Norwood
operations. Transcatheter aortic valve replacement was
initiated in 2015. Many high-risk very old patients withaortic valve stenosis were successfully treated.
The University of Tokyo Tissue Bank was founded
in 1997, based on the Department of Cardiovascular
Surgery. The Bank has been actively promoting
procurement, preservation and shipping of humanvalve and blood vessel allograft in Japan. We take thelead in surgical treatment using allograft for severe
active endocarditis or infection of aortic aneurysm or
vascular prosthesis. Surgical treatment using allograft
was approved for health insurance coverage by theGovernment in 2018. As of March 2020, 145 cases ofheart transplantation including 14 pediatric patientsand 347 cases of ventricular assist device (VAD)
implantation including 217 implantable continuousflow VADs were performed in The University Hospitalwith excellent long-term survival.

Teaching Activities
We have the chair of systematic review of cardiovascular surgery in the spring term at the 2nd grade of
medical course. We expose the students to daily clinicalworks as well as research works during the course of“Free Quarter” and “Research Lab Visit”, which arescheduled in the summer and spring vacations at 1st and2nd grade. Joint lectures with the Cardiology
Department are scheduled 3rd through 4th grades. Eachstudent is assigned one or two cardiovascular surgicalcases in the Regular Clinical Clerkship, in which he/she
is required to learn preoperative patient evaluation andmanagement, surgical treatment and postoperative care,based on participatory practice. There are also fifteen
small key-lectures on cardiovascular surgery. Hands-on
practice is provided during the Advanced ClinicalClerkship one-month course in the last months of 3rd
grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/subspecialty training
programs to allow the residents to pass Cardiovascular
Board Examination by 9-10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments, it isessential for cardiothoracic surgical department of the
University to have active research programs in clinicaland basic subjects. The Cardiothoracic Department of
the University of Tokyo has created highly active
research programs in the every field of cardiothoracic
surgery, played an internationally leading role andcontributed to its development. A research meeting isheld once a month on a research project for every
member of the department to understand and to makefree thorough discussions of the subject.
Basic and/or clinical research activities are focusedon 1) establishment of recovery and weaning protocolsof left ventricular assist device, 2) basic and clinicalresearch on cryopreserved allograft, 3) application ofregenerative medicine to end-stage heart failure, 4)analysis of cardiomyocytes matured and differentiatedfrom iPS cells, 5) mechanism analysis of right heart
failure and development of effective pharmacologicaltherapy, 6) development of versatile suture device, 7)

205

clinical research to test the safety and efficacy ofartificial pancreas during open heart surgery.

References
1. Kinoshita O, Yamauchi H, Motomura N, Ono M.:
Lanthanum carbonate, a phosphate binder, inhibits
calcification of implanted aortic allografts in a rat
model. Gen Thorac Cardiovasc Surg. Gen Thorac
Cardiovasc Surg. 2019 May; 67(5): 413-419.
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Morishita Y, Yanagawa M, Nonaka Y, Ohno Y,
Maruyama S, Oyama K, Seguchi K, Sakurai Y,
Tanaka H, Suzuki M, Masunaga S, Ono K, Higashi
S, Ono M, Nakajima J, Eriguchi M, Takahashi H:
Pilot Study of Single Dose Toxicity Evaluation of
10BSH entrapped WOW emulsion on intra-arterialdelivery in Pig for Neutron Capture Therapy to
Hepatocellular Carcinoma. KUR Report 2019; 29:
11-3
3. Tsuji M, Amiya E, Hatano M, Nitta D, Maki H,
Bujo C, Saito A, Hosoya Y, Minatsuki S, Hara T,
Nemoto M, Kagami Y, Endo M, Kimura M,
Kinoshita O, Nawata K, Morita H, Ono M,
Komuro I.: Abdominal skeletal muscle mass as apredictor of mortality in Japanese patients
undergoing left ventricular assist device implantation. ESC Heart Fail. 2019 Jun; 6(3): 526-535.
PMID: 30929311
4. Imamura T, Kinugawa K, Ono M, Kinoshita O,
Fukushima N, Shiose A, Matsui Y, Yamazaki K,
Saiki Y, Usui A, Niinami H, Matsumiya G, Arai H,
Sawa Y.: Implication of Preoperative Existence ofAtrial Fibrillation on Hemocompatibility-Related
Adverse Events During Left Ventricular Assist
Device Support. Circ J. 2019 May 24; 83(6): 12861292. PMID: 31019163
5. Harada S, Aoki K, Okamoto K, Kinoshita O,
Nawata K, Ishii Y, Tateda K, Sasaki M, Saga T,
Doi Y, Yotsuyanagi H, Moriya K, Ono M.: Leftventricular assist device-associated endocarditis
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patterns. Int J Infect Dis. 2019 Jul; 84: 44-47.
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6. Minegishi S, Kinoshita O, Hoshino Y, Komae H,
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7. Shimamura J, Mizuno T, Takewa Y, Tsukiya T,
Naito N, Akiyama D, Iiduka K, Katagiri N,
Nishimura T, Ono M, Tatsumi E.: Miniaturizedcentrifugal ventricular assist device for bridge todecision: preclinical chronic study in a bovine
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Sato T, Isagawa T, Kido Y, Sakamoto M, Manabe
I, Hirata Y, Komuro I, Ono M.: Therapeutictargeting of mitochondrial ROS ameliorates
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J Pharmacol Sci. 2019 Sep; 141(1): 56-63. PMID
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9. Terada R, Ikeda T, Mori Y, Yamazaki S,
Kashiwabara K, Yamauchi H, Ono M, Yamada Y,
Okazaki H.: Comparison of two point of carewhole blood coagulation analysis devices andconventional coagulation tests as a predicting toolof perioperative bleeding in adult cardiac surgerya pilot prospective observational study in Japan.
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206

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Komuro I, Saiki Y, Saito Y, Sakata Y, Sato N,
Sawa Y, Shiose A, Shimizu W, Shimokawa H,
Seino Y, Node K, Higo T, Hirayama A, Makaya M,
Masuyama T, Murohara T, Momomura SI, Yano
M, Yamazaki K, Yamamoto K, Yoshikawa T,
Yoshimura M, Akiyama M, Anzai T, Ishihara S,
Inomata T, Imamura T, Iwasaki YK, Ohtani T,
Onishi K, Kasai T, Kato M, Kawai M, Kinugasa Y,
Kinugawa S, Kuratani T, Kobayashi S, Sakata Y,
Tanaka A, Toda K, Noda T, Nochioka K, Hatano
M, Hidaka T, Fujino T, Makita S, Yamaguchi O,
Ikeda U, Kimura T, Kohsaka S, Kosuge M,
Yamagishi M, Yamashina A; Japanese Circulation
Society and the Japanese Heart Failure Society
Joint Working Group.: JCS 2017/JHFS 2017
Guideline on Diagnosis and Treatment of Acuteand Chronic Heart Failure - Digest Version. Circ J.
2019 Sep 25; 83(10): 2084-2184. PMID: 31511439
14. Shimada S, Nawata K, Kinoshita O, Ono M:
Mechanical circulatory support for the rightventricle in combination with a left ventricularassist device. Expert Rev Med Devices. 2019 Aug;16(8): 663-673. PMID: 31216915
15. Tsuji M, Hatano M, Yamauchi H, Ono M, Komuro
I: Multiple arteriovenous fistulas after laser leadextraction in heart transplant patient. Eur Heart J
Cardiovasc Imaging. 2019 May 1; 20(5): 511.
PMID: 30629131
16. Tsuji M, Nitta D, Minatsuki S, Maki H, Hosoya Y,
Amiya E, Hatano M, Takimoto E, Kinoshita O,
Nawata K, Ono M, Komuro I.: Emergency
percutaneous coronary intervention for left main
trunk thrombus following orthotopic hearttransplantation. ESC Heart Fail. 2019 Jun; 6(3):575-578. PMID: 30854779
17. Kiriyama H, Kaneko H, Itoh H, Uehara M, Kodera
S, Kiyosue A, Yamauchi H, Daimon M, Ando J,
Morita H, Ono M, Komuro I.: Left Main Coronary
Artery Obstruction by Huge Noncoronary Cusp
Calcification After Transcatheter Aortic Valve
Replacement. JACC Cardiovasc Interv. 2019 Jul 8;12(13): 1285-1287. PMID: 31202950

18. Bujo C, Amiya E, Hatano M, Tsuji M, Maki H,
Hosoya Y, Fujii E, Kamon T, Kojima T, Nawata K,
Kinoshita O, Kimura M, Ono M, Komuro I.:
Clinical impact of newly developed atrial
fibrillation complicated with longstanding
ventricular fibrillation during left ventricular assist
device support: A case report. BMC Cardiovasc
Disord. 2019 Jun 21; 19(1): 151. PMID: 31226943
19. Nakamura M, Hori M, Nakagaito M, Kuwahara H,
Kinoshita O, Ono M, Yokoyama S, Doi T,
Fukahara K, Kinugawa K.: A case of cardiogenic
shock due to acute coronary syndrome successfully
recovered by percutaneous and paracorporeal left
ventricular assist device. J Artif Organs. 2019
Sep;22(3):249-252. PMID: 30937678
20. Tsuji S, Nawata K, Shimada S, Hirata Y, Ono M.:
A superior vena cava to right pulmonary arteryshunt for severe right ventricular outflow tract
stenosis caused by an unresectable cardiac tumor.
J Cardiol Cases. 2019 Nov 13; 21(3):97-100.
eCollection 2020 Mar. PMID: 32153682
21. Hirata Y, Hirahara N, Murakami A, Motomura N,
Miyata H, Takamoto S. Current status ofcardiovascular surgery in Japan, 2015 and 2016: areport based on the Japan Cardiovascular Surgery
Database. 1-congenital heart surgery. Gen Thorac
Cardiovasc Surg. 2019 Sep;67(9):731-735. PMID:
31327137.
22. Sassa T, Nakayama A, Saito A, Soma K, Inuzuka
R, Hirata Y, Komuro I. Combination Therapy ofFenestrated-Fontan Procedure with Medication
Improved Double-outlet Right Ventricle in
Adulthood. J Cardiovasc Imaging. 2019 Oct;27(4):288-289. PMID: 31614402
23. Shimizu H, Endo S, Natsugoe S, Doki Y, Hirata Y,
Kobayashi J, Motomura N, Nakano K, Nishida H,
Okada M, Saiki Y, Saito A, Sato Y, Tanemoto K,
Toh Y, Tsukihara H, Wakui S, Yokomise H,
Masuda M, Yokoi K, Okita Y. Thoracic andcardiovascular surgery in Japan in 2016 : Annual
report by The Japanese Association for Thoracic
Surgery. Gen Thorac Cardiovasc Surg. 2019 Apr;
67(4):377-411. PMID: 30877649.
24. Ozawa Y, Asakai H, Shiraga K, Shindo T, Hirata
Y, Hirata Y, Inuzuka R. Cardiac Rhythm
Disturbances in Heterotaxy Syndrome. Pediatr

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Cardiol. 2019 Jun; 40(5): 909-913. PMID:
30877320.
25. Saito A, Amiya E, Hatano M, Shiraishi Y, Nitta D,
Minatsuki S, Maki H, Hosoya Y, Tsuji M, Bujo C,
Nawata K, Kinoshita O, Kimura M, Endo M,
Kagami Y, Nemoto M, Ikeda Y, Morita H, Ono M,
Komuro I.: Controlling Nutritional Status Score As
a Predictive Marker for Patients With Implantable
Left Ventricular Assist Device. ASAIO J. 2020
Feb; 66(2): 166-172. PMID: 30913100
26. Owada Y, Oshiro Y, Inagaki Y, Harada H,
Fujiyama N, Kawagishi N, Yagisawa T, Usui J,
Akutsu N, Itabashi Y, Saito K, Watarai Y,
Ichimaru N, Imamura R, Kyakuno M, Ide K,
Shibuya Y, Okabe Y, Ono M, Sasaki K, Shiose A,
Yamagishi K, Ohnishi H, Nagashima S, Takahashi
M, Yuzawa K, Okamoto H, Ohkohchi N.: A
Nationwide Survey of Hepatitis E Virus Infection
and Chronic Hepatitis in Heart and Kidney
Transplant Recipients in Japan. Transplantation.
2020 Feb; 104(2): 437-444. PMID: 31205267
27. Watanabe A, Amiya E, Hatano M, Watanabe M,
Ozeki A, Nitta D, Maki H, Hosoya Y, Tsuji M,
Bujo C, Saito A, Endo M, Kagami Y, Nemoto M,
Nawata K, Kinoshita O, Kimura M, Ono M,
Komuro I.: Significant impact of left ventricularassist device models on the value of flow-mediateddilation: effects of LVAD on endothelial function.
Heart Vessels. 2020 Feb; 35(2): 207-213. PMID:
31327031
28. Kinugawa K, Nishimura T, Toda K, Saiki Y,
Niinami H, Nunoda S, Matsumiya G, Nishimura M,
Arai H, Morita S, Yanase M, Fukushima N,
Nakatani T, Sakata Y, Ono M; J-MACS investigators.: The second official report from Japaneseregistry for mechanical assisted circulatory support(J-MACS): first results of bridge to bridge strategy.
Gen Thorac Cardiovasc Surg. 2020 Feb; 68(2):102-111. PMID 31646476
29. Imamura T, Ono M, Kinugawa K, Fukushima N,
Shiose A, Matsui Y, Yamazaki K, Saiki Y, Usui A,
Niinami H, Matsumiya G, Arai H, Sawa Y, UrielN.: Hemocompatibility-related Adverse Events
Following HeartMate II Left Ventricular Assist
Device Implantation between Japan and UnitedStates. Medicina (Kaunas). 2020 Mar; 56(3): 126.
PMID: 32183082

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Department of
Gastrointestinal Surgery
Professor
Yasuyuki Seto M.D., Ph.D.

Associate Professor
Sachiyo Nomura M.D., Ph.D.

Lecturer
Hiroharu Yamashita M.D., Ph.D.

Associates
Koichi Yagi

M.D., Ph.D.

Takako Wakeda M.D., Ph.D.
Yasuhiro Okumura M.D., Ph.D.
Haruki Ogawa M.D.

Homepage

Kotaro Wakamatsu M.D., Ph.D.
Kosuke Hirano M.D., Ph.D.
Haruna Onoyama M.D., Ph.D.
Miho Miyaji M.D.

http://todai3ge.umin.jp/

Bariatric & Metabolic Care (Social Cooperation
Program)
Project Associate Professor
Susumu Aikou M.D., Ph.D.

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 lifespan209

provides a wealth of valuable information concerning
the appropriateness of current treatment strategy, theestablishment of new surgical designs, the development of new basic research activities which can muchcontribute to clinical fields, and indications ofdesirable modes of terminal care.
Fostering good surgeons as well as scientists whomeet both clinical and academic needs has always
been the guiding principle of our department.

Educational Activities:
The new system of clinical clerkship for medical
students has begun from 2013. During those periods,
the students are educated strictly and gently by staffs.
Clinical exercises, e.g., blood sampling, injection, andligation, etc., are performed. They can attend theoperations as an assistant.
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.

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Generally, elective surgery is scheduled on Tuesday，
Wednesday and Thursday. The statistics shows 160
gastric and 80 esophageal cancer surgeries are
performed a year, respectively. Hernia surgery is also
performed. Laparoscopic sleeve gastrectomy formorbid obesity has started in June 2016, and thenumber of cases is steadily increasing. All residents
and medical personnel work with high motivation for
the good of the patients.

References
1. Oya S, Yamashita H, Iwata R, Kawasaki K,
Tanabe A, Yagi K, Aikou S, Seto Y. Perioperative
fluid dynamics evaluated by bioelectrical
impedance analysis predict infectious surgicalcomplications after esophagectomy. BMC Surg.
19(1):184. doi: 10.1186/s12893-019-0652-z、2019
2. Sugawara K, Yagi K, Okumura Y, Nishida M,
Aikou S, Yamashita H, Yamashita H, Seto Y.
Long-term outcomes of multimodal therapy
combining definitive chemoradiotherapy andsalvage surgery for T4 esophageal squamous cell
carcinoma. Int J Clin Oncol. doi: 10.1007/s10147019-01590-z,2019
3. Sugawara K, Yamashita H, Okumura Y, Yagi K,
Yoshimura S, Kawasaki K, Tanabe A, Aikou S,
Seto Y. Relationships among body composition,muscle strength, and sarcopenia in esophageal
squamous cell carcinoma patients. Support Care
Cancer. doi: 10.1007/s00520-019-05110-7,2019
4. Zhang CD, Yamashita H, Seto Y. Gastric cancer
surgery: historical background and perspective inWestern countries versus Japan. Ann Transl Med.
7(18):493. doi: 10.21037/atm.2019.08.48,2019
5. Sasahara A, Tanabe M, Hayashi K, Konishi T,
Oya M, Sakiyama K, Morizono A, Harada M,
Otsuji K, Ishibashi Y, Sato A, Kikuchi Y, Niwa T,
Hinata M, Nishioka K, Seto Y. A case of primarybreast angiosarcoma with multiple discontinuous
small lesions. Surg Case Rep.5(1):157. doi: 10.
1186/s40792-019-0704-8,2019
6. Sugawara K, Yamashita H, Seto Y. Optimal
postoperative surveillance strategy in patients
undergoingneoadjuvant
chemoradiotherapy
followed by surgery for esophageal carcinoma. J

Thorac Dis. 11(Suppl 15):S1874-S1876. doi: 10.
21037/jtd.2019.08.89,2019
7. Urabe M, Yamashita H, Seto Y. Prognostic
significance of neutrophil-to-lymphocyte ratio insolid tumors: a note on methodological concerns.
Biomark Med. 13(17):1429-1432, 2019
8. Seto Y. National Clinical Database (NCD) shows
the trend for centralization of major surgery:
Should it depend on hospital or surgeon volume ?
Ann Gastroenterol Surg. 3(4):340-342,2019
9. Urabe M, Yamashita H, Nishida M, Seto Y. Giant
Brunner's gland adenoma of the duodenum
manifested by melena. ANZ J Surg. 89(9):11661167,2019
10. Sugawara K, Yoshimura S, Yagi K, Nishida M,
Aikou S, Yamagata Y, Mori K, Yamashita H,
Seto Y. Long-term health-related quality of life
following robot-assisted radical transmediastinal
esophagectomy. Surg Endosc. doi: 10.1007/
s00464-019-06923-7.2019
11. Urabe M, Yamashita H, Akamatsu N, Seto Y.
Gastric cancer with solitary liver metastasis
accompanied by cyst formation. ANZ J Surg.
89(6):784-785.2019
12. Zong L, Hattori N, Yasukawa Y, Kimura K, MoriA, Seto Y, Ushijima T. LINC00162 confers
sensitivity to 5-Aza-2'-deoxycytidine via modulation of an RNA splicing protein, HNRNPH1.
Oncogene. 38(26):5281-5293,201913. Sugawara K, Mori K, Yagi K, Aikou S, Uemura Y,
Yamashita H, Seto Y. Association of preoperative
inflammation-based prognostic score withsurvival in patients undergoing salvage esophagectomy. Dis Esophagus. 32(4). pii: doy066. doi:
10.1093/dote/doy066.2019
14. Sugawara K, Yamashita H, Uemura Y, Yagi K,
Nishida M, Aikou S, Nomura S, Seto Y.
Preoperative lymph node status on computed
tomography influences the survival of pT1b, T2
and T3 esophageal squamous cell carcinoma. Surg
Today. 49(5):378-386, 201915. Higashizono K, Fukatsu K, Watkins A, Watanabe
T, Noguchi M, Ri M, Murakoshi S, Yasuhara H,
Seto Y. Influences of Short-Term Fasting andCarbohydrate Supplementation on Gut Immunityand Mucosal Morphology in Mice. JPEN J
Parenter Enteral Nutr. 43(4):516-524,2019

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Hepato-biliary-Pancreatic Surgery
Division and Artificial Organ
and Transplantation Division
Professor and Chairman
Kiyoshi Hasegawa, M.D., Ph.D.

Associate Professor
Junichi Arita, M.D., Ph.D.

Lecturers
Junichi Kaneko, M.D., Ph.D.

Nobuhisa Akamatsu, M.D., Ph.D.

Takeaki Ishizawa, M.D., Ph.D.

Homepages

http://www.h.u-tokyo.ac.jp/patient/depts/hbps_md/index.html
http://www.h.u-tokyo.ac.jp/patient/depts/1512ishokugeka/index.html

Introduction and Organization
The Hepato-Biliary-Pancreatic Surgery Division,
Artificial Organ and Liver Transplantation Division,
Department of Surgery (HPB Surg Division) is
originated from Second Department of Surgery (2ndDept of Surg), which was established in 1893. This
department has a history of over 125 years and has
made tremendous contribution to the Japanese
surgical advancement, such as the foundation ofJapanese Surgical Society. As departments in the styleof graduate school have been increasingly founded in
The Tokyo University, and organ-specific medication
has been progressively recommended, 2nd Dept ofSurg has been replaced to HPB Surg Division sinceJune 1st, 1998.

Clinical Activities
Our division deals with patients with hepato-biliarypancreatic malignancies, liver cirrhosis, and HBP
benign diseases. We specialize in hepatectomies for
HCC and colorectal metastasis, Whipple’s procedure,
and liver transplantations, mainly from living donors.
The overall number of operation is about 500/year.

Elective operations are carried out on Monday,
Wednesday and Friday. The perioperative management is strictly controlled, with nearly zero mortality.
Adjuvant chemotherapy is performed in a style ofprospective clinical trials.

Education
Education for medical students includes systematic
lectures of surgery for M2 students, and clinicallectures and bed-side practice for M3 and M4 students,
in accordance with other surgical and non-surgicaldepartments. Since 2013, the bed-side practice wasrearranged as “Clinical Clerkship,” more practical
medical training than conventional “Bed-Side
Teaching”. Our division precedes Clinical Clerkshipin the Tokyo University Hospital, and recommends
students to aggressively attend the surgical activities.
Clinical Clerkship is designed to consist of 2 parts;
2 weeks clinical practice in Tokyo University and1 week practice in other hospitals. Medical students
are expected to join the surgical team and the surgicaloperations. They can learn about preoperative examinations & care of the patients, informed consents,
diagnosis, presentation at the conferences, operative

212

procedures, and postoperative managements. They
also are expected to submit a report on a theme of
specific surgical topics.

Research
We have published papers mainly on Hepato-BiliaryPancreatic Surgery and liver transplantations. 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 forhepatocellular carcinoma, metastatic colorectal cancer,
neoadjuvant chemotherapy for borderline resectablepancreatic cancer, utility of contrast-enhanced
intraoperative ultrasonography, and preoperative
navigation for hepatic surgery.

Publications (2018-2019)
1. Maki H, Kaneko J, Arita J, Akamatsu N, Kaneko J,
et al. Proximal total splenic artery embolization forrefractory hepatic encephalopathy. J Surg Oncol.
2018;11(2):156.
2. Hoshikawa M, Aoki T, Matsushita H, et al. NK celland IFN signatures are positive prognostic
biomarkers for resectable pancreatic cancer.
Biochem Biophys Res Commun. 2018;495(2):2058.
3. Igaki H. A systematic review of publications on
charged particle therapy for hepatocellular
carcinoma. J Surg Oncol. 2018;23(3):423.
4. Ito K, Kawaguchi Y, Sakamoto Y, et al. Predictors of
Postoperative Non-Chylous Massive Discharge after
Pancreaticoduodenectomy for Pancreatic Ductal
Adenocarcinoma. Dig Surg. 2018;35(3):252.
5. Kaibori M, Yoshii K, Hasegawa K, et al. Treatment
Optimization for Hepatocellular Carcinoma in
Elderly Patients in a Japanese Nationwide Cohort.
Ann Surg. 2018.
6. Kawaguchi Y, Fuks D, Kokudo N, et al. Difficulty of
Laparoscopic Liver Resection: Proposal for a New
Classification. Ann Surg. 2018;267(1):13.
7. Kobayashi Y, Omichi K, Kawaguchi Y, et al.
Intraoperative real-time tissue elastography during
laparoscopic
hepatectomy.
HPB(Oxford).
2018;20(1):93.
8. Kokudo T, Kokudo N, Hasegawa K. Negative phase3 study of (90)Y microspheres versus sorafenib in
HCC. Lancet Oncol. 2018;19(2):e68.
9. Mizumoto M, Okumura T, Hasegawa K, et al.
Partial TIPE ALPPS for Perihilar Cancer. Int J Clin
Oncol. 2018;267(2):e18.
10. Okinaga H, Yasunaga H, Hasegawa K, et al.
Short-Term Outcomes following Hepatectomy in
Elderly Patients with Hepatocellular Carcinoma: An
Analysis of 10, 805 Septuagenarians and 2,381
Octo- and Nonagenarians in Japan. Liver Cancer.
2018;7(1):55.
11. Shimizu A, Hasegawa K, Masuda K, et al. Efficacy
of Hyaluronic Acid/Carboxymethyl Cellulose-Based
Bioresorbable Membranes in Reducing Perihepatic
Adhesion Formation: A Prospective Cohort Study.
Dig Surg. 2018;35(2):95.
12. Shinkawa H, Yasunaga H, Hasegawa K, et al.
Mortality and morbidity after hepatic resection inpatients undergoing hemodialysis: analysis of anational inpatient database in Japan. Surgery. 2018.
13. Shirata C, Hasegawa K, Kokudo T, et al. SurgicalSite Infection after Hepatectomy for Hepatocellular
Carcinoma. Dig Surg. 2018;35(3):204.
14. Takamoto T, Mise Y, Satou S, et al. Feasibility of
Intraoperative Navigation for Liver Resection Using
Real-time Virtual Sonography With Novel
Automatic Registration System. World J Surg. 2018;
42(3):841.
15. Tani K, Shindoh J, Akamatsu N, et al. Management of disappearing lesions after chemotherapy
for colorectal liver metastases: Relation between
detectability and residual tumors. J Surg Oncol
2018;117(2):191.
16. Shirata C, Hasegawa K, Kokudo T, et al. Liver
Resection for Hepatocellular Carcinoma in
Patients with Renal Dysfunction. World J Surg.
2018;42(12):4054-4062.
17. Yamaguchi T, Kokudo T, Akamatsu N, et al. Liver
Regeneration is Preserved After At Least Four
Repeated Liver Resections for Hepatocellular
Carcinoma. World J Surg. 2018;42(12):40704080.
18. Kobayashi K, Kawaguchi Y, Arita J, et al.
Parenchyma-sparing liver resection for hepatocellular carcinoma in left lateral section isassociated with better liver volume recovery. HPB(Oxford). 2018; 20(10): 949-955

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19. Takemura N, Aoki T, Hasegawa K, et al.
Hepatectomy for hepatocellular carcinoma after
perioperative management of portal hypertension.
Br J Surg 2019;106(8):1066-1074.
20. Matsumura M, Yamashita S, Ishizawa T, et al.
Oncological benefit of complete metastasectomy
for simultaneous colorectal liver and lungmetastases. Am J Surg 2020;219(1):80-87.
21. Ito D, Arita J, Yamamoto M, et al. Effect of homeenteral nutrition after pancreaticoduodenectomy.
Nutrition 2019;60:206-211.
22. Shinkawa H, Yasunaga H, Hasegawa K, et al.
Mortality and morbidity after pancreatoduodenectomy in patients undergoing hemodialysis:
Analysis using a national inpatient database.
Surgery 2019;165(4):747-750.
23. Sawai Y, Kokudo T, Sakamoto Y, et al. Stent
placement for benign portal vein stenosis
following pancreaticoduodenectomy in a hybrid
operating room. Biosci Trends. 2019;12(6):641644.
24. Hiroyoshi J, Arita J, Gonoi W, et al. Significanceof Glisson's capsule invasion in patients withcolorectal liver metastases undergoing resection.
Am J Surg 2019;218(5):887-893.
25. Inagaki Y, Kokudo T, Kamiya M, et al. A novel
liver-specific fluorescent anti-cancer drugdelivery system using indocyanine green. Sci Rep
2019;9(1):3044.
26. Shirata C, Kokudo T, Arita J, et al.
Albumin-Indocyanine Green Evaluation (ALICE)
grade combined with portal hypertension topredict post-hepatectomy liver failure. Hepatol
Res 2019;49(8):942-949.
27. Ito K, Matsuura K, Mihara Y, et al. Delivery of
pancreatic digestive enzymes into the gastrointestinal tract by pancreatic exocrine tissuetransplant. Sci Rep 2019;9(1):5922.
28. Kiritani S, Kaneko J, Miyata Y, et al. A selective
oral vasopressin V2-receptor antagonist forpatients with end-stage liver disease awaiting
liver transplantation: a preliminary study. Biosci
Trends 2019;13(2):189-196.
29. Allard MA, Nishioka Y, Beghdadi N, et al.
Multicentre study of perioperative versus adjuvant
chemotherapy for resectable colorectal liver
metastases. BJS Open. 2019;3(5):678-686.

30. Akamatsu N, Hasegawa K, Kokudo N. Response
to Comment on "Factors Associated With the
Early Outcome in Living Donor Liver
Transplantation in Reply to Sonbare". Ann Surg
2019;269(6):e79-e80.
31. Kaibori M, Yoshii K, Hasegawa K, et al.
Treatment Optimization for Hepatocellular
Carcinoma in Elderly Patients in a Japanese
Nationwide Cohort. Ann Surg 2019;270(1):121130.
32. Kokudo T, Hasegawa K, Shirata C, et al.
Assessment of Preoperative Liver Function for
Surgical Decision Making in Patients with
Hepatocellular Carcinoma. Liver Cancer 2019;8(6):447-456.
33. Mise Y, Hasegawa K, Kokudo N. Response toComment on "The Virtual Hepatectomy Changed
the Practice of Liver Surgery: More Details, MoreSignificance". Ann Surg 2019;270(2):e33.
34. Kobayashi K, Kaneko J, Yamaguchi T, et al.
Late-Evening Carbohydrate and Branched-Chain
Amino Acid Snacks Improve the Nutritional
Status of Patients Undergoing Hepatectomy Basedon Bioelectrical Impedance Analysis of Body
Composition. Gastrointest Tumors 2019;6(3-4):
81-91.
35. Shirata C, Hasegawa K. Albumin-indocyanine
green evaluation model in Western population. J
Hepatobiliary Pancreat Sci. 2019;26(9):E7.
36. Kokudo N, Takemura N, Hasegawa K, et al.
Clinical practice guidelines for hepatocellular
carcinoma: The Japan Society of Hepatology
2017 (4th JSH-HCC guidelines) 2019 update.
Hepatol Res 2019;49(10):1109-1113.
37. Shirata C, Hasegawa K, Halkic N, et al. Laennec's
capsule does not exist around the peripheral
hepatic veins. J Hepatobiliary Pancreat Sci. 2019;26(10):E13.
38. Bae SK, Akamatsu N, Togashi J, et al. Hepatitis B
virus recurrence after living donor livertransplantation of anti-HBc-positive grafts: A 22year experience at a single center. Biosci Trends
2019;13(5):448-455.

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

Associate Professor
Motofumi Suzuki, M.D., Ph.D.

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

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

Homepage

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

Introduction and Organization
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 Tuesday, Wednesday, Thursday and Friday. 1481
operations were performed in 2019. The numbers of
main operations are adrenalectomy 16, nephrectomy
27, partial nephrectomy 44, nephroureterectomy 20,
radical cystectomy 19, radical prostatectomy 151,transurethral resection of the bladder tumor (TUR-Bt)
211, transurethral resection of the prostate (TUR-P) 9,
and Robot assisted surgery 200 (radical prostatectomy
151, partial nephrectomy 40, radical cystectomy 9).
At the weekly professor’s round on Wednesday, data

215

of all in patients are presented and appropriate
treatment strategies are recommended for them. On
Wednesday evening, a clinical conference is held for
discussing cases with difficult problems in detail andthe best treatment is chosen for each case.
In out-patient clinic, services are provided from
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 24,896 patientdays from January 2019 to December 2019.

Teaching activities
Systematic urological lectures are provided for second
year medical students. Both clinical lectures and bed
side teaching are scheduled for third and fourth year
medical students. Thirteen times of systematic lectures
are performed by professor, associate professors andinstructors concerning their specialties.
Bed side teaching is concentrated on practical care of
the patients. Teachers give lectures mainly regarding
pre- and post-operative management, indication ofoperation, surgical anatomy and surgical techniques.

Research activities
There are 9 research themes for research as below.
The basic principles for research are program insurgical techniques and therapy for incurable diseases,
which include advanced cancer, renal insufficiency,
sexual dysfunction, and interstitial cystitis. We havepublished approximately 50 English papers every
year.
Renal tumor
Urolithiasis
Kidney Transplantation
Prostate diseases
New surgical technique
Urinary disturbance/ Female Urology
Andrology
Virology

References
1． Stolp J, Zaitsu M, Wood KJ. Immune Tolerance
and Rejection in Organ Transplantation. Methods
Mol Biol, 1899, 159-180,2019.
2． Yoshida M, Matsunaga A, Igawa Y, Fujimura T,
Shinoda Y, Aizawa N, Sato Y, Kume H, Homma
Y, Haga N, Sanada H. May perioperative
ultrasound-guided pelvic floor muscle training
promote early recovery of urinary continence after
robot-assisted radical prostatectomy?. Neurourol
Urodyn, 38(1), 158-164,2019.1.
3． Tsushima T, Miura T, Hachiya T, Nakamura I,
Yamato T, Kishida T, Tanaka Y, Irie S, Meguro N,
Kawahara
T,
Nakajima
N.
Treatment
Recommendations for Urological Symptoms inCancer Patients: Clinical Guidelines from theJapanese Society for Palliative Medicine. J Palliat
Med, 22(1), 54-61,2019.1.
4． Urakami S, Ogawa K, Oka S, Hayashida M,
Hagiwara K, Nagamoto S, Sakaguchi K, Yano A,
Kurosawa K, Okaneya T. Macroscopic hematuria
caused by running‐induced traumatic bladdermucosal contusions. IJU case reports, 2(1), 27-29.
2019.1.
5． Sakamoto S, Miyazawa K, Yasui T, Iguchi T,
Fujita M, Nishimatsu H, Masaki T, Hasegawa T,
Hibi H, Arakawa T, Ando R, Kato Y, Ishito N,
Yamaguchi S, Takazawa R, Tsujihata M, Taguchi
M, Akakura K, Hata A, Ichikawa T.
Chronological changes in epidemiologicalcharacteristics of lower urinary tract urolithiasis
in Japan. Int J Urol, 26(1), 96-101,2019.1.
6． Hakozaki Y, Matsushima H, Murata T, Masuda T,
Hirai Y, Oda M, Kawauchi N, Yokoyama M,
Kume H. Detection rate of clinically significant
prostate cancer in magnetic resonance imaging
and ultrasonography-fusion transperineal targetedbiopsy for lesions with a prostate imaging
reporting and data system version 2 score of 3-5.
Int J Urol, 26(2), 217-222,2019.2.
7． Sugihara T, Yasunaga H , Matsui H, Kamei J ,Fujimura T, Kume H. Regional clinical practicevariation in Urology: Usage Example of the Open
Data of National Database of Health Insurance
Claims and Specific Health Checkups of Japan.
Int J Urol, 26(2), 303-305,2019.2.

216

8． Aizawa N, Ohshiro H, Watanabe S, Kume H,
Homma Y, Igawa Y. RQ-00434739, a novel
TRPM8 antagonist, inhibits prostaglandin E2induced hyperactivity of the primary bladderafferent nerves in rats. Life Sci, 218, 89-95,
2019.2.
9． Zaitsu M, Kaneko R, Takeuchi T, Sato Y,
Kobayashi Y, Kawachi I. Occupational class andmale cancer incidence: Nationwide, multicenter,
hospital-based case-control study in Japan. Cancer
Med, 8(2), 795-813,2019.2.
10． Igawa Y. Peripheral neural control of the lower
urinary tract. Neurourology Theory and Practice,27-36,2019.3.
11． Andersson K-E, Madersbacher H, Altaweel W,
Vasudeva P, Igawa Y. Drug Treatment.
Neurourology Theory and Practice, 231-260,
2019.3.
12． Cuevas AG, Trudel-Fitzgerald C, Cofie L, Zaitsu
M, Allen J, Williams DR. Placing prostate cancer
disparities within a psychosocial context:
challenges and opportunities for future research.
Cancer Causes Control, 30(5), 443-456,2019.3.
13． Yoshihara T, Zaitsu M, Shiraishi F, Arima H,
Takahashi-Yanaga F, Arioka M, Kajioka S,
Sasaguri T. Influence of genetic polymorphisms
and habitual caffeine intake on the changes inblood pressure, pulse rate, and calculation speed
after caffeine intake: A prospective, double blind,randomized trial in healthy volunteers. J
Pharmacol Sci, 139(3), 209-214,2019.3.
14． Kubota S, Zaitsu M, Yoshihara T. Growth
Patterns of Neonates Treated with Thermal
Control in Neutral Environment and Nutrition
Regulation to Meet Basal Metabolism. Nutrients,
11(3), E592,2019.3.
15． Zaitsu M, Kato S, Kim Y, Takeuchi T, Sato Y,
Kobayashi Y, Kawachi I. Occupational Class andRisk of Cardiovascular Disease Incidence inJapan: Nationwide, Multicenter, Hospital-Based
Case-Control Study. J Am Heart Assoc, 8(6),e011350,2019.3.
16． Fujimura T, Igawa Y, Aizawa N, Niimi A,
Yamada Y, Sugihara T, Kamei J, Sato Y,
Matsunaga A, Yoshida M, Shinoda Y, Fukuhara
H, Nakagawa T, Homma Y, Kume H.
Longitudinal change of comprehensive lower

urinary tract symptoms and various types ofurinary incontinence during robot-assisted radical
prostatectomy. Neurourol Urodyn, 38(4), 10671075,2019.4.
17． Azuma T, Sugihara T, Honda S, Yoshizaki U,
Niimi F, Tsuru I, Kume H. Metastatic renal cell
carcinoma regains sensitivity to tyrosine kinase
inhibitor after nivolumab treatment: A case report.
Oncol Lett, 17(4), 4011-4015,2019.4.
18． Watanabe S, Hayashi K, Toh K, Kim HJ, Liu X,
Chaya H, Fukushima S, Katsushima K, Kondo Y,
Uchida S, Ogura S, Nomoto T, Takemoto H,
Cabral H, Kinoh H, Tanaka HY, Kano MR,
Matsumoto Y, Fukuhara H, Uchida S, Nangaku M,
Osada K, Nishiyama N, Miyata K, Kataoka K. In
vivo rendezvous of small nucleic acid drugs withcharge-matched block catiomers to target cancers.
Nat Commun, 10(1), 1894,2019.4.
19． Urakami S, Ogawa K, Oka S, Hagiwara K,
Nagamoto S, Anjiki H, Hayashida M, Yano A,
Sakaguchi K, Kurosawa K, Okaneya T. Effect oftadalafil add-on therapy in patients with persistantstorage symptoms refractory to α1 -adrenoceptor
antagonist monotherapy for benign prostatic
hyperplasia: A randomized pilot trial comparing
tadalafil and solifenacin. Low Urin Tract
Symptoms, 11(3), 109-114,2019.5.
20． Kamei J, Watanabe D, Homma Y, Kume H,
Igawa Y. Feasibility of approximate measurementof bladder volume in male patients using the
Lilium α-200 portable ultrasound bladder scanner.
Low Urin Tract Symptoms, 11(3), 169-173,
2019.5.
21． Zaitsu M, Kim Y, Lee HE, Takeuchi T,
Kobayashi Y, Kawachi I. Occupational classdifferences in pancreatic cancer survival: A
population-based cancer registry-based study inJapan. Cancer Med, 8(6), 3261-3268,2019.6.
22． Takeuchi M, Sato J, Manaka K, Tanaka M,
Matsui H, Sato Y, Kume H, Fukayama M, Iiri T,
Nangaku M, Makita N. Molecular analysis andliterature-based hypothesis of an immunonegative
prostate small cell carcinoma causing ectopic
ACTH syndrome. Endocr J, 66(6),547-554,
2019.6.
23． Suzuki M, Ikegaya H, Idota N, Kawai T,Sato Y,
Kume H. Penile size and stretched rate in a

217Japanese male population: A cross‐sectionalcadaveric study. Int J Urol, 936-7,2019.7.
24． Kawatani M, Yamamoto K, Yamada D, Kamiya
M, Miyakawa J, Miyama Y, Kojima R, Morikawa
T, Kume H, Urano Y. Fluorescence Detection of
Prostate Cancer by an Activatable Fluorescence
Probe for PSMA Carboxypeptidase Activity. J
Am Chem Soc, 141(26), 10409-10416,2019.7.
25． Kume H, Homma Y, Shinohara N, Obara W,
Kondo T, Kimura G, Fujimoto H, Nonomura N,
Hongo F, Sugiyama T, Takahashi M, Kanayama
HO, Fukumori T, Eto M. Perinephric invasion asa prognostic factor in non-metastatic renal cell
carcinoma: analysis of a nation-wide registry
program. Jpn J Clin Oncol, 49(8), 772-779,
2019.8.
26． Akiyama Y, Maeda D, Katoh H, Morikawa T,
Niimi A, Nomiya A, Sato Y, Kawai T, Goto A,
Fujimura T, Fukuhara H, Nakagawa T, Igawa Y,
Ishikawa S, Fukayama M, Kume H, Homma Y.
Molecular Taxonomy of Interstitial Cystitis/
Bladder Pain Syndrome Based on Whole
Transcriptome Profiling by Next-Generation RNA
Sequencing of Bladder Mucosal Biopsies. J Urol,202(2), 290-300,2019.8.
27． Suzuki M, Ikegaya H, Idota N, Kawai T, Sato Y,
Kume H. Penile size and stretched rate in a
Japanese male population: A cross-sectionalcadaveric study. Int J Urol, 26(9), 936-937,
2019.9.
28． Nakamura M, Tsukada H, Seki G, Satoh N,
Mizuno T, Fujii W, Horita S, Moriya K, Sato Y,
Kume H, Nangaku M, Suzuki M. Insulin
promotes sodium transport but suppresses
gluconeogenesis via distinct cellular pathways inhuman and rat renal proximal tubules. Kidney Int,
S0085-2538(19), 30848-8,2019.9.
29． Honda H, Kato H, Olsen MA, Reske KA, Senoh
M, Fukuda T, Tagashira Y, Mahe C, Dubberke
ER, Horiuchi H, Chiba H, Suzuki D, Hosokawa N,
Kitazono H, Norisue Y, Kume H, Mori N,
Morikawa H, Kashiwagura S, Higuchi A, Kato H,
Nakamura M, Ishiguro S, Morita S, Ishikawa H,
Watanabe T, Kojima K, Yokomaku I, Bando T,
Toimoto K, Moriya K, Kasahara K, Kitada S,
Ogawa J, Saito H, Tominaga H, Shimizu Y,
Masumoto F, Tadera K, Yoshida J, Kikuchi T,

Yoshikawa I, Watanabe T, Honda M, Yokote K,
Toyokawa T, Miyazato H, Nakama M. Risk
factors for Clostridioides difficile infection in
hospitalized patients and associated mortality inJapan: a multi-centre prospective cohort study. J
Hosp Infect, S0195-6701(19), 30400-1,2019.9.
30． Nozaki K, Kawai T, Fujimura T, Matsui H,
Teshima T, Oshina T, Takahashi A, Sato Y,
Yamada D, Azuma T, Hotta M, Nakajima K,
Nakayama H, Minamimoto R, Kume H. Carbon
11-choline positron emission tomography/
computed tomography and palliative local therapy
for castration-resistant prostate cancer. Int Urol
Nephrol, 51(10), 1763-1769,2019.10.
31． Suzuki H, Uemura H, Mizokami A, Hayashi N,
Miyoshi Y, Nagamori S, Enomoto Y, Akaza H,
Asato T, Kitagawa T, Suzuki K. Phase I trial of
TAK-385 in hormone treatment-naïve Japanesepatients with nonmetastatic prostate cancer.
Cancer Med, 8(13), 5891-5902,2019.10.
32． Matsuzawa Y, Iwatsuki-Horimoto K, Nishimoto
Y, Abe Y, Fukuyama S, Hamabata T, Okuda M,
Go Y, Watanabe T, Imai M, Arai Y, FouchierRAM, Yamayoshi S, Kawaoka Y. Antigenic
Change in Human Influenza A(H2N2) Viruses
Detected by Using Human Plasma from Aged andYounger Adult Individuals. Viruses, 11(11), E978,2019.10.
33． Kaneko R, Zaitsu M, Sato Y, Kobayashi Y. Riskof cancer and longest-held occupations inJapanese workers: A multicenter hospital-based
case-control study. Cancer Med, 8(13), 6139-6150,
2019.10.
34． Fujimura T.Current status and future perspective
og robot-assisted radical cystectomy for invasive
bladder cancer. Int J Urol, 26(11), 1033-1042,
2019.11.
35． Enomoto Y, Namba Y, Hoshika Y, Komemushi Y,
Mitani K, Kume H, Kobayashi E, Miyama Y,
Homma Y, Ushiku T, Seyama K. A case of
Birt-Hogg-Dubé syndrome implying reduced or
no wild-type folliculin without mutated protein ispathogenic. Eur J Med Genet, 103820,2019.11.
36． Taguchi S, Shiraishi K, Fujimura T, Naito A,
Kawai T, Nakagawa K, Abe O, Kume H,
Fukuhara H. Robot-assisted radical prostatectomy
versus volumetric modulated arc therapy:

218

Comparison of front-line therapies for localized
prostate cancer. Radiother Oncol, 140, 62-67,
2019.11.
37． Tsumura K, Arai E, Tian Y, Shibuya A, Nishihara
H, Yotani T, Yamada Y, Takahashi Y, Maeshima
AM, Fujimoto H, Nakagawa T, Kume H, Homma
Y, Yoshida T, Kanai Y. Establishment of
permutation for cancer risk estimation in theurothelium based on genome-wide DNA
methylation analysis. Carcinogenesis, 40(11),1308-1319,2019.11.
38． Senoh M, Kato H, Honda H, Fukuda T, TagashiraY, Horiuchi H, Chiba H, Suzuki D, Hosokawa N,
Kitazono H, Norisue Y, Kume H, Mori N,
Morikawa H, Kashiwagura S, Higuchi A, Kato H,
Nakamura M, Ishiguro S, Morita S, Ishikawa H,
Watanabe T, Kojima K, Yokomaku I, Bando T,
Toimoto K, Moriya K, Kasahara K, Kitada S,
Ogawa J, Saito H, Tominaga H, Shimizu Y,
Masumoto F, Tadera K, Yoshida J, Kikuchi T,
Yoshikawa I, Watanabe T, Honda M, Yokote K,
Toyokawa T, Miyazato H, Nakama M, Mahe C,
Reske K, Olsen MA, Dubberke ER. Performanceof laboratory tests for detection for Clostridioides
difficile: A multicenter prospective study in Japan.
Anaerobe, 60, 102107,2019.12.
39． Kume H, Homma Y, Shinohara N, Obara W,
Kondo T, Kimura G, Fujimoto H, Nonomura N,
Hongo F, Sugiyama T, Takahashi M, Kanayama
HO, Fukumori T, Eto M. Corrigendum to:Perinephric invasion as a prognostic factor in
non-metastatic renal cell carcinoma: analysis of anation-wide registry program. Jpn J Clin Oncol,
49(11), 1067,2019.12.
40． Nakato R, Wada Y, Nakaki R, Nagae G, Katou Y,
Tsutsumi S, Nakajima N, Fukuhara H, Iguchi A,
Kohro T, Kanki Y, Saito Y, Kobayashi M,
Izumi-Taguchi A, Osato N, Tatsuno K, Kamio A,
Hayashi-Takanaka Y, Wada H, Ohta S, Aikawa M,
Nakajima H, Nakamura M, McGee RC, Heppner
KW, Kawakatsu T, Genno M, Yanase H, Kume H,
Senbonmatsu T, Homma Y, Nishimura S,
Mitsuyama T, Aburatani H, Kimura H, Shirahige
K. Comprehensive epigenome characterization
reveals diverse transcriptional regulation acrosshuman vascular endothelial cells. Epigenetics
Chromatin, 12(1), 77,2019.12.

41． Takayama T, Kubo T, Yamazaki M, Takeshima S,
Komatsubara M, Kameda T, Kamei J, Sugihara T,
Fujisaki A, Ando S, Kurokawa S, Fujimura T.
Sunitinib versus sorafenib for patients withadvanced renal cell carcinoma with renal
impairment before the immune-oncology therapy
era. Jpn J Clin Oncol, 49(12), 1164-1171,2019.12.

219

Department of Surgical Oncology
Professor
Soichiro Ishihara, M.D., Ph.D.

Associate Professor
Hiroaki Nozawa, M.D., Ph.D.

Lecturer
Kazushige Kawai, M.D., Ph.D.
Toshiaki Tanaka, M.D., Ph.D.

Assistant Professor
Keisuke Hata, M.D., Ph.D., Takeshi Nishikawa, M.D., Ph.D., Yasutaka Shuno, M.D., Ph.D.
Kazuhito Sasaki, H.D., Ph.D., Manabu Kaneko, M.D. Ph.D., Shigenobu Emoto, M.D., Ph.D.,
Koji Murono, M.D., Ph.D., Hiroaki Ishii, 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 ten Assistant Professors. The
outpatient office is located on the third floor of the
Outpatient Building. The ward is situated on theeighth floor of the Ward Building. The administrative
office and research laboratories are located in the
Administration and Research Building. Current
activities of the Department of Surgical Oncology inclinical practice, education, and research aresummarized as follows.

Clinical activities
The Department of Surgical Oncology provides
comprehensive evaluation, diagnosis, treatment andmanagement for adult patients with both general andoncologic surgical problems, in the ambulatory as wellas inpatient setting. In particular, we are trying to
identify the best way to treat each patient with theleast surgical stress by minimally invasive surgery
such as laparoscopic surgery and robotic surgery (daVinci Surgical System), and preoperative chemoradiotherapy for rectal cancer. The department is also wellknown for its innovative therapy for inflammatory
bowel disease. Department specialists have expertisein biological cancer immunotherapy, chemotherapy
for a variety of malignancies, and radiotherapy forrectal cancer. The outpatient clinic is open from
Monday through Friday, and twenty-four-hour consultation is available for urgent or emergency problems.
The outpatient clinic is specialized in the lower GI
tract. The Department was responsible for 544
surgically treated inpatients in the year of 2019. 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,220

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
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) Cancer surveillance in ulcerative colitis
3) Carcinogenesis in ulcerative colitis
4) Laparoscopically assisted colon surgery
5) Local immunity in colorectal cancer
6) 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
surgery22126) Application of 3D images and 3D printers incolorectal surgery

References
1. Aoki T, Yamada A, Aoyama K, Saito H, Fujisawa
G, Odawara N, Kondo R, Tsuboi A, Ishibashi R,
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Ishihara S, Matsuda T, Nakahori M, Tanaka S,
Koike K, Tada T. Clinical usefulness of a deeplearning-based system as the first screening on
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2. Aoki T, Yamada A, Aoyama K, Saito H, Tsuboi A,
Nakada A, Niikura R, Fujishiro M, Oka S,
Ishihara S, Matsuda T, Tanaka S, Koike K, Tada T.
Automatic detection of erosions and ulcerations inwireless capsule endoscopy images based on a
deep convolutional neural network. Gastrointest
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3. Arakawa K, Hata K, Nozawa H, Kawai K, Tanaka
T, Nishikawa T, Sasaki K, Shuno Y, Kaneko M,
Hiyoshi M, Emoto S, Murono K, Sonoda H,
Okada S, Ishihara S. Molecular subtypes are
frequently discordant between lesions in patientswith synchronous colorectal cancer: molecularanalysis of 59 patients. Anticancer Res. 2019;39(3): 1425-1432
4. Emoto S, Nozawa H, Kawai K, Hata K, Tanaka T,
Shuno Y, Nishikawa T, Sasaki K, Kaneko M,
Hiyoshi M, Murono K, Ishihara S. Venous
thromboembolism
incolorectal
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Incidence, risk factors, and prophylaxis. Asian J
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5. Hata K, Okada S, Shinagawa T, Tanaka T, Kawai
K, Nozawa H. Meta 窶 紳 nalysis of theassociation of extraintestinal manifestations withthe development of pouchitis in patients withulcerative colitis. BJS open. 2019; 3(4): 436-444.
6. Hata K, Anzai H, Ikeuchi H, Futami K,
Fukushima K, Sugita A, Uchino M, Higashi D,
Itabashi M, Watanabe K, Koganei K, Araki T,
Kimura H, Mizushima T, Ueda T, Ishihara S,
Suzuki Y. Surveillance colonoscopy for ulcerative
colitis-associated colorectal cancer offers betteroverall survival in real-world surgically resectedcases. Am J Gastroenterol. 2019; 114(3): 483-9.

7. Hata K, Watanabe H, Ishihara S, Toyoshima O.
Gauze-like appearance of the sigmoid colon.
Lancet Gastroenterol Hepatol. 2019; 4(5): 412.
8. Hiyoshi M, Nozawa H, Inada K, Koseki T, Nasu
K, Seyama Y, Wada I, Murono K, Emoto S,
Kaneko M, Sasaki K, Shuno Y, Nishikawa T,
Tanaka T, Hata K, Kawai K, Maeshiro T,
Miyamoto S, Ishihara S. Cecal cancer withessential thrombocythemia treated by laparoscopic ileocecal resection: a case report. Surgicalcase reports. 2019; 5(1):101.
9. Hojo D, Murono K, Nozawa H, Kawai K, Hata K,
Tanaka T, Oba K, Ishihara S. Utility of aThree-Dimensional Printed Pelvic Model for
Lateral Pelvic Lymph Node Dissection Education:
A Randomized Controlled Trial. Journal of theAmerican College of the Surgeons. 2019; 229(6):552-559.e3.
10. Hojo D, Nishikawa T, Takayama T, Hiyoshi M,
Emoto S, Nozawa H, Kawai K, Hata K, Tanaka T,
Shuno Y, Kaneko M, Sasaki K, Murono K, Ishii
H, Sonoda H, Hoshina K, Ishihara S. 3D printed
model-based simulation of laparoscopic surgery
for descending colon cancer with a concomitant
abdominal aortic aneurysm. Techniques inColoproctology. 2019; 23(8): 793-797.
11. Horie Y, Yoshio T, Aoyama K, Yoshimizu S,
Horiuchi Y, Ishiyama A, Hirasawa T, Tsuchida T,
Ozawa T, Ishihara S, Kumagai Y, Fujishiro M,
Maetani I, Fujisaki J, Tada T. Diagnostic
outcomes of esophageal cancer by artificial
intelligence using convolutional neural networks.
Gastrointest Endosc. 2019; 89(1): 25-32.
12. Ichihashi Y, Komatsu T, Kyo E, Matsuzaki H,
Hata K, Watanabe T, Ueno T, Hanaoka K, Urano
Y. Separation-Based Enzymomics Assay for the
Discovery of Altered Peptide-Metabolizing
Enzymatic Activities in Biosamples. Anal Chem.
2019; 91(18): 11497-11501.
13. Kanemitsu Y, Shida D, Tsukamoto S, Ueno H,
Ishiguro M, Ishihara S, Komori K, Sugihara K;
Study Group for Nomogram of the JapaneseSociety for Cancer of the Colon and Rectum.
Nomograms predicting survival and recurrence incolonic cancer in the era of complete mesocolic
excision. BJS Open. 2019; 3(4): 539-548.
14. Kitamura C, Sonoda H, Nozawa H, Kano K,

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Emoto S, Murono K, Kaneko M, Hiyoshi M,
Sasaki S, Nishikawa T, Shuno Y, Tanaka T, Hata
K, Kawai K, Aoki J, Ishihara S. The component
changes of lysophospholipid mediators incolorectal cancer. Tumor Biology. 2019; 41(5):1010428319848616.
15. Kohsaka S, Tatsuno K, Ueno T, Nagano M,
Shinozaki-Ushiku A, Ushiku T, Takai D, Ikegami
M, Kobayashi H, Kage H, Ando M, Hata K, Ueda
H, Yamamoto S, Kojima S, Oseto K, Akaike K,
Suehara Y, Hayashi T, Saito T, Takahashi F,
Takahashi K, Takamochi K, Suzuki K, Nagayama
S, Oda Y, Mimori K, Ishihara S, Yatomi Y, Nagase
T, Nakajima J, Tanaka S, Fukayama M, Oda K,
Nangaku M, Miyazono K, Miyagawa K,
Aburatani H, Mano H. Comprehensive assay forthe molecular profiling of cancer by target
enrichment
fromformalin-fixedparaffinembedded specimens. Cancer Sci. 2019; 110(4):1464-1479.
16. Kumagai Y, Takubo K, Kawada K, Aoyama K,
Endo Y, Ozawa T, Hirasawa T, Yoshio T, Ishihara
S, Fujishiro M, Tamaru JI, Mochiki E, Ishida H,
Tada T. Diagnosis using deep-learning artificial
intelligence based on the endocytoscopic observation of the esophagus. Esophagus. 2019; 16(2):180-187.
17. Miyake H, Murono K, Nagata H, Nozawa H,
Kawai K, Hata K, Tanaka T, Nishikawa T, Shuno
Y, Sasaki K, Ishihara S. Prognostic significance of
doubling time in patients undergoing radical
surgery for metachronous peritoneal metastases ofcolorectal cancer. Int J Colorectal Dis. 2019;34(5): 801-809
18. Murono K, Nagata H, Ishimaru K, Emoto S,
Kaneko M, Hiyoshi M, Sasaki K, Otani K, Shuno
Y, Nishikawa T, Tanaka T, Hata K, Kawai K,
Nozawa H, Muro K, Ishihara S. Safety of
intraperitoneal paclitaxel combined with conventional chemotherapy for colorectal cancer withperitoneal carcinomatosis: a phase I trial. Cancer
Chemother Pharmacol. 2019; 83(1): 145-150.
19. Nagata H, Ishihara S, Abe H, Ushiku T,
Kishikawa J, Tanaka T, Hata K, Kawai K,
Fukayama M, Nozawa H. LGR5 expression
predicts peritoneal recurrence after curative
resection of primary colon cancer. Br J Cancer.

2019; 9 (1): 996-1002.
20. Nagata H, Ishihara S, Oba K, Tanaka T, Hata K,
Kawai K, Nozawa H. Development and Validationof a Prediction Model for Organ-Specific
Recurrences After Curative Resection of Colon
Cancer. Dis Colon Rectum. 2019; 62 (9): 10431054.
21. Nishikawa T, Kawai K, Emoto S, Murono K,
Hiyoshi M, Kaneko M, Sonoda H, Sasaki K,
Shuno Y, Tanaka T, Hata K, Nozawa H. The
influence of pulmonary comorbidities ontreatment choice and short-term surgical outcomesamong elderly patients with colorectal cancer.
IJCD. 2019; 34(8): 1497-1501.
22. Nishikawa T, Kawai K, Hata K, Emoto S, Murono
K, Sasaki K, Tanaka T, Nozawa H, Ishihara S.
Clinical outcomes of preoperative chemoradiotherapy in octogenarian with locally advanced
rectal cancer. Molecular and Clinical Oncology.
2019; 11(2): 181-188.
23. Nishikawa T, Kawai K, Ishii H, Emoto S, Murono
K, Kaneko M, Sasaki K, Shuno Y, Tanaka T, Hata
K, Nozawa H, Ishihara S. The impact of
indocyanine-green fluorescence imaging on intraluminal perfusion of J-shaped pouch. Techniquesin Coloproctology. 2019; 23(9): 931-932.
24. Nishikawa T, Nozawa H, Kawai K, Sasaki K,
Otani K, Tanaka T, Hata K, Watanabe T. Shortand long-term outcomes of minimally invasive
versus open multivisceral resection for locallyadvanced colorectal cancer. Dis Colon Rectum.
2019; 62(1): 40-46.
25. Nozawa H, Hata K, Ushiku T, Kawai K, Tanaka T,
Shuno Y, Nishikawa T, Sasaki K, Emoto S,
Kaneko M, Murono K, Sonoda H, Ishihara S.
Accelerated perineural invasion in colitisassociated cancer -a retrospective cohort study-.
Medicine. 2019; 98(42): e17570.
26. Nozawa H, Morikawa T, Kawai K, Hata K,
Tanaka T, Nishikawa T, Sasaki K, Shuno Y,
Kaneko M, Hiyoshi M, Murono K, Emoto S,
Sonoda H, Fukayama M, Ishihara S. Obstruction
is associated with perineural invasion in T3/T4
colon cancer. Colorectal Dis. 2019; 21(8): 917924.
27. Nozawa H, Takiyama H, Hasegawa K, Kawai K,
Hata K, Tanaka T, Nishikawa T, Sasaki K, Kaneko

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M, Murono K, Emoto S, Sonoda H, Nakajima J.
Adjuvant chemotherapy improves prognosis ofresectable stage IV colorectal cancer: A
comparative study using inverse probability oftreatment weighting. Ther Adv Med Oncol. 2019;11: 1758835919838960.
28. Oka S, Uraoka T, Watanabe K, Hata K, Kawasaki
K, Mizuno K, Misawa M, Hosoe N, Moriyama T,
Kawachi H. Endoscopic diagnosis and treatmentof ulcerative colitis-associated neoplasia. Dig
Endosc. 2019: 31 Suppl 1: 26-30.
29. Okada M, Emoto S, Kaneko M, Yamada D,
Nozawa H. Laparoscopic resection of a urachal
abscess caused by migration of a fish bone: casereport. ANZ J Surg. 2019; 89(11): 536-537.
30. Okada S, Hata K, Kawai K, Yamamoto Y, Tanaka
T, Nishikawa T, Sasaki K, Kaneko M, Emoto S,
Murono K, Nozawa H. Association between
KRAS G13D mutations and anastomotic recurrence in colorectal cancer: Two case reports.
Medicine (Baltimore). 2019; 98(12):e14781.
31. Okada S, Hata K, Shinagawa T, Noguchi T,
Tanaka T, Kawai K, Nozawa H, Ishihara S. A
Polymorphism in Interleukin-1 ﾎ ｲ Gene Is
Associated with the Development of Pouchitis inJapanese Patients with Ulcerative Colitis.
Digestion. 2019; 31-Oct: 1-10.
32. Okuno T, Kanazawa T, Kishi H, Anzai H, Yasuda
K, Ishihara S. Filiform Polyposis with Sigmoid
Colon Adenocarcinoma: A Case Report. Surgical
Case Reports. 2019; 5: 184.
33. Ozawa T, Hashiguchi Y, Yagi T, Fukushima Y,
Shimada R, Hayama T, Tsuchiya T, Nozawa K,
Iinuma H, Ishihara S, Matsuda K. Angiotensin
I-converting enzyme inhibitors/angiotensin II
receptor blockers may reduce tumor recurrence in
left-sided and early colorectal cancers. Int J
Colorectal Dis. 2019; 34: 1731-1739.
34. Ozawa T, Ishihara S, Fujishiro M, Saito H,
Kumagai Y, Shichijo S, Aoyama K, Tada T. Novelcomputer-assisted diagnosis system for endoscopic disease activity in patients with ulcerative
colitis. Gastrointest Endosc. 2019; 89: 416-421.
35. Ozawa T, Ishihara S, Okada Y, Ohno K, Yagi T,
Fukushima Y, Shimada R, Hayama T, Tsuchiya T,
Nozawa K, Matsuda K, Matsuoka R, Mori I,
Fukuzawa R, Takiyama A, Takao Y, Shimizu N,

Kikuchi K, Hashiguchi Y. Laparoscopic subtotal
colectomy for a patient with chronic idiopathic
colonic pseudo-obstruction. Asian J Endosc Surg.
2019; 12: 469-472.
36. Shichijo S, Endo Y, Aoyama K, Takeuchi Y,
Ozawa T, Takiyama H, Matsuo K, Fujishiro M,
Ishihara S, Ishihara R, Tada T. Application of
convolutional neural networks for evaluating
Helicobacter pylori infection status on the basis ofendoscopic images. Scand J Gastroenterol. 2019;54(2): 158-163.
37. Shinagawa T, Hata K, Morikawa T, Takiyama H,
Emoto S, Murono K, Kaneko M, Sasaki K,
Nishikawa T, Tanaka T, Kawai K, Fukayama M,
Nozawa H. Pine-cone and villi patterns areendoscopic signs suggestive of ulcerative colitisassociated colorectal cancer and dysplasia.
Gastrointest Endosc. 2019; 89(3): 565-575.
38. Shiratori H, Kawai K, Hata K, Tanaka T,
Nishikawa T, Otani K, Sasaki K, Kaneko M,
Murono K, Emoto S, Sonoda H, Nozawa H. The
combination of temsirolimus and chloroquine
increases radiosensitivity in colorectal cancer
cells. Oncology Reports. 2019; 41(1): 337-385.
39. Shiratori H, Kawai K, Hata K, Tanaka T,
Nishikawa T, Sasaki K, Kaneko M, Murono K,
Emoto S, Morikawa T, Fukayama M, Nozawa H.
Correlations between the Recurrence Patterns andSizes of Lateral Pelvic Lymph Nodes before andafter Chemoradiotherapy in Patients with Lower
Rectal Cancer. Oncology. 2019; 96(1): 33-43.
40. Taira T, Koji M, Hiroaki N, Daisuke H, Kazushige
K, Keisuke H, Toshiaki T, Soichiro I. A crosssectional study to investigate internal hernia post
left-sided colectomy preserving superior rectal
artery. Ann Med Surg. 2019; 48: 124-128.
41. Takamura M, Koga K, Emoto S, Kawai K, Osuga
Y, Ishihara S. Desmoid Tumor at the Site ofEndometriosis Surgery, Coincident with the Useof Oral Contraceptives. J Minim Invasive
Gynecol. 2019; 26(7): 1396-1399.
42. Uchino M, Ikeuchi H, Hata K, Okada S, Ishihara
S, Morimoto K, Sahara R, Watanabe K,
Fukushima K, Takahashi K, Kimura H, Hirata K,
Mizushima T, Araki T, Kusunoki M, Nezu R,
Nakao S, Itabashi M, Hirata A, Ozawa H, Ishida
T, Okabayashi K, Yamamoto T, Noake T, Arakaki

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J, Watadani Y, Ohge H, Futatsuki R, Koganei K,
Sugita A, Higashi D, Futami K. Changes in therate of and trends in colectomy for ulcerative
colitis during the era of biologics and calcineurin
inhibitors based on a Japanese nationwide cohort
study. Surg Today. 2019; 49(12): 1066-1073.

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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
Toshihiko Isaji, M.D., Ph.D., Mitsuru Matsukura M.D., Ph.D.
Takafumi Akai, 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.

226

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.

22720) Prediction of dilated morphology of aortic
aneurysm by airbag simulation.
21) Quantification of hand movements during sutureusing Leap Motion and its clinical feedback.
22) Study of intimal hyperplasia using aorta-inferior
vena cava fistula model.

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

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

228

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

229

Department ofBreast and Endocrine Surgery
Professor
Yasuyuki Seto M.D., Ph.D.

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

Lecturer
Kotoe Nishioka M.D., Ph.D.

Associates
Takayoshi Niwa M.D., Ph.D.

Takako Wakeda M.D., Ph.D.

Mayumi Harada M.D., Ph.D.

Arisa Morizono M.D.

Ayaka Sato M.D., Ph.D.

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

Clinical Activities
Endocrine Surgery had not been so familiar withJapanese; however, it has been a long time to bestudied this area by top level surgeons in westerncountries. We have started our activities for this area
since 1987 and our department has been establishedwith reconstruction of our hospital structure in 1997.
This is a result of the growth of demand nationally andinternationally and it is caused by not only treatment
for malignant disease but also functional one or giving
more attention to quality of life.
Professional skill and wider knowledge of
endocrine system are required for this area. Diseases
we treat at our department are breast, thyroid, andparathyroid. In additional to treatment for malignant
cases of these diseases, we perform surgical procedures as well as systemic treatment. We co-work withthe department of endocrine internal medicine andhave about 250 surgical procedures annually in total.
In breast surgery, more than a half of the mammary
cancer patients undergo the breast-preserving surgery.
In addition, sentinel node navigation surgery has been
adopted, resulting in better quality of postoperative
life. Reconstruction surgery for the breast cancer islikely to provide much better QOL. In this field, we
have started collaboration with the Department of
Plastic Surgery. Chemotherapy, hormone therapy andmolecular- targeting therapy play important roles intreatment of the breast cancer. We have accumulated a
lot of experience and achievement in this field.
Our clinical themes are 1) establishment of safe
procedures for endocrine surgery without complications; 2) diagnosis and treatment of micro-breast
lesions under ultrasonographic guides; 3) preoperative
diagnosis for thyroid neoplasms and breast tumors.

Research Activities
We investigate wide areas related to breast cancer,
thyroid disease, and parathyroid disease. Most of our230

studies are performed with other good institutions.
1) Hereditary Breast and Ovarian Cancer syndrome2) Precision medicine based on Todai OncoPanel
3) Clinical significance of Ki67 in the area of earlybreast cancer.
4) Clinical evaluation for the developing drugs inbreast cancer and thyroid cancer.
5) Studies in the area of sentinel node biopsy inbreast cancer.
6) Studies about management of the toxic effects ofchemotherapies.
7) Cover makeup studies for cancer patients.
8) Epigenetic changes critical for breast cancer
development.
9) Cancer stem cells in breast cancer.
10) Quantification of HER2 expression using Digital
PCR.
11) Development of molecular target drugs in the areaof TGF beta
12) Analysis of MED12 mutation and TERT promoter
mutation in breast fibroadenoma and phyllodes
tumor.

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

Surgical Sciences
2. Sensory and Motor System Medicine

232

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

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

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

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

Sayaka shibata,M.D.,PhD.

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

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

Tetsuo Toyama, M.D., Ph.D.

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

Tomomi Miyake,M.D.

Hiroaki Kamijo M.D., Ph.D.

Naoyuki Senda, M.D., Ph.D.

Kojiro Nagai, M.D.

Yoshio Hayashi, M.D.

Home page

http://www.h.u-tokyo.ac.jp/der/Introduction and Organization

Clinical Activities

The Department of dermatology celebrated its
100th anniversary in 1990. Originally it was foundedas the Department of Dermatology and Urology,
which also encompassed venereology. In 1946, theDepartment of Dermatology was separated from thatof Urology. Regarding venereology, sexually transmitted diseases only related to skin manifestations are
now dealt with in our department.
The professor, one associate professors, four
lecturers, two hospital lecturer and six associates takepart in inpatient and outpatient cares as well as
research and teaching activities. Fifty-two doctors
who basically belong to our department are currently
out in affiliated hospitals mainly engaged in clinicalworks there. Additionally, eight staff members areabroad at present, mainly involved in advanced
research activities in cell biology and molecularbiology.

In the outpatient clinic we see around 200 patients aday. Incisional and excisional biopsies are frequently
performed under local anesthesia at the outpatient
operation facilities belonging to our department.
Clinical and histological discussions by all staff
members including Professor and Associate Professors
are held regularly, which always gives us invaluablelessons.
Concerning the inpatient clinic, there are about ten
staff members under the supervision of the ward-chief.
Surgical operations such as removal of malignancies
and skin grafting that require general anesthesia arealso performed weekly in the central surgical facilities.

Education
We have twenty dermatologists who are studying in
the postgraduate course under the guidance of staff
members of our department.

233

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. Fukayama M, Asano Y, Shinozaki-Ushiku A, SatoS. Estrogen dermatitis: Case report and examination of estrogen receptor-beta in the skin. J
Dermatol.2019;46(3):263-266.
2. Senda N, Miyagaki T, Oka T, Nonogaki A,
Yoshizaki A, Shibata S, Sato S. A Case of
Purpuric Drug Eruption Probably Induced by
Panitumumab. J Dermatol.2019;46(6):e221-e222.
3. Hayashi Y, Masui Y, Miyagawa T, Yamada D,
Miyagaki T, Ikegami M, Kobayashi H, ShinozakiUshiku A, Takekoshi T, Sato S. Osteogenic
melanoma of the right fifth toe. J Dermatol.
(Letter) 2019;46(7):e265-e266.
4. Matsuda K, Nakamura K, Kobayashi M,
Yoshizaki A, Miyazaki M, Suga H, Sato S. A caseof erythema multiforme major presenting withvaricella-likemanifestations.
Journalof
Cutaneous Immunology and Allergy. 2019; 2(1):39-40..
5. Saigusa R, Yamashita T, Miura S, Hirabayashi M,
Nakamura K, Miyagawa T, Fukui Y, Yoshizaki A,
Sato S, Asano Y.A potential contribution of
decreased galectin-7 expression in stratified

epithelia to the development of cutaneous andesophageal manifestations in systemic sclerosis.
Exp Dermatol. 2019;28(5):536-542.
6. Suga H, Oka T, Sugaya M, Sato Y, Ishii T,
Nishida H, Ishikawa S, Fukayama M, Sato S.
Keratinocyte Proline-Rich Protein Deficiency In
Atopic Dermatitis Leads to Barrier Disruption. J
Invest Dermatol.2019;139(9):1867-1875
7. Kuzumi A, Yoshizaki A, Fukasawa T, Ebata S,
Miura S, Yoshizaki A, Sumida H, Asano Y, SatoS.
Serum levels of human β-defensin 2: possible
association with fibrosis and vasculopathy inpatients with systemic sclerosis. J Eur Acad
Dermatol Venereol. 2019;33(7):e272-e274.
8. Shono Y, Suga H, Kamijo H, Fujii H, Oka T,
Miyagaki T, Takahashi-Sisido N, Sugaya M, Sato
S. Expression of CCR3 and CCR4 suggests a
poorprognosis in mycosis fungoides and Sézary
syndrome. Acta Derm Venereol. 2019;99(9):809812.
9. Miura S, Someya M, Toyama S, Kawai T,
Yamashita T, Shishido N, Sato S, Asano Y.
A case of scleroderma en coup de sabre with
ipsilateral hearing loss and aphakia. Eur J
Dermatol 2019;29(4):423-425.
10. Fukui Y, Miyagawa T, Hirabayashi M, Yamashita
T, Saigusa R, Miura S, Nakamura K, Yoshizaki A,
Sato S, Asano Y. A possible association of
decreased serum CXCL14 levels with digitalulcers in patients with systemic sclerosis. J
Dermatol. 2019;46(7):584-589.
11. Asano Y, Takahashi T, Saigusa R. Systemic
Sclerosis: Is the Epithelium a Missing Piece of the
Pathogenic Puzzle?. J Dermatol Sci. 2019;94(2):259-265.
12. Suga H and Sato S.IL-10-producing regulatory B
cells in skin diseases. J Cutan Immunol Allergy.
2019;2(3):68-74.
13. Oka T, Miyagaki T, Kamijo H, Nakajim R,
Shishido-Takahashi N, Senda N, Suga H, Sugaya
M, Sato S. Increased serum activin A levels in thesera of patients with mycosis fungoides andSézary syndrome. Acta Derm Venereol. 2019;99(11):1039-1040..
14. Matsuda KM, Yoshizaki A, Kuzumi A, Fukasawa
T, Ebata S, Miura S, Toyama T, Yoshizaki A,
Sumida H, Asano Y, Oba K, Sato S. Skin

234

thickness score as a surrogate marker of organ
involvements in systemic sclerosis: a retrospective observational study. Arthritis Res Ther.
2019;21(1):129.
15. Oka T, Miyagaki T Novel and future therapeutic
drugs for advanced mycosis fungoides and Sezary
syndrome. Front Med. 2019; 29;6:116..
16. Nakata Y, Suga H, Awaji K, Oka T, Miyagaki T,
Sugaya M, Sato S.A case of mycosis fungoides
with small intestinal involvement. J Cutan
Immunol Allergy 2019;2(3):89-90.
17. Suzuki H, Miyagaki T, Sato S.YKL-40 augments
the proliferation of HaCaT cells via theextracellular regulatory kinase pathway. J
Dermatol 2019;46(6):551-552.
18. Asano Y, Masui Y, Toyama T, Sato S.A uniquecorrelation profile of adiponectin and retinolbinding protein 4 in patients with systemicsclerosis. J Dermatol. 2019;46(9):819-820..
19. Toyama S, Sato S, Asano Y.Localized scleroderma
manifesting skin lesions associated withmechanical stress. Eur J Dermatol. 2019;29(4):439-440.
20. Suga H, Sato S.Novel topical and systemic
therapies in atopic dermatitis. Immunol Med.
2019; 42(2):84-93.
21. Kamijo H, Miyagaki T, Hayashi Y, Akatsuka T,
Watanabe-Otobe S, Oka T, Shishido-Takahashi N,
Suga H, Sugaya M, Sato S. Increased interleukin26 expression promotes Th17 and Th2-associatedcytokine production by keratinocytes in atopic
dermatitis. J Invest Dermatol. Epub 2019 Aug 26
22. Matsuda KM, Nakamura K, Kobayashi M, Suga H,
Sato S. Recurrent widespread blisters and skinerosion in a 54-year-old woman: A Quiz. Acta
Derm Venereol. 2019;99(11):1057-1058..
23. Yamashita T, Asano Y, Saigusa R, Taniguchi T,
Hirabayashi M, Miyagawa T, Nakamura K, Miura
S, Yoshizaki A, Trojanowska M, Sato S.
Cyclophosphamide Pulse Therapy Normalizes
Vascular Abnormalities in a Mouse Model of
Systemic Sclerosis Vasculopathy. J Invest
Dermatol. 2019;139(5):1150-1160.
24. Sumida H. Dynamics and clinical significance ofintestinal intraepithelial lymphocytes. Immunol
Med. 2019;42(3):117-123.

25. Nakajima R, Miyagaki T, Kamijo H, Oka T,
Shishido-Takahashi N, Suga H, Sugaya M, Sato
S.Possible therapeutic applicability of galectin-9
in cutaneous T-cell lymphoma. J Dermatol Sci.
2019; 96(3):134-142.
26. Toyama S, Kanda H, Tateishi S, Yamada A, Sato S,
Asano Y.A case of concurrent psoriasis andulcerative colitis developing arthritis duringadalimumab treatment. Eur J Dermatol. 2019;29(6):651-653..
27. Kamijo H, Sugaya MTwo distinct variants ofmycosis fungoides (MF); folliculotropic MF anderythrodermic MF. J Dermatol. 2019;46(12):11361140.
28. Matsuda KM, Nakamura K, Watanabe H,
Kobayashi M, Omatsu J, Suga H, Yamada D, Sato
S. A case of papuloerythroderma secondary tocrusted scabies. J Cutan Immunol Allergy 2019;2(6):174-175.
29. Kamijo H, Miyagaki T, Takahashi-Shishido N,
Nakajima R, Oka T, Suga H, Sugaya M, Sato S.
Thrombospondin-1 promotes tumor progression
in cutaneous T-cell lymphoma via CD47.
Leukemia Epub 2019 Nov 11.
30. Nakamura K, Sato S, Asano Y. An overlap case of
systemic sclerosis and sarcoidosis with mutually
exclusive disease activities, a case report andanalysis of previous studies. European Journal of
Dermatology ejd. 2019.3683.
31. Sakakibara M, Yamada D, Toyama S, Funamizu K,
Omatsu J, Takahashi-Shishido N, Sato S, AsanoY. Tumoral calcinosis in systemic lupus
erythematosus associated with fat necrosis.
Journal of Dermatology Epub 2019 Dec 22.

235

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

Associate Professor
Takuya Iida, M.D.

Lecturer
Shimpei Miyamoto, M.D.

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

Associate
Yoko Tomioka, M.D.,

Koji Kanayam, M.D.,

Daisuke Mito M.D.,

Kazuya Ogawa, M.D.

Homepage

Takeo Numahata, M.D.,

http://www.h.u-tokyo.ac.jp/plastic/english/index.html

Organization
The present faculty of the Department of Plastic andReconstructive Surgery consists of 1 professor, 1
associate professor, 1 lecturer, 2 project lecturers, 5associates, 5 physicians, and 4 residents. There areabout 100 doctors in the department, but most areserving in rotation at affiliated hospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 20 available beds on the 10th floor in the New
Ward. Our faculty room is located in the Medical
Laboratory Building and laboratory rooms in the East
Laboratory Building.
The present status of the educational, research andclinical activities of the department is as follows.

Clinical Activities
The outpatient clinic is opened every morning from
Monday to Friday. There are several specialized
clinics for facial paralysis, breast reconstruction, headand neck reconstruction, congenital anomalies,
vascular malformations, critical limb ischemia,
lymphedema, keloid, abdominal hernia, and cosmetic
surgery including cosmetic dermatology. 1088 newpatients visited our department, including 808 patientsin emergency. 1461 surgeries were performed. Eachweek, the professor goes the round of inpatients on
Friday morning. Preoperative and postoperative
conferences that all members of the department should
attend are held on Tuesday and Wednesday evening
respectively.

Teaching Activities
In regard to pregraduate education, the department
has the duty of lecturing to 2nd and 4th year medical
students, and also of instructing 4th medical students
in bed side practice. The subjects taken up in thelectures include general concepts of plastic surgery,wound healing, congenital malformations, skin grafts
and flaps, microsurgery, head and neck reconstruction,
hand surgery, craniomaxillofacial surgery, burn and236

trauma, cosmetic surgery, and regenerative medicine.
In the bed side practice the students have theopportunity of seeing various diseases and disorders in
the field of plastic surgery and attending inpatientsand surgical operations and clinical lectures by faculty
members. For graduate school students, microsurgicaltraining program is undertaken in the laboratory room.
In the postgraduate course, after completing the 6-yeartraining program, a trainee can sit for the board
examination of the Japan Society of Plastic andReconstructive Surgery.

Research Activities
Basic and clinical researches are performed ingroups. The major research subjects are as follows:
1) Blink examination for appropriate closing-eye
function in patients with facial paralysis.
2) Studies on monitoring tissue circulation using
flexible optical probe.
3) ICG examination for evaluating blood and lymph
flow.
4) In vivo reprogramming of wound-resident cells
generates skin epithelial tissue
5) Clinical studies on fat regeneration using suctioned fat tissue and adipose stromal progenitor
cells.
6) Studies on hair regrowth using epidermal stem
cells, dermal papilla cells and dermal sheath cells.
7) Basic studies on free tissue transfer using
microsurgery.

References (2019)
1. Mito D, Kurita M, Miyamoto S, Okazaki M.
Miniaturization of Indocyanine Green Fluorescence Imaging Device Using a Smartphone. Plast
Reconstr Surg. 2020 Jan;145(1):230e-232e. doi:
10.1097/PRS.0000000000006365. PubMed PMID:
31651701.
2. Kurita M, Izpisua Belmonte JC, Suzuki K,
Okazaki M. Development of de novo epithelialization method for treatment of cutaneous ulcers. J
Dermatol Sci. 2019 Jul;95(1):8-12. doi: 10.1016/j.
jdermsci.2019.06.006. Epub 2019 Jun 22. Pub
Med PMID: 31255469.

3. Martinez-Redondo
P,
Guillen-Guillen
I,
Davidsohn N, Wang C, Prieto J, Kurita M,
Hatanaka F, Zhong C, Hernandez-Benitez R,
Hishida T, Lezaki T, Sakamoto A, Nemeth AN,
Hishida Y, Esteban CR, Shojima K, Huang L,
Shokhirev M, Nuñez-Delicado E, Campistol JM,
Guillen-Vicente I, Rodriguez-Iñigo E, LopezAlcorocho JM, Guillen-Vicente M, Church G,
Reddy P, Guillen-Garcia P, Liu GH, Belmonte JCI.
αKLOTHO and sTGFβR2 treatment counteract
the osteoarthritic phenotype developed in a rat
model. Protein Cell. 2020 Mar;11(3):219-226.
doi: 10.1007/s13238-019-00685-7. PubMed PMID:
31950348; PubMed Central PMCID: PMC
7026267.
4. Suzuki K, Yamamoto M, Hernandez-Benitez R, Li
Z, Wei C, Soligalla RD, Aizawa E, Hatanaka F,
Kurita M, Reddy P, Ocampo A, Hishida T, Sakurai
M, Nemeth AN, Nuñez Delicado E, Campistol JM,
Magistretti P, Guillen P, Rodriguez Esteban C,
Gong J, Yuan Y, Gu Y, Liu GH, López-Otín C, Wu
J, Zhang K, Izpisua Belmonte JC. Precise in vivo
genome editing via single homology arm donor
mediated intron-targeting gene integration forgenetic disease correction. Cell Res. 2019 Oct;29(10):804-819. doi: 10.1038/s41422-019-0213-0.
Epub 2019 Aug 23. PubMed PMID: 31444470;
PubMed Central PMCID: PMC6796851.
5. Karakawa R, Iida T, Yoshimatsu H, Kanayama K,
Yamasoba T. Functional and Aesthetic Reconstruction for Microtia Using the Combination ofSuperficial Circumflex Iliac Artery Perforator
Superthin Flap Transfer and Skin Grafting. Plast
Reconstr Surg Glob Open. 2019 Jul 5;7(7):e2312.
doi: 10.1097/GOX.0000000000002312. eCollection2019 Jul. PubMed PMID: 31942344; PubMed
Central PMCID: PMC6952158.
6. Yoshimatsu H, Hayashi A, Yamamoto T, Visconti
G, Karakawa R, Fuse Y, Iida T. Visualization ofthe "Intradermal Plexus" Using Ultrasonography
in the Dermis Flap: A Step beyond Perforator
Flaps. Plast Reconstr Surg Glob Open. 2019 Nov
14; 7(11): e2411. doi: 10.1097/GOX.00000000
00002411. eCollection 2019 Nov. PubMed PMID:
31942282; PubMed Central PMCID: PMC
6908357.

237

7. Iida T, Yoshimatsu H, Karakawa R, Kanayama K,
Harima M, Okazaki M. Additional venous
anastomosis in free profunda artery perforator flap
transfer using the posterior accessory saphenous
vein. J Plast Reconstr Aesthet Surg. 2019 Dec; 72(12):1936-1941. doi: 10.1016/j.bjps.2019.09.013.
Epub 2019 Sep 24. PubMed PMID: 31631004.
8. Yoshimatsu H, Yamamoto T, Hayashi A, Fuse Y,
Karakawa R, Iida T, Narushima M, Tanakura K,
Weninger WJ, Tzou CHJ. Use of the transverse
branch of the superficial circumflex iliac artery asa landmark facilitating identification anddissection of the deep branch of the superficial
circumflex iliac artery for free flap pedicle: Anatomical study and clinical applications. Microsurgery. 2019 Nov;39(8):721-729. doi: 10.1002/
micr.30518. Epub 2019 Oct 8. PubMed PMID:
31591765.
9. Miyamoto S, Nakao J, Higashino T, Yoshimoto S,
Hayashi R, Sakuraba M. Clavien-Dindo classification for grading complications after totalpharyngolaryngectomy and free jejunum transfer.
PLoS One. 2019 Sep 12;14(9):e0222570. doi: 10.
1371/journal.pone.0222570. eCollection 2019.
PubMed PMID: 31513680; PubMed Central
PMCID: PMC6742376.
10. Miyamoto S, Arikawa M, Kagaya Y. The use oflower abdominal perforator flaps in soft-tissuereconstruction after sarcoma resection. Microsurgery. 2020 Mar;40(3):353-360. doi: 10.1002/
micr.30539. Epub 2019 Dec 13. PubMed PMID:
31833597.
11. Miyamoto S, Arikawa M, Kagaya Y, Kageyama D,
Fukunaga Y. Large-to-Small End-to-Side Venous
Anastomosis in Free Flap Transfer. J Surg Res.
2020 Jan; 245:377-382. doi: 10.1016/j.jss.2019.07.
084. Epub 2019 Aug 16. PubMed PMID:
31425879.
12. Tashiro K, Arikawa M, Kagaya Y, Kobayashi E,
Kawai A, Miyamoto S. Flap reconstruction aftergroin and medial thigh sarcoma resection reduces
the risk of lower-extremity lymphedema. J Plast
Reconstr Aesthet Surg. 2019 Apr;72(4):685-710.
doi: 10.1016/j.bjps.2019.01.009. Epub 2019 Jan
12. PubMed PMID: 30661914.
13. Miyamoto S, Arikawa M, Fujiki M. Deep inferior
epigastric artery perforator flap for maxillaryreconstruction. Laryngoscope. 2019 Jun; 129(6):1325-1329. doi: 10.1002/lary.27646. Epub 2018
Dec 20. PubMed PMID: 30570138.
14. Mimura H, Akita S, Fujino A, Jinnin M, Ozaki M,
Osuga K, Nakaoka H, Morii E, Kuramochi A,
Aoki Y, Arai Y, Aramaki N, Inoue M, Iwashina Y,
Iwanaka T, Ueno S, Umezawa A, Ozeki M, Ochi J,
Kinoshita Y, Kurita M, Seike S, Takakura N,
Takahashi M, Tachibana T, Chuman K, Nagata S,
Narushima M, Niimi Y, Nosaka S, Nozaki T,
Hashimoto K, Hayashi A, Hirakawa S, Fujikawa
A, Hori Y, Matsuoka K, Mori H, Yamamoto Y,
Yuzuriha S, Rikihisa N, Watanabe S, Watanabe S,
Kuroda T, Sugawara S, Ishikawa K, Sasaki S.
Japanese clinical practice guidelines for vascularanomalies 2017. Pediatr Int. 2020 Mar;62(3):257-304. doi: 10.1111/ped.14077. Pubmed PMID:
32202048
15. Nakagami G, Schultz G, Kitamura A, Minematsu
T, Akamata K, Suga H, Kurita M, Hayashi C,
Sanada H. Rapid detection of biofilm by woundblotting following sharp debridement of chronicpressure ulcers predicts wound healing: A
preliminary study. Int Wound J. 2020 Feb;17(1):191-196 Pubmed PMID: 31680469
16. Mori Y, Nakagami G, Kitamura A, Minematsu T,
Kinoshita M, Suga H, Kurita M, Hayashi C,
Kawasaki A, Sanada H. Effectiveness of biofilmbased wound care system on wound healing inchronic wounds. Wound Repair Regen. 2019 Sep;
27(5):540-547. Pubmed PMID: 31145519
17. Wong M, Ozaki M, Kurita M, Ihara A, Iwashina Y,
Takushima A. Soft Tissue Reconstruction andFacial Reanimation With Bilateral Latissimus
Dorsi Flaps After Extensive Resection of Headand Neck Arteriovenous Malformation: A Case
Report. Ann Plast Surg. 2019 Jul;83(1):73-77.
Pubmed PMID: 31135509
18. Kato M, Watanabe S, Watanabe A, Iida T:
Flow-oriented venous anastomosis to control
lymph flow of lymphatic malformation. Plastic
and Reconstructive Surgery Global Open. 29;7(7):e2199, 2019. doi: 10.1097/GOX.000000000000
2199. eCollection 2019 Jul. PubMed PMID:
31942325
19. Kato M, Watanabe S, Watanabe A, Utsunomiya H,
Yokoyama T, Iida T: A Simple skin incision

238

design for pediatric superficial branch ofsuperficial circumflex iliac artery. Plastic andReconstructive Surgery Global Open. 2;7(4):e2159, 2019. doi: 10.1097/GOX.000000000000
2159. eCollection 2019 Apr. PubMed PMID:
31321173

239

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

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

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

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

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

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

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

AssociateFujihara Yuko, D.D.S., Ph.D.

Mari Okayasu, D.D.S., Ph.D.

Keigo Kubota, D.D.S., Ph.D.

Natsuko Uchino, D.D.S., Ph.D.

Asako Taniguchi, D.D.S., Ph.D.

Rika Narita, D.D.S., Ph.D.

Noriko Komatsu, D.D.S., Ph.D.

Yoko Uchida, D.D.S., Ph.D.

Homepage

http://plaza.umin.ac.jp/%7Eoralsurg/

Introduction and Organization
Department of Oral and Maxillofacial Surgery,commenced by Dr. Hisashi Ishihara in 1900, is one ofthe oldest departments in Graduate School of
Medicine, the University of Tokyo. This department
consists of wide variety of specialists, such as oral
surgeons, orthodontists and prosthodontists. We
handle all diseases in the oral-maxillofacial region,such as congenital anomalies, jaw deformities, benign
and malignant tumors, trauma and inflammation. In
particular, we have established and practiced
medical system for cleft lip and palate since around2000. In November 2016, we established the Cleft Lip
and Palate Center, which we become the center fororal surgeons, orthodontists, and others. Specialists
suchas
prosthodontists,
otolaryngologists,
anesthesiologists,obstetricians,
pediatricians,
pediatric surgeons, speech therapists, nurses, dental

hygienists, and dental technicians form a team to deal
with illnesses from all directions and provide
multidisciplinary treatment. Dental care for thepatients who have systemic disorders or under medical
control is another field of our department.
Multidisciplinary treatment teamed by these
specialists is characteristic and has performed
excellent results in clinical works. In research fields,
all staffs participate in the clinical and basic researchto support the treatment scientifically and to develop
new treatment protocols, and we have mainly performed the experimental studies on the regenerative
abilities of tissues such as bone, periosteum, cartilage,
perichondrium, vessels, nerve, and skin. At present,
we are focusing on tissue engineering in researchworks especially in bone, cartilage and vessels.
Professor Takato had established Tissue Engineering
Division in the University of Tokyo Hospital and ourdepartment has an endowment department: Depart-

240

ment of Cartilage and Bone Regeneration (FUJI SOFT
Inc.). The department has 1 associate professor, 1assistant professor, and several graduate students.
These staffs are focusing on translational researchworks in maxillofacial regions.

Clinical activities
In the outpatient clinic, we have 12 dental treatment
booths, one operation room and one speech therapy
room. Average number of patients treated at outpatient
clinic is approximately 100 per day.
Our department has two sections mainly; one is oral
and maxillofacial surgery and another is dental andorthodontic dentistry.
In outward dispensary, oral surgery section performs
dental surgeries such as extraction of impacted teeth,
amputation of infected dental root and gingivoplasty
in the operation room. Patients who had been performed surgical treatment are also followed up after
release from the hospital.
Dentistry and orthodontic dentistry performs facial
growth control and tooth movements for patients withcongenital orofacial anomalies such as cleft lip andpalate, jaw deformities and other congenital
deformities. Speech therapy for the patients with cleft
lip and palate is also performed by speech therapists inour department.
Special section for patients of congenital deformities
is on Monday afternoon examined by plastic surgeon,oral and maxillofacial surgeons, orthodontists.
In the ward, we have approximately 400 new
inpatients and surgical treatment is performed on
approximately 300 cases per year. The main surgicaltreatments are chiloplasty and palatoplasty for cleft lip
and palate patients, bone grafting in alveolar cleft,orthognatic surgery of orofacial deformities, fixationof orofacial fractures, resection of malignant tumors
combined with reconstruction surgery.
Peculiarity of our treatment strategy is team approachthat consists of oral and maxillofacial surgeons,orthodontists and prosthodontists. In our department,
patients with congenital dento-facial deformity aretreated by utilizing several techniques such as distraction technique, autologous bone graft technique, andthe original artificial bone graft technique in addition
to orthognatic surgery. The original bone graft is madefrom patient’s three dimensional images of CT data
and this technique is now applied for patients.

Education
Teaching activities are divided into two parts; forundergraduate medical students and for postgraduate
dental students. For undergraduate students, we make5 systematic lectures in their second year of
specialized course, and one lecture and one week
bedside learning in final year. Through thesecurriculums, we demonstrate the characteristics andtreatments of the diseases in oral-maxillofacial region.
Teaching is focused on following points; congenital
anomalies such as cleft lip and palate and branchialarch syndromes, dentofacial deformities caused bydevelopmental and acquired problems, surgicalresection and functional reconstruction of benign andmalignant tumors, temporomandibular joint disorders,
inflammation and maxillofacial trauma. Minimum
dental knowledge concerning jaw movement, toothpain, periodontal disease, malocclusion and dental
restorations are instructed.
For postgraduate dental students, we have two-yearresident course. This course aims to train for a wide
range of dental treatments and to learn about medical
cares. Various specialists instruct dental treatments forthem in outpatient clinic. Dental caries treatments,
periodontal cares and applications of dentures are
instructed. Tooth extractions and orthodontic
treatment are instructed by oral surgeons andorthodontists. Medical cares in the ward are taught by
medical doctors and oral surgeons.
After two-year residential course, research training at
postgraduate school is positively recommended. Ouraim for education of clinician is to raise up specialists
mastered both clinic and research skills.

Research
Our research project consists of clinic and basic
sections. Each research themes are closely related on
the aim of clinical improvement.
The main projects are as follows.
Clinical research:
1) Treatment of facial deformities in patients withcleft lip/palate and/or congenital anomaly

2412) Treatment of jaw deformity, oral and maxillofacial
traumas and temporomandibular disorders
3) Treatment of head and neck cancer
4) Distraction osteogenesis of maxillofacial skeleton
using distractor
5) Treatment of facial deformities in patients withcleft lip/palate
6) Clinical study for safety and efficacy oftransplantation of implant-type tissue-engineered
cartilage for cleft lip-nose patients
7) Speech disorder in patients with cleft lip/palate8) Growth and development in patients withcranio-maxillofacial anomaly9) Evaluation of treatment in patients with cleft
lip/palate
10) Surgery, chemotherapy and radiotherapy for headand neck cancer11) Orthognathic surgery in patients with jaw
deformity12) Computer assisted surgery using computer vision
and augmented reality
13) Evaluation of treatment in temporomandibular
disorder patients
14) Repair and occlusal reconstruction by regenerated
bone in oral and maxillofacial area
Basic and experimental research:
1) Regeneration of bone and cartilage in oral andmaxillofacial area by regenerative medicine
2) Basic research for producing implant-type
tissue-engineered cartilage using human cells
3) Cartilage regenerative research using iPS cells4) Role of cell cycle-related molecules in control
mechanism of osteochondral cell differentiation
5) Role of transcription factors in pluripotency ofmesenchymal cells6) Bone and cartilage regeneration using bonemarrow mesenchymal stem cells7) Epigenetic abnormalities of oral cancers andpremalignant lesions8) A study on the involvement of tumor associatedmacrophages in immunosuppression mechanismof oral squamous cell carcinoma

Publication(Original articles，Case reports)
1. Yonenaga K, Hoshi K, Miyamoto Y, Kitahara Y,
Kamatsuka M, Fujihara Y, Suenaga, H, Takato T.
Investigating the Efficacy of Intraoral Wet Sheets.
Tokai J Exp Clin Med. 2019 Apr 20;44(1):15-19.
2. Komura M, Komura H, Satake R, Suzuki K,
Yonekawa H, Ikebukuro K, Komuro H,Hoshi K,
Takato T, Moriwaki T, Nakayama Y. Fabricationof an anatomy-mimicking BIO-AIR-TUBE withengineered cartilage. Regen Ther. 2019 Aug 8; 11:
176-181.
3. Ma Q, Kobayashi E, Hara K, Suenaga H, Sakuma
I, Masamune K. Development and preliminary
evaluation of an autonomous surgical system fororal and maxillofacial surgery. Int J Med Robot.
2019 Aug;15(4):e1997.
4. Abe T, Sato T, Yoda T, Hoshi K. The period
circadian clock 2 gene responds to glucocorticoids
and regulates osteogenic capacity. Regen Ther.
2019 Aug 24;11:199-206.
5. Komatsu N, Watanabe E, Yoshimura R, Suzuki Y,
Hoshi K, Takato T, Yamamoto K, Fukuta J.
Importance of professional oral hygiene forprevention of aspiration pneumonia caused byprogressive central nervous system disorders in
Type 2 Gaucher Disease. J Oral Maxillofac Surg
Med Pathol. 2019 Sept;31(5):346-349
6. Noda A, Abe M, Shinozaki-Ushiku A, Ohata Y,
Zong L, Abe T, Hoshi K. A Bilocular Radicular
Cyst in the Mandible with Tooth Structure
Components Inside. Case Rep Dent. 2019 Sep 3;
2019:6245808.
7. Hara K, Ma Q, Suenaga H, Kobayashi E, Sakuma
I, Masamune K. Orthognathic surgical robot witha workspace limitation mechanism. IEEE/ASME
Trans Mechatron. 2019 Oct;24(6):2652-2660.
8. ASM Rafiul Haque, Masafumi Moriyama, Keigo
Kubota, Noriko Ishiguro, Mizuki Sakamoto, Akira
Chinju, Keita Mochizuki, Taiki Sakamoto, Naoki
Kaneko, Ryusuke Munemura, Takashi Maehara,
Akihiko Tanaka, Jun-Nosuke Hayashida, Shintaro
Kawano, Tamotsu Kiyoshima, Seiji Nakamura.
CD206 + Tumor-Associated Macrophages Promote Proliferation and Invasion in Oral Squamous
Cell Carcinoma via EGF Production. Sci Rep.

242

2019 Oct 10;9(1):14611.
9. Okubo R, Asawa Y, Watanabe M, Nagata S, Nio
M, Takato T, Hikita A, Hoshi K. Proliferation
medium in three-dimensional culture of auricularchondrocytes promotes effective cartilage
regeneration in vivo. Regen Ther. 2019 Oct 15;
11:306-315.
10. Tsai CH, Ting CC, Wu SY, Chiu JY, Chen H,
Igawa K, Lan TH, Chen CM, Takato T, Hoshi K,
Ko EC. Clinical significance of buccal branchesof the facial nerve and their relationship with the
emergence of Stensen's duct: An anatomical study
on adult Taiwanese cadavers. J Craniomaxillofac
Surg. 2019 Nov;47(11):1809-1818.
11. Kashiwagi M, Abe T, Komiyama Y, Komatsu N,
Tateishi S, Hoshi K. Efficacy of etanercept with
jaw-training for rheumatoid arthritis with firstly
temporomandibular joint symptoms: a case report.
Rheumatic Diseases and Treatment Journal. 2019
Dec; 1(1):6-9.
12. Soutome S, Hasegawa T, Yamguchi T, Aoki K,
Kanamura N, Mukai T, Yamazoe J, Nishikawa M,
Isomura E, Hoshi K, Umeda M; Joint ResearchCommittee of Japanese Society of Oral Care. Prevention of postoperative pneumonia by perioperative oral care in patients with esophageal cancer
undergoing surgery: a multicenter retrospective
study of 775 patients. Support Care Cancer. 2020
Jan 2.
13. Kokubu S, Inaki R, Hoshi K, Hikita A.
Adipose-derived stem cells improve tendon repair
and prevent ectopic ossification in tendinopathy
by inhibiting inflammation and inducing
neovascularization in the early stage of tendon
healing. Regen Ther. 2020 Jan 17;14:103-110.
14. Komura M, Komura H, Ishimaru T, Konishi K,
Komuro H, Hoshi K, Takato T. Tracheal cartilage
growth promotion by intra-tracheal administrationof basic FGF. Pediatr Surg Int. 2020 Jan; 36(1):33-41.
15. Fujihara Y, Abe T, Asawa Y, Nishizawa S, Saijo H,
Hikita A, Hoshi K. Influence of DamageAssociated Molecular Patterns from Chondrocytes
in Tissue-Engineered Cartilage. Tissue Eng Part A.
2020 Feb 19.
16. Nishizawa S, Kanazawa S, Fujihara Y, Asawa Y,
Nagata S, Harai M, Hikita A, Takato T, Hoshi K.

Glial Fibrillary Acidic Protein as Biomarker
Indicates Purity and Property of Auricular
Chondrocytes. Biores Open Access. 2020 Mar 3;9(1):51-63.
17. Komatsu N, Komatsu M, Ohashi R, Horii A,
Hoshi K, Takato T, Abe T, Hamakubo T. Saponin
Facilitates Anti-Robo1 Immunotoxin Cytotoxic
Effects on Maxillary Sinus Squamous Cell
Carcinoma. J Oncol. 2020 Mar 11;2020:9593516.
18. Aoki E, Asawa Y, Hikita A, Hoshi K.
Establishment of a new technique for the
fabrication of regenerative cartilage with amicroslicer device to prepare three dimensional
diced cartilage. Biomed Res. 2020 Apr 1; 41(2):67-80
19. Fujihara Y, Abe T, Hoshi K. Controlling the
Phenotype of Macrophages Promotes Maturationof Tissue-Engineered Cartilage. Tissue Eng Part A.
2020 Apr 13.
20. Kawakami H, Yonenaga K, Sunega H, Masanobu
A, Takato T, Hoshi K. A difficult‐to‐diagnose
case of extranodal NK/T‐cell lymphoma, nasal
type, primary to maxillary gingival ulcers thatdeveloped after living‐donor liver transplantation.
Oral Sci Int. 2020 May; 17(2);97-102. First
Published 2019 Nov. 26.
21. Tsujimura T, Takase O, Yoshikawa M, Sano E,
Hayashi M, Hoshi K, Takato T, Toyoda A, Okano
H, Hishikawa K. Controlling gene activation byenhancers through a drug-inducible topologicalinsulator. Elife. 2020 May 5;9.
22. Keigo Kubota, Shinsaku Arai, Takeshi Mitsuyasu,
Kaori Matsumura, Hideto Saijo, Kazuto Hoshi,
Seiji Nakamura. Prader-Willi syndrome with acleft palate: A case report. J Oral Maxillofac Surg
Med Pathol. 2019 Dec 13.
23. Kitano VJ, Ohyama Y, Hayashida C, Ito J,
Okayasu M, Sato T, Ogasawara T, Tsujita M,
Kakino A, Shimada J, Sawamura T, Hakeda Y.
LDLuptake-dependent phosphatidylethanolaminetranslocation to the cell surface promotes fusionof osteoclast-like cells. J Cell Sci.
24. Ma Q, Kobayashi E, Suenaga H, Hara K, Wang J,
Nakagawa K, Sakuma I, Masamune K.
Autonomous surgical robot with camera-based
markerless navigation for oral and maxillofacial
surgery. IEEE/ASME Trans Mechatron.

243

25. Kawakami H, Yonenaga K, Suenaga H, Abe M,
Takato T, Hoshi K. A difficult-to-diagnose case of
extranodal NK/T-cell lymphoma, nasal type,primary to maxillary gingival ulcers thatdeveloped after living-donor liver transplantation.
Oral Sci Int.
26. Wang X, Xu Y, Guo S, Zhang J, Abe M, Tan H,
Wang S, Chen P, Zong L. T1-2N1M0
triple-negative breast cancer patients from the
SEER database showed potential benefit frompost-mastectomy radiotherapy. Oncology Letters.
27. Moriguchi K, Iffah-Rasyiqah F, Abe M,
Kiyokawa K, Yamamoto S, Suzuki K. Targeting
Antibiotic Resistance Genes Is a Better Approachto Block Acquisition of Antibiotic ResistanceThan Blocking Conjugal Transfer by Recipient
Cells: A Genome-Wide Screening in Escherichia
coli. Frontiers in Microbiology.
28. Komatsu N, Komatsu M, Ohashi R, Horii A,
Hoshi K, Takato T, Abe T, Hamakubo T. Saponinfacilitates anti-Robo1 immunotoxin cytotoxic
effects on maxillary sinus squamous cell
carcinoma. Journal of Oncology, 2020.
29. Inaki R, Sugiyama M, Shojima M, Narushima M,
Taniguchi A, Saijo H, Abe T, Hoshi K. Local
Sclerotherapy to Control Recurrent Bleeding from
Mandibular Arteriovenous Malformation during
the Eruption of Permanent Teeth. Hospital
Dentistry & Oral-Maxillofacial Surgery 2020;32(1).
(Review articles)
1. Kurabayashi K, Abe T, Abe M, Ikemura M,
Takato T, Hoshi K：A rare case of myoepithelial
carcinoma gradually changed of malignancy: areport and literature review. Oral Science
International, 16(2):100-105, 2019.
2. Abe M, Watanabe K, Shinozaki-Ushiku A, Ushiku
T, Abe T, Fujihara Y, Amano Y, Zong L, Wang CP,
Kubo E, Inaki R, Kinoshita N, Yamashi S, Takai
D, Ushijima T, Nagase T, Hoshi K：Identificationof a metastatic lung adenocarcinoma of the palate
mucosa through genetic and histopathologicalanalysis: A rare case report and literature review.
BMC Cancer, 19(1), 52, 2019.
3. Ogasawara T, EC Ko, J Yu. Application of StemCells in the Oral and Maxillofacial Region. StemCells Int.

(Patents)
1. Wang J, Suenaga H, Sakuma I, Kobayashi E,
Hoshi K: Surgical navigation system, surgicalnavigation method and program (U.S. Patent No.
US10492872 B2)244

Department ofOrthopaedic Surgery
Professor
Sakae Tanaka, M.D., Ph.D.

Associate Professors
Taku Saito, M.D., Ph.D.

Yasushi Oshima, M.D., Ph.D.

Lecturers
Shuji Taketomi, M.D., Ph.D.

Hiroshi Inui, M.D., Ph.D.

Takumi Matsumoto, M.D., Ph.D.

Hiroshi Kobayashi, M.D., Ph.D.

Associates
Takeyuki Tanaka, M.D.

Keita Okada, M.D., Ph.D.

Yoshitaka Matsubayashi, M.D.

Kousuke Uehara, M.D.

So Kato, M.D., Ph.D.

Hideki Nakamoto, M.D., Ph.D.

Chan Sonnho, M.D., Ph.D.

Maenohara Yuji, M.D., Ph.D.

Ryuji Sakamoto, M.D.

Samejima Shin, M.D.

Hiroaki Nakarai, M.D.

Shin Asai, M.D.

Zhang Liuzhe, M.D.

Takafumi Miyake, M.D.

Homepage

http://www.u-tokyo-ortho.jp/

Introduction and Organization
In 1906 our department was established as the firsteducational institute of orthopedic surgery in Japan,
by the first professor Yoshinori Tashiro who hadlearned orthopedic surgery in Germany and Austria.
Initially, the department treated patients with
infectious disorders and congenital malformations,such as poliomyelitis, tuberculosis of the spine,congenital clubfoot and hip dislocation. The numberof outpatients visiting our department in 1910 was
estimated to be no more than 3.3% of that of the twosurgical departments in the University of Tokyo
Hospital.
The number and characteristics of the patients,
however, have changed dramatically in these 100

years. This is because our department addressed theacute needs of society from the beginning. Prof.
Tashiro believed that trauma should be treated byorthopedists, so he provided his pupils with thistraining. Since 1950’s, the department has increasingly been involved in the treatment of traffic andindustrial accident victims. Prof. Tashiro and his
successor professor Kenji Takagi devoted themselvesto the establishment of an institute for children withdisabilities. The arthroscopy was developed by Prof.
Takagi, and is now considered to represent a breakthrough in the development of minimally invasive
surgery. We have recently been conducting manystudies related to the ossification of spinal ligaments(OPLL), rheumatoid arthritis, biomechanics, and thedegenerative skeletal disorders such as osteoporosis

245

and osteoarthritis in response to the progressive agingof our society.
Our department is now adept in the entire field of
medical science and medical practice related to thehuman locomotor system, the importance of which is
now clearly recognized not only in Japan, but also all
over the world. To meet the expanding needs ofsociety, we have been conducting the teaching,clinical, and research activities described below.
Faculty members of the department are one
professor, two associate professors, four lecturers, 14
associates, nine medical staff members, and sevensenior residents.

Teaching activities
As for undergraduate education, our department
provides a comprehensive series of lectures, physicalassessment classes and problem-based learning (PBL)
program to 4th year medical students, clinicalclerkship programs to 5th year students and elective
clinical clerkship programs to 6th year medical
students.
A comprehensive series of lectures provides basic
knowledge of the physiology, pathology, diagnosis
and treatment of various musculoskeletal disorders.
Twelve consecutive lectures in total cover a whole
field of orthopaedics: basic science, pediatricdisorders, rheumatic diseases, metabolic bone diseases,
musculoskeletal neoplasm, trauma and regional
disorders of the musculoskeletal system (spine,
shoulder, elbow, hand, hip, knee, ankle and foot). In
the physical assessment classes, we have provided
physical diagnostic maneuvers and the radiologicalassessment of a variety of musculoskeletal diseases.
PBL has been introduced to a small group of students
to learn medical humanity and to develop a practicalmethodology to resolve clinical problems.
During the 3-week period of clinical clerkshipprogram, students have opportunities to join one ofclinical teams and experience patient care andorthopaedic practice with residents and faculty
members. We have developed an original text for the
students to learn on-site orthopedics effectively. They
are encouraged to participate in clinical conferences
and surgeries. They are also required to submit
reports on the cases they are involved in. They learn

how to conduct a medical interview, check physicalfindings and draw up actual plans for a diagnosis andtreatment including surgery.
Elective clinical clerkship provides 4 weeks ofmore intensive exposure to the clinical practice. The
students are attached to a clinical team and are
involved in most of the clinical activities performedby the team.
For postgraduate education, junior residents join
our department for 1-8 months. In 8 doctors-intraining completed our program during this fiscal year.
Since the training period is short, they are encouraged
to experience emergency cases as often as possible tolearn primary care. For senior residents, 1-year
clinical programs were conducted in corporation with
our affiliated hospitals. A postgraduate seminar and abasic research conference are held weekly.
Including the postgraduate training, an eight-year
course has been adopted with clinical and researchtraining taking place either in the University of Tokyo
Hospital or in our 40 affiliated hospitals.

Clinical activities
We have the outpatient clinic open from Monday
through Friday, with specialized divisions for spine,
hip, rheumatoid arthritis, tumor, scoliosis, limb
reconstruction and bone lengthening, knee, hand,elbow, shoulder, sports, peripheral nerves, bonesystemic disorders, and foot. A total of 36,291 patients
visited the outpatient clinic in fiscal 2019.
The ward has approximately 60 to 70 beds available
and is divided into the subgroups above. The members
are on duty for daily patient care under the supervisionof faculty members. The weekly official activities ofour department include ward rounds by the professoron Thursday. Post- and preoperative case conferences
are held on Monday evening, Wednesday evening andThursday morning.
1,464 operations were performed in fiscal 2019.
These include 364 spine surgeries, 73 surgeries forrheumatoid arthritis patients, 115 hip surgeries, 313
knee surgeries (including 31 computer-assisted ACL
reconstructions, 140 computer-assisted TKA, 21
UKA), 237 hand surgeries, 52 foot and ankle surgeries,
44 pediatric surgeries, 153 surgeries for bone and soft
tissue tumor, and 177 trauma surgeries.

246

The main disorders of cervical spine surgery weremyelopathy due to spondylosis or OPLL. We
successfully adopted double-door open laminoplasty
by splitting the spinal processes for most of thesecases. This procedure was invented and developed inour department and is now used nationwide. Difficult
operations such as subluxation of the cervical spine
due to rheumatoid arthritis, Down’s syndrome or
cerebral palsy were treated using a navigation systemthat has been officially approved as a high-leveladvanced medical treatment.
The spine group is now converting open surgeries
to minimum invasive surgeries using endoscopic
technique.
The scoliosis group used the navigation systemespecially for patients with complex deformity. In
addition to the conventional correction surgery,
growth-assist techniques such as dual growing rods
are utilized.
Main operations performed by the rheumatoid
arthritis clinic group were total joint arthroplasty.
They are using image-free navigation system in total
knee arthroplasty operation, which is useful for theaccurate placement of the implants.
The hip surgery group treated mainly acetabular
dysplasia and osteoarthritis of the hip joint. They
performed not only total hip replacements, but also
several osteotomies including rotational acetabularosteotomy (RAO). The RAO was originated andestablished in our department. They conducted aclinical trial for a new artificial hip joint using the
MPC polymer in collaboration with the Department ofMaterials Engineering in Tokyo University.
The knee clinic group developed a new anterior
cruciate ligament reconstruction technique using thenavigation system based on intraoperative threedimensional fluoroscopic image to realize ideal graft
placement.
The peripheral nerve clinic group has developed"costal nerve transfer to the musculocutaneous nerve"
for brachial plexus injury.
The tumor group managed multidisciplinary treatment for musculoskeletal sarcoma including chemotherapy, limb sparing surgery and radiotherapy incoorporation with other departments.
Limb reconstruction operations using external
fixators included non-union, leg lengthening anddeformity correction. One of the main interests of thisgroup is the development of a system to analyze themechanical properties of a skeletal system. During
this period of analysis, the mechanical properties ofthe fracture site in vivo are to be evaluated bymonitoring the motion of a dynamic pin clamp during
simulated walking.

Research activities
Our research activities cover the full range of themusculoskeletal system medicine, using the in-depthsciences of biology and technology. Especially in thefield of molecular biology of bone and cartilage
metabolism, we are regarded as being on the leadingedge in the world. Basic research is performed under
the supervision of the faculty staff members. Four
endowment departments take an active role inresearch activities in close collaboration with ourdepartment. They deal with regenerative medicine,clinical research, and material engineering.
As for research of bone resorption, we have been
researching and released some important reports aboutbone metabolism, especially in differentiation,
activation and apoptosis of osteoclast. Recently wehave been getting achievement in the new research
topics such as “Osteoimmunology”, a new research
field studying on signaling cross-talk between bonemetabolism and immunology, or “Epigenetics”, newresearch concept in spotlight using comprehensive
analysis technique.
As for research of cartilage, we have researchedmolecular biology of cartilage with the students of thegraduate school and the members of Bone andCartilage Regenerative Medicine, Division of Tissue
Engineering. Our research activities cover thegeneration and differentiation of chondrocytes, thejoint formation, the degeneration of joint cartilage,
and the regenerative methods.
Our clinical groups also take part in many
multicenter clinical studies conducted by Japan
Musculoskeletal Oncology Group (JMOG), National
Database of Rheumatic Diseases by iR-net in Japan(NinJa), and other multicenter groups.

247

References
1. Shibayama K, Sugaya H, Matsuki K, Takahashi N,
Tokai M, Onishi K, Tanaka S: Repair Integrity
and Functional Outcomes After Arthroscopic
Suture Bridge Subscapularis Tendon Repair.
Arthroscopy 2018,34:2541-2548
2. Tanaka T, Takao M, Sakai T, Hamada H, Tanaka S,
Sugano N: Variations in sagittal and coronal stem
tilt and their impact on prosthetic impingement in
total hip arthroplasty. Artif Organs 2018, Epub
3. Kawaguchi K, Michishita K, Manabe T, Akasaka
Y, Arakawa T, Higuchi J: Mucoid degeneration of
the cruciate ligaments in osteoarthritis underprimary total knee arthroplasty. Asia-Pacific
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Rehabilitation and Technology 2018,12:1-4
4. Ono K, Hirose J, Chang SH, Kubota M, Kinkawa
J, Noguchi M, Takedani H: Orthotropic live
transplantation for cirrhosis from hepatitis C virus
leads to correction of factor IX deficiency
allowing for ankle arthroplasty without factor
replacement in a patient with moderate haemophilia B. Blood Coagul Fibrinolysis 2018, 29(1):131-134
5. Tsuda Y, Ogura K, Shinoda Y, Kobayashi H,
Tanaka S, Kawai A: The outcomes and prognostic
factors in patients with osteosarcoma according toage: a Japanese nationwide study with focusing on
the age differences. BMC Cancer 2018, 18(1):614
6. Oka H, Matsudaira K, Takano Y,Kasuya D, Niiya
M, Tonosu J,Fukushima M, Oshima Y, Fujii T,
Tanaka S, Inanami H: A comparative study ofthree conservative treatments in patients withlumbar spinal stenosis: lumbar spinal stenosis
with acupuncture and physical therapy study(LAP study). BMC Complement Altern Med 2018,
Jan 19;18(1)7. Yamada K, Muranaga S, Shinozaki T, Nakamura
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8. Doi T, Inoue H, Arai Y, Shirado O, Doi T,
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9. Fujii T, Oka H, Katsuhira J, Tonosu J, Kasahara S,
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10. Tonosu J, Inanami H, Oka H, Takano Y, Koga H,
Yuzawa Y, Shiboi R, Oshima Y, Baba S, Tanaka S,
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Y, Chikuda H, Riew KD, Tanaka S: Nutrient
foramen location on the laminae provides alandmark for pedicle screw entry: a cadaveric
study. BMC Musculoskelet Disord 2018, 19(1):293
12. Omiya T, Hirose J, Hasegawa T, Amizuka N,
Omata Y, Izawa N, Yasuda H, Kadono Y,
Matsumoto M, Nakamura M, Miyamoto T, Tanaka
S: The effect of switching from teriparatide toanti-RANKL antibody on cancellous and corticalbone in ovariectomized mice. Bone 2018,107:
18-26
13. Chang SH, Matsumoto T, Okajima K, Naito M,
Hirose J, Tanaka S: Heterotopic Ossification of
the Peroneus Longus Tendon in the Retromalleolar Portion with the Peroneus Quartus
Muscle: A Case Report. Case Rep Orthop 2018,
Jul 29
14. Kobayashi H, Ikegami M, Ushiku T, Anraku M,
Ohki T, Shinoda Y, Tanaka S, Kawano H:
Secondary Chondrosarcoma Presenting with
Symptoms Similar to Thoracic Outlet Syndrome.
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Juji T: Bilateral Stress Fractures of the Talus
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Total Hip Arthroplasty in a Patient with
Oto-Spondylo-Megaepiphyseal Dysplasia Plannedby Three-Dimensional Motion Analyses andFull-Scale Three-Dimensional Plaster Model ofBones. Case Rep Orthop 2018, Jan 23

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17. Omata Y, Frech M, Primbs T, Lucas S, Andreev D,
Scholtysek C, Sarter K, Kindermann M,
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18. Ogata T, Ideno Y, Akai M, Seichi A, Hagino H,
Iwaya T, Doi T, Yamada K, Chen AZ, Li Y,
Hayashi K: Effects of glucosamine in patientswith osteoarthritis of the knee: a systematic
review and meta-analysis. Clin Rheumatol 2018,
37(9):2479-2487
19. Oshina M, Horii C, Hirai S, Matsubayashi Y,
Taniguchi Y, Hayashi N, Tanaka S, Oshima Y:
Lewis SJ, Mohanty C, Gazendam AM, Kato S,
Keshen SG, Lewis ND, Magana SP, Perlmutter D,
Cape J: Posterior column reconstruction improves
fusion rates at the level of osteotomy in threecolumn posterior-based osteotomies. Eur Spine J
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20. Comparison of Freehand Sagittal Trajectories forInserting Pedicle Screws Between C7) and T5.
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22. Oshina M, Tanaka M, Oshima Y, Tanaka S, Riew
KD: Correlation and differences in cervicalsagittal alignment parameters between cervicalradiographs and magnetic resonance images. Eur
Spine J 2018,27(6):1408-1415
23. Maenohara Y, Taniguchi A, Tomiwa K,
Tsuboyama D, Kurokawa H, Kumai T, Tanaka S,
Tanaka Y: Outcomes of Bilateral vs Unilateral
Ankle Arthrodesis. Foot Ankle Int 2018,39:530534
24. Matsumoto T, Gross CE, Parekh SG: Short-Term
Radiographic Outcome After Distal Chevron
Osteotomy for Hallux Valgus Using Intramedullary Plates With an Amended Algorithm for
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25. Oshina M, Oshima Y, Tanaka S, Riew KD:
Radiological Fusion Criteria of Postoperative

Anterior Cervical Discectomy and Fusion: A
Systematic Review. Global Spine J 2018, 8(7):739-750
26. Lewis SJ, Keshen SG, Kato S, Dear TE,
Gazendam AM: Risk Factors for Postoperative
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27. Kobayashi H, Okuma T, Oka H, Okajima K,
Ishibashi Y, Zhang L, Hirai T, Ohki T, Tsuda Y,
Ikegami M, Sawada R, Shinoda Y, Akiyama T,
Kawano H, Goto T, Tanaka S: Body composition
as a predictor of toxicity after treatment witheribulin for advanced soft tissue sarcoma. Int J
Clin Oncol 2018, Epub
28. Kobayashi H, Okuma T, Oka H, Hirai T, Ohki T,
Ikegami M, Sawada R, Shinoda Y, Akiyama T,
Sato K, Abe S, Kawano H, Goto T, Tanaka S:
Neutrophil-to-lymphocyte ratio after pazopanib
treatment predicts response in patients withadvanced soft-tissue sarcoma. Int J Clin Oncol
2018, 23(2):368-374
29. Hosoi I, Kobayashi E, Chang SH, Matsumoto T,
An Q, Anzai E, Ohta Y, Sakuma I: Developmentof intraoperative planter pressure measuringsystem considering weight bearing axis. Int J
Comput Assist Radiol Surg 201830. Hosoi I, Kobayashi E, Chang SH, Matsumoto T,
An Q, Anzai E, Ohta Y, Sakuma I: Developmentof intraoperative plantar pressure measuringsystem considering weight bearing axis. Int J
Comput Assist Radiol Surg. 2018 Epub
31. Taii T, Matsumoto T, Tanaka S, Nakamura I, Ito K,
Juji T: Wrist Arthrodesis in Rheumatoid Arthritis
Using an LCP Metaphyseal Locking Plate versus
an AO Wrist Fusion Plate. Int J Rheumatol 2018,
Jul 1032. Kojima T, Ishikawa H, Tanaka S, Haga N, Nishida
K, Yukioka M, Hashimoto J, Miyahara H, Niki Y,
Kimura T, Oda H, Asai S, Funahashi K, Kojima M,
Ishiguro N: Target setting for lower limb joint
surgery using the Timed Up and Go test in
patients with rheumatoid arthritis: A prospective
cohort study. Int J Rheum Dis 2018,21:1801-1808
33. Kojima T, Ishikawa H, Tanaka S, Haga N, Nishida
K, Yukioka M, Hashimoto J, Miyahara H, Niki Y,
Kimura T, Oda H, Asai S, Funahashi K, Kojima M,
Ishiguro N: Validation and reliability of the Timed249

Up and Go test for measuring objective functional
impairment in patients with long-standing
rheumatoid arthritis: a cross-sectional study. Int J
Rheum Dis 2018, 21:1793-1800
34. Tanaka T, Moro T, Takatori Y, Oshima H, Ito H,
Sugita N, Mitsuishi M, Tanaka S: Evaluation of
the three-dimensional bony coverage before andafter rotational acetabular osteotomy. Int Orthop
2018, 42(11):2527-2534
35. Kyomoto M, Shoyama Y, Saiga K, Moro T,
Ishihara K: Reducing fretting-initiated crevice
corrosion in hip simulator tests using a zirconiatoughened alumina femoral head. J Biomed Mater
Res B Appl Biomater 2018, Nov 106(8)36. Yamane S, Kyomoto M, Moro T, Hashimoto M,
Takatori Y, Tanaka S, Ishihara K: Wear resistanceof poly(2-methacryloyloxyethyl phosphorylcholine)-grafted carbon fiber reinforced poly(ether ether
ketone) liners against metal and ceramic femoral
heads. J Biomed Mater Res B Appl Biomater
2018, 106(3):1028-1037
37. Kodama R, Muraki S, Iidaka T, Oka H, Teraguchi
M, Kagotani R, Asai Y, Hashizume H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Tanaka S,
and Yoshimura N: Serum levels of matrix
metalloproteinase-3 and autoantibodies related torheumatoid arthritis in the general Japanese
population
and
their
association
withOsteoporosis and Osteoarthritis: The ROAD
Study 2018,36:246-253
38. Miura T, Ando M, Tanaka S, Uehara K:
Assessment of Dorsal Subluxation in Thumb
Carpometacarpal Osteoarthritis. J Hand Microsurg
2018,10:125-129
39. Inui H, Taketomi S, Yamagami R, Shirakawa N,
Kawaguchi K, Tanaka S: The Relationshipbetween Soft-Tissue Balance and Intraoperative
Kinematics of Guided Motion Total Knee
Arthroplasty. J Knee Surg 2018,32:91-96
40. Taketomi S, Inui H, Yamagami R, Shirakawa N,
Kawaguchi K, Nakagawa T, Tanaka S:
Bone-Patellar Tendon-Bone Autograft versus
Hamstring Tendon Autograft for Anatomical
Anterior Cruciate Ligament Reconstruction withThree-Dimensional Validation of Femoral andTibial Tunnel Positions. J Knee Surg 2018,31:
866-874

41. Kyomoto M, Moro T, Yamane S, Watanabe K,
Hashimoto M, Tanaka S, Ishihara K: A
phospholipid polymer graft layer affords highresistance for wear and oxidation under load
bearing conditions. J Mechan Behav Biomed
Mater 2018,79:203-212
42. Hirose J, Takedani H, Nojima M, Koibuchi T:
Risk factors for postoperative complications oforthopedic surgery in patients with hemophilia:
Second report. J Orthop 2018, 15(2):558-562
43. Fukushima M, Oshima Y, Oka H, Chang C,
Matsubayashi Y, Taniguchi Y, Matsudaira K,
Tanaka S: Potential pathological mechanisms of
L3 degenerative spondylolisthesis in lumbar
spinal stenosis patients: A case-control study. J
Orthop Sci 2018, Dec 27
44. Nagata K, Ando T, Nakamoto H, Kato S, Sasaki K,
Oshima Y: Adaptation and limitation of anterior
column reconstruction for pyogenic spondylitis inlower thoracic and lumbar spine. J Orthop Sci
2018, Epub
45. Taketomi S, Inui H, Yamagami R, Kawaguchi K,
Nakazato K, Kono K, Kawata M, Nakagawa T,
Tanaka S: Surgical timing of anterior cruciate
ligament reconstruction to prevent associatedmeniscal and cartilage lesions. J Orthop Sci 2018,
23:546-551
46. Tanaka S: Emerging anti-osteoclast therapy forrheumatoid arthritis. J Orthop Sci 2018, 23:717721
47. Makii Y, Asaka M, Setogawa S, Fujiki S, Hosaka
Y, Yano F, Oka H, Tanaka S, Fukui N, Yanagihara
D, Saito T: Alteration of gait parameters in amouse model of surgically induced knee
osteoarthritis. J Orthop Surg (Hong Kong) 2018,
May-Aug;26(2)48. Inanami H, Saiki F, Oshima Y: Microendoscopeassisted posterior lumbar interbody fusion: atechnical note. Journal of Spine Surgery 2018,4:
408-413
49. Inomata Y, Oshima Y, Inoue H, Takano Y, Inanami
H, Koga H: Percutaneous endoscopic lumbar
discectomy via adjacent interlaminar space forhighly down-migrated lumbar disc herniation: atechnical report. Journal of Spine Surgery 2018, 4:
483-489
50. Ishibashi K, Oshima Y, Inoue H, Takano Y, Iwai H,

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Inanami H, Koga H: A less invasive surgery using
a full-endoscopic system for L5 nerve root
compression caused by lumbar foraminal stenosis.
Journal of Spine Surgery 2018,4:594–601
51. Kaneko T, Oshima Y, Inoue H, Iwai H, Takano Y,
Inanami H, Koga H: Successful treatment oflumbar ligamentum flavum hematoma using a
spinal full-endoscopic system. Journal of Spine
Surgery 2018,4
52. Tonosu J, Oka H, Watanabe K, Abe H,
Higashikawa A, Yamada K, Kuniya T, Nakajima
K, Tanaka Matsudaira K: Validation study of adiagnostic scoring system for sacroiliac jointrelated pain. J Pain Res 2018,11:1659-1663
53. Kondo M, Oshima Y, Inoue H, Takano Y, Inanami
H, Koga H: Significance and pitfalls of
percutaneous endoscopic lumbar discectomy forlarge central lumbar disc herniation. J Spine Surg
2018,4:79-85
54. Inui H, Taketomi S, Yamagami R, Kawaguchi K,
Nakazato K, Tanaka S: The relationship between
anteroposterior stability and medial-lateralstability of the bi-cruciate stabilized total knee
arthroplasty. Knee 2018,25:1247-1253
55. Kawaguchi K, Inui H, Taketomi S, Yamagami R,
Nakazato K, Shirakawa N, Tanaka S:
Intraoperative mobile-bearing movement in
Oxford unicompartmental knee arthroplasty. Knee
Surg Sports Traumatol Arthrosc 2018, Jul 21
56. Kawata M, Sasabuchi Y, Taketomi S, Inui H,
Matsui H, Fushimi K, Yasunaga H, Tanaka S:
Atopic dermatitis is a novel demographic risk
factor for surgical site infection after anterior
cruciate ligament reconstruction. Knee SurgSports Traumatol Arthrosc 2018,26:3699-3705
57. Taniguchi Y, Oichi T, Ohya J, Chikuda H, Oshima
Y, Matsubayashi Y, Matsui H, Fushimi K, Tanaka
S, Yasunaga H: In-hospital mortality andmorbidity of pediatric scoliosis surgery in Japan:
Analysis using a national inpatient database.
Medicine (Baltimore) 2018, 97(14):e0277
58. Fujimoto Y, Fujii T, Oshima Y, Oka H, Tanaka S,
Matsudaira K: The association between neckand shoulder discomfort-Katakori-and highsomatizing tendency. Mod Rheumatol 2018, Nov
28:1-1459. Izawa N, Hirose J, Fujii T, Oka H, Uehara K,

Naito M, Matsumoto T, Tanaka S, Tohma S: Theutility of 25-question Geriatric Locomotive
Function Scale for evaluating functional ability
and disease activity in Japanese rheumatoid
arthritis patients: A cross-sectional study using
NinJa database. Mod Rheumatol 2018, Apr 18:1-7
60. Matsumoto T, Maenohara Y, Chang SH, Hirose J,
Juji T, Ito K, Tanaka S: Lateral collapse of thetarsal navicular in patients with rheumatoid
arthritis: Implications for pes planovarus
deformity. Mod Rheumatol 2018, 28(5):800-807
61. Oka H, Kadono Y, Ohashi S, Yasui T, Ono K,
Matsudaira K, Nishino J, Tanaka S: Assessing
joint destruction in the knees of patients withrheumatoid arthritis by using a semi-automatedsoftware for magnetic resonance imaging:therapeutic effect of methotrexate plus etanercept
compared with methotrexate monotherapy. Mod
Rheumatol 2018,28:235-241
62. Oka H, Nomura T, Asada F, Takano K, Nitta Y,
Uchima Y, Sato T, Kawase M, Sawada S,
Sakamoto K, Yasue M, Arima S, Katsuhira J,
Kawamata K, Fujii T, Tanaka S, Konishi H,
Okazaki H, Miyoshi K, Watanabe J, Matsudaira
K: The effect of the "One Stretch" exercise on the
improvement of low back pain in Japanese nurses:
a large-scale, randomized, controlled trial. Mod
Rheumatol 2018, Aug 22:1-17
63. Tanaka S, Tanaka Y, Ishiguro N, Yamanaka H,
Takeuchi T: RANKL: A therapeutic target forbone destruction in rheumatoid arthritis. Mod
Rheumatol 2018,28:9-16
64. Ogura K, Hosoda F, Arai Y, Nakamura H, Hama N,
Totoki Y, Yoshida A, Nagai M, Kato M, Arakawa
E, Mukai W, Rokutan H, Kawai A, Tanaka S,
Shibata T: Integrated genetic and epigenetic
analysis of myxofibrosarcoma. Nat Commun 2018,
Jul 17;9(1):2765
65. Lucas S, Omata Y, Hofmann J, Bottcher M,
Iljazovic A, Sarter K, Albrecht O, Schulz O,
Krishnacoumar B, Kronke G, Herrmann M,
Mougiakakos D, Strowig T, Schett G, Zaiss MM:
Short-chain fatty acids regulate systemic bonemass and protect from pathological bone loss. Nat
Commun 2018,9:55
66. Inoue M, Okamoto K, Terashima A, Nitta T, Muro
R, Negishi-Koga T, Kitamura T, Nakashima T,

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Takayanagi H: Arginine methylation controls thestrength of γc-family cytokine signaling in T cellmaintenance. Nature Immunology 2018,19:12651276
67. Yoshimura N, Muraki S, Oka H, Iidaka T,
Kodama R, Horii C, Kawaguchi H, Nakamura K,
Akune T, Tanaka S: Do sarcopenia and/or
osteoporosis increase the risk of frailty? A 4-year
observation of the second and third ROAD study
surveys. Osteporos International 2018
68. Fujii T, Oka H, Katsuhira J, Tonosu J, Kasahara S,
Tanaka S, Matsudaira K: Association between
somatic symptom burden and health-related
quality of life in people with chronic low backpain. PLoS One 2018, Feb 20;13(2):e0193208
69. Kawata M, Sasabuchi Y, Taketomi S, Inui H,
Matsui H, Fushimi K, Chikuda H, Yasunaga H,
Tanaka S: Annual trends in arthroscopic meniscus
surgery: Analysis of a national database in Japan.
PLoS One 2018:Apr 3;13(4):e0194854
70. Maeda T, Hashizume H, Yoshimura N, Oka H,
Ishimoto Y, Nagata K, Takami M, Tsutsui S,
Iwasaki H, Minamide A, Nakagawa Y, Yukawa Y,
Muraki S, Tanaka S, Yamada H, Yoshida M:
Factors associated with lumbar spinal stenosis in alarge-scale,population-based
cohort:
The
Wakayama Spine Study. PLoS One 2018,Jul 18;
13(7):e0200208
71. Ogihara S, Yamazaki T, Inanami H, Oka H,
Maruyama T, Miyoshi K, Takano Y, Chikuda H,
Azuma S, Kawamura N, Yamakawa K, Hara N,
Oshima Y, Morii J, Okazaki R, Takeshita Y,
Tanaka S, Saita K: Risk factors for surgical site
infection after lumbar laminectomy and/or
discectomy for degenerative diseases in adults: A
prospective multicenter surveillance study withregistry of 4027 cases. PLoS One 2018, Oct 16;
13(10):e0205539
72. Sasaki T, Yoshimura N, Hashizume H, Yamada H,
Oka H, Matsudaira K, Iwahashi H, Shinto K,
Ishimoto Y, Nagata K, Teraguchi M, Kagotani R,
Muraki S, Akune T, Tanaka S, Kawaguchi H,
Nakamura K, Minamide A, Nakagawa Y, Yoshida
M: MRI-defined paraspinal muscle morphology inJapanese population: The Wakayama Spine Study.
PLoS One 2018,12: e0187765
73. Murahashi Y, Yano F, Kobayashi H, Makii Y, Iba

K, Yamashita T, Tanaka S, Saito T: Intra-articularadministration of I ﾎ ｺ B ﾎ ｱ kinase inhibitor
suppresses mouse knee osteoarthritis via
downregulation of the NF-kB/HIF-2α axis. Sci
Rep 2018,8:16475
74. Oshina M, Oshima Y, Tanaka S, Tan LA, Li XJ,
Tuchman A, Riew KD: Utility of Oblique Sagittal
Reformatted and Three-dimensional Surface
Reconstruction Computed Tomography in
Foraminal Stenosis Decompression. Sci Rep 2018,
8(1):16011
75. Yamada K, Abe H, Higashikawa A, Tonosu J,
Kuniya T, Nakajima K, Fujii H, Niwa K,
Shinozaki T, Watanabe K, Sakae T, Okazaki H:
Evidence-based Care Bundles for Preventing
Surgical Site Infections in Spinal Instrumentation
Surgery. Spine (Phila Pa 1976) 2018, 43:17651773
76. Anno M, Oshima Y, Taniguchi Y, Matsubayashi Y,
Kato S, Soma K, Oka H, Hayashi N, Tanaka S:
Prevalence and Natural Course of Transverse
Ligament of the Atlas Calcification in
Asymptomatic Healthy Individuals. Spine (Phila
Pa 1976) 2018,43(24):E1469-E1473
77. Kato S, Fehlings MG, Lewis SJ, Lenke LG,
Shaffrey CI, Cheung KMC, Carreon LY,
Dekutoski MB, Schwab FJ, Boachie-Adjei O,
Kebaish KM, Ames CP, Qiu Y, Matsuyama Y,
Dahl BT, Mehdian H, Pellis F, Berven SH: An
Analysis of the Incidence and Outcomes of Major
Versus Minor Neurological Decline After
Complex Adult Spinal Deformity Surgery: A
Subanalysis of Scoli-RISK-1 Study. Spine (Phila
Pa 1977) 2018, 43(13):905-912
78. Kato S, Fok KL, Lee JW, Masani K: Dynamic
Fluctuation of Truncal Shift Parameters During
Quiet Standing in Healthy Young Individuals.
Spine (Phila Pa 1978) 2018, 43(13):E746-E751
79. Kato S, Nouri A, Reihani-Kermani H, Oshima Y,
Cheng J, Fehlings MG: Postoperative Resolutionof Magnetic Resonance Imaging Signal Intensity
Changes and the Associated Impact on Outcomesin Degenerative Cervical Myelopathy: Analysis ofa Global Cohort of Patients. Spine (Phila Pa 1979)
2018, 43(12):824-831
80. Kato S, Nouri A, Wu D, Nori S, Tetreault L,
Fehlings MG: Impact of Cervical Spine

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Deformity on Preoperative Disease Severity andPostoperative Outcomes Following Fusion
Surgery for Degenerative Cervical Myelopathy:
Sub-analysis of AOSpine North America andInternational Studies. Spine (Phila Pa 1980) 2018,
43(4):248-254
81. Kato S, Oshima Y, Matsubayashi Y, Taniguchi Y,
Tanaka S, Takeshita K: Minimum Clinically
Important Difference and Patient Acceptable
Symptom State of Japanese Orthopaedic Association Score in Degenerative Cervical Myelopathy
Patients. Spine (Phila Pa 1981) 2018, Epub
82. Oichi T, Oshima Y, Matsui H, Fushimi K, Tanaka
S, Yasunaga H: Can Elective Spine Surgery be
Performed Safely Among Nonagenarians?
Analysis of a National Inpatient Database in Japan.
Spine (Phila Pa 1982) 2018, Epub
83. Oichi T, Taniguchi Y, Soma K, Chang SH, Yano F,
Tanaka S, Saito T: A Mouse Intervertebral Disc
Degeneration Model by Surgically Induced
Instability. Spine (Phila Pa 1983) 2018, 43(10):E557-E564
84. Fehlings MG, Kato S, Lenke LG, Nakashima H,
Nagoshi N, Shaffrey CI, Cheung KMC, Carreon L,
Dekutoski MB, Schwab FJ, Boachie-Adjei O,
Kebaish KM, Ames CP, Qiu Y, Matsuyama Y,
Dahl BT, Mehdian H, Pellise-Urquiza F, Lewis SJ,
Berven SH: Incidence and risk factors of
postoperative neurologic decline after complex
adult spinal deformity surgery: results of the
Scoli-RISK-1 study. Spine J 2018, 18(10):17331740
85. Horii C, Yamazaki T, Oka H, Azuma S, Ogihara S,
Okazaki R, Kawamura N, Takano Y, Morii J,
Takeshita Y, Maruyama T, Yamakawa K,
Murakami M, Oshima Y, Tanaka S: Does
intrawound vancomycin powder reduce surgicalsite infection after posterior instrumented spinal
surgery? A propensity score-matched. Spine J
2018, 18(12):2205-2212
86. Kato S, Hozumi T, Yamakawa K, Saiki H, Sugita
S, Oshima Y, Tanaka S: Letter to the Editor
concerning "The META score for differentiating
metastatic from osteoporotic vertebral fractures:
an independent agreement assessment" by Besa
etal.. Spine J 2018,18(11):2167-2168
87. Oichi T, Oshima Y, Chikuda H, Ohya J, Matsui H,

Fushimi K, Tanaka S, Yasunaga H: In-hospitalcomplication rate following microendoscopic
versus open lumbar laminectomy: a propensity
score-matched analysis. Spine J 2018, 18(10)88. Emoto S, Kaneko M, Murono K, Sasaki K, Otani
K, Nishikawa T, Tanaka T, Hata K, Kawai K, Imai
H, Saito N, Kobayashi H, Tanaka S, Ikemura M,
Ushiku T, Nozawa H: Surgical management for ahuge presacral teratoma and a meningocele in an
adult with Currarino triad: a case report. Surg
Case Rep 2018, Jan 19;4(1):989. Uehara K, Zhao C, Amadio PC: Fibrin glue as analternative to peripheral sutures does not increase
tendon repair strength in an in vitro model. J Hand
Surg Eur Vol 2018,43:995-997
90. Ogura K, Uehara K, Akiyama T, Shinoda Y, Iwata
S, Tsukushi S, Kobayashi E, Hirose T, Yonemoto
T, Endo M, Tanzawa Y, Nakatani F, Kawano H,
Tanaka S, Kawai A: Development of apatient-oriented disease specific outcome measureof health-related quality of life (HRQOL) formusculoskeletal oncology patients. J Orthop Sci
2018, Nov 13. pii:S0949-2658(18)30317-8
91. Izawa N, Hirose J, Fujii T, Oka H, Uehara K,
Naito M, Matsumoto T, Tanaka S, Tohma S: Theutility of 25-question Geriatric Locomotive
Function Scale for evaluating functional ability
and disease activity in Japanese rheumatoid
arthritis patients: A cross-sectional study using
NinJa database. Mod Rheumatol 2018,18
92. Saita K, Monobe Y, Ogihara S, Kobayashi Y, SatoK, Nishimura K, Tanabe M: A case of vertebral
fracture associated with diffuse idiopathic skeletal
hyperostosis treated by successful conservative
treatment. Spine Surgery and Related Research
2018, Epub

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Department of Ophthalmology
Professor
Makoto Aihara, M.D., Ph.D.

Associate Professor
Satoshi Kato, M.D., Ph.D., Megumi Honjo, M.D., Ph.D.

Lecturer
Ryo Obata, M.D., Ph.D., Takashi Miyai, M.D., Ph.D.
Hiromasa Sawamura, M.D., Ph.D., Tomoyasu Shiraya, M.D., Ph.D.

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

Homepage

http://www.todaiganka.jp/

Introduction and Organization
The Department of Ophthalmology, University ofTokyo School of Medicine, was founded in 1889.
Since then, the department has contributed to Japanese
ophthalmology not only by educating many eminent
ophthalmologists in Japan but also by producing
significant basic research in ophthalmology.
The department has been active in collaboration with
ophthalmologists around the world, sponsoring
international ophthalmological meetings, educating
fellows from foreign countries, and sending our staff
and fellows abroad.

Clinical activities
Altogether, approximately 3000 new outpatients areseen every year in our hospital, which has a total of 30
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 6400
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254

postgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

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

Publications
1. Aihara M, Kuwayama Y, Miyata K, Ohtani S,
Ideta R, Hashimoto Y, Sasaki N, Shirato S.
Twelve-month efficacy and safety of glaucoma
filtration device for surgery in patients withnormal-tension glaucoma. Jpn J Ophthalmol.
2019;63:402-9.
2. Azuma K, Tan X, Asano S, Shimizu K, Ogawa A,
Inoue T, Murata H, Asaoka R, Obata R. The
association of choroidal structure and its responseto anti-VEGF treatment with the short-time
outcome in pachychoroid neovasculopathy. PLoS
One. 2019;14:e0212055.
3. Fukushima M, Inoue T, Miyai T, Obata R. Retinal
dystrophy associated with Danon disease andpathogenic mechanism through LAMP2-mutatedretinal pigment epithelium. Eur J Ophthalmol.
2019:1120672119832183.
4. Hashimoto Y, Inoue T, Ono T, Lee J, Tsuneyoshi S,
Fujita A, Inoue Y, Ogawa S, Asaoka R, Obata R. A
Novel Method for the Objective Identification ofHyperautofluorescent
Ring
inRetinitis
Pigmentosa Using Binarization Processing. Transl
Vis Sci Technol. 2019;8:20.
5. Hayashi T, Tabuchi H, Masumoto H, Morita S,
Oyakawa I, Inoda S, Kato N, Takahashi H. A
Deep Learning Approach in Rebubbling After
Descemet's Membrane Endothelial Keratoplasty.
Eye Contact Lens. 2019.
6. Igarashi N, Honjo M, Asano S, Takagi K, Aihara
M. Optic disc cupping characteristics of normalpressure hydrocephalus patients with normaltension glaucoma. Sci Rep. 2019;9:3108.
7. Kaburaki T, Nakahara H, Tanaka R, Okinaga K,
Kawashima H, Hamasaki Y, Rungrotmongkol T,
Hannongbua S, Noguchi H, Aihara M, Takeuchi F.
Lymphocyte proliferation induced by high-affinity
peptides for HLA-B*51:01 in Behcet's uveitis.
PLoS One. 2019;14:e0222384.
8. Minami T, Ishida W, Kishimoto T, Nakajima I,
Hino S, Arai R, Matsunaga T, Fukushima A,
Yamagami S. In vitro and in vivo performance ofepinastine hydrochloride-releasing contact lenses.
PLoS One. 2019;14:e0210362.
9. Miyai T, Vasanth S, Melangath G, Deshpande N,
Kumar V, Benischke AS, Chen Y, Price MO, Price

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FW, Jr., Jurkunas UV. Activation of PINK1Parkin-MediatedMitophagy
DegradesMitochondrial Quality Control Proteins in Fuchs
Endothelial Corneal Dystrophy. Am J Pathol.
2019;189:2061-76.
10. Nagano N, Honjo M, Kawaguchi M, Nishimasu H,
Nureki O, Kano K, Aoki J, Komatsu T, Okabe T,
Kojima H, Nagano T, Aihara M. Development of
a novel Intraocular-Pressure-Lowering therapy
targeting ATX. Biol Pharm Bull. 2019;42:
1926-35.
11. Nakagawa A, Sakai O, Tokushige H, Fujishiro T,
Aihara M. Development and characterization of a
new rat ocular hypertension model induced byintracameral injection of conjunctival fibroblasts.
Sci Rep. 2019;9:6593.
12. Nakahara H, Kaburaki T, Tanaka R, Yoshida A,
Takamoto M, Kawata M, Fujino Y, Kawashima H,
Aihara M. Comparisons of Clinical Features inJapanese Patients with Behcet's Uveitis Treated in
the 1990s and the 2000s. Ocul Immunol Inflamm.
2019:1-8.
13. Nakamura N, Tsunoda K, Mizuno Y, Usui T,
Hatase T, Ueno S, Kuniyoshi K, Hayashi T,
Katagiri S, Kondo M, Kameya S, Yoshitake K,
Fujinami K, Iwata T, Miyake Y. Clinical stages ofoccult macular dystrophy based on opticalcoherence
tomographic
findings.
InvestOphthalmol Vis Sci. 2019;60:4691-700.
14. Omoto T, Toyono T, Inoue T, Shirakawa R,
Yoshida J, Miyai T, Yamagami S, Usui T.
Comparison of 5-Year Clinical Results of Descemet and Non-Descemet Stripping AutomatedEndothelial Keratoplasty. Cornea. 2019.
15. Ono T, Iwasaki T, Yukawa C, Mori Y, Nejima R,
Tokunaga T, Amano S, Miyata K. Effect of topicalsteroid instillation on central corneal thickness ineyes with bullous keratopathy. Jpn J Ophthalmol.
2019;63:229-33.
16. Saito H, Araie M. A nationwide survey of factors
influencing adherence to ocular hypotensive
eyedrops in Japan. Int Ophthalmol. 2019 Feb;
39(2):375-383.
17. Glaucoma. 2019;28:289-93.
18. Sakata R, Yoshitomi T, Iwase A, Matsumoto C,
Higashide T, Shirakashi M, Aihara M, Sugiyama
K, Araie M. Factors associated with progressionof Japanese Open-Angle glaucoma with lower
normal intraocular pressure. Ophthalmology.
2019;126:1107-16.
19. Shirahama S, Kaburaki T, Nakahara H, Tanaka R,
Komae K, Fujino Y, Kawashima H, Aihara M.
Association
betweensubfovealchoroidal
thickness and leakage site on fluoresceinangiography in Behcet's uveitis. Sci Rep. 2019;9:
8612.
20. Tanaka R, Kaburaki T, Nakahara H, Komae K.
Ocular inflammation associated with relapsingpolychondritis in Japanese patients: a review of 11
patients. Int Ophthalmol. 2019;39:2649-59.
21. Terao R, Honjo M, Totsuka K, Miwa Y, Kurihara
T, Aihara M. The role of sphingosine 1-phosphate
receptors on retinal pigment epithelial cells barrier
function and angiogenic effects. Prostaglandins
Other Lipid Mediat. 2019;145:106365.
22. Yamanishi R, Nakamura N, Tsunoda K. Recoveryof vision following enzyme replacement therapy
in a patient with mucopolysaccharidosis type II,
Hunter Syndrome. Case Rep Ophthalmol. 2019;10:186-94.
23. Yanagisawa M, Murata H, Matsuura M, Fujino Y,
Hirasawa K, Asaoka R. Investigating thestructure-function relationship using Goldmann V
standard automated perimetry where glaucomatous damage is advanced. Ophthalmic Physiol Opt.
2019;39:441-50.

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Department ofOtorhinolaryngology and Head& Neck Surgery
Professor
Tatsuya Yamasoba, M.D., Ph.D.

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

Lecturer
Mizuo Ando, M.D., Ph.D.

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

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

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

Research Associate
Yuki Saito, M.D., Ph.D.

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

Chisato Fujimoto, M.D., Ph.D.

Hironobu Nishijima, M.D., Ph.D.

Osamu Fukuoka, M.D.

Takao Goto, M.D.

Akihito Yamauchi , M.D., Ph.D.

Yuya Shimizu, M.D.

Taku Sato, M.D.

Toshihiko Sakai, M.D.

Teru Kamogashira, M.D., Ph.D.

Homepage

http://utokyo-ent.org/

Introduction and Organization
The Department of Otorhinolaryngology was
founded in 1899 by Prof. Waichiro Okada who studiedin Germany. This is the first department ofotorhinolaryngology of the national university in Japan.
Our department covers all otorhinolaryngologicaldiseases and associated systemic diseases, and has
specialized clinics in middle ear and inner ear diseases,
hearing impaired infant and children, adult and elderly
patients, facial paresis, vertigo and balance disorders,olfactory disorders and paranasal diseases, voice andspeech disorders, taste and swallowing respiratory
disorders, aphasia, central auditory disorders and head& neck cancers.

A professor, associate professors, lecturers (assistantprofessors) and associates participate in surgery, outpatient and in-patient care as well as research andeducational activities. Moreover 8 Japanese graduate
students and two Chinese foreign graduate students
participate in basic research.
Weekly preoperative and postoperative conferences
are held to discuss surgical cases in detail. Special
lectures on leading research activities are presented byinvited guests on a regular basis. A weekly journal clubis held to introduce current research papers.

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

257

are provided to approximately 150 out-patients on adaily basis in all areas of otorhinolaryngology andrelated specialties, and approximately 300 new patients
visit monthly.
In the new inpatient hospital, 33 beds are preparedfor patients under the supervision of lecturers andsenior residents from each subspecialty group
including head & neck surgery, middle ear surgery andcochlear implant surgery; voice and bronchoesophagological surgery, and paranasal surgery andother minor surgery. Preoperative and postoperative
problems are checked and discussed by each group, theprofessor’s and associate professor’s rounds.
Approximately 700 operations are performed annually.
Cochlear implant surgery over 400 cases has been
actively performed for infants, children and adultpatients with profound hearing loss and is very
successful to provide new hearing. Head and necksurgery is performed to extirpate malignant tumor withneighboring tissues and reconstruct upper respiratory
and swallowing functions at one stage operationcooperating with plastic surgeons. Reconstructive
surgery of microtia and atresia to reconstruct external
ear is routinely performed with plastic surgeons.
Auditory brainstem response is routinely examinedin order to diagnose peripheral and central deafness inneonates, infants and children.
Treatment of acoustic tumor using an ɤ-knife andauditory brainstem implant are performed inconsultation with neurosurgeons.

Teaching activities
For the fourth year medical students’ serial lecturesand for the fifth and sixth year medical students special
lectures on current topics are provided by the professor
and associate professor.
Clinical training is provided for the sixth year classof medical students on a one-to-one basis with staff
doctors. They are requested to write reports on aclinical case or a clinical problem. The students
participate to see surgery, special clinics and clinicalexaminations such as otoscope, fiberscope, pure-toneaudiometry, auditory brainstem response, and caloric
test. Interview with patient is encouraged. They arequestioned on many aspects of clinical problems inseminars by professor and associate professor.

Research activities
Clinical and basic research activities are highly
encouraged. Clinical research, which is supervised bysenior doctors, is very actively pursued even by young
residents. Case reports presentation and writing skills
are regarded as important experience in order todevelop young doctors’ research activity andinvestigate important findings in patients. The clinicalresearch is related to ear surgery, neurotology, audiology, head and neck surgery, bronchoesophagology andrhinology and is related to case research, clinical statistics and clinical electrophysiology. Basic research isalso encouraged to solve essence of clinical problems
and to elucidate basic phenomena or anatomical andcellular structures. Our research topics cover:1) Morphology and neurophysiology of the inner ear
focusing on sensory neural deafness: human
temporal bone pathology, electron microscopic
study in animal models, gene therapy, proteintransduction, and nanotechnology2) Speech perception and language development indeaf children.
3) Analysis of balance disorders using vestibularfunction tests4) Development of novel diagnosis methods forbalance disorders
5) Development of novel therapeutic methods forbalance disorders by galvanic vestibular
stimulation
6) Predicting and elucidating the pathogenesis ofvestibular disorders using machine learning7) Establishment of animal models of vestibulardiseases and development of treatments
8) Hair cell physiology and pathology andintroduction of hair cell regeneration in theauditory and vestibular end organ.
9) Clinical neurophysiology of the facial nerves
focusing on degeneration and regeneration inpatients.
10) Therapeutic effects of growth factors on facial
nerve and laryngeal regeneration after injury11) Analysis of olfactory system in development,
injury and aging.
12) Metabolic conversion of odorant molecules bynasal mucus

25813) Analysis of eosinophilic chronic sinusitis using
human samples and animal models
14) Pulmonary inflammatory responses by contrast
agent aspiration
15) Swallowing mechanisms using pathological andelectrophysiological analysis and VR system16) Evaluation of swallowing physiology withpharyngo-esophageal high-resolution manometry17) Esophageal Motility in Neuromuscular Disorders18) Kinetics of vocal cord movement using high-speed
video system
19) Histochemical, molecular biological, and genome
analysis of head and neck cancer
Various clinical and basic researches are conductedby staffs, residents, and graduate students as well as
doctors at affiliated hospitals.

References
1. Ando M, Saito Y, Xu G, Bui N, Medetgul-Ernar K,
Pu M, Fisch K, Ren S, Sakai S, Fukusumi T, Liu C,
Haft S, Pang J, Mark A, Gaykalova D, Guo T,
Favorov A, Yegnasubramanian S, Fertig E, Ha P,
Tamayo P, Yamasoba T, Ideker T, Messer K,
Califano J. Chromatin dysregulation and DNA
methylation at transcription start sites associatedwith transcriptional repression in human cancers.
Nat Commun 10 : 2188, 2019
2. Azuma S, Kikuta S, Yoshida M, Ando M, Kondo
K, Yamasoba T. High CT attenuation values
relative to the brainstem may predict squamous cell
carcinoma arising from inverted papilloma. Acta
Otolaryngol 139 : 1030-1037, 2019
3. Fujimoto C, Kinoshita M, Kamogashira T, Egami
N, Kawahara T, Uemura Y,Yamamoto Y,
Yamasoba T, Iwasaki S. Noisy galvanic vestibular
stimulation has a greater ameliorating effect on
posture in unstable subjects: a feasibility study. Sci
Rep 9 : 17189, 2019
4. Fujimoto C, Yagi M, Murofushi T. Recent
advances in idiopathic bilateral vestibulopathy: aliterature review. Orphanet J Rare Dis 14 : 202,2019
5. Fujimoto C, Yamasoba T. Mitochondria-Targeted
Antioxidants for Treatment of Hearing Loss: A
Systematic Review. Antioxidants (Basel) 8 : 109,2019
6. Haft S, Ren S, Xu G, Mark A, Fisch K, Guo T,
Khan Z, Pang J, Ando M, Liu C, Sakai A,
Fukusumi T, Califano J. Mutation of chromatin
regulators and focal hotspot mutations characterize
HPV positive oropharyngeal squamous cell
carcinoma. Cancer 125 : 2423-2434, 2019
7. Ijichi C, Wakabayashi H, Sugiyama S, Ihara Y,
Nogi Y, Nagashima A, Ihara S, Niimura Y,
Shimizu Y, Kondo K, Touhara K. Metabolism ofOdorant Molecules in Human Nasal/Oral Cavity
Affects the Odorant Perception. Chem Senses 44 :465-481, 2019
8. Inoue A, Iwasaki S, Fujimoto C, Kinoshita M,
Yamasoba T. Progression of Peripheral Vestibular
Dysfunctions in Patients With a Mitochondrial
A3243G Mutation. Otol Neurotol 40 :359-364,
2019
9. Iwamura H, Kondo K, Kikuta S, Nishijima H,
Kagoya R, Suzukawa K, Ando M, Fujimoto C,
Toma-Hirano M, Yamasoba T. Caloric restriction
reduces basal cell proliferation and results in thedeterioration of neuroepithelial regeneration
following olfactotoxic mucosal damage in mouseolfactory mucosa. Cell Tissue Res 378 : 175-193,
2019
10. Kanda A, Kondo K, Hosaka N, Kobayashi Y, Bui
DV, Yun Y, Suzuki K, Sawada S, Asako M,
Nakamura A, Tomoda K, Sakata Y, Tsuta K,
Dombrowicz D, Kawauchi H, Fujieda S, Iwai H.
Eosinophilic Upper Airway Inflammation in a
Murine Model Using an Adoptive Transfer System
Induces Hyposmia and Epithelial Layer Injury with
Convex Lesions. Med Sci (Basel) 7 : 22, 2019
11. Kato M, Ueha R, Sugasawa S, Sato T, Goto T,
Yamauchi A, Yamasoba T. Choice of Aspiration
Prevention
Surgeryfor
Patients
with
Neuromuscular Disorders: Report of Three Cases.
Front Surg 6 : 66, 2019
12. Kinoshita M, Fujimoto C, Iwasaki S, Kashio A,
Kikkawa S Y, Kondo K, Okano H, Yamasoba T.
Alteration of Musashi1 intra-cellular distribution
during regeneration following gentamicin-induced
hair cell loss in the guinea pig crista ampullaris.
Front. Cell. Neurosci 13 : 481, 2019
13. Kobayashi K, Yoshimoto S, Matsumoto F, AndoM, Murakami N, Omura G, Hukasawa M,

259

Matsumoto Y, Matsumura S, Akamatsu M,
Hiraoka N, Eigitsu R, Mori T. All-exon TP53
sequencing and protein phenotype analysis
addurately predict clinical outcome after surgicaltreatment of head and neck squamous cell
carcinoma. Ann Surg Oncol 26 :2294-2303, 2019
14. Koebis M, Urata S, Shinoda Y, Okabe S,
Yamasoba T, Nakao K, Aiba A, Furuichi T.
LAMP5 in presynaptic inhibitory terminals in thehindbrain and spinal cord: a role in startle response
and auditory processing. Molecular brain 12 : 20,
2019
15. Kohsaka S, Tatsuno K, Ueno T, Nagano M,
Shinozaki-Ushiku A, Ushiku T, Takai D, Ikegami
M, Kobayashi H, Kage H, Ando M, Hata K, Ueda
H, Yamamoto S, Kojima S, Oseto K, Akaike K,
Suehara Y, Hayashi T, Saito T, Takahashi F,
Takahashi K, Takamochi K, Suzuki K, Nagayama
S, Oda Y, Mimori K, Ishihara S, Yatomi Y, Nagase
T, Nakajima J, Tanaka S, Fukayama M, Oda K,
Nangaku M, Miyazono K, Miyagawa K, Aburatani
H, Mano H. Comprehensive assay for themolecular profiling of cancer by using DNA andRNA hybridization capture-based target enrichment from formalin- fixed paraffin-embedded
specimens. Cancer Sci 110 : 1464-1479, 2019
16. Koizumi M, Ishimaru M, Matsui H, Fushimi K,
Yamasoba T, Yasunaga H. Outcomes ofendoscopic sinus surgery for sinusitis-induced
intracranial abscess in patients undergoingneurosurgery. Neurosurg Focus 47 : E12, 2019
17. Koizumi M, Ishimaru M, Matsui H, Fushimi K,
Yamasoba T, Yasunaga H.Tranexamic acid andpost-tonsillectomy hemorrhage: propensity score
and instrumental variable analyses. European
Archives of Oto-Rhino-Laryngology 276 : 249254, 201918. Miwa T, Ikeda K, Ishibashi T, Kobayashi M,
Kondo K, Matsuwaki Y, Ogawa T, Shiga H,
Suzuki M, Tsuzuki K, Furuta A, Motoo Y, Fujieda
S, Kurono Y. Clinical practice guidelines for the
management of olfactory dysfunction - Secondary
publication. Auris Nasus Larynx 46 : 653-662,
2019
19. Rikitake R, Tsukada Y, Ando M, Yoshida M,
Iwamoto M, Yamasoba T, Higashi T. Use of
intensity-modulated
radiationtherapyfornasopharyngeal cancer in Japan: analysis using anational database. Jpn J Clin Oncol 49 : 639-645,
2019
20. Sato T, Nito T, Ueha R, Goto T, Yamasoba T.
Investigation of the Safety of Injection
Laryngoplasty under Antithrombotic Therapy.
ORL J Otorhinolaryngol Relat Spec 81 : 215-223,
2019
21. Sato T, Nito T, Ueha R, Goto T, Yamasoba T.
Laryngeal fractures treated with titanium meshfixation. Auris Nasus Larynx 46 : 474-478, 201922. Shin M, Hasegawa H, Miyawaki S, Kakigi A,
Takizawa T, Kondo K, Shiode T, Kin T, Saito N.
Endoscopic transmastoid posterior petrosal
approach for locally aggressive tumors in the
petrous part of the temporal bone involving theinternal auditory canal, jugular foramen, andhypoglossal canal. J Neurosurg 27 : 1-13, 201923. Ueha R, Zelter NN, Sato T, Goto T, Nito T,
Belafsky CP, Yamasoba T.Acute inflammatory
response to contrast agent aspiration and its
mechanisms in the rat lung. Laryngoscope 129 :
1533-1538, 201924. Ueha R, Zelter NN, Sato T, Goto T, Nito T,
Tsunoda K, Belafsky CP, Yamasoba T. Chronic
inflammatory response in the rat lung to commonlyused contrast agents for videofluoroscopy.
Laryngoscope Investigative Otolaryngology 4 :335–340, 201925. Ueha R. Molecular mechanism of smoking smell
and elucidation of regeneration environment ofolfactory epithelium. Impact 6 : 68–70, 201926. Urata S, Iida T, Suzuki Y, Lin SY, Mizushima Y,
Fujimoto C, Matsumoto Y, Yamasoba T. A Novel
Technique for Imaging and Analysis of Hair Cells
in the Organ of Corti Using Modified Sca/eS andMachine Learning. Bio-protocol 9 : 16, 201927. Urata S, Iida T, Yamamoto M, Mizushima Y,
Fujimoto C, Matsumoto Y, Yamasoba T, Okabe S.
Cellular cartography of the organ of Corti based on
optical tissue clearing and machine learning. Elife
8 : e40946, 201928. Tsujimura T, Ueha R, Yoshihara M, Nagoya K,
Shiraishi N, Magara J, Inoue M. Involvement of
the epithelial sodium channel in initiation of
mechanically evoked swallows in anaesthetized
rats. The Journal of Physiology 597 : 2949-2963,

260

2019
29. Wang Z, Feng X, Molinolo A, Martin D, VitaleCross L, Nohata N, Ando M, Wahba A,
Amornphimoltham P, Wu X, Gilardi M, Allevato
M, Wu V, Steffen D, Tofilon P, Sonenberg N,
Califano J, Chen Q, Lippman S, Gutkind S. 4EBP1 is a head and neck cancer tumor suppressor
protein unleashed by mTOR inhibition. Cancer Res
79 : 1438-1450, 2019

261

Department of
Rehabilitation Medicine
Professor
Nobuhiko Haga, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The Department of Rehabilitation Medicine wasestablished by Ministry of Education, Culture, Sports,
Science and Technology in April 2001. It is one of thenewest fields in Graduate School of Medicine, theUniversity of Tokyo. It belongs to the Sensory andMotor System Science Course of the Surgical Science
Division. Current authorized staff is only one
professor.
This department derives from the establishment of
the physical therapy room in the central diagnostic
and therapeutic sections in order to develop theclinical practice of rehabilitation medicine in 1963.
The chair of professor was set up as a full-time director of the central rehabilitation service in 1984, but theformal title remained a physical therapy department.
Rehabilitation medicine is a newly establishedclinical section which was born in development of themodern principle of the medical health service bywhich it came to value the enhancement of not only
adding years of patient's life but also adding life to theyears. Regardless of the rapid expansion of needs,
acknowledgment of rehabilitation medicine wasdelayed in the frame of the old-fashioned clinicaldepartments. In our country, it was 1996 when the
rehabilitation specialty was authorized as formal
clinical practice by the former Ministry of Health andWelfare.
On the other hand, it was positioned as an
assistance instructor in the sensory and motor system
medicine department with shifting to the graduate
school course systems since 1995 to 97 in the
University of Tokyo. Finally, the rehabilitation

medicine field was installed in the sensory and motor
system medicine department by a budget step of 2001.
We have accepted the graduate school student
formally since fiscal year 2001. However, thearrangement of additional teaching staff is not stillmaterialized. Therefore, the staff of the graduate
school is only one professor. Seventeen students haveentered the graduate school by 2016, and thirteen 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 30 people per day at theoutpatient rehabilitation setting. The numerical ratioof outpatient is being reduced in order to give priority
to the clinical service corresponding to needs
expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year
medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such as262

cerebrovascular disturbances, respiratory disorders,
neuromuscular diseases, bone and joint diseases, andpediatric disorders as well as on outline ofrehabilitation, and amputation/prostheses. We haveprovided a clinical practice in small group, so-calledclinical clerkship for 5th and 6th year students from
Wednesday to Friday every week. They experience a
few patients and learn how to take a patients’ history,
physical findings, functional evaluation, and how toplan rehabilitation programs. We have introduced a
few of elective students for elective clinical clerkshipto our collaborating hospitals with specialized
rehabilitation ward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with otherdepartments in our hospital, other faculties in our
university, and institutions outside the University ofTokyo. The ongoing projects are as follows.
1) 3D Motion analysis of patients with musculoskeletal disorders
2) Study on the relationship between sensory deficit
and motor control
3) Rehabilitation and long-term outcome in patientswith skeletal dysplasias
4) Pathology and treatment for patients withcongenital limb deficiencies
5) Analysis of rehabilitation outcome using DPC
data

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

2. Mano H, Fujiwara S, Haga N: Body knowledge inchildren with congenital lower limb deficiency.
Pediatr Int 61(2): 158-165, 2019
3. Matsushita M, Kitoh H, Mishima K, Yamashita S,
Haga N, Fujiwara S, Ozono K, Kubota T, Kitaoka
T, Ishiguro N: Physical, mental and social
problems of adolescent and adult patients withachondroplasia. Calc Tissue Int 104(4): 364-372,
2019
4. Nakahara Y, Kitoh H, Nakashima Y, Toguchida J,
Haga N: The longitudinal study of activities ofdaily living and quality of life in Japanese patientswith fibrodysplasia ossificans progressiva. Disabil
Rehabil 41(6): 699-704, 2019
5. Taya M, Amiya E*, Hatano M, Maki H, Hosoya Y,
Ishida J, Bujo C, Tsuji M, Konishi Y, Yokota K,
Haga N, Komuro I: Inspiratory muscle training foradvanced heart failure with lamin-related muscular
dystrophy. J Cardiol Cases 2019, jccase 20(6): 232234, 2019.9
6. Yamoto K, Saitsu H, Nishimura G, Kosaki R,
Takayama S, Haga N, Tonoki H, Okumura A, Horii
E, Okamoto N, Suzumura H, Ikegawa S, Kato F,
Fujisawa Y, Nagata E, Takada S, Fukami M, Ogata
T: Comprehensive clinical and molecular studies in
split hand/foot malformation: identification of twoplausible candidate genes (LRP6 and UBA2). Eur J
Hum Genet 27: 1845-1857, 2019
7. Yoshida M, Matsunaga A, Igawa Y, Fujimura T,
Shinoda Y, Aizawa N, Sato Y, Kamei J, Kume H,
Homma Y, Haga N, Sanada H*: May preoperative
ultrasound-guided pelvic floor muscle training
promote early recovery of urinary continence after
robot-assisted radical prostatectomy? Neurourol
Urodyn 38(1): 158-164, 2019
8. Ogura K, Uehara K, Akiyama T, Shinoda Y, Iwata
S, Tsukushi S, Kobayashi E, Hirose T, Yonemoto T,
Endo M, Tanzawa Y, Nakatani F, Kawano H,
Tanaka S, Kawai A: Development of a patientoriented disease specific outcome measure ofhealth-related quality of life (HRQOL) formusculoskeletal oncology patients. J Orthop Sci
24(3): 539-547, 2019
9. Fujimura T, Igawa Y, Aizawa N, Niimi A, Yamada
Y, Sugihara T, Kamei J, Sato Y, Matsunaga A,
Yoshida M, Shinoda Y, Fukuhara H, Nakagawa T,
Homma Y, Kume H: Longitudinal change of263

comprehensive lower urinary tract symptoms andvarious types of urinary incontinence during
robot-assisted radical prostatectomy. Neurourol
Urodyn 38(4): 1067-1075, 201910. Shinoda Y, Sawada R, Yoshikawa F, Oki T, Hirai T,
Kobayashi H, Matsudaira K, Oka H, Tanaka S,
Kawano H, Haga N: Factors related to the qualityof life in patients with bone metastases. Clin Exp
Metastasis 36(5): 441-448, 201911. Shinoda Y, Kobayashi H, Kaneko M, Ohashi S,
Bessho M, Hayashi N, Oka H, Imanishi J, Sawada
R, Ogura K, Tanaka S, Haga N, Kawano H:
Prediction of the pathological fracture risk during
stance and fall-loading configurations formetastases in the proximal femur, using acomputed tomography-based finite element method.
J Orthop Sci 24(6): 1074-1080, 201912. Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Kudo N, Azechi H, Okada N,
Koshiyama D, Shiino T, Fukunaga M, Watanabe Y,
Ikeda M, Kasai K, Hashimoto R: Eye‐movement
characteristics of schizophrenia and theirassociation with cortical thickness. Psychiatry Clin.
Neurosci. 73: 508–9, 201913. Morita K, Miura K, Kasai K, Hashimoto R: Eyemovement characteristics in schizophrenia: A
recent update with clinical implications. Neuropsychopharmacol Rep. Epub ahead of print, 201914. Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Kudo N, Azechi H, Okada N,
Koshiyama D, Ikeda M, Kasai K, Hashimoto R:
Eye movement abnormalities and their association
with cognitive impairments in schizophrenia.
Schizophr. Res. 209: 255–62, 2019

Surgical Sciences
3. Vital Care Medicine

265

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

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

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

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

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

Mori Yoshiteru, M.D.

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

Associate
Masaaki Asamoto, M.D.,

Miki Shinokawa, M.D.,

Yuho Tamai, M.D.,

Ayako Hirai, M.D.,

Atsuko Kato, M.D.,

Takuma Hiraiwa, M.D.,

Seiichiro Kawashima, M.D.,
Hayato Narita, M.D.,

Yoshiomi Kusakabe, M.D., Ph.D.

Michiko Ushio, M.D.,

Yuko Araki, M.D.,

Takuya Ohata, M.D., Mizuho Sato, M.D.,

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

Kohshi Hattori, M.D., Ph.D.

Satoshi Kasahara, M.D., Makoto Uranaka, M.D.,

Yuji Ueda, M.D.,

Kanae Tsutsumi, M.D.,

Tomoaki Nakamura, M.D.

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/aprc_md/index.html
http://www.anes.umin.ne.jp/
Introduction and Organization
The Department of Anesthesiology was establishedin 1952, the oldest department specialized inanesthesiology in Japan. Currently, our department has
29 faculty staffs, 6 graduate students and 14 residents.
We introduce the activities about Teaching, Researchand Clinical work of our department.

Clinical activities
Our clinical services include perioperative management for patients undergoing surgeries, treatment forpatients suffering acute / chronic pain, and palliative
care for patients with malignancies.
Number of cases undergoing surgery is increasing in
our hospital and annual number of surgery cases
exceeds 11,000. Recently, the number of high risk or

geriatric patients is increasing. Especially surgery fororgan transplant, such as heart, liver and lung requires
tight and meticulous anesthetic care. Our aim is toprovide optimal perioperative care including proper
preoperative assessment of patients, efficient plan for
intraoperative management, meticulous intraoperativeand / or postoperative care. We are a part ofperioperative management team established in our
hospital recently to play pivotal role in perioperative
patient care. Especially for patients with multiple
comorbidities, we provide preoperative assessment /consult clinic and accept 1,600 patients annually. Pain
clinic services are provided for outpatients (including
patients in the ward of the other departments) on a daily
basis in all areas of diseases accompanied with pain.
From April 2019 to March 2020, the number of
ambulatory patients was about ten thousands; two266

hundreds and seventy of those were newcomer patients.
Currently we have one bed in the ward. We take care
40 patients in our ward and approximately 100 in otherwards annually, with multidisciplinary approach incollaboration with neurologists, psychiatrist, andorthopedists. Our palliative care team manages varied
somatic symptoms and psychological distress of
inpatients and outpatients with cancer. Further, wemanage the “cancer treatment-related chronic pain
management” outpatient clinic and also the second
opinion outpatient clinic for cancer pain patients withadvanced and terminal cancer stages.

Teaching activities
We give lectures for fourth year medical students andprovide clinical education (Clinical Clerkship) for fifthand sixth year medical students on a man-to-man basiswith our faculty staff members. The lectures of the lastyear were the history of anesthesia, the mechanisms ofanesthesia, inhalational anesthesia, intravenous
anesthesia, anesthesia and respiratory/circulatory
system, the balance of body fluid, acid-base balance,
muscle relaxants, management of the patient during
anesthesia, monitoring, resuscitation, pain clinic andthe physiology and the management of pain.
The curriculum of Clinical Clerkship consists ofthree major contents: learning a practice of anesthetic
management for patients undergoing surgeries,
observing a practice of pain management for outpatients suffering from intractable pain, and interactive
lectures on specific topics. During the practice ofanesthetic management, we teach students how toevaluate patients in the perioperative period. Throughthe practice of pain management, we teach students
causes of intractable pain as well as treatment of pain
including nerve block, functional therapy, andcognitive-behavioral therapy. We provide 5 miniseminars that cover essential knowledge of clinicalanesthesia for medical students, each of them entitled“introduction to anesthesiology”, “airway management”, “central venous catheterization”, “spinal
anesthesia” and “pain clinic”. Moreover, students canexperience procedures of tracheal intubation, central
venous catheterization and spinal anesthesia using
simulators. Each student is required to submit a reportor a case that summarizes the procedures and medicine

applied perioperatively. We discuss the contents of thereports and summaries with students at the end of
Clinical Clerkship, for their further understandings.

Research activities
We have seven research groups and their fields
include respiration, circulation, pain, immune systemand shock.
These are recent major subjects of our research.
1) A role of cytokine signaling in acute lung injury2) Evaluation of optimal ventilatory strategy for
respiratory failure3) Modulation of immune system by anesthetics
4) Signal transduction pathway related to apoptosis
activated by sepsis or ischemia-reperfusion5) Pathophysiology of shock6) A role of lipid mediators in organ damage mediatedby ischemia-reperfusion injury7) A role of lipid mediators in the formation of
hyperalgesia
8) Antihyperalgesic and antipruritic effects of alpha2-adrenergic agonists
9) A role of spinal microglial cells in the developmentof inflammation-mediated neuropathic pain
10) Spinal contribution for analgesic pathway11) Mechanism of Pruritoceptive and Neurogenic Itch
12) Genetic analyses of pain intensity and opioid
sensitivity in clinical pain patients
13) Analysis of electroencephalography during generalanesthesia
14) Clinical evaluation of neurological sequelae after
cardiac surgery15) Retrospective analysis of large administrative
database to explore rare complications related toanesthesia and / or association between anesthetic
drug and postoperative outcome16) Effect of anesthetics on glucose metabolism in vivo17) Role of new plasma substitutes on hemorrhagicshock18) Mechanisms of chemotherapy-induced neuronal
dysfunction

Publications
1. Aoyama H, Uchida K, Aoyama K, Pechlivanoglou
P, Englesakis M, Yamada Y, and Fan E: Assessmentof Therapeutic Interventions and Lung Protective

267

2.

3.

4.

5.

6.

7.

8.

Ventilation in Patients With Moderate to Severe
Acute Respiratory Distress Syndrome. A
Systematic Review and Network Meta-analysis.
JAMA Netw Open. 2019; 2(7):e198116. doi:10.
1001/jamanetworkopen.2019.8116
Uchida K: Post-surgical immune suppression:
Another target to improve postoperative outcomes.
Journal of Anesthesia. 2019; 33: 625-627
Hattori K, Asamoto M, Otsuji M, Ito N, Kasahara
S, Hashimoto Y, Yamada Y. Quantitativeevaluation of stress in Japanese anesthesiology
residents based on heart rate variability andpsychological testing. J Clin Monit Comput. 2019
Apr 1. ePub
Takahashi N, Takatsuki K, Kasahara S, Yabuki S.
Multidisciplinary pain management program forpatients with chronic musculoskeletal pain in
Japan: a cohort study. Journal of Pain Research.
2019:21(12);2563-2576
Ushio M, Sumitani M, Abe H, Mietani K, Hozumi
J, Iniue R, Tsuchida R, Ushida T, Yamada Y.
Characteristics of locomotive syndrome inJapanese patients with chronic pain and results ofa path analysis confirming the relevance of avicious cycle involving locomotive syndrome,musculoskeletal pain, and its psychological factors.
JMA journal. 2019: 2(2);184-9
Mietani K, Sumitani M, Ogata T, Shimojo N,
Inoue R, Abe H,
Kawamura G, Yamada Y.
Dysfunction of the blood-brain barrier inpostoperative delirium patients, referring to theaxonal damage biomarker phosphorylated neurofilament heavy subunit. PLOS ONE. 2019;14:e0222721
Hayakawa K, Kurano M, Ohya J, Oichi T, Kano K,
Nishikawa M, Uranbileg B, Kuwajima K, Sumitani
M, Tanaka S, Aoki J, Yatomi Y, Chikuda H.
Lysophosphatidic acids and their substratelysophospholipids in cerebrospinal fluid asobjective biomarkers for evaluating the severity oflumbar spinal stenosis. Scientific Reports. 2019:
9(9144); 1−9
Kuwajima K, Chang K, Furuta A, Bougaki M,
Uchida K, Sawamura S, Yamada Y. Synergistic
cytoprotection by co-treatment with dexamethasone and rapamycin against proinflammatory
cytokine-induced alveolar epithelial cell injury.

Journal of Intensive Care. 2019:7(12);1−13
9. Hattori K, Yoshitani K, Kato S, Kawaguchi M,
Kawamata M, Kakinohana M, Yamada Y,
Yamakage M, Nishiwaki K, Izumi S, Yoshikawa Y,
Mori Y, Hasegawa K, Onishi Y. Association
Between Motor-Evoked Potentials and Spinal Cord
Damage Diagnosed With Magnetic ResonanceImaging After Thoracoabdominal and Descending
Aortic Aneurysm Repair. Journal of Cardiothoracic
and Vascular Anaesthesia. 2019: 33(7);1835-1842
10. Baasanjav U, Ito N, Kurano M, Saigusa D, Saito R,
Uruno A, Kano K, Ikeda H, Yamada Y, Sumitani M,
Sekiguchi M, Aoki J, Yatomi Y. Alteration of thelysophosphatidic acid and its precursor
lysophosphatidylcholine levels in spinal cordstenosis: A study using a rat cauda equina
compression model. Scientific Reports. 2019;9:
16578

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

Associate Professor
Kent Doi, M.D.

Lecturer
Chiaki Toida, M.D.

Takehiro Matsubara, M.D.

Project Lecturer
Yoshihiro Ueda, M.D.

Takahiro Hiruma, M.D.

Naoki Hayase, M.D.

Mio Kurimoto, M.D.

Naho Misawa, M.D.

Hitomi Nakamura, M.D.

Jinsuke Mizuno, M.D.

Daisuke Takai, M.D.

Go Takeda, M.D.

Hiroyasu Mizuhara, M.D.

Research Associate

Project Research Associate
Atsushi Shimada, M.D.

Homepagehttps://www.tokyodam.com/

Introduction and Organization
Department of Emergency and Critical Care
Medicine was established in 1965, as the emergency
service within the Central Clinical Service Facilities of
the University of Tokyo Hospital and at the same timeas the intensive care service for in-hospital patients, it
became a tertiary emergency care and critical carecenter in the metropolitan Tokyo and also became theprincipal teaching facility of the University of Tokyo.
It is a designated Level I Trauma Center, and also thehome of one of the newest Life Flight aeromedical
services in the country.
The Emergency Center sees approximately 17,000
patients per year. It contains major trauma and cardiac
resuscitation rooms complete with STAT X-ray and fullmonitoring and resuscitation equipment. There are 9
treatment spaces including space for orthopedics,
gynecology, and Ophthalmology-ENT evaluations.
10 overnight-stay monitored beds, X-ray, rapid spiralCT, ultrasound, angiography and STAT Lab are locatedadjacent to the Emergency Center.
In September, 2001, the University of Tokyo
Hospital opened the In-patient Ward A and ourdepartment has necessarily extended services for
management of critical patients, in the new Critical
Care Center now containing adult ICU/CCU of 16 bedsin ICU1, 18 beds in ICU2 and 6 beds in Emergency
ICU.
The Emergency Care Center and the Critical Care
Center see an excellent mix of multiple trauma, highacuity medical, surgical, pediatric, and gynecologic
patients. The Life Flight service provides anotheropportunity for exposure to critically ill patients.
Consult services are available from all of the clinicaldepartments of the Medical School. The university ofTokyo hospital was officially designated as emergency
medical care center in December 2010.

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Clinical activities
Our clinical activities are divided into four
categories as follows:
1) Emergency medicine
Our department is responsible for not only tertiary
emergency but also primary and secondary
emergency care on 24-hour-a-day basis. In 2017
fiscal year, we had about 6595 ambulance patientsout of total 17607 ER outpatients.
The new ER, four times the size of the previous
ER was built in November, 2006. The facility has 5
consultation rooms, 4 specialized consultation rooms
for dentistry, ophthalmology, otorhinolaryngology
and gynecology, 3 resuscitation bays, and 4
observation beds.
2) Intensive care
Staff members specialized in internal medicine,cardiovascular medicine, orthopedic surgery, surgery,neurosurgery or anesthesiology create “the semiclosed ICU” model. We are responsible for the entire
care of the critically ill patients (i.e. patients withrespiratory insufficiency such as ARDS, with sepsis,with MOF, with shock), post-operative patients, andtertiary emergency patients, placing an emphasis on
evidence-based medical therapy. We had 2,300
ICU/CCU patients in the 2016.
3) Bed management
The objective of bed management services is toprovide a timely and appropriate bed allocation for
all the patients. In our hospital, patients are allocatedto three types of wards, that is, general ward, ICU2
and ICU/CCU in accordance with their criticalcondition. The ICU2 undertakes the leading bed
management in the hospital to ensure maximum
performance as an acute hospital.
4) Risk management
It is split into two categories – in-hospital and outof hospital disasters. In regard to in-hospital risk
management, including “code blue emergency”, weare responsible for patient safety on 24-hour/365-day
basis. And in regard to out of hospital risk
management, our hospital has been authorized by the
Tokyo Metropolitan Government as a disaster basehospital, and also the Government has requested theformation of Disaster Medical Assistant Team(DMAT). We have oxygen and medical suction
equipment on the passageways in the ER in case oftreating the large number of disaster patients.

Teaching activities
The topics of lectures for the 2nd year medical
student include the prehospital emergency care, theinitial evaluation of emergency patients, disastermedicine, serious infections disease, and trauma. BasicLife Support. exercise is also mandatory for the 2ndyear medical student.
One month of elective clinical clerkship for the 3rdyear. Immediate Cardiac Life Support (ICLS) courseand 1 day Hospital MIMMS (Major Incident Medical
Management and Support) course are held for theparticipants in the clinical clerkship program, andsuccessful completion of each course will enable
students to be certified as providers.
Clinical integrated lecture for the 4th year students
includes diagnosis and treatment of serious patientsusing case studies of shock, conscious disorder, trauma,
intoxication, infections disease, burns, hypothermia,
and convulsion. Moreover, after exercise of Advanced
Life Support, students experience a real practice of
emergency medicine as fellow passengers in theambulances and as one day trainees in the emergency
centers of the affiliated hospitals.
In conformity with the guideline by Ministry of
Health, Labor and Welfare, all residents learn andpractice emergency medicine and primary care at every
level, primary, secondary and tertiary. The residents
attend the ICLS course during resident year to obtainthe knowledge and skills in CPR.
Junior residents are also assigned to ICU services togain the knowledge of intensive care from
pathophysiological and internal medicine’s point ofview.
According to the senior resident program in 2006, wetrain the senior residents to be skilled in advanced
critical care medicine including primary care trauma,
MOF, shock, and equipment support.

Research activities
Basic research by using the histone injection-induced
ARDS model and the ischemia reperfusion injury
models on several different organs including intestine

270

and kidney has been conducted to clarify themechanisms of remote organ injury in multiple organ
dysfunction syndrome. Our clinical studies revealed
that organ network disruption could be observed by
network analysis with clinical parameters and new
biomarkers of ICU patients.

References
1. Yoshida T, Matsuura R, Komaru Y, Miyamoto Y,
Yoshimoto K, Hamasaki Y, Noiri E, Morimura N,
Nangaku M, Doi K. Kinetic estimated glomerular
filtration rate as a predictor of successful
continuous renal replacement therapy discontinuation. Nephrology (Carlton). 2019 Mar;24(3):287293.
2. Homma Y, Shiga T, Funakoshi H, Miyazaki D,
Sakurai A, Tahara Y, Nagao K, Yonemoto N,
Yaguchi A, Morimura N; SOS-KANTO 2012
Study Group. Association of the time to firstepinephrine administration and outcomes in outof-hospital cardiac arrest: SOS-KANTO 2012
study. Am J Emerg Med. 2019 Feb;37(2):241-248.
3. Nakamura K, Inokuchi R, Fukushima K, Naraba H,
Takahashi Y, Sonoo T, Hashimoto H, Doi K,
Morimura N. Single versus divided administrationof intravenous immunoglobulin for sepsis: aretrospective and historical control study. Minerva
Anestesiol. 2019 Feb;85(2):156-163.
4. Yoshida M, Yoshida T, Masui Y, Fujitani S, TairaY, Kitamura N, Tahara Y, Sakurai A, Yonemoto N,
Nagao K, Yaguchi A, Morimura N. Association
Between Therapeutic Hypothermia and Outcomesin Patients with Non-shockable Out-of Hospital
Cardiac Arrest Developed After Emergency
Medical Service Arrival (SOS-KANTO 2012
Analysis Report). Neurocrit Care. 2019 Apr;30(2):429-439.
5. Asada T, Doi K, Inokuchi R, Hayase N, Yamamoto
M, Morimura N. Organ system network analysis
and biological stability in critically ill patients. Crit
Care. 2019 Mar 12;23(1):83.
6. Nakashima T, Noguchi T, Tahara Y, Nishimura K,
Ogata S, Yasuda S, Onozuka D, Morimura N,
Nagao K, Gaieski DF, Asai Y, Yokota H, Nara S,
Hase M, Atsumi T, Sakamoto T; SAVE-J Group.
Patients With Refractory Out-of-Cardiac Arrestand Sustained Ventricular Fibrillation as
Candidates for Extracorporeal Cardiopulmonary
Resuscitation - Prospective Multi-Center Observational Study. Circ J. 2019 Apr 25;83(5):10111018.
7. Nakamura K, Inokuchi R, Fukushima K, Naraba H,
Takahashi Y, Sonoo T, Hashimoto H, Doi K,
Morimura N. Pectin-containing liquid enteralnutrition for critical care: a historical control andpropensity score matched study. Asia Pac J Clin
Nutr. 2019;28(1):57-63.
8. Akutsu K, Yoshino H, Shimokawa T, Ogino H,
Kunihara T, Takahashi T, Usui M, Watanabe K,
Tobaru T, Hagiya K, Shimizu W, Niino T, Kawata
M, Masuhara H, Watanabe Y, Yoshida N,
Yamamoto T, Nagao K, Takayama M; Tokyo CCU
Network and Tokyo Acute Aortic Super Network.
Is systolic blood pressure high in patients withacute aortic dissection on first medical contact
before hospital transfer? Heart Vessels. 2019 Nov;
34(11):1748-1757.
9. Oi Y, Morimura N, Shirasawa A, Honzawa H,
Oyama Y, Niida S, Abe T, Imaki S, Takeuchi I.
Quantitative capillary refill time predicts sepsis inpatients with suspected infection in the emergency
department: an observational study. J Intensive
Care. 2019 May 6;7:29.
10. Sakurai A, Kinoshita K, Maeda Y, Homma Y,
Tahara Y, Yonemoto N, Nagao K Yaguchi A,
Morimura N; SOS-KANTO 2012 Study Group.
Confirmed cardiac output on emergency medical
services arrival as confounding by indication: anobservational study of prehospital airway
management in patients with out-of-hospital
cardiac arrest. Emerg Med J. 2019 Jul;36(7):410415.
11. Nakajima K, Taniguchi H, Abe T, Yamaguchi K,
Doi T, Takeuchi I, Morimura N.Does theconventional landmark help to place the tip of
REBOA catheter in theoptimal position? A noncontrolled comparison study. World J Emerg Surg.
2019 Jul16;14:35.
12. Hayase N, Doi K, Hiruma T, Matsuura R,
Hamasaki Y, Noiri E, Nangaku M,Morimura N.
Recombinant Thrombomodulin on Neutrophil
Extracellular Traps inMurine Intestinal Ischemia-

271

Reperfusion. Anesthesiology. 2019 Oct;131(4):866-882.
13. Nakamura K, Kihata A, Naraba H, Kanda N,
Takahashi Y, Sonoo T, Hashimoto H,Morimura N.
Efficacy of belt electrode skeletal muscle electricalstimulation on reducing the rate of muscle volume
loss in critically ill patients: A randomized
controlled trial. J Rehabil Med. 2019 Oct 3;
51(9):705-711.

Health Sciences and Nursing
1. Health Sciences

273

Department of Mental HealthProfessor
Norito Kawakami, M.D., Ph.D.

Associate Professor
Daisuke Nishi, M.D., Ph.D.

Project Lecturer
Kotaro Imamura, Ph.D.

Research Associate
Kazuhiro Watanabe, Ph.D.

Homepage

http://plaza.umin.ac.jp/heart/

Introduction and Organization
The department was firstly established as
Department of Fourth Clinical Medical Nursing in
School of Health Care and Nursing in 1957. When the
School of Health Care and Nursing was reorganized as
the School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two
departments have been working cooperatively eversince. Since 2007, Department of Mental Healthbecame a part of School of Public Health, with aperspective of “public mental health.”
The department currently has faculty members
introduced above, an associate professor, a project
lecturer, a research associate, part-time lecturers, atechnical specialist, visiting research fellows, 10
doctoral course students, 2 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.

274

Research activities
The department conducts research on mental healthand psychosocial support and provides education/
training of professionals in related fields from global
perspectives. The World Mental Health Japan survey,
which is part of a WHO international collaboration, isa largest epidemiologic study of common mental
disorders in the community in Japan. Assessment ofhealth effects of job stressors and effectiveness ofinterventions to reduce job stress are also coreresearch activities of the department. Current issues
around occupational mental health (e.g., intervention
program using Internet-based cognitive behavioral
therapy) are also actively investigated. Furthermore,
research in the department includes various othertopics, such as perinatal mental health, traumaticstress and resilience, supporting rehabilitation andrecovery of people with chronic mental illness, suicide
prevention, social disparity in mental health, disastermental health, and global mental health. Most of theresearch has been conducted in a close collaboration
with researchers in other domestic and foreign
institutions/universities.

References
1. Hidaka Y, Imamura K, Sekiya Y, Watanabe K and
Kawakami N. Effects of a transdiagnostic
preventive intervention on anxiety and depression
among workers in Japan: a pre- and post-test
study. Journal of Occupational and Environmental
Medicine [in press]
2. Okazaki E, Nishi D, Susukida R, Inoue A,
Shimazu A, Tsutsumi A. Association between
working hours, work engagement and work
productivity in employees: a cross-sectional studyof the Japanese Study of Health, Occupation, andPsychosocial Factors Relates Equity. Journal of
Occupational Health 61(2):182-188, 2019
3. Yoshikawa E, Nishi D, Kashimura M, Matsuoka
JY. Role of resilience for the association between
trait hostility and depressive symptoms inJapanese company workers. Current Psychology
2019 DOI: 10.1007/s12144-019-0166-y
4. Shalev AY, Gevonden M, Ratanatharatom A,
Laska E, van der Mei WF, Lowe S, Lai BS,
Bryant RA, Delahanty D, Matsuoka YJ, Olff M,

Schnyder U, Seedat S, deRoon-Cassini TA,
Kessler RC, Koenen KC, International
Consortium to Prevent PTSD. Estimating the riskof PTSD in recent trauma survivors: results of theInternational Consortium to Predict PTSD (ICPP).
World Psychiatry 18(1):77-87, 2019
5. Barbano AC, van der Mei WF, deRoon-Cassini
TA, Grauer E, Lowe SR, Matsuoka YJ, O'Donnell
M, Olff M, Qi W, Ratanatharathorn A, Schnyder
U, Seedat S, Kessler RC, Koenen KC, Shalev AY,
On behalf of the International Consortium toPrevent PTSD. Differentiating PTSD from anxiety
and depression: Lessons from the ICD-11 PTSD
diagnostic criteria. Depression and Anxiety 36(6):490-498, 2019
6. Nishi D, Su KP, Usuda K, Chang PC, Hamazaki K,
Ishima T, Sano Y, Ito H, Isaka K, Tachibana Y,
Tanigaki S, Suzuki T, Hashimoto K, Matsuoka YJ.
Plasma estradiol levels and antidepressant effectsof omega 3 fatty acids in pregnant women. Brain,
Behavior, and Immunity 2019 (Epub ahead ofprint)
7. Nishi D, Imamura K, Watanabe K, Ishikawa H,
Tachimori H, Takeshima T, Kawakami N.
Psychological distress with and without a historyof depression: Results from the World Mental
Health Japan 2nd Survey (WMHJ2). Journal of
Affective Disorders 2019 (Epub ahead of print)
8. Nishi D, Ishikawa H, Kawakami N. Prevalence ofmental disorders and mental health service use inJapan. Psychiatry and Clinical Neurosciences
73(8):458-465, 2019
9. M Fukasawa, N Kawakami, M Umeda, T
Akiyama, N Horikoshi, S Yasumura, H Yabe, Y
Suzuki, and EJ. Bromet. Longitudinal associationsof radiation risk perceptions and mental healthamong non-evacuee residents of Fukushima
prefecture seven years after the nuclear power
plant disaster. SSM-Population Health (in press)
10. Yasuma N, Narita Z, Sasaki N. et al.
Psychologicalintervention
foruniversal
prevention of antenatal and postnatal depression
among pregnant women: protocol for a systematic
review and meta-analysis. Syst Rev 8, 297 (2019)
DOI: 10.1186/s13643-019-1238-7.
11. Yasuma N, Watanabe K, Iida M, Nishi D,
Kawakami N (2019) Personal values in275

adolescence and psychological distress in adults:
A cross-sectional study based on a retrospective
recall. PLOS ONE 14(11): e0225454. DOI: 10.
1371/journal.pone.0225454.
12. Fukasawa M, Kawakami N, Nakayama C, andYasumura S. Relationship between use of media
and radiation anxiety among the residents ofFukushima 5.5 years after the nuclear power plant
accident. Disaster Medicine and Public HealthPreparedness [in press]
13. Kuribayashi K, Imamura K, Watanabe K,
Miyamoto Y, Takano A, Sawada U, Sasaki N,
Suga M, Sugino A, Hidaka Y, Iida M, Sudo M,
Tokita M, Kawakami N. Effects of an internetbased cognitive behavioral therapy (iCBT)
intervention on improving depressive symptoms
and work-related outcomes among nurses inJapan: a protocol for a randomized controlled trial.
BMC Psychiatry. 2019 Aug 7;19(1):245. DOI:
10.1186/s12888-019-2221-5.
14. Imamura K, Tsutsumi A, Asai Y, Arima H, Ando E,
Inoue A, Inoue R, Iwanaga M, Eguchi H, Otsuka
Y, Kobayashi Y, Sakuraya A, Sasaki N, Tsuno K,
Hino A, Watanabe K, Shimazu A, Kawakami N.
Association between psychosocial factors at workand health outcomes after retirement: a protocol
for a systematic review and meta-analysis. BMJ
Open. 2019 Aug 27;9(8):e030773. DOI: 10.1136/
bmjopen-2019-030773.
15. Watanabe K, Imamura K, Inoue A, Otsuka Y,
Shimazu A, Eguchi H, Adachi H, Sakuraya A,
Kobayashi Y, Arima H, Kawakami N. Measuring
eudemonic well-being at work: a validation study
for the 24-item The University of Tokyo
Occupational Mental Health well-being scale
among Japanese workers. Ind Health. 2019. DOI:
10.2486/indhealth.2019-0074. [Epub ahead ofprint]
16. Yasuma, N., Watanabe, K., Matsunaga, A., Nishi,D., & Kawakami, N. (2019). Personal values inadolescence and suicidality: a cross-sectional
study based on a retrospective recall. BMC
Psychiatry, 19(1), 214. DOI: 10.1186/s12888-0192194-4.
17. Komase Y, Watanabe K, Imamura K, Kawakami
N. Effects of a newly developed gratitude intervention program on work engagement among

Japanese workers: a pre- and post-test study.
Journal of Occupational and Environmental
Medicine. (in press)
18. Imamura K, Tran TTT, Nguyen HT, Kuribayashi
K, Sakuraya A, Nguyen AQ, Bui TM, Nguyen QT,
Nguyen KT, Nguyen GTH, Tran XTN, Truong TQ,
Zhang MWB, Minas H, Sekiya Y, Sasaki N,
Tsutsumi A, Kawakami N. Effects of two types ofsmartphone-based stress management programmes on depressive and anxiety symptoms amonghospital nurses in Vietnam: a protocol forthree-arm randomised controlled trial. BMJ Open.
2019 Apr 8; 9(4): e025138. DOI: 10.1136/
bmjopen-2018-025138.
19. Yasuma N, Watanabe K, Nishi D, Ishikawa H,
Tachimori H, Takeshima T, et al. Urbanization andInternet addiction in a nationally representative
sample of adult community residents in Japan: A
cross-sectional, multilevel study. Psychiatry
research. 2019; 273: 699-705. DOI: 10.1016/j.
psychres.2019.01.094.
20. Miki T, Eguchi M, Kuwahara K, Kochi T, Akter S,
Kashino I, Hu H, Kurotani K, Kabe I, Kawakami
N, Nanri A, Mizoue T. Breakfast consumption andthe risk of depressive symptoms: the Furukawa
Nutrition and Health Study. Psychiatry Research.
2019 (in press)

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

Associate Professor
Koji Oba, Ph.D.

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

Homepage

http://www.epistat.m.u-tokyo.ac.jp/en/

Introduction and Organization
The Department of Epidemiology andBiostatistics evolved from the Department of
Epidemiology in 1992. Since then, we have been
responsible for providing educational courses on
methodology of epidemiologic research and biostatistics to undergraduate students. We belong to
Graduate School of Medicine as Departments ofBiostatistics/ Epidemiology and Preventive Health
Sciences, providing education for undergraduate aswell as graduate-school students and consultation toclinical researchers.
Unfortunately, education programs for biostatistics and epidemiological methodology are notsufficient in Japanese universities and graduate
schools compared to the situation in the US andEuropean countries. Nevertheless, the necessity forcollaboration among biostatisticians and clinicalresearchers/ epidemiologists has been claimed inrecent years. Hence, the central missions of oureducational courses are devoted to provide students
expert knowledge and extensive experience inbiostatistics and epidemiology to take part in clinical/
epidemiological research as biostatisticians or
methodologists. We do not only focus on practicalaspects on statistical analysis in medical research but
also place emphasis on the methodological principles
of biostatistics/epidemiology.
Our main research area is the development ofmethodology for clinical/epidemiological research. Of
course, it requires keeping in touch with real clinical/
epidemiological problems. So, another indispensable
research area is a support for real-world clinical andepidemiological studies including clinical trials. To
achieve these requirements simultaneously, a nonprofit organization the Japan Clinical Research
Support Unit (current EP-CRSU, Co., Ltd.) wasestablished in 2001 by the former faculty members inour department. This organization J-CRSU hadprovided research support and coordination in design,
data management, and statistical analysis in many
projects inside/outside the university. Our experiencein J-CRSU is the basis of our supportive activities forclinical research that we work through today.

Teaching activities
 Undergraduate Courses
1) Epidemiology (2 credits)
2) Biostatistics (2 credits; named “Statistics” inmedical doctor course)

2773) Applied Mathematics (2 credits)
4) Biostatistics Practice (1 credit)
5) Practical Examples in Clinical andEpidemiologic Research (1 credit)
6) Medical Data Analysis, and its Practice (2credits each)7) Theoretical Epidemiology (2 credits) School of Public Health (Graduate School)
1) Statistical Analysis of Medical Research(2 credits)
2) Practice of Biostatistics (2 credits)3) Design of Medical Research (2 credits) Doctoral Courses (Graduate School)
1) Biostatistics (4 credits)
2) Epidemiology and Preventive Health Sciences(4 credits)
3) Introduction to Medical Statistics(2 credits; for the School of Medicine)
The faculty of the department had provided
lectures in a series of educational courses organizedby “The Clinical Bioinformatics Research Unit” in
2002-2007.

Research activities
1. Methodology for designing and analyzing clinical
trials: Interim analysis
 Adaptive designs
 Multiplicity
 Data management of large-scale multicenter
clinical trials
2. Methodology of Biostatistics and theoreticalepidemiology:
 Analysis of longitudinal (time-to-event and/or
repeated measures) data
 Analysis of missing/incomplete data Causal inference Semiparametric modeling
3. International collaboration of individual-levelmeta-analysis on gastric cancer
4. Coordination and data analysis of collaborative
epidemiological/clinical research:
 Japan Arteriosclerosis Longitudinal Study Japan Diabetes Collaborative Study Chronic Kidney Disease Japan Cohort
5. Validity/reliability studies of QOL questionnaires
and other rating scales
6. Pharmacoeconomic assessment of medical technology
We had been supporting some of the above
collaborative clinical/epidemiologic studies throughthe aforementioned J-CRSU (a non-profit organization), which aims to support investigator- initiatedstudies and to provide education to researchers andsupport staffs. Currently, we are officially conducting
a consultation for design and analysis of clinical trials
assisted by the Clinical Research Promotion Center of
the University of Tokyo Hospital.
From FY2016, the industry, academia, andgovernment-collaborative program “Support Programfor Biostatisticians” was launched by Japan Agency
for Medical Research and Development for“cultivating talent of excellent biostatisticians,
supports the efforts of training them throughcollaboration between graduate schools that conduct
school education, and hospitals that conduct practicaltraining.” (AMED website, July 4, 2017) AMED
selected the University of Tokyo as one of the 2centers for conducting the project (principal
investigator: Professor Matsuyama). Our department
is also officially participating in the program, and will
provide more and more educational/practical supports
to future biostatisticians on the basis of our richexperience in biostatistical education and support invariety of research.

References
1. Yamamoto T, Aida J, Shinozaki T, Tsuboya T,
Sugiyama K, Yamamoto T, Kondo K, Osaka K.
Cohort study on laryngeal cough reflex,
respiratory disease, and death: a mediation
analysis. J Am Med Dir Assoc. 2019;20:971–976.
2. Shinozaki T, Mansournia MA. Hazard ratio
estimators after terminating observation withinmatched pairs in sibling and propensity scorematched designs. Int J Biostat. 2019;15:1.
3. Nagata H, Ishihara S, Oba K, Tanaka T, Hata K,
Kawai K, Nozawa H. Development and Validation

278

of a Prediction Model for Organ-Specific
Recurrences After Curative Resection of Colon
Cancer. Dis Colon Rectum. 2019;62:1043–1054..
4. Sugiyama T, Oba K, Kobayashi Y. Risk-Stratified
Incidence of Renal Replacement Therapy
Initiation: A Longitudinal Analysis Using Medical
Claims and Health Checkup Data. Tohoku J Exp
Med. 2019;248:125–135.
5. Okada Y, Oba K, Furukawa N, Kosaka Y, Okita K,
Yuki S, Komatsu Y, Celio L, Aapro M. One-Day
Versus Three-Day Dexamethasone in Combination with Palonosetron for the Prevention ofChemotherapy-Induced Nausea and Vomiting: A
Systematic Review and Individual Patient
Data-Based Meta-Analysis. Oncologist. 2019;24:
1593–1600.
6. Kozuma K, Shinozaki T, Kozuma K, Kashiwabara
K, Oba K, Aoki J, Awata M, Nanasato M, Shiode
N, Tanabe K, Yamaguchi J, Kimura T, Matsuyama
Y. Impact of residual stenosis on the angiographicedge restenosis of second-generation drug-eluting
stent: integrated analysis of quantitative coronary
angiography from four post-marketing surveillances of cobalt-chromium everolimus-eluting
stent in Japan. Int Heart J. 2019;60:1050–1060.
7. Ota K, Fukui K, Oba K, Shimoda A, Oka M, Ota
K, Sakaue M, Takasu A. The role of ultrasoundimaging in adult patients with testicular torsion: asystematic review and meta-analysis. J Med
Ultrason (2001). 2019;46:325–334.
8. Shinozaki T, Nojima M. Misuse of regression
adjustment for additional confounders following
insufficient propensity-score balancing. Epidemiology. 2019;30:541–548.
9. Yokota I, Matsuyama Y. Dynamic prediction of
repeated events data based on landmarking model:
application to colorectal liver metastases data.
BMC Med Res Methodol. 2019;19:31.
10. Takao T, Matsuyama Y, Suka M, Yanagisawa H,
Kasuga M. Analysis of the duration and extent of
the legacy effect in patients with type 2 diabetes:
A real-world longitudinal study. J Diabetes
Complications. 2019;33: 516–522.
11. Trotta L, Kabeya Y, Buyse M, Doffagne E, Venet
D, Desmet L, Burzykowski T, Tsuburaya A,
Yoshida K, Miyashita Y, Morita S, Sakamoto J,
Praveen P, Oba K. Detection of atypical data in

multicenter clinical trials using unsupervised
statistical monitoring. Clin Trials. 2019;16:512–
522.
12. Maeda H, Hazama S, Iwamoto S, Oba K,
Tsunedomi R, Okayama N, Suehiro Y, Yamasaki T,
Nakagami Y, Suzuki N, Nagano H, Sakamoto J,
Mishima H, Nagata N. Association between
polymorphisms in EGFR and tumor response
duringcetuximab
andoxaliplatin-based
combination therapy in metastatic colorectal
cancer: Analysis of data from two clinical trials.
Oncol Lett. 2019;18:4555–4562.
13. Munemoto Y, Nakamura M, Takahashi M, Kotaka
M, Kuroda H, Kato T, Minagawa N, Noura S,
Fukunaga M, Kuramochi H, Touyama T,
Takahashi T, Miwa K, Satake H, Kurosawa S,
Miura T, Mishima H, Sakamoto J, Oba K, Nagata
N. SAPPHIRE: a randomised phase II study ofplanned discontinuation or continuous treatmentof oxaliplatin after six cycles of modified
FOLFOX6 plus panitumumab in patients withcolorectal cancer. Eur J Cancer. 2019;119:158167.
14. Taniguchi Y, Kitamura A, Kaito S, Yokoyama Y,
Yokota I, Shinozaki T, Seino S, Murayama H,
Matsuyama Y, Ikeuchi T, Fujiwara Y, Shinkai S.
Albumin and hemoglobin trajectories and incident
disabling dementia in community-dwelling older
Japanese. Dement Geriatr Cogn Disord. 2019;47:233–242.
15. Taniguchi Y, Kitamura A, Ishizaki T, Fujiwara Y,
Shinozaki T, Seino S, Mitsutake S, Suzuki H,
Yokoyama Y, Abe T, Ikeuchi T, Yokota I,
Matsuyama Y, Shinkai S. Association of
trajectories of cognitive function with causespecific mortality and medical and long-term carecosts. Geriatr Gerontol Int. 2019;19:1236–1242.
16. Taniguchi Y, Kitamura A, Nofuji Y, Ishizaki T,
Seino S, Yokoyama Y, Shinozaki T, Murayama H,
Mitsutake S, Amano H, Nishi M, Matsuyama Y,
Fujiwara Y, Shinkai S. Association of trajectories
of higher-level functional capacity with mortality
and medical and long-term care costs amongcommunity-dwelling older Japanese. J Gerontol A
Biol Sci Med Sci. 2019;74:211–218.
17. Tabuchi T, Shinozaki T, Kunugita N, Nakamura M,
Tsuji I. Study Profile: The Japan “Society and279

New Tobacco” Internet Survey (JASTIS): alongitudinal internet cohort study of heat-not-burntobacco products, electronic cigarettes andconventional tobacco products in Japan. J
Epidemiol. 2019;29:444–450.
18. Oba K, Kuchiba A. Sample Size Calculations for
Phase III Trials in Oncology. In: Halabi S,
Michiels S (Eds.) Textbook of Clinical Trials in
Oncology: A Statistical Perspective. CRC Press,
FL, 2019.
(Only main publications)280

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
Keiichiro Yamamoto, Ph.D.

Homepage

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

Introduction and Organization
The former Department of Health Administration wasestablished in 1967 and Dr. Tsuneo Tanaka became its
first professor in 1974. He devoted himself to thedevelopment of the community health care system inJapan and published numerous papers concerning thesocial theory of health administration and data
management systems for community health care. He
also contributed to the establishment of the School of
Health Sciences. In 1985, Dr. Atsuaki Gunji became
the second professor of the department. During Dr.
Gunji’s tenure, two major research projects were
undertaken. One was “The effects of physical activity
and inactivity on health.” From 1990, a 20-day bed
rest human experimental study was conducted every
year in the context of an international cooperative
research project that was supported by government
grants. The other project concerned health caresystems, especially health care economics and thequality of hospital care.
In 1996, the Department of Health Administration developed into two departments: the Department
of Health Economics and the Department of Health

Promotion Sciences. Both were established as
departments of the Graduate School of Medicine. In
1998, Dr. Yasuki Kobayashi became the professor of
the Department of Health Economics. He conducted
research into health care delivery systems in Japan. In
2001, he moved to the Department of Public Health.
From 1996 to 2002, Dr. Kiyoshi Kawakubo tookcharge of the Department of Health Promotion
Sciences as the associate professor.
In June 2002, Dr. Akira Akabayashi became
professor of the Department of Health Economics.
Professor Akabayashi’s area of research is biomedical
ethics. In April 2003, the Department of Health
Economics was restructured and named the Department of Biomedical Ethics. From 2007, Dr. Jung Su
Lee became the associate professor and took charge of
the Department of Health Promotion Sciences. In
2017, Dr. Yoshiyuki Takimoto acceded to the chair of
the Department of Health Promotion Sciences. In
2019, the Department of Health Promotion Sciences
was consolidated into the Department of Biomedical
Ethics.
Staff members of the department include a281

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

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,
Biomedical ethics (Lecture)7) Integrated Lecture of Clinical Medicine,
Biomedical ethics and Geriatric Medicine(Lecture)8) Social Medicine (Lecture)9) Biomedical Ethics II (2 credits, lecture)10) Clinical Ethics (2 credits, lecture)11) Public Health Ethics (2 credits, lecture)12) Global Bioethics (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2828) Historical analyses for the term “bioethics” in theJapanese context

References
1. Akabayashi A, Nakazawa E. Akabayashi A. 2019.
Implementation of Japan’s first clinical research
regulatory law: background, overview, andchallenges. HEC Forum 2019;31(4):283–294.
2. Akabayashi A, Nakazawa E, Ino H. Incidence of
thyroid cancer among children and young adults
in Fukushima, Japan. JAMA Otolaryngol Head
Neck Surg. 2019;145(8):769–770.
3. Akabayashi A, Nakazawa E, Jecker NS. What areconsidered ‘good facts’? J Med Ethics. 2019;45(7):473–475.
4. Akabayashi A, Nakazawa E, Jecker NS. Adhering
to ethical benchmarks in neurology clinical trials
using iPSCs. Neurotherapeutics. 2019.
5. Ino H, Nakazawa E, Akabayashi A. Health andwelfare in Japan. Lancet. 2019 Nov 2-8;394(10209):1614–1615.
6. Jecker NS, Miwa E. What do we owe the newly
dead? An ethical analysis of findings from Japan's
corpse hotels workers. Bioethics. 2019; 33(6):691–698.
7. Nakada H, Inoue Y, Yamamoto K, Matsui K, Ikka
T, Tashiro S. Public attitudes toward thesecondary uses of patient records forpharmaceutical companies’ activities in Japan.
Therapeutic Innovation & Regulatory Science.
2019 October;1–8.
8. Nakazawa E, Yamamoto K, Akabayashi A, Shaw
MH, Demme RA, Akabayashi A. Will you givemy kidney back? Organ restitution in living
related kidney transplantation: Ethical analyses. J
Med Ethics. 2020;46:144–150.
9. Nakazawa E, Yamamoto K, Ozeki-Hayashi R,
Akabayashi A. A global dialogue on withholding
and withdrawal of medical care: An East Asian
perspective. Am J Bioeth. 2019;19(3):50–52.
10. Nakazawa E, Yamamoto K, Ozeki-Hayashi R,
Akabayashi A. Why can’t Japanese people
decide? Withdrawal of ventilatory support in
end-of-life scenarios and their indecisiveness.
Asian Bioeth Rev. 2019;11:343–347.
11. Ozeki-Hayashi R, Fujita M, Tsuchiya A, Hatta T,

Nakazawa E, Takimoto Y, Akabayashi A. Beliefs
held by breast surgeons that impact the treatment
decision process for advanced breast cancer
patients: a qualitative study. Breast Cancer (Dove
Med Press). 2019 Jul 17;11:221–229.
12. Sadato N, Morita K, Kasai K, Fukushi T,
Nakamura K, Nakazawa E, Okano H, Okabe S.
Neuroethical issues of the Brain/MINDS projectof Japan. Neuron. 2019 Feb 6;101:385–389.

Health Sciences and Nursing
2. Preventive and Administrative Nursing

284

Department of
Nursing Administration/
Advanced Clinical Nursing
Associate Professor
Yukie Takemura, Ph.D., R.N., C.N.A.

Assistant Professor
Keiko Kunie, Ph.D., R.N.
Naoko Ichikawa, Ph.D., R.N.

Project Assistant Professor
Ryohei Kida, MSN, R.N.

Homepage

http://nurs-adm.umin.jp/

Introduction and Organization

Teaching activities

The Department of Nursing Administration/
Advanced Clinical Nursing has 60 years of history andtradition. It was first established as the Department ofFundamental Nursing in the School of Health Care andNursing in 1954. The School of Health Care andNursing was composed of two basic medical
departments and six nursing departments. When it was
reorganized as the School of Health Sciences in 1965,
only one nursing department remained, so thedepartment was renamed as Department of Nursing; it
was the department responsible for nursing education.
In 1992, the School of Health Sciences became the
School of Health Sciences and Nursing, two new
departments of nursing were established, so the
Department of Nursing became once again the
Department of Fundamental Nursing. As the result of
this shift to the chair of the Graduate School of
Medicine in 1996, two departments were established,
the Department of Nursing Administration and
Department of Advanced Clinical Nursing. Our
department is responsible for the fundamental nursing
education for undergraduate students.

Undergraduate Courses

In the undergraduate program, our department
oversees lectures and clinical practicums for
Introduction of Nursing Science, Fundamental Nursing
I, Fundamental Nursing Ⅱ, Basic nursing skills, andNursing Administration.
Introduction of Nursing Science (1 credit, lectures)
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,
lectures)This course provides knowledge and nursing skills
for understanding patients and providing care. Students
learn about the nursing process and nursing skills
necessary for knowing and caring for patients, which
are essential for providing appropriate nursing care.
Theory and methodology of nursing Ⅱ (2 credits,elective course, lectures)This course offers perspectives on the nursing
profession through a series of lectures from various

285

experts and discussion.
Basic nursing skills (2 credits, lectures)This course provides the basics for 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 with case discussion.
Practicum: basic nursing skills(2 credits, practicum)
Under instructors’ supervision, students haveopportunities to apply their fundamental knowledge
and nursing skills in a variety of settings. Students willassess clients’ health and needs through applications of
the nursing process.
Nursing Administration (1 credit, lectures)This course introduces students to roles of nurse
administrators/managers in all types of healthcare
settings, such as institutions, organizations, communities, and politics. Students will learn 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 nursing administrative
practicum in units or divisions in hospitals. They willlearn care delivery systems such as staffing and patientclassification systems, nursing informatics, andbudgetary issues (e.g., cost effectiveness and quality
improvement).

Graduate Courses

In the graduate program, our department oversees
the lectures and seminar for Nursing Administration
and Advance Clinical Nursing.
Nursing Administration I, II (2 credits each)
During this course, students acquire the knowledge
and perspectives necessary to become actively
involved within an organization and to conduct
research that has a focus on organizational phenomena
through lectures on and a critical analysis of relevantorganizational and human resource management
theories, the environment surrounding nursing scienceand nursing practice, and political decision-making.

Advance Clinical Nursing I (2 credits)
This course offers a critical reading of previous
research theories and discussions on relevant areas.
SeminarWe have an accredited departmental seminar where
members discuss their own research project plans.

Research activities
We aim to clarify the systems and methodologythat fulfill the organizational and human resource
potential to contribute to the wellbeing of patients,
nurses, and other health care professions as well associety in general.
The Development of Research Methods for
Depicting Organizational Phenomena
The careful extraction and accumulation ofknowledge from organizational case studies isnecessary to develop nursing administration andcontribute to clinical practice. For this reason, whenanalyzing such cases, we clarify phenomena sharedacross individuals and facilities in multiple cases anddevelop research methods to vividly describe thedynamic processes of complex workplace-related
and organizational processes. For instance, we
conduct studies on workplace experiences fromstudies of multiple organizations as well as describe
organizational management processes based on theexperiences of those providing support and thosereceiving the support
Discovering Knowledge Required for Effective
Organization Management and Organizational
Development
It is important that workers, including nursing
administrators, are able to use their abilities to thefullest and function effectively to provide quality
care to patients, families, and society in general. We
engage in research that clarifies the key elements andprocesses involved. Concrete examples include
researching nursing organizational operation models
during times of crisis based on case studies following
the 2011 earthquake and tsunami in Fukushima as
well as explaining how nursing mangers’
competencies and leadership are connected to staff
development, professional commitment, on-the-job
behavior, job satisfaction, workplace culture, and286

employee turnover rates.
Creating Workplaces Where Staff and Teams Can
Demonstrate Their Abilities
We engage in research that contributes to thecreation of workplaces where staff and teams candemonstrate their latent abilities to the fullest. This
includessupporting
individuals,
teams,
organizational development, and the improvement of
individuals and team environments. Concrete
examples include organizational learning, intraorganization communication and roles, and theemotional and psychological development of nursing
professionals.
Creating Mechanisms that Sustainably Provide
High-Quality Medical Care and Nursing
We engage in research that contributes to thecreation of sustainable organizations and careenvironments, including securing nursing humanresources, maintaining the quality of such resources,
and creating systems in organizational environments.
Examples include research investigating thedevelopment of nursing careers and professionals’
expertise, people returning to work in the nursing
profession, the functions of hospital departments,and hospital ward construction. During the present
academic year, we conducted a survey on the
improvement of working hours and environment ofnurses for nursing professionals and nursing
administrators. This was a Ministry of Health, Labor,and Welfare Policy Research Project.

References
1. Takemura Y, Kunie K, Ichikawa N. The effect ofwork environment on burnout among nurse
directors: a cross sectional study. Journal of
Nursing Management. (accepted 19 Nov. 2019)
doi: 10.1111/jonm.12909
2. Ozawa M, Takehara K, Takemura Y, Kunie K,
Ichikawa N. Workplace environmental factors
related to the nursing assessment implementation
for cancer patients before beginning outpatientchemotherapy for the first time: Focusing on
psychological and social aspects. Journal of theJapan Academy of Nursing Administration and
Policies. (accepted 25 Nov. 2019) [in Japanese]

3. Endo Y, Komagata K, Takemura Y, Ikeda M,
Takehara K, Iimura D. Nurses’ knowledge,
perceptions and attitudes towards stuttering and thework environment of nurses who stutter: A crosssectional study. Journal of the Japan Academy of
Nursing Administration and Policies, 2019; 23(1):28-39. doi: 10.19012/janap.23.1_28 [in Japanese]
4. Saiki M, Kunie K, Takemura Y, Takehara K. &Ichikawa N. The perceptions of nursing assistants’roles among nurses and nursing assistants:
Development of measurement scale. Hospitals,
2019; 78, 358-363. [in Japanese]

287

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

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

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

Homepage

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

Introduction and Organization

Research

This department was established in 1992. Four
faculty members currently serve the department: aprofessor, a lecturer, and two assistant professors.
Enrolled at present are 5 doctoral students, 2 master’s
students, 33 visiting researchers, and 4 administrative
staff.

Our department researches family with healthproblems, developmental task or encounter withchanges in the community to which the family belongs.
We aim to reveal the fluctuation that have occurred in
the family system and create family support.. Our
on-going, specific research theme include thefollowing:
1. Development of a Pediatric Quality of Life (QOL)
Inventory for children with chronic illness andtheir parents;
2. Lifetime support for survivors of childhood
cancer and their families: treatment and care in
their late effects, special needs education, andworking;
3. International collaborative research about
posttraumatic growth (PTG);
4. Transitional care for children, adolescent andyoung adult with childhood-onset chronic
diseases;
5. Research about prevention of deterioration of
postpartum depression, child abuse and neglect;
6. International collaborative research about family
polyvictimization;
7. Caregiving burden and utilization behavior ofsocial services in families of children withmedical complexity;
8. Livelihood supports for families of elderly people

Education
1. Graduate Courses, School of Health Sciences andNursing (credit hours)
Advanced Family Nursing I (2)Advanced Family Nursing II (2)Laboratory and/or Field Work on Family Nursing(16)
Practicum in Translational Research Nursing (2)2. Undergraduate Courses for Students in the Schoolof Integrated Health Sciences (credit hours)
Family Health (2)Health Communication (1)3. Undergraduate Courses for Nursing Students in the
School of Integrated Health Sciences (credit hours)
Pediatric and Child Health Nursing (4)Clinical Practicum in Pediatric and Child HealthNursing (2)Integrated Clinical Practinum in Nursing (1)288with dementia;
9. Support for bereavement from family members.
Studies on “ Development of a Pediatric Quality ofLife (QOL) Inventory for children with chronic illness
and their parents” and “Lifetime support for survivorsof childhood cancer and their families: treatment andcare in their late effects, special needs education, andworking” have been ongoing, in collaboration withpediatric cancer researchers and a variety of family
support organizations across the country. Funding forthese research projects was granted through a
2004-2006 Ministry of Education, Culture, Sports,
Science and Technology Grant-in-Aid for Scientific
Research, and currently through a Practical Research
for Innovative Cancer Control (AMED) and a
2014-2016 Ministry of Education, Culture, Sports,
Science and Technology Grant-in-Aid for Scientific
Research. Based on the department’s rich collective
research experiences, we founded the Center for
Quality of Life Research in April 2012 to study QOL
across wide developmental stages and healthconditions. Using this platform, we aim to accumulate,integrate, and disseminate scientific research andknowledge on QOL in a more systematic manner.
Additionally, the department members are conducting
and publishing research that explore the various
experiences of children with cancer and their families
who were extensively affected by the Tohoku
Earthquake of 2011.
Studies focusing on transition such as “Transitionalcare for children, adolescent and young adult withchildhood-onset chronic diseases” in patients withchild chronic diseases has been conducted since 2016.
We established a transition outpatient clinic in the
University of Tokyo Hospital in June 2016 and havebeen providing transitional cares for patients withcongenital heart disease, epilepsy, chromosomal
abnormality, hematologic disease, and endocrine
disease in the clinic. We also developed the tool “My
Health Passport” in order for patients to summarize
the information about their disease and share theirexperiences with others (e.g., friends and coworkers)
and established an evidence of its effectiveness. We
collaborate with the evidence-based clinic, with regard
to research, practice and graduate education.
In addition to our research activities, we holdbimonthly Family Care Group Supervisions, whereby

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

Publications
1. Kita S, Chan KL, Tobe H, Hayashi M, Umeshita
K, Matsunaga M, Uehara N, Kamibeppu K. A
follow-up study on the continuity and spillover
effects of intimate partner violence during pregnancy on postnatal child abuse. Journal of Interpersonal Violence. 2019 Jan; 0886260518821460.
2. Kita S, Umeshita K, Tobe H, Hayashi M,
Kamibeppu K. Intimate partner violence, negative
attitudes towards pregnancy, and mother-to-fetus
bonding failure among Japanese pregnant woman.
Violence and Victims. 2019 Jan; 34(3): 536-547.
3. Soejima T, Sato I, Takita J, Koh K, Kaneko T,
Inada H, Ozono S, Kamibeppu K. Do childhood
cancer and physical late effects increase worries
about future employment in adulthood? Cancer
Reports. 2019 Jun; 2(3): e1175.
4. Tobe H, Sakka M, Kamibeppu K. The efficacy ofa resilience-enhancement program for mothers inJapan based on emotion regulation: study protocol
for a randomized controlled trial. BMC
Psychology. 2019 Nov; 7: 69.
5. Sakka M, Goto J, Kita S, Sato I, Soejima T,
Kamibeppu K. Associations among behavioral
and psychological symptoms of dementia, careburden, and family-to-work conflict of employedfamily caregivers. Geriatrics & Gerontology
International. 2019 Jan; 19(1): 51-55.
6. Oshiro R, Kopitz J, Soejima T, Kibi S, Kamibeppu
K, Sakamoto S, Taku K. Perceptions of positive
and negative changes for posttraumatic growthand depreciation: Judgments from Japanese
undergraduates. Personality and Individual
Differences. 2019 Jan; 137: 17-21
7. Otsuka-Ono H, Hori N, Ohta H, Uemura Y,
Kamibeppu K. A childhood immunization
education program for parents delivered duringlate pregnancy and one-month postpartum: arandomized controlled trial. BMC Health Services
Research. 2019 Nov; 19: 798.

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8. Nakajima S, Setoyama A, Sato I, Fukuchi T,
Tanaka H, Inoue M, Watanabe K, Koh K, Takita J,
Tokuyama M, Watanabe K, Kamibeppu K.
Predictors of parental distress during acute phaseof pediatric hematopoietic stem cell transplantation in Japan: A multicenter prospective
study. Blood Cell Therapy. 2019 Aug; 2(3): 39-49.
9. Fukui C, Fujisaki-Sueda-Sakai M, Yokouchi N,
Sumikawa Y, Horinuki F, Baba A, Suto M, Okada
H, Ogino R, Park H, Okata J. Needs of persons
with dementia and their family caregivers indementia cafés. Aging Clinical and Experimental
Research. 2019 Dec; 31(12): 1807–1816.
10. Koishizawa M, Kurihara K, Kita S, Takagi S,
Omori M, Nakamoto C, Yoshiuchi K, Kamibeppu
K. Peer support and hope in mothers of children
with eating disorders. Asian Journal of Family
Therapy. 2019 Jul; 3(1): 63-80.
11. Suzuki S, Oshiro R, Kobayashi A, Kamibeppu K.
Nursing support for family decision-making
regarding treatment for a neonate with alife-threatening condition. Journal of Family
Nursing. 2019 Nov; 25(4): 634.

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

Lecturer
Takashi Naruse, Ph.D., R.N., P.H.N.

Assistant Professor
Chie Teramoto, Ph.D., R.N., P.H.N.
Riho Iwasaki, Ph.D., R.N., P.H.N.

Project Assistant Professor
Chikako Honda, PhD,RN,PHN.

Homepage

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

Introduction and Organization
Department of Community Health Nursing wasestablished in June 1992. Department of Public HealthNursing was established related to opening of mastercourse for public health nurses in 2006. In addition,
program for public health nurse license was started in2014, and our department is in charge of it.

Teaching activities
In the undergraduate program, we lecture about
fundamental methodologies and theories of healthpromotion for individuals, families, and specificpopulations living in the community. The titles are
below; Home Health Nursing, Community HealthNursing, Home Health Nursing Practice. There is a
total of four credits of lectures and two credits ofnursing placement training.
In the graduate program, we lecture about theadvanced methodologies and theories in community
health nursing and public health nursing. The titles are

below; Advanced Community Health Nursing I,
Advanced Community Health Nursing II, Advanced
Community Health Nursing Seminar I, II and PracticeI, II. There are a total of 12 credits: 4 credits oflectures and 8 credits of exercises and practicaltraining.
We also provide additional eight kinds oflectures/practical training as a part of the education
program for public health nurse licenses. The titles are
below; Skills for Public Health Nursing I, Skills for
Public Health Nursing II, Public Health Nursing I,
Public Health Nursing II, Public Health Nursing III,
Public Administration for Nurses, Public HealthNursing Practice I, Public Health Nursing Practice II.
There are 12 credits of lectures and five credits ofpractical training.
And we also assist undergraduate/graduate students
with their thesis.

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Research activities
Our research focuses on the development andevaluation of health care programs, establishment ofcommunity health care systems, and standardizationof skills among public health nurses in response to thehealth care needs of individuals, families, aggregatesand communities. Our research is supported by aGrant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science andTechnology, Health Science research, and otherfoundations.
Ongoing research projects in our department are listed
below.
1. Developing a community care system and fosteringcollaboration between home-care service providers.
Fostering collaboration between home-care service
providers is an international concern in community
care, especially elderly health care. We are conducting
a study to measure the status of collaboration between
care providers in a community setting; it also aims todevelop efficient and feasible strategies to improve
this status.
2. Discharge planning
Discharge planning is an interdisciplinary process that
is ideally available to aid patients and their families indeveloping a feasible plan for the next step of care.
Demand for discharge planning is increasing. We areattempting to standardize discharge planning activities
and develop outcome indicators and an educational
program on discharge planning for ward nurses. We
are also conducting research on the discharge planningsystem, developing guidelines for multi-sectional andinter-agency cooperation among nurses, nurses’
support at outpatient settings.
3. Support for families with infants and children
Recently, custodial parents have faced manydifficulties and challenges. To address this, we areconducting research on children's injury prevention
and social environments for child-rearing parents.
4. Community health care for the elderly
We are conducting research on the health of theelderly to support favorable living conditions for thispopulation. Our research includes (1) identification ofservice needs among frail elderly persons incommunity dwellings, (2) evaluation of community
care services’ impact on the elderly and their family
caregivers, and (3) the development of an approach
aimed at providing care for the terminally ill incommunity settings (e.g., monitoring of resident
transfers).
5. Skills of public health nurses
Public health nurses use high-level support skills;
however, many of these skills have not been identified
through research. We aim to identify and standardize
the skills of public health nurses, focusing inparticular on skills regarding new community
diagnostic method and group dynamics.

References
1. Mitsutake S, Ishizaki T, Tsuchiya-Ito R, Teramoto
C, Shimizu S, Yamaoka T, Kitamura A, Hideki Ito.
Association of pharmacological treatments for
hypertension, diabetes, and dyslipidemia withhealth checkup participation and identification of
disease control factors among older adults inTokyo, Japan. Preventive Medicine Reports, 2019.
2. Teramoto C, Ishizaki T, Mitsutake S, Fukuda H,
Naruse T*, Shimizu S, Ito H. Impact of a national
medical fee schedule revision on the cessation ofphysician home visits among older patients inTokyo: A retrospective study.Health Soc Care
Community. 2019 Jul;27(4):899-906. DOI: 10.
1111/hsc.12707.
3. Mitsutake S, Ishizaki T, Teramoto C, Shimizu S,
Ito H. Patterns of Co-Occurrence of Chronic
Disease Among Older Adults in Tokyo, Japan.
Preventing Chronic Disease 16, 2019.
4. Iwasaki R, Hirai K, Aminaka K. Why don't older
persons attend senior salons? Interviews witholder persons living in a rural area of Japan.
Japanese Journal of Health and Human Ecology,
85(4): 141-149. 2019.
5. Iwasaki R, Hirai K, Kageyama T, Satoh T, Fukuda
H, Kai H et al. Supporting Elder Persons in Rural
Japanese Communities through Preventive Home
Visits by Nursing Students: A Qualitative

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6.

7.

8.

9.

Descriptive Analysis of Students’ Reports. Public
Health Nursing, 36: 557-563. 2019.
Matsumoto H, Igarashi A, Suzuki M, andYamamoto-Mitani N. Association between
neighborhood convenience stores and independent
living in older people. Australas J Ageing. 2019
Jan 30;38(2):116-23.
Son BK, Akishita M, Uchiyama E, Imaeda S,
Taniguchi S, Sumikawa Y, Unyaporn S,
Matsubara T, Tanaka S, Tanaka T, Otsuki T, Okata
J, Iijima K. Multiple turns: Potential risk factor
for falls on the way to the toilet. Geriatr Gerontol
Int. 2019 Dec;19(12):1293-1295.
Yuka SUMIKAWA, Takashi NARUSE, Satoko
NAGATA. Postdischarge support by dischargeplanning nurses for older adults at acute hospitals:
A 30-day prospective observational study.
Japanese Journal of Health and Human Ecology.
85(5) 166-177.2019.
Akari Maeda, Satoko Nagata. Information
Gathering by Outpatient Nurses to Recognize
Outpatients’ Home Care Needs (in Japanese).
Journal of Japan Academy of Community HealthNursing. 22(3), 17-25, 2019.

Health Sciences and Nursing
3. Clinical Nursing

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Department of GerontologicalHome Care and Long-term Care
Nursing/Palliative Care Nursing
Professor
Noriko Yamamoto-Mitani, Ph.D., R.N.

Assistant Professor (Senior)
Ayumi Igarashi, Ph.D., R.N.

Assistant Professor (Junior)
Maiko Noguchi-Watanabe, Ph.D., R.N.
Mariko Sakka, Ph.D., R.N.

Homepage

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

Introduction and Organization
The Department of Adult Health Nursing/ Palliative
Care Nursing has almost 50 years of history andtradition. Originally the department was started as the
Department of Adult Health in 1965 and it underwent
several re-organizations. The current structure with
two sub-divisions of Adult Health Nursing and
Palliative Care Nursing has started in 2006. Further,
Adult Health Nursing was renamed to GerontologicalHome Care and Long-term Care Nursing in 2016.
Noriko Yamamoto-Mitani has been responsible foradministration as a department chair since 2012.

Education
In the undergraduate program, our department is incharge of the lectures and clinical practicums for adult
health nursing. In graduate education, we aim to
educate students into independent researchers andcompetent clinicians who effectively use research. For
this purpose we respect each student’s researchinterest that they derived from their clinicalexperiences. Each student completes his/her Master’s
thesis or doctoral dissertation from developing

research question from their own scientific interests
regarding nursing practice for older people or adults inchronic stage.
In education, we emphasize critical thinking
process as a researcher who conduct unique andoriginal research: from cultivating perspectives as a
researcher to come up with original research topic,
developing research topic into unique researchquestions/ hypotheses, choosing appropriate researchmethods, and to developing valid research protocols.

Research
In research, we aim to contribute to the development of nursing science and improvement in quality ofnursing practice through collaborative research withclinicians. Especially we aim to develop new nursing
knowledge grounded on Japanese culture, as needed in
tomorrow’s aged society.
Faculty members conduct studies on various topics
in the field of adult and gerontological nursing.
As research methods, along with conventional
statistical methods, we often utilize qualitative
methods in order to understand experiences ofindividual patients and/or nurses and to conceptualize

295

and theorize them.
1) Quality assurance and improvement for long-termcare for the elderly
The goal of long-term care nursing is to allow older
adults live as high quality lives as possible, even withdiseases/disabilities; the paradigm of long-term care isdifferent from that of acute care that typically aim tohave the patients recover promptly from disease
conditions. There has not been enough attention to
long-term care nursing in today’s healthcare practice;there has been little research on quality assurance andimprovement in long-term care field in Japan. In thisdepartment, we have been conducting multiple studies
on long-term care in facilities and homecare nurse
agencies regarding care quality assurance andimprovement.
First, we attempt to develop intervention models toimprove care quality in close collaboration withclinicians, including nurses and care workers. We aim
to develop sustainable systems to improve their dailycare practice, collaborating with nurses at long-termcare facilities and homecare nurse agencies.
Second, we develop indicators to assess quality oflong-term care, including home care nursing. We havebeen developing them as a part of overall assessment
system needed for long-term care nursing.
Quality assurance and improvement for long-termcare facilities and home-care nurse agencies grow inimportance, given the educational opportunities forhealthcare provider working at long-term carefacilities and homecare nurse agencies are limited
compared to that working at critical hospital.
2) Establishing a case study method to develop
nursing science from clinical sites
We attempt to develop a new research method thatclinicians could use to conduct effective case studies.
Although case study has been used for long time, it
has not had a standardized method. We aim to develop
a protocol on conducting case study that contributes todevelop nursing science.
3) Establishment of support system for the elderly in
the integrated community care
In the Japanese aged society, it is an urgent problem
to establish a local structure supporting the life of theelderly persons by the community. As one of themeasures to solve the problem, the evaluation of theappropriateness of the public services in thecommunity is necessary. We have been examined what
combination of services the elderly persons are using
and what its related factors are. We will also examine
the outcomes affected by the combination of the used
services.
In addition, in the integrated community care, theutilization of the local resources, including
nongovernmental services, is demanded. We havediscussed the possibility of utilizing convenience
stores, which exist closely in local communities inJapan, as a hub of the elderly support. We haveconducted an action research to promote collaboration
with the convenience stores in the elderly support incommunity.
4) End-of-life care decision making in communitydwelling elderly people
We conduct a research about end of life carepreference of community dwelling elderly people(including facility for the elderly). In the Asian region,
Japan, Hong Kong, and South Korea, which are aging
society, need to promote Advanced Care Planning, andhas been designed institutional plan. By conducting
collaborate research in the three countries, we will
clarify common issues in the Asian region andproblems inherent to Japan and propose concrete
policies that the administration should do. Hence, we
aim to contribute to promotion of Advanced Care
Planning considering cultural factor.
5) Supporting employed family caregivers
In the super-aged society, the number of family
members who have two roles, working and providing
care to their own parents, are increasing. Our
department will develop the program for employedfamily caregivers to prevent leaving their job becauseof care giving for their parents with dementia, andenhance their work-life balance.
6) Prevention of turnover among homecare nurses
who support community dwelling persons
Homecare nursing is one of the services which areessential to support community-dwelling persons. We
have conducted a cohort study to examine the factors

296

related to actual homecare nurse’s turnover.
Furthermore, we have developed and evaluated thecase-based program to prevent homecare nurse’turnover.
We also conduct studies on a range of topics innursing of chronic conditions, from preventive to
end-of-life phase. We have been conducting studies
which are expected to allow us to understand the stateof individuals who require nursing in those periods,
and investigate effective and efficient nursing care forsuch individuals.

Publications
1. Sakka M, Goto J, Kita S, Sato I, Soejima T,
Kamibeppu K. Associations among behavioral
and psychological symptoms of dementia, careburden, and family-to-work conflict of employedfamily caregivers. Geriatrics & Gerontology
International. 2019 Jan;19(1):51-55.
2. Matsumoto H, Igarashi A, Suzuki M,
Yamamoto-Mitani N. Association between
Japanese neighborhood convenience stores andindependent living in older people. Australasian
Journal on Ageing 2019. Jan 30. doi: 10.1111/
ajag.12607.
3. Go H, Tanaka M, Yamamoto-Mitani N, Suzuki M,
Kawakami A, Masaki N, Shimada M. Medication
dherence among patients with chronic hepatitis
receiving antiviral treatment. Gastroenterol Nurs.
2019 Mar/Apr;42(2):140-149.
4. Noguchi-Watanabe M, Maruyama-Sakurai K,
Yamamoto-Mitani N, Matsumoto Y, Yoshie S,
Iijima K, Yamanaka T, Akishita M. A communitybased program promotes interprofessional collaboration among home healthcare professionals: A
non-randomized controlled study. Geriatrics &Gerontology International. 2019 Jul; 19(7):660666.
5. Igarashi A, Matsumoto H, Takaoka M, Kugai H,
Suzuki M, Yamamoto-Mitani N. Educational
program for promoting collaboration between
community care professionals and convenience
stores. Journal of Applied Gerontology. 2019 Sep
3:733464819871878.
6. Hama T, Takai Y, Noguchi-Watanabe M,

Yamahana R, Igarashi A, Yamamoto-Mitani N.
Clinical practice and work-related burden among
second career nurses: A cross-sectional survey. J
Clin Nurs. 2019 Sep;28(17-18):3288-3298
7. Futami A, Noguchi-Watanabe M, Mikoshiba N,
Yamamoto-Mitani N. Critical thinking disposition
among hospital nurses in Japan: Impact oforganizational versus personal factors. Japan
Journal of Nursing Science. 2019 Oct 22:e12298.
doi: 10.1111/jjns.12298.
8. Eguchi H, Kachi Y, Koga K H, Sakka M, Tokita
M, Shimazu A. Validation of the Japanese versionof the multidimensional measure of family
supportive supervisor behaviors (FSSB-J). Front
Psychol. 2019 Nov 22;10:2628.
9. Tobe H, Sakka M, Kamibeppu K. The efficacy ofa resilience-enhancement program for mothers inJapan based on emotion regulation: study protocol
for a randomized controlled trial. BMC
Psychology, 2019 Nov 6;7(1):69.
10. Futami A, Noguchi-Watanabe M, YamamotoMitani N. Relationship between critical thinking
disposition and use of research-based information
among nurses in Japan ． Jour nal of Japan
Academy of Nursing Science. 2019; 39:261-269.

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Department ofMidwifery and Women's HealthProfessor
Megumi Haruna, Ph.D., R.N.M., P.H.N.

Assistant Professor
Emi Sasagawa, Ph.D., M.P.H., R.N.M.

Assistant Professor
Kaori Yonezawa, Ph.D., R.N.M., P.H.N.

Homepage

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

Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
It has 3 faculty members introduced above, 16
graduate students (10 in master’s courses, 6 indoctoral courses), a project researcher, and 5 visiting
researchers.

Teaching activities
We have graduate and undergraduate courses.
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health I(2 credits, lectures)
2) Advanced Midwifery and Women’s Health II(2 credits, lectures)
2. Graduate Courses, School of Health Sciences andNursing for midwifery
1) Midwifery I (2 credits, lectures)
2) Midwifery II (2 credits, lectures)
3) Midwifery III (2 credits, lectures)
4) Midwifery IV (2 credits, lectures)
5) Midwifery V (2 credits, lectures)
6) Midwifery VI (1 credit, lectures)
7) Clinical Practicum of Administration for

Midwifery (1 credit, practices)8) Clinical Practicum in Midwifery I(2 credits, practices)9) Clinical Practicum in Midwifery II(8 credits, practices)
3. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
1) Maternal-Newborn Nursing(2 credits, lectures)
2) First AID course(1 credit, lecture)3) Clinical Practicum in Maternal-Newborn
Nursing (2 credits, practices)

Research activities
Our research activities cover the field of maternal andchild health emphasizing on the promotion of
women’s health and quality of life at every stage oflife.
We conduct the following research projects:
1. Creating evidence of health guidance during
pregnancy
1) Adequate maternal nutrition and weight
management
This study examines the maternal bodycomposition, lipid metabolic biomarkers, andnutritional
intaketooptimizeweight298

management and a healthy lifestyle during
pregnancy to prevent low birth weight. Based on
our investigations on the optimal maternal
nutritional status and gestational weight gain, we
propose a health guidance that can help lower
the risk of pregnancy complications and adverse
birth outcomes in pregnant women.
2) Effect of physical activity during pregnancy
This study investigates the effect of physicalactivity on the mental and physical health of
pregnant women. It aims to provide basic data
for appropriate health guidance during
pregnancy.
3) Secondhand smoke exposure during pregnancy
and its related factors in Mongolia
This study uses biomarkers to investigate theprevalence of secondhand smoke (SHS)
exposure during pregnancy and the effects of
SHS on birth outcomes in Mongolia. Data werecollected through investigations to create aneffective health education.
4) Factors associated with mental health among
working pregnant womenThis study explores factors associated with work
engagement among working pregnant women.
2. Development of a support system for reliablechildbirth1) Development of assessment methods of birthcanal using transperineal ultrasonography
This study aims to develop the objective assessment methods of birth canal and the relationshipbetween birth canal and delivery mode usingtransperineal ultrasonography.
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 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.

3. Development of a support system for women’s
health1) Life and sleep among working mothers ofinfants and toddlers
This study investigates the cadences of daily lifeand conditions of sleep such as excessive
daytime sleepiness and other related factors
among working mothers.
2) Support for continuous breastfeeding of working
mothers
This study investigates the factors related tobreastfeeding continuation among working
mothers.
3) Intimate partner violence (IPV) and its related
factors
This study clarifies associations between IPV
during pregnancy, mother-to-infant bonding
failure, and postnatal depressive symptoms.
4) Prevalence of anemia among adult womenThis study uses health check-up database toinvestigate the prevalence of anemia among
women of reproductive age and factors related
to the condition.
5) Prevalence of mastitis and breast abscess amongpostpartum womenThis study uses a health insurance claims
database to investigate the prevalence of mastitis
and breast abscess among postpartum womenand factors associated with their surgicaltreatment.
6) Factors related to postpartum parenting
self-efficacy
This study investigates factors related tomaternal parenting self-efficacy (self-esteem)
during the postpartum period.
7) Prevalence of pelvic floor disorders amongpostpartum womenThis study evaluates the effect of pelvic floor
muscle training in prevention of postpartum
pelvicfloor
disorders(e.g.,
urinaryincontinence). Furthermore, this study aims todevelop the pelvic floor muscle training
program.
4. Creating evidence of health guidance for neonatalskin care1) Development of an effective skin care299intervention to prevent neonatal skin problems.
This study investigates the effect of moisturizing
skin care improving skin barrier functions
among healthy neonates.
In addition, we investigate the relationshipbetween newborns’ skin problems and allergies(i.e., food allergy or atopic dermatitis).
2) Effect of skin care on skin barrier function andnormal bacterial flora
This study investigates the effect of skin care,including bathing, on infants’ skin. It focuses onskin barrier function and normal bacterial flora
as a skin condition.

Publications
1. Haruna M, Matsuzaki M, Ota E, Shiraishi M,
Hanada N, Mori R. Guided imagery for treating
hypertension in pregnancy. Cochrane Database
Syst Rev. 2019 Apr 27;4: CD011337
2. Hikita N, Haruna M, Matsuzaki M, Sasagawa E,
Murata M, Yura A, Oidovsuren O. Is highmaternal body mass index associated withcaesarean section delivery in Mongolia? A
prospective observational study. Asian/PacificIsland Nursing Journal. 2019;4(3).
3. Hikita N, Haruna M, Matsuzaki M, Sasagawa E,
Murata M, Yura A, Oidovsuren O. Comparison of
Knowledge about smoking and passive smoking
and urinary cotinine levels in pregnant womenand their partners in Mongolia: A cross-sectional
study. Asian/Pacific Island Nursing Journal. 2019;
4(1).
4. Yonezawa K, Haruna M. Short-term skinproblems in infants aged 0–3 months affect foodallergies or atopic dermatitis until 2 years of age,among infants of the general population. Allergy
Asthma Clin Immunol. 2019;15, 74.
5. Kita S, Haruna M, Matsuzaki M, Kamibeppu K.
Does antenatal social support affect therelationships between intimate partner violence
during pregnancy and perinatal mental health?
Violence Against Women. 2019;3:1077801219835
052.
6. Rönnerhag M, Severinsson E, Haruna M,
Berggren I. Risk management-evaluation ofhealthcare professionals’ reasoning about andunderstanding of maternity care. J Nurs Manag.
2019;Apr 5.
7. Usui Y, Haruna M, Shimpuku Y. Validity andreliability of the Karitane Parenting Confidence
Scale among Japanese mothers. Nurs Health Sci.
2019;doi: 10.1111/nhs.12633.
8. Hisa K, Haruna M, Hikita N, Sasagawa E,
Yonezawa K, Suto M, Ota E. Prevalence of andfactors related to anemia among Japanese adultwomen: Secondary data analysis using healthcheck-up database. Sci Rep. 2019; 19;9(1):17048.
9. Sannomiya M, Sasagawa E, Yonezawa K, Hikita
N, Haruna M. The Proportions, regulations, andtraining plans of male midwives worldwide: A
descriptive study of 77 countries. International
Journal of Childbirth. 2019;9(1):5–18.
10. Kikuchi-Noguchi H, Shiraishi M, Matsuzaki M,
Haruna M. Physical activity levels in the second
trimester of pregnancy and related demographic
factors: A cross-sectional secondary data analysis.
Cogent Medicine. 2019;6:1704607.
11. Emi S，Megumi H, Kaori Y，Naoko H. From
“Care in Normal Birth” to “Intrapartum care for apositive childbirth experience”: How was the
WHO guideline on normal birth changed? Journalof Japan Academy of Midwifery, 2019; 33(1),50–60. (in Japanese)

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Department of Psychiatric Nursing
Professor
Norito Kawakami, M.D., Ph.D.

Associate Professor
Yuki Miyamoto, R.N., P.H.N., P.S.W., Ph.D.

Project Research Associate
Akiko Inagaki , R.N., P.H.N, Ph.D.

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,
7 doctoral course students, 5 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.

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Research
Our research field covers mental health andpsychiatric nursing. Our department has many
research projects across diverse fields as follows:
study of self-management in mental health; recovery
in people with mental health difficulties; community
support system for the people with mental healthneeds; peer support; stigma; social inclusion; mental
health in people with substance use disorder orphysical diseases; mental health in nurses or otherworkers; disaster mental health nursing; and reducing
the use of seclusion and restraint. We are conducting
studies in collaboration with researchers in otherinstitutions and universities.

Publications
1. Nishi D, Imamura K, Watanabe K, Ishikawa H,
Tachimori H, Takeshima T, Kawakami N.
Psychological distress with and without a historyof depression: Results from the World Mental
Health Japan 2nd Survey (WMHJ2). Journal of
Affective Disorders. 2020 Mar 15;265: 545-551.
DOI: 10.1016/j.jad.2019.11.089. Epub 2019 Nov
13.
2. Nishi D, Ishikawa H, Kawakami N. Prevalence ofmental disorders and mental health service use inJapan. Psychiatry and Clinical Neurosciences.
2019 Aug; 73(8):458-465. DOI: 10.1111/pcn.
12894.
3. Fukasawa M, Kawakami N, Umeda M, Akiyama
T, Horikoshi N, Yasumura S, Yabe H, Suzuki Y,
Bromet EJ. Longitudinal associations of radiation
risk perceptions and mental health among nonevacuee residents of Fukushima prefecture sevenyears after the nuclear power plant disaster.
SSM-Population Health. 2019 Nov 29;10:100523.
DOI: 10.1016/j.ssmph.2019.100523.
4. Yasuma N, Narita Z, Sasaki N, Obikane E, Sekiya
J, Inagawa T, Nakajima A, Yamada Y, Yamazaki R,
Matsunaga A, Saito T, Watanabe K, Imamura K,
Kawakami N, Nishi D. Psychological intervention
for universal prevention of antenatal and postnatal
depression among pregnant women: protocol for asystematic review and meta-analysis. Syst Rev.
2019 Dec 1; 8(1):297. DOI: 10.1186/s13643-0191238-7.

5. Yasuma N, Watanabe K, Iida M, Nishi D,
Kawakami N. Personal values in adolescence andpsychological distress in adults: A cross-sectional
study based on a retrospective recall. PLOS ONE.
2019 Nov 21; 14(11):e0225454. DOI: 10.1371/
journal.pone.0225454.
6. Fukasawa M, Kawakami N, Nakayama C,
Yasumura S. Relationship between use of media
and radiation anxiety among the residents ofFukushima 5.5 years after the nuclear power plant
accident. Disaster Medicine and Public HealthPreparedness. 2019 Nov 29;1-8. DOI: 10.1017/
dmp.2019.132.
7. Kuribayashi K, Imamura K, Watanabe K,
Miyamoto Y, Takano A, Sawada U, Sasaki N,
Suga M, Sugino A, Hidaka Y, Iida M, Sudo M,
Tokita M, Kawakami N. Effects of an internetbased cognitive behavioral therapy (iCBT) intervention on improving depressive symptoms andwork-related outcomes among nurses in Japan: aprotocol for a randomized controlled trial. BMC
Psychiatry. 2019 Aug 7;19(1):245. DOI: 10.1186/
s12888-019-2221-5.
8. Imamura K, Tsutsumi A, Asai Y, Arima H, Ando E,
Inoue A, Inoue R, Iwanaga M, Eguchi H, Otsuka
Y, Kobayashi Y, Sakuraya A, Sasaki N, Tsuno K,
Hino A, Watanabe K, Shimazu A, Kawakami N.
Association between psychosocial factors at workand health outcomes after retirement: a protocol
for a systematic review and meta-analysis. BMJ
Open. 2019 Aug 27;9(8):e030773. DOI: 10.1136/
bmjopen-2019-030773.
9. Watanabe K, Imamura K, Inoue A, Otsuka Y,
Shimazu A, Eguchi H, Adachi H, Sakuraya A,
Kobayashi Y, Arima H, Kawakami N. Measuring
eudemonic well-being at work: a validation study
for the 24-item The University of Tokyo
Occupational Mental Health well-being scale
among Japanese workers. Ind Health. 2020 Apr 2;
58(2):107-131. DOI: 10.2486/indhealth.20190074. Epub 2019 Aug 1.
10. Yasuma N, Watanabe K, Matsunaga A, Nishi D,
Kawakami N. Personal values in adolescence andsuicidality: a cross-sectional study based on aretrospective recall. BMC Psychiatry. 2019 Jul
9;19(1): 214. DOI: 10.1186/s12888-019-2194-4.

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11. Komase Y, Watanabe K, Imamura K, Kawakami
N. Effects of a newly developed gratitudeintervention program on work engagement among
Japanese workers: a pre- and post-test study.
Journal of Occupational and Environmental
Medicine. 2019 Sep;61(9):e378-e383. DOI: 10.
1097/JOM.0000000000001661.
12. Morita Y, Miyamoto Y, Takano A, Kawakami N,
Coulombe S. Reliability and validity of theJapanese version of the Mental Health Selfmanagement Questionnaire among people withmental illness living in the community. BMC
Psychology. 2019 22;7(1):30. DOI: 10.1186/
s40359-019-0301-4.
13. Imamura K, Tran TTT, Nguyen HT, Kuribayashi
K, Sakuraya A, Nguyen AQ, Bui TM, Nguyen QT,
Nguyen KT, Nguyen GTH, Tran XTN, Truong TQ,
Zhang MWB, Minas H, Sekiya Y, Sasaki N,
Tsutsumi A, Kawakami N. Effects of two types ofsmartphone-based stress management programmes on depressive and anxiety symptoms amonghospital nurses in Vietnam: a protocol forthree-arm randomised controlled trial. BMJ Open.
2019 Apr 8; 9(4):e025138. DOI: 10.1136/
bmjopen-2018-025138.
14. Yasuma N, Watanabe K, Nishi D, Ishikawa H,
Tachimori H, Takeshima T, Umeda M, Sampson L,
Galea S, Kawakami N. Urbanization and Internet
addiction in a nationally representative sample ofadult community residents in Japan: A crosssectional, multilevel study. Psychiatry research.
2019 Mar; 273:699-705. DOI: 10.1016/j.psychres.
2019.01.094. Epub 2019 Jan 30.
15. Miki T, Eguchi M, Kuwahara K, Kochi T, Akter S,
Kashino I, Hu H, Kurotani K, Kabe I, Kawakami
N, Nanri A, Mizoue T. Breakfast consumption andthe risk of depressive symptoms: the Furukawa
Nutrition and Health Study. Psychiatry Research.
2019 Mar; 273:551-558. DOI: 10.1016/j.psychres.
2019.01.069. Epub 2019 Jan 24.
16. Chiba R, Umeda M, Goto K, Miyamoto Y,
Yamaguchi S. Factors related to recovery
knowledge and attitudes among professionals inmental health in Japan. Japan Journal of Nursing
Science, 2019 Aug 27; e12295. DOI: 10.1111/jjns.
12295

17. Nakanishi M, Miyamoto Y, Nakashima T, Shindo
Y, & Nishida A. Care preferences of healthy,
middle‐aged adults in Japan and the USA if theyacquired dementia: A cross ‐ sectional
observational study. Geriatrics & Gerontology
International, 2019 Jul 7; 19(8), 829-833. DOI: 10.
1111/ggi.13729

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Department ofGerontological Nursing /Wound Care Management
Professor
Hiromi Sanada, R.N., W.O.C.N., F.A.A.N., Ph.D.

Associate Professor
Gojiro Nakagami, R.N., Ph.D.

Associate
Aya Kitamura, R.N., Ph.D., Yuko Mugita, R.N., Ph.D.

Project Research Associate
Kenneth Scott Barton, M.A.

Homepage

http://www.rounenkango.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
The Department of Gerontological Nursing wasestablished in June 2003, followed by the establishmentof the Department of Wound Care Management in April
2006. We have been promoting the education ofundergraduate and graduate students, clinical activities
in hospital relating to pressure ulcers and diabetic foot,and research activities on the topics of gerontologicalnursing, wound care management, and nursing scienceand engineering.
Our department has recently established several
departments: Department of Life Support Technology(Molten), Department of Advanced Nursing
Technology, Department of Skincare Science, andDepartment of Imaging Nursing Science. We have beenpromoting collaborative research among government,
industry and academia, as well as integrating multiple
disciplines across campus.
Especially noteworthy, the Department of Advanced
Nursing Technology, which was established in
December 2012, works as a social cooperation program
to promote team nursing intervention and research
involving the clinical division, the nursing department

at hospital, and the Division of Health Sciences andNursing at the Graduate School of Medicine. Throughthis program, nurses can scientifically study the subjectof nursing, including research in epidemiologicalsurveys and molecular- and gene-level topics.
Furthermore, the technology and medical equipment
developed by companies can be evaluated in thehospital, offering new nursing technologies suitable forneeds in clinical sites.
In April 2017, the Global Nursing Research Center(GNRC) was established with the aim to create a transdisciplinary research and educational environment that
fosters young researchers in nursing science in order topromote care innovation. Professor Sanada has been
the director, and faculty staff members in our
department have been involved in the Division of Care
Innovation in GNRC as a concurrent position.
Gerontological Nursing and Wound CareManagement is currently headed by one professor andassisted by an associate professor, two research
associates, a project research associate, a project
academic support staff member, two part-time lecturers
for undergraduate courses, and seven part-time

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lecturers for graduate courses. The student bodyconsists of eight doctoral course students, ten master’scourse students, and two undergraduate students. Our
mission statement is “We wish to create a society that
respects the beauty of aging and recognizes it as to bea joyful process in life.”

Teaching activities
1. Undergraduate course
For undergraduate education, our department takes partin lectures of Health Support Practice, Overview ofClinical Medicine, and Observation of Human
Anatomy, as well as lectures, exercises, and clinicalpractice about gerontological nursing and nursing
science and engineering.
1) Health Support Practice (W in 2nd yr; 1 credit)
Nursing is a science of searching for ways to support
health and the achievement of self-actualization, and it
is practiced in various social situations, including
hospitals, healthcare centers or medical facilities. The
aim of this practice 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 2019, ourprogram included themes related to:a) Policy creation for solving problems confronted innursingb) Health support servicesc) Nursing-based hospital managementd) Development of medical devices for supporting
patients’ lives.
2) Overview of Clinical Medicine (S2 in 3rd yr; 2credits)
The aim of this series of lectures is to learn the basic
knowledge and thought process for understanding
clinical medicine, and to learn the pharmaceutics
required for nursing practice. The main content themesin the 2019 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 2019 curriculum included:a) Introduction to anatomical pathologyb) Case studyc) Introduction to anatomicopathological researchd) Approaches to anatomical pathologye) Autopsy room practicef) Medical specimen room visit
4) Gerontological Nursing (A2 in 3rd yr; 2 credits)
A series of lectures with the aim of understanding thephysical, psychological, and social characteristics ofthe elderly population; to learn fundamental theories ofgerontological nursing; and to promote anunderstanding of the ailments and conditions required
to provide proper care to the elderly. The main themes
covered in the 2019 session were as follows:a) Practical simulation for gerontological nursingb) Physical, psychological, and social characteristicsof the elderly from a nursing standpointc) Geriatric syndrome and nursing (i.e., dementia,
feeding and swallowing difficulty, pressure ulcer,
incontinence, support for walking and movement)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) Relationship-building and communication skills
with the elderlyl) Group work
A portion of the above lectures was provided throughcooperation from the Department of Geriatric Medicine
and other departments at The University of Tokyo

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Hospital.

fields and critically evaluated.

5) Nursing Science and Engineering (S2 in 4th yr; 2credits)
Gaining a thorough understanding of a given medical
situation, as well as determining the appropriate
medical intervention for a patient require theknowledge and skills from Nursing Science andEngineering. These include the processes involved intranslational research: clinical observation, explorationof the mechanisms underlying the patient's symptoms,
development of objective measurement methods, andthe development of devices and systems forintervention and the clinical evaluation. This series oflectures is to learn about cutting-edge research, and tounderstand the linkage between research and clinicalactivities. Our 2019 program included the following:a) Necessity and importance of Nursing Science andEngineeringb) Methods and application of the research of Nursing
Science and Engineering

2) Gerontological Nursing II (A1; 2 credits)
Gerontological Nursing II provided lectures regarding
recent topics around gerontological medicine andnursing from broad viewpoints, including biological,
individual, and social aspects, by part-time lecturers
and specialists from each research field. The aim of thiscourse was to understand and learn scientific ways ofthinking about gerontological considerations of the
future Japanese community. The main titles in 2019were as follows:a) Up-to-date ultrasonographic examination andhands-on lecture of ultrasonography for the headand neck areab) Dysphagiac) Biochemistry of wound healing, protein synthesis,
and nutritional management in cancer patientsd) How do cells sense stress?
e) Activities of perianesthesia nurses and research onskinf) How can we approach aging and skin health?
g) Innovations in basic nursing education: on movingfrom ‘home care nursing’ to ‘community and homecare nursing’6) Clinical Practice in Gerontological Nursing (A1in 4th yr; 2 credits)
The aim of this practicum is to learn about the current
state of gerontological nursing through practice (orpractical training) in a long-term care facility. The
program in 2019 was supported by the long-term carefacility owned by Medical Corporation Tatsuoka.
7) Bachelor’s thesis
The following research themes were submitted in 2019:
 “New methods for the estimation of weight andbody composition of wheelchair users, validatedwith able-bodied subjects” (in Japanese) “Association
betweenwound
temperature
distribution obtained with a thermography andhealing process in pressure ulcer” (in Japanese)
2. Graduate course
1) Gerontological Nursing I (S1; 2 credits)
The main theme of Gerontological Nursing I in 2019was to understand the latest research related to the careof elderly persons and to discuss future perspectives ingerontological nursing from three viewpoints: basic
biology, engineering, and clinical nursing research.
Recent research papers were selected from these three

3) Wound Care Management I (S2; 2 credits)
The main topic of Wound Care Management I in 2019was the acquisition of the basic knowledge (i.e., basic
biology, clinical research, and engineering) necessary
to understand wound management studies. The topics
were as follows:a) Structure and function of skin; wound healing andmanagementb) Basics of biological research and its application to
wound care nursingc) Basics of engineering research and its application to
wound care nursingd) Basics of ultrasound technology and its application
to wound care nursinge) Basics of pressure ulcer and efforts of nursing
4) Wound Care Management II (A2; 2 credits)
The main theme of Wound Care Management II in 2019was to obtain deeper insight in our own researchknowledge through lectures and discussion by
specialists from various basic and advanced research

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fields in the Division of Care Innovation in GNRC. The
topics were as follows:5) Master’s theses
The following research themes were submitted in 2019:
 “Reliability and validity of skin blotting
examination for non-invasive assessment of thephysiological status of the skin”
 “Developing a pressure ulcer monitoring tool using
electrical impedance tomography and spectroscopy:
Phantom study and preliminary human trial”
 “Incidence, characteristics and timing of peripheral
intravenous catheter failure in patients receiving
chemotherapy with hematological malignancy; aprospective descriptive study”
 “Polymorphism analysis of candidate risk genes forpressure ulcers in older Japanese patients: A crosssectional study at a long-term care hospital”
 “Skin characteristics associated with foot callus inpeople with diabetes: A cross-sectional study
focused on adhesion molecules in corneocytes”

Research activities
1. Activity policy
Our gerontological nursing research focuses on those
suffering from geriatric syndromes, such as pressure
ulcers, incontinence, malnutrition, pain, dysphagia,
osteoporosis and dementia. Our wound caremanagement research focuses on pressure ulcers,
diabetic foot ulcers, ulcers with peripheral vasculardiseases, and malignant fungating wounds.
The majority of our clinical research has been
conducted at The University of Tokyo Hospital. We
regularly participate in pressure ulcer multidisciplinary team rounds. We also attend the Foot Care
Outpatient Clinic held by the Department of Metabolic
Diseases and the Stoma Outpatient Clinic held by the
Departments of Urology and Colorectal Surgery.
In July 2019, we organized the 6th introductory
seminar for bioengineering nursing research involving
many nursing researchers and clinical nurses. In thisseminar, a new research framework “Bioengineering
Nursing” which consists of nursing biology (whichinvestigates, in detail, the mechanisms of a target
phenomenon), nursing engineering (which develops
technologies for the clarified target), and nursing

translational
research(whichevaluatesthetechnologies in the clinical field and further explores
new clinical problems) was introduced. Furthermore,
we organized an advanced hands-on seminar of
bioengineering nursing research methodologies for
those who attended the introductory seminar and wereinterested in this research framework.
Regarding international activities, we attended theInternational summer school in Nottingham Trent
University in September 2019. Researchers fromseveral countries discussed chronic wounds, skincare,and lymphoedema. Additionally, our department has
been promoting collaborative research with researchersin universities around the world. Our counterparts
include: University of California, Los Angeles (USA),
Florida University (USA), Curtin University(Australia), and The University of Nottingham (UK).
Professor Sanada has been working as Continental
Board for World Union of Wound Healing Societies
and a member of the International Board of Directors
for International Lymphoedema Framework. Her
research activities on the globalization ofinterdisciplinary research have been highly evaluated,and she was recommended as a Fellow of American
Academy of Nursing (FAAN).
2. Research fields and themes in 20191) Basic experimental studies
・ Development of a novel method for controllingwound infection focusing on gene expression ofbacteria and hosts
・Evaluation of wound condition using exudates
・Skin blotting for analyzing physiological status of theskin
・Development of a new technique for detecting woundbiofilm・Cutaneous wound healing and diabetes mellitus
・Research on scalp care science・Research on the mechanisms of wound pain
2) Nursing engineering
・Development of a new air mattress equipped withinterface pressure-sensing system and automaticpressure control
・Non-invasive detection of tissue injury and pre-injury
status using ultrasonography and thermography
・Early detection of complications of peripheral intravascular catheter by thermography

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・Development of an insole-type measurement system
for the simultaneous measurement of plantarpressure and shear force during gait・ Development of a fitting device for non-invasive
positive pressure ventilation oral-nasal mask using athree-dimensional solution
・Development of apps using communication robots
for the elderly
・Development of an absorbent pad for the preventionof incontinence-associated dermatitis
・Introduction of text mining to nursing3) Clinical studies
・Novel assessment technologies for pressure ulcers
・Cross-sectional study of diabetic foot (e.g., ulcers,
calluses, fissures, onychomycosis) and its risk
factors
・Cross-sectional study of malignant wounds in breast
cancer patients and their risk factors
・ Survey and international comparison of lymphoedema
・Methods for predicting skin tear development
・Establishment of a novel diagnosis method of latentdysphagia
・ Establishment of a novel assessment method of
constipation using ultrasonography
・Cross-sectional study of the skin of elderly people ina nursing home・Cross-sectional study of the skin of obese people
・Survey of the skin condition of wheelchair basketballathletes・Survey on the relationship between the microbiota inthe bed environment and the development ofpressure ulcer infections
・Survey of the effectiveness of biofilm removal on
wound healing
・Cross-sectional study of catheter failure and its risk
factors
・ Evaluation of the effectiveness of nurses whocompleted advanced nursing procedure training
Several awards were given for our research, as follows:
・The 8th Asia Pacific Enterostomal Therapy Nurse
Association Best Oral Award
Nakagami G, Sanada H, Mori Y, Minematsu T,
Kitamura A. Biofilm-based wound care system fortreating chronic wounds. 2019. (The 8th Asia PacificEnterostomal Therapy Nurse Association, Taipei

International Convention Center, Taipei, Taiwan,
22nd Nov)
・The 8th Asia Pacific Enterostomal Therapy Nurse
Association Best Moderated Poster Award
Nakai A, Tsukatani T, Tamai N, Urai T, Mori Y,
Weijie K, Minematsu T, Takada C, Sanada H.
Relationship between type IV collagen positivity via
skin blotting and conventional risk factors of skintears. 2019. (The 8th Asia Pacific Enterostomal
Therapy Nurse Association, Taipei International
Convention Center, Taipei, Taiwan, 22nd Nov)
・The 8th Asia Pacific Enterostomal Therapy Nurse
Association Best Moderated Poster Award
Minematsu T, Tsukatani T, Weijie K, Nakai A,
Tomida S, Nakagami G, Sanada H. Intra-rater
reliability of albumin measurement by skin blottingin healthy volunteers. 2019. (The 8th Asia PacificEnterostomal Therapy Nurse Association, Taipei
International Convention Center, Taipei, Taiwan,
22nd Nov)
・First-place award from the 21st Japanese Society ofPressure Ulcers Board Meeting.
Maeda T, Tamai N, Minematsu T, Noguchi H,
Nakagami G, Yabunaka K, Sanada H. Relationshipbetween pressure ulcers and dynamic buttock
pressure distributions during performance inwheelchair basketball athletes. Journal of JapaneseSociety of Pressure Ulcers. 2019;21(3):309. (The
21st Japanese Society of Pressure Ulcers Board
Meeting, Kyoto, 23rd Aug)・Award from the 28th Annual Congress of JapaneseSociety of Wound, Ostomy, and ContinenceManagement.
Minematsu T, Ogata M, Tamai N, Yabunaka K,
Maeda T, Nakagami G, Noguchi H, Sanada H. Deeptissue injury in wheelchair basketball athletes: skincharacteristics related to deep tissue injury. Journalof Japanese Society of Wound, Ostomy andContinence Management. 2019;23(2):242. (The 28th
Annual Congress of Japanese Society of Wound,
Ostomy, and Continence Management, Nara, 25thMay)
・Good design award 2019
Dai M, Batelplus Inc, Yoshida Tsukasa Inc,
Murayama ， Murayama H. Elastic Stockings forPatients with Lymphedema "Cool lala"308

References
1. Hasegawa Y, Yoshida M, Sato A, Fujimoto Y,
Minematsu T, Sugama J, Sanada H. Temporalmuscle thickness as a new indicator of nutritional
status in elderly individuals. Geriatrics &Gerontology International. 2019;19(2):135-40.
2. Suzuki M, Miyazaki H, Kamei J, Yoshida M,
Taniguchi T, Nishimura K, Igawa Y, Sanada H,
Homma Y. Ultrasound-assisted prompted voiding
care for managing urinary incontinence in nursing
homes: A randomized clinical trial. Neurourology
Urodynamics. 2019;38(2):757-63.
3. 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 robotassisted radical prostatectomy. Neurourology
Urodynamics. 2019 Ap;38(4):1067-1075.
4. Higuchi S, Yoshida S, Minematsu T, Ichinose T.
Detection of inflammatory cytokines by skinblotting as an objective measure of neonatal skinproblems. Journal of Nursing Science andEngineering. 2019;6(1):33-40. [doi]5. Matsumoto M, Yabunaka K, Yoshida M, Nakagami
G, Sanada H. Validity assessment of two bladdervolume estimation methods using hand-held
ultrasonography devices: verification with a small
amount of bladder urine. Journal of Nursing
Science and Engineering. 2019;6(1):22-32.
6. Kunimitsu M, Nakagami G, Kitamura A, Mugita Y,
Akamata K, Sasaki S, Hayashi C, Mori Y, Sanada
H. The combination of high bacterial count andpositive biofilm formation is associated with the
inflammation of pressure ulcers. Chronic Wound
Care Management and Research. 2019;6:1-7.
7. Nakai A, Minematsu T, Tamai N, Sugama J, Urai T,
Sanada H. Prediction of healing in category I
pressure ulcers by skin blotting with plasminogenactivator inhibitor 1, interleukin-1α, vascularendothelial growth factor C, and heat shock protein
90α: A pilot study. Journal of Tissue Viability.
2019;28(2):87-93.
8. Takehara K, Oe M, Ohashi Y, Tsunemi Y,
Kadowaki T, Sanada H. Differences between

subjective and objective symptoms of the foot inpatients with diabetes. Journal of Wound, Ostomy
and Continence Nursing. 2019;46(2):113-6.
9. Kumagai A, Ohno N, Miyati T, Okuwa M,
Nakatani T, Sanada H, Sugama J. Investigation ofeffects of urethane foam mattress hardness on skinand soft tissue deformation in the prone position
using magnetic resonance imaging. Journal of
Tissue Viability. 2019;28(1):14-20.
10. Dai M, Nakagami G, Sugama J, Kobayashi N,
Kimura E, Arai Y, Sato A, Mercier G, Moffatt C,
Murray S, Sanada H. The prevalence andfunctional impact of chronic edema andlymphedema in Japan: LIMPRINT Study.
Lymphatic Research and Biology. 2019;17(2):195201.
11. Noyori S, Nakagami G, Noguchi H, Mori T,
Sanada H. Unintentional body movement
parameters and pulse rate variability parameters
are associated with the desire to void. Medical
Engineering & Physics. 2019;68:116-21.
12. Kitamura A, Yoshimura M, Nakagami G,
Yabunaka K, Sanada H. Changes of tissue images
visualised by ultrasonography in the process ofpressure ulcer occurrence. Journal of Wound Care.
2019;28(sup4):18-22.
13. Mori Y, Nakagami G, Kitamura A, Minematsu T,
Kinoshita M, Suga H, Kurita HM, Kawasaki A,
Sanada H. Effectiveness of biofilm-based woundcare system on wound healing in chronic wounds.
Wound Repair and Regeneration. 2019;27(5):5407.
14. Takahashi T, Murayama R, Yabunaka K, Tanabe H,
Sanada H. Using tablet-type ultrasonography toassess peripheral veins for intravenous
catheterization: A pilot study. Journal of the
Association for Vascular Access. 2019;24(3):1-6.
15. Goto T, Nakagami G, Minematsu T, Shinoda M,
Sanada H. Applicability of the von Frey test to themeasurement of mechanical withdrawal thresholdon full-thickness cutaneous wounds in rats. Journalof Wound Care. 2019;28(11):762-72.
16. Goto T, Nakagami G, Minematsu T, Tomida S,
Shinoda M, Iwata K, Sanada H. Topically injected
adrenocorticotropic hormone induces mechanicalhypersensitivity on a full-thickness cutaneous

309

wound model in rats. Experimental Dermatology.
2019.;28(9):1010-6.
17. Matsumoto M, Tsutaoka T, Yabunaka K, H, a M,
Yoshida M, Nakagami G, Sanada H. Development
and evaluation of automated ultrosonographic
detection of bladder diameter for estimation of
bladder urine volume. PLOS ONE. 2019; 14(9):e0219916.
18. Kitamura A, Minematsu T, Nakagami G, Miyagaki
T, Sasaki S, Hayashi C, Sanada H. Assessing
subclinical inflammation by peroxidase detection
in patients with pressure ulcers. Journal of Wound
Care. 2019;28(9):586-91.
19. Nakagami G, Gregory S, Kitamura A, Minematsu
T, Akamata K, Suga H, Kurita M, Hayashi C,
Sanada H. Rapid detection of biofilm by woundblotting following sharp debridement of chronicpressure ulcers predicts wound healing: A
preliminary study. International Wound Journal.
2019;17(1):191-6.
20. Takahashi T, Minematsu T, Murayama R,
Nakagami G, Mori T, Sanada H. Catheter tips are apossible resource for biological study on catheter
failure. Drug Discoveries & Therapeutics. 2019;13(5):280-7.
21. Okawa Y, Fukudo S, Sanada H. Specific foods can
reduce symptoms of irritable bowel syndrome andfunctional constipation: a review. BioPsychoSocial
Medicine. 2019;13:10.
22. Abe-Doi M, Murayama R, Yabunaka K, Tanabe H,
Komiyama C, Sanada H. Ultrasonographic assessment of an induration caused by extravasation of anon-vesicant anti-cancer drug: A case report.
Medicine. 2019;98(14):e15043.
23. Astrada A, Nakagami G, Suriadi, Sanada H.
Successful wound treatment of a diabetic foot ulcer
exposing bone with Trigona honey: a case study.
Journal of Wound Care. 2019;28(Sup12):S4-S8.
24. Noguchi H, Koyano Y, Mori H, Komiyama C,
Sanada H, Mori T. Exploration of communication
robot use for older patients in an acute hospital
based on case trials. Journal of Nursing Scienceand Engineering. 2019;6(2):70-82.
25. Murayama R, Oya M, Abe-Doi M, Oe M,
Komiyama C, Sanada H. Characteristics ofsubcutaneous tissues at the site of insertion of
peripheral infusion in patients undergoing

paclitaxel and carboplatin chemotherapy. Drug
Discoveries & Therapleutics. 2019;13(5):288-93.

International Health
1. International Social Medicine

311

Department of
Global Health Policy
Professor
Masahiro Hashizume, MD, PhD

Assistant Professor
Md. Mizanur Rahman, MSc, PhD

Project Assistant Professor
Shuhei Nomura, MSc, PhD
Ashraful Alam, MSc, PhD

Homepage

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

Introduction and Organization
As of March 2020 the department, headed by Professor
Masahiro Hashizume, included the following staff
complement; one assistant professors (Md. Mizanur
Rahman); one project assistant professors (Shuhei
Nomura, Ashraful Alam); five post-doctoral fellows;
10 adjunct lecturers; 14 doctoral students; and eightmaster’s students.
The priority areas of research are:
- Health impacts of climate, climate change and air
pollution.
- Health outcome research (mortality, morbidity anddisability; health service research; health technology
assessment and cost-effectiveness; disease modeling; and comparative risk factor analysis);- Health system performance assessment, including
the analysis of health system inputs, outputs, andimpact;- Health and foreign policy (e.g. global healtharchitecture and governance, the G7 and global
health, donor commitments, and innovations in
global health).
Finally, the fundamental role of the department is to

produce the next generations of leaders in global health.

Education
All lectures in the department are conducted in English,
in order to ensure that student writing and presentation
skills are held to an international standard.
Master's program
The Master's program is a demanding, interdisciplinary
program emphasizing student-directed learning,problem-solving, and the acquisition of fundamental
public health skills required for global health practices(health policy, statistics, epidemiology, and social
sciences). Students are required to complete aminimum of 30 course credits and a master’s thesis.
Beyond the program and concentration requirements,
students are encouraged to consult with faculty
advisers to choose elective courses best suited to theirneeds.
PhD program
The PhD program is designed to train the next
generation of leaders in global health. PhD students are
required to complete a minimum of 24 course credits
and a doctoral thesis with which needs to be publishedin a peer-reviewed journal. PhD students without MPH

312

degree should take the lectures to acquire fundamental
public health skills such as health policy, biostatistics
and epidemiology.
Global Health Policy I and IIThis course introduces the principles and theories ofglobal health problems, as well as practical applicationsof quantitative methods (demography, statistics,
epidemiology and econometrics) to analyze andinterpret issues and challenges for policy.
The followings are the topics covered in the academic
year 2018:- Innovations in global health- Global health policy- Global health governance- Social determinants of health- Universal health coverage- Global health diplomacy- Quantifying health outcomes- Using GBD to inform policies- Old and new challenges in global health- Comparative risk assessment- Health system performance assessment- Health service quality- Monitoring and evaluation- Financing health systems
GHP Monday seminar
Every Monday, 13:00-15:00 pm
1) Journal clubStudents present a brief summary of research articles
from the major medical, social science, economics
journals, which are relevant for global health policy.
The major objective is to share knowledge, evoke
debates and facilitate discussions.
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
A comprehensive study on the comparative risk
assessment and utilization of health outcomes byprefecture in Japan. Grant-in-Aid for Scientific
Research(C) (Ministry of Education, Culture, Sports,

Science and Technology). PI: Shuhei Nomura
Research on nutrition and dietary policies using DALY
as an indicator for increasing healthy life. Joint
Research (Ajinomoto Co., Inc.). PI: Shuhei Nomura
Research on cancer risk assessment and prevention
guideline recommendations through active utilizationof the research collaboration infrastructure in Japan andoverseas. (National Cancer Center Research andDevelopment Fund). PI: Shuhei Nomura
Establishing an effective presence at the World Health
Assembly in Japan. Research on Global Health Issues(Ministry of Health, Labour and Welfare). PI: Shuhei
NomuraExposure to air pollution in Japan and its impact on
health and wellbeing (Dyson Technology) PI: Shuhei
NomuraTechnology based innovative solutions for improving
perinatal care utilization: a network meta-analysis(Oxford Policy Management) PI: Rahman Mizanur
Impact of mobile phone short messaging (SMS)intervention on antenatal and delivery care in
Bangladesh: a cluster-randomized controlled trial,
Grant-in-Aid for Scientific Research (Young
Researcher) (Ministry of Education, Culture, Sports,
Science and Technology). PI: Rahman Mizanur
Projections of excess mortality due to climate change- a multi-country environmental epidemiology study.
Grant-in-Aid for Scientific Research (B) (Ministry of
Education, Culture, Sports, Science and Technology)
PI: Masahiro Hashizume
The role of the private health sector in UHC: challenges
and opportunities in Asia,(World Health Organization).
PI: Kenji Shibuya
A comprehensive study of the burden of disease inJapan. Grant-in-Aid for Scientific Research(A)(Ministry of Education, Culture, Sports, Science andTechnology). PI: Kenji Shibuya
Development of health system performance evaluation
methods by prefecture in Japan. Research on Region

313

Medical (Ministry of Health, Labour and Welfare). PI:
Kenji Shibuya
Development and research of strategic and effective
interventions in the field of international health inJapan, based on the analysis of international healthpolicies in each country. Research on Policies for
Global Health Issues (Ministry of Health, Labour andWelfare). PI: Kenji Shibuya

Selected Publications
1. Yoneoka D, Nomura S, Kurotani K, Tanaka S,
Nakamura K, Uneyama H, Hayashi N, Shibuya K.
Does Japan's national nutrient-based dietaryguideline improve lifestyle-related disease
outcomes? A retrospective observational crosssectional study. PLoS ONE. 2019; 14(10):e0224042.
2. Khaing HT, Nomura S, Yoneoka D, Ueda P,
Shibuya K. Risk factors and regional variations ofmalnutrition among children under 5 in Myanmar:cross-sectional analyses at national andsubnational levels. BMJ Open. 2019;9:e030894.
3. Yamamoto K, Nomura S, Tsubokura M, et al.
Internal exposure risk due to radiocesium and theconsuming behaviour of local foodstuffs among
pregnant women in Minamisoma City near the
Fukushima nuclear power plant: a retrospective
observational study. BMJ Open. 2019;9:e023654.
4. Hasegawa M, Murakami M, Nomura S,
Takebayashi Y, Tsubokura M. Worsening Health
Status among Evacuees: Analysis of Medical
Expenditures after the 2011 Great East Japan
Earthquake and Nuclear Disaster in Fukushima.
Tohoku J. Exp. Med. 2019, 248, 115-123
5. Nomura S, Matsuzaki Y, Sato Y, Takasaki J,
Sonoda Y, Shimmura H, Kodama Y. A Comparative
Survival Analysis Between Evacuees andNonevacuees Among Dialysis Patients inFukushima Prefecture After Japan's 2011
Fukushima Nuclear Incident. Disaster Med Public
Health Prep. 2019:1-7.
6. Zhang C, Rahman MS, Rahman MM, Yawson AE, ,Shibuya K. Trends and projections of universal
health coverage indicators in Ghana, 1995-2030: anational and subnational study. PLoS ONE. 2019;14(5): e0209126.
7. Nomura S, Oikawa T, Tsubokura M. Low dosefrom external radiation among returning residents
to the former evacuation zone in Minamisoma City,
Fukushima Prefecture. J Radiol Prot . 2019; 39(2):548–563.
8. Yang JJ, Yu D, Wen W, Saito E, Rahman MS, Shu
XO et al. Association of diabetes with all-cause andcause-specific mortality in Asia: a pooled analysis
of more than 1 million participants. JAMA Netw
Open. 2019;2(4):e192696.
9. Ghaznavi C, Sakamoto H, Yoneka D, Nomura S,
Shibuya K, Ueda P. Trends in heterosexual
inexperience among young adults in Japan:
analysis of national surveys, 1987 - 2015. BMC
Public Health. 2019; 19:355.
10. Yang JJ, Yu D, Wen W, Shu XO, Saito E, Rahman
MS, Gupta et al. Tobacco Smoking and Mortality
in Asia: A Pooled Meta-analysis. JAMA Network
Open. 2019; 2(3), e191474-e191474.
11. Amimo F, Moon TD, Magit A, Sacarlal J, Lambert
B, Nomura S. Trends in comparative efficacy andsafety of malaria control interventions for maternaland child health outcomes in Africa: a study
protocol for a Bayesian network meta-regression
exploring the effect of HIV and malaria endemicity
spectrum. BMJ Open. 2019; 9(2): e024313.
12. Nishikawa Y, Tsubokura M, Takahashi Y, Nomura
S, Ozaki A, Kimura Y, Morita T, Sawano T, Oikawa
T, Nakayama T. Change of access to emergency
care in a repopulated village after the 2011
Fukushima nuclear disaster: a retrospective
observational study. BMJ Open. 2019; 9(2):e023836.
13. Tanaka S, Sawada N, Yamaji T, Goto A, Iwasaki M,
Inoue M, Tsugane S. Female reproductive factors
and risk of lymphoid neoplasm: The Japan Public
Health Center‐based Prospective Study. Cancer
Science. 2019. Online first.
14. Sakamoto H, Lee S, Ishizuka A, Hinoshita E, Hori
H, Ishibashi N, Komada K, Norizuki M, Katsuma
Y, Akashi H, Shibuya K. Challenges andopportunities for eliminating tuberculosis leveraging political momentum of the UN highlevel meeting on tuberculosis. BMC Public Health.
2019;19:76.

314

Department of Community andGlobal HealthProfessor, Academic Leader
Masamine Jimba, MD, PhD, MPH

Assistant Professors
Akira Shibanuma, PhD
Junko Kiriya, PhD
Ken I.C. Ong, PhD

Website: http://www.ich.m.u-tokyo.ac.jp/en/index.html
Introduction and Organization
The Department of Community and Global Health(formerly Department of International Community
Health) has been headed by four professors since
1993: Professors Gen Ohi (1993-1996), Som-Arch
Wongkhomthong (1996-1999), Susumu Wakai (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 developing
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. As
of April 2019, the members of the department include
the department chair and professor, 3 assistantprofessors, 3 secretaries, 12 visiting lecturers, 19
doctoral students, 19 master's degree students, and 38
visiting scientists. More than half of the students inthis department are international students.

International Cooperation
Activities
As part of our international cooperation activities,
we provided technical assistance of developing thematernal and child health handbook in China throughParent and Child Health Handbook Promotion
Association of Japan. As Regional Vice-President for
Northern Part of Western Pacific of International
Union for Health Promotion and Education, Professor
Jimba contributed to enhancing health promotion at
the global and regional level. In addition, as the
President of Asia-Pacific Academic Consortium for
Public Health, Professor Jimba takes a leading role in
improving public health research and practices in theregion.

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.

315

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 assistancein 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
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.

Publications
1. Miller R, Tomita Y, Ong KIC, Shibanuma A,
Jimba M. Mental well-being of internationalmigrants to Japan: a systematic review. BMJ
Open. 2019 Nov 3;9(11):e029988.
2. Carandang RR, Shibanuma A, Kiriya J, Vardeleon
KR, Marges MA, Asis E, Murayama H, Jimba M.
Leadership and Peer Counseling Program:
Evaluation of Training and Its Impact on Filipino
Senior Peer Counselors.Int J Environ Res Public
Health. 2019 Oct 24;16(21).
3. Okitsu S, Khamrin P, Takanashi S, Thongprachum
A, Hoque SA, Takeuchi H, Khan MA, Hasan SMT,
Iwata T, Shimizu H, Jimba M, Hayakawa S,
Maneekarn N, Ushijima H. Molecular detectionof enteric viruses in the stool samples of children
without diarrhea in Bangladesh.Infect Genet Evol.
2019 Oct 17;77:104055.
4. Carandang RR, Asis E, Shibanuma A, Kiriya J,
Murayama H, Jimba M. Unmet Needs and Coping
Mechanisms
Among
Community-Dwelling
Senior Citizens in the Philippines: A Qualitative
Study.Int J Environ Res Public Health. 2019 Oct
4;16(19).
5. Dhital R, Shibanuma A, Miyaguchi M, Kiriya J,
Jimba M. Effect of psycho-social support byteachers on improving mental health and hope ofadolescents in an earthquake-affected district in
Nepal: A cluster randomized controlled trial.PLoS
One. 2019 Oct 1;14(10):e0223046.
6. Jimba
M,
Fujimura
MS,
Ong
KIC.
[Correspondence] Developing country: an
outdated term in The Lancet. Lancet. 2019 Sep
14;394(10202):918.
7. Okawa S, Gyapong M, Leslie H, Shibanuma A,
Kikuchi K, Yeji F, Tawiah C, Addei S, Nanishi K,
Oduro AR, Owusu-Agyei S, Ansah E, Asare GQ,
Yasuoka J, Hodgson A, Jimba M; Ghana
EMBRACE Implementation Research ProjectTeam. Effect of continuum-of-care intervention
package on improving contacts and quality of316

maternal and newborn healthcare in Ghana: acluster randomised controlled trial. BMJ Open.
2019 Sep 11;9(9):e025347.
8. Lin RT, Chien LC, Jimba M, Furuya S, Takahashi
K. Implementation of national policies for a total
asbestos ban: a global comparison.Lancet Planet
Health. 2019 Aug;3(8):e341-e348.
9. Dhital R, Silwal RC, Simkhada P, Teijlingen EV,
Jimba M. Assessing knowledge and behaviouralchanges on maternal and newborn health among
mothers following post-earthquake healthpromotion in Nepal. PLoS One. 2019 Jul 25;
14(7):e0220191.
10. Adjei KK, Kikuchi K, Owusu-Agyei S, Enuameh
Y, Shibanuma A, Ansah EK, Yasuoka J, PokuAsante K, Okawa S, Gyapong M, Tawiah C,
Oduro AR, Sakeah E, Sarpong D, Nanishi K,
Asare GQ, Hodgson A, Jimba M; Ghana
EMBRACE Implementation Research ProjectTeam. Women's overall satisfaction with healthfacility delivery services in Ghana: a mixedmethods study. Trop Med Health. 2019 Jul 5;
47:41.
11. Takeuchi H, Khan MA, Ahmad SM, Hasan SMT,
Alam MJ, Takanashi S, Hore SK, Yeasmin S,
Jimba M, Iwata T. Concurrent decreases in theprevalence of wheezing and Ascaris infection
among 5-year-old children in rural Bangladesh
and their regulatory T cell immunity after the
implementation of a national deworming program.
Immun Inflamm Dis. 2019 Sep;7(3):160-169.
12. Jimba
M,
Fujimura
MS,
Ong
KIC.
[Correspondence] How can we avoid making
universal health coverage a white elephant?
Lancet. 2019 Jun 15;393(10189):2394.
13. Shrestha RM, Ghimire M, Shakya P, Ayer R,
Dhital R, Jimba M. School health and nutrition
program implementation, impact, and challenges
in schools of Nepal: stakeholders' perceptions.
Trop Med Health. 2019 May 14;47:32.
14. Kosugi H, Shibanuma A, Kiriya J, Wafula SW,
Jimba M. Consistent condom use among highly
effective contraceptive users in an HIV-endemic
area in rural Kenya. PLoS One. 2019 May
6;14(5):e0216208.
15. Okawa S, Win HH, Leslie HH, Nanishi K,
Shibanuma A, Aye PP, Jimba M. Quality gap inmaternal and newborn healthcare: a crosssectional study in Myanmar. BMJ Glob Health.
2019 Mar 19;4(2):e001078.
16. Sakuma S, Yasuoka J, Phongluxa K, Jimba M.
Determinants of continuum of care for maternal,
newborn, and child health services in rural
Khammouane, Lao PDR. PLoS One. 2019 Apr 23;
14(4):e0215635.
17. Saw YM, Than TM, Thaung Y, Aung S, WenShuan Shiao L, Win EM, Khaing M, Tun NA,
Iriyama S, Win HH, Sakisaka K, Jimba M,
Hamajima N, Saw TN. Myanmar's humanresources for health: current situation and its
challenges. Heliyon. 2019 Mar 27;5(3):e01390.
18. Okawa S, Win HH, Leslie HH, Nanishi K,
Shibanuma A, Aye PP, Jimba M. Quality gap inmaternal and newborn healthcare: a crosssectional study in Myanmar. BMJ Glob Health.
2019 Mar 19;4(2):e001078.
19. Okawa S, Win HH, Nanishi K, Shibanuma A, Aye
PP, Saw TN, Jimba M. Advice on healthy
pregnancy, delivery, motherhood and information
on non-communicable diseases in the maternalcare programme in Myanmar: a cross-sectional
study. BMJ Open. 2019 Mar 30;9(3):e025186.
20. Sarhan BAM, Kitamura A, Fujiya R, Jimba M,
Giacaman R. Perceptions of adolescent healthliteracy in the Palestinian social context: aqualitative study. Japanese Journal of Health
Education and Promotion. 2019;27(1):29-42.
21. Ong KIC, Iwagami M, Araki H, Khattignavong P,
Soundala P, Keomalaphet S, Prasayasith P,
Lorpachan L, Xangsayalath P, Pongvongsa T,
Hongvanthong B, Brey PT, Kano S, Jimba M.
Prevalence of G6PD Viangchan variant in malaria
endemic areas in Lao PDR: an implication formalaria elimination by 2030. Malar J. 2019 Mar
12;18(1):75.
22. Yasukawa K, Sawada T, Hashimoto H, Jimba M.
[Correspondence] Health-care disparities forforeign residents in Japan. Lancet. 2019 Mar 2;
393(10174):873-874.
23. Pokhrel KN, Pokhrel KG, Sharma VD, Poudel KC,
Neupane SR, Mlunde LB, Jimba M. Mental healthdisorders and substance use among people livingwith HIV in Nepal: their influence on nonadherence to anti-retroviral therapy. AIDS Care.

3172019 Mar 5:1-9.
24. Carandang RR, Shibanuma A, Kiriya J, Asis E,
Chavez DC, Meana M, Murayama H, Jimba M.
Determinants of depressive symptoms in Filipino
senior citizens of the community-based ENGAGE
study. Arch Gerontol Geriatr. 2019 Feb 19; 82:
186-191.
25. Takahashi K, Jimba M .In Memoriam: Professor
Takusei Umenai (1941-2018): Hi, Let's Create a
Novel Paradigm for Health Science! Asia Pac J
Public Health. 2019 Feb 22:1010539519832477.
26. Thandar MM, Kiriya J, Shibanuma A, Ong KIC,
Tin KN, Win HH, Jimba M. Women's knowledge
on common non-communicable diseases andnutritional need during pregnancy in threetownships of Ayeyarwaddy region, Myanmar: across-sectional study. Trop Med Health. 2019 Jan
29;47:12.
27. Natukunda J, Kirabira P, Ong KIC, Shibanuma A,
Jimba M. Virologic failure in HIV-positiveadolescents with perfect adherence in Uganda: across-sectional study. Trop Med Health. 2019;
47:8.
28. Shrestha S, Shibanuma A, Poudel KC, Nanishi K,
Koyama Abe M, Shakya SK, Jimba M. Perceived
social support, coping, and stigma on the qualityof life of people living with HIV in Nepal: amoderated mediation analysis. AIDS Care. 2019;31(4):413-420.

International Health
2. International Biomedical Sciences

319

Department of Human Genetics
Professor
Akihiro Fujimoto, Ph.D.

Assistant professor
Mihoko Shimada, Ph.D.

Project Assistant researcher
James WONG Jing Hao, Ph.D.、Saeideh ASHOURI, Ph.D.

Homepage

http://www.humgenet.m.u-tokyo.ac.jp/index.html

Introduction and Organization
The Department of Human Genetics wasestablished in 1992. Currently, the department has 1
professor, 1 assistant professor, 2 research associate, 2
graduate student, 3 undergraduate students, and 2
research assistants/technicians. We also accept a few
graduate students from other Universities for their
PhD studies.

Teaching activities
For students at the Graduate School of International
Health, courses that cover basic principles as well as
the clinical application of human genetics areprovided.
As to undergraduate students, a series of lectures isgiven to each of the sophomore (Human Genetics I,
compulsory) and junior (Human Genetics II, elective)classes at the School of Health Sciences. A series oflectures is also provided to the first year (M0) students
at the School of Medicine (compulsory).

Research activities
Human Genetics is a field focusing on the diversityof the human genome, and can include studies into themolecular mechanisms of genetics, evolutionary
history of homo sapiens, cancer genome, as well as
susceptibility genes for common and rare diseases.
The findings of such genetic studies have provenuseful in many applications, from supporting clinicaldiagnosis of diseases to drug development and therapy.
Recent advancements in genomic analyses haveallowed us to obtain enormous amounts of genetic andtranscriptomic data. Such data will continue to growin size and utilization in society, reflecting theincreasing importance of the field of human genetics.
Our department dives headlong into analyses ofgenomic, transcriptomic and epigenomic data toevaluate diversity in the human genome, as well as
identifying variants and elucidating their functional
importance and potential therapeutic applications. Our
approach is holistic, focusing not only on data analysis,
but also on practical experiments to reach our goal of
uncovering new knowledge.

References
1. Fujimoto A*, Fujita M, Hasegawa T, Wong JH,
Maejima K, Oku-Sasaki A, Nakano K, Shiraishi Y,
Miyano S, Yamamoto G, Akagi K, Imoto S, andNakagawa H (2020) Comprehensive Analysis ofIndels in Whole-genome Microsatellite Regions
and Microsatellite Instability across 21 Cancer
Types. Genome Research 30:334–34
2. The ICGC/TCGA Pan-Cancer Analysis of Whole
Genomes Consortium. (2020) Pan-cancer analysisof whole genomes. Nature 578: 82-93.
3. Shimada M, Miyagawa T, Takeshima A, Kakita A,
Toyoda H, Niizato K, Oshima K, Tokunaga K, andHonda M (2020) Epigenome-wide association
study of narcolepsy-affected lateral hypothalamic

320

brains, and overlapping DNA methylation profiles
between narcolepsy and multiple sclerosis. Sleep
43.
4. Mizuno K, Akamatsu S, Sumiyoshi T, Wong J1.
Mizuno K, Akamatsu S, Sumiyoshi T, Wong JH,
Fujita M, Maejima K, Nakano K, Ono A, Aikata
H, Ueno M, Hayami S, Yamaue H, Chayama K,
Inoue T, Ogawa O, Nakagawa H and Fujimoto A*(2019) eVIDENCE: a practical variant filtering
for low-frequency variants detection in cell-freeDNA. Sci Rep 9: 15017
5. Wong JH, Shigemizu D, Yoshii Y, Akiyama S,
Tanaka A, Nakagawa H, Narumiya S, Fujimoto
A* (2019) Identification of intermediate-sized
deletions and inference of their impact on gene
expression in a human population. Genome
Medicine 11:44

321

Department of Developmental
Medical Sciences
Professor
Masashi Mizuguchi, M.D., Ph.D.

Associate Professor
Teruyuki Tanaka, M.D., Ph.D.

Research Associate
Sayaka Takanashi, M.D., Ph.D.

Homepage

Ai Hoshino, M.D., Ph.D.

http://www.sih.m.u-tokyo.ac.jp/devt.html

Introduction and Organization
Founded in 1966 as the Department of Maternal andChild Health, our department was the first one
established in Japan. With the subsequent expansionof research activities and the foundation of the
Graduate School of Medicine, it was renamed in 1998
as the Department of Developmental Medical
Sciences. Up to now, it has been engaged in experimental and epidemiologic studies to provide thescientific bases for all the activities to promote thephysical and mental health of mothers and children.
The experimental studies include those on the nervousand endocrine systems, infection, immunity andmetabolism, whereas the epidemiologic studies deal
with development, mother-to-child relationship,vaccination and health promotion. In 2007, joined by
new members, the department has entered a new era,putting more emphasis than ever on the research on
developmental disorders of the human nervous
system.
At present, our department consists of one professor,
one associate professor, two research associates, one
assistant clerk, one technical assistant, seventeen
visiting lecturers, fifteen visiting researchers, andeight graduate students (including one overseas
student) and one research student.
Our department gives lectures to undergraduate andpostgraduate students, have weekly meetings of thewhole department and of individual research groups,
communicate with other investigators inside oroutside the University of Tokyo, and have seminars
and meetings with researchers invited from abroad.
We have collaborated with many laboratories in the
United States, Canada, Brazil, Italy, Greece, China,
Taiwan, Korea, Thailand, Viet Nam, Laos, Malaysia,
Myanmar, Indonesia, Bangladesh, Pakistan, Sri Lanka
and Australia, in order to promote the mothers’ andchildren’s health all over the world. We also haveaccepted many young students from these countries,
for the purpose of bringing up professionals whoeither perform medical research or lead local healthpolicies.

Teaching activities
1. Undergraduate course, Faculty of Medicine, Schoolof Integrated Health Sciences
1) Human growth and development
2) Immunity and defense mechanism3) Infectious diseases
4) Topics in life and environmental sciences
5) Maternal and child health6) School health7) International health8) Experiments in life sciences
9) Exercises in life sciences

32210) Introduction to general health science
2. Graduate course, the Graduate School of Medicine,
School of International HealthIn addition to lectures and laboratory courses by ourown staff, special lectures are given by experts both
inside and outside the University.

Research activities(1) Clinical, genetic and pathologic studies of acuteencephalopathy: Acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures
and late reduced diffusion, acute encephalitis
with refractory, repetitive partial seizures, andclinically mild encephalitis/encephalopathy witha reversible splenial lesion.
(2) Pharmacological studies on the pathogenesis andtreatment of developmental disorders, such as
autism spectrum disorder and attention deficit/
hyperactivity disorder, using genetically engineered animals.
(3) Medical genetic studies on congenital anomalies
caused by abnormal intracellular signal transduction, such as tuberous sclerosis, Noonan
syndrome and Ellis-van Creveld syndrome.
(4) Molecular pathologic and translational studies onchildhood intractable epilepsy and developmental
disorders, such as CDKL5 deficiency disorder,using genetically engineered animals.
(5) Molecular genetic and cell biologic studies
combined with post-genomic approaches on molecules regulating neuronal migration, such as
Doublecortin and Cdk5.
(6) Studies on the nutrition, immunity, brain andepigenetics of human fetuses and neonates.
(7) International studies on the maternal and childhealth.
(8) Studies on the virulence, drug resistance andvaccines of herpesviruses and poxviruses.
(9) Molecular epidemiology of pediatric viral
infections, in particular gastrointestinal diseases(rotavirus, norovirus, sapovirus and bocavirus),
respiratory infections (influenza, RS virus andrhinovirus), exanthematous diseases (rubella) andHIV infection.

References
1. Fujii H, Harada S, Yoshikawa T, Yamada S,
Omura N, Shibamura M, Inagaki T, Kato H,
Hukushi S, Saijo M. Differences in the likelihoodof acyclovir resistance-associated mutations in thethymidine kinase genes of herpes simplex virus 1
and varicella-zoster virus. Antimicrobial Agentsand Chemotherapy 2019; 63(5): e00017-19.
2. Hoque SA, Iizuka I, Kobayashi M, Takanashi S,
Anwar KS, Islam MT, Hoque SA, Khamrin P,
Okitsu S, Hayakawa S, Ushijima H. Determining
effectiveness of rotavirus vaccine by immunechromatography and reverse transcriptase polymerase chain reaction: A comparison. Vaccine
2019; 37(39): 5886-5890.
3. Hoque SA, Thongprachum A, Takanashi S,
Mostafa SM, Saito H, Anwar KS, Nomura A,
Hoque SA, Begum R, Sultana UN, Hossain T,
Khamrin P, Okitsu S, Hayakawa S, Ushijima H.
Alarming situation of spreading enteric viruses
through sewage water in Dhaka city: Molecularepidemiological evidences. Food and Environmental Virology 2019; 11(1): 65-75.
4. Kaneko M, Takanashi S, Inoue M, Sakiyama H,
Okitsu S, Mizuguchi M, Ushijima H.
Detectionof mutations in the VP7 gene of vaccine-derived
strains shed by monovalent rotavirus vaccine
recipients. Access Microbiology 2019; acmi.0.
000033
5. Kawata K, Hikita T, Takanashi S, Hikita H, Ogita
K, Okitsu S, Hoque SA, Phan TG, Ushijima H.
Diagnosis of acute gastroenteritis with immunechromatography and effectiveness of rotavirus
vaccine in a Japanese clinic. Access Microbiology
2019; acmi.0.000085.
6. Kobayashi Y, Kanazawa H, Hoshino A,
Takamatsu R, Watanabe R, Hoshi K, Ishii W,
Yahikozawa H, Mizuguchi M, Sato S. Acutenecrotizing encephalopathy and a carnitine
palmitoyltransferase 2 variant in an adult. Journalof Clinical Neuroscience 2019; 61: 264-266.
7. Kondo T, Niida Y, Mizuguchi M, Nagasaki Y,
Ueno Y, Nishimura A. Autopsy case of rightventricular rhabdomyoma in tuberous sclerosis
complex. Legal Medicine (Tokyo). 2019; 36:
37-40.

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8. Mizuguchi M, Ikeda H, Kagitani-Shimono K,
Yoshinaga H, Suzuki Y, Aoki M, Endo M,
Yonemura M, Kubota M. Everolimus for epilepsy
and autism spectrum disorder in tuberous sclerosis
complex: EXIST-3 substudy in Japan. Brain andDevelopment 2019; 41(1): 1-10.
9. Nguyen TQN, Doan NMT, Trinh HT, Mizuguchi
M. Novel mutation in EFCAB7 alters expression
and interaction of Ellis-van Creveld ciliary
proteins. Congenital Anomalies (Kyoto). 2019;59(2): 49-50.
10. OkitsuS,
KhamrinP,
Takanashi
S,
Thongprachum A, Hoque SA, Takeuchi H, Khan
MA, Hasan SMT, Iwata T, Shimizu H, Jimba M,
Hayakawa S, Maneekarn N, Ushijima H.
Molecular detection of enteric viruses in the stool
samples of children without diarrhea in
Bangladesh. Infection, Genetics and Evolution
2020; 77: 104055.
11. Shibata A, Kasai M, Hoshino A, Miyagawa T,
Matsumoto H, Yamanaka G, Kikuchi K, Kuki I,
Kumakura A, Hara S, Shiihara T, Yamazaki S,
Ohta M, Yamagata T, Takanashi JI, Kubota M,
Oka A, Mizuguchi M. Thermolabile polymorphism of carnitine palmitoyltransferase 2: A
genetic risk factor of overall acute encephalopathy.
Brain and Development 2019; 41(10): 862 -869.
12. Takeuchi H, Khan MA, Zaman K, Takanashi S,
Hasan SMT, Yunus M, Iwata T. Classification ofwheezing children in rural Bangladesh byintensity of Ascaris infection, total and specificIgE levels, history of pneumonia, and other risk
factors. Journal of Immunology Research 2019;2019: 4236825.
13. Takeuchi H, Khan MA, Ahmad SM, Hasan SMT,
Alam MJ, Takanashi S, Hore SK, Yeasmin S,
Jimba M, Iwata T. Concurrent decreases in theprevalence of wheezing and Ascaris infection
among 5-year-old children in rural Bangladesh
and their regulatory T cell immunity after the
implementation of a national deworming program.
Immunity, Inflammation and Disease 2019; 7(3):160-169.
14. Vlasova AN, Takanashi S, Miyazaki A,
Rajashekara G, Saif LJ. How the gut microbiome
regulates immune responses to viral vaccines.
Current Opinion in Virology 2019; 37: 16-25.

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Department of Human Ecology
Professor
Masahiro UMEZAKI, Ph.D.

Associate Professor
Shoko KONISHI, Ph.D.

Research Associates
Satoko KOSAKA, Ph.D.
Lena TAKAYASU, Ph.D.

Homepage: http://www.humeco.m.u-tokyo.ac.jp/en/
Introduction and Organization
The Department of Human Ecology was founded when
Kenji Uraguchi was appointed to the professorship of the
Human Ecology Department on April 1, 1965. Following
the retirement of Professor Uraguchi as of March 31,
1966, Professor Haruo Katsunuma (also appointed as
professor of the Public Health Department, School of
Medicine) became a joint professor of the Human
Ecology Department. Tsuguyoshi Suzuki was appointed
as an associate professor and worked in the Departmentt
until August 31, 1971, when he was transferred to the
Faculty of Medicine, Tohoku University, as a professor.
After Professor Katsunuma left the Departmentnt on
March 31, 1972, Professor Akira Koizumi became thehead of the Human Ecology Department on April 1, 1972.
Professor Koizumi was transferred to the Public Healthprogram, School of Medicine on March 31, 1976, andAssociate Professor Shosuke Suzuki served as a
Department head from April 1, 1976 to April 15, 1979.
Tsuguyoshi Suzuki was appointed as a professor of the
Human Ecology program as of April 16, 1979. He
founded the theoretical framework of the current humanecology curriculum, which is based on studying theadaptation mechanisms of humans to the environment.
After Associate Professor Shosuke Suzuki was transferredto the Faculty of Medicine, Gunma University, as
professor on July 31, 1981, Ryutaro Ohtsuka was
appointed as an associate professor on September 1 of thesame year. Associate professor Ohtsuka established themethodology of collecting quantitative information on
demography, nutrition, and subsistence targeting smallscale populations based on extensive fieldwork, themethodology of which continues to be utilized by current
Department members. Following the retirement ofProfessor Tsuguyoshi Suzuki on March 31, 1992, Ryutaro
Ohtsuka was appointed as a professor as of April 1 of thesame year.
Chiho Watanabe was appointed as an associate
professor in December 1997. He expanded methodologies
that examine relations between the environment andhealth by utilizing various tools, such as measuringbiomarkers in biological specimens collected in the field
and animal experiments. Professor Ohtsuka retired on
March 31, 2005, and Chiho Watanabe was appointed as aprofessor as of April 1, 2005. Masahiro Umezaki was
appointed as an associate professor in August 2005. While
relying on quantitative research based on fieldwork, he
has also been exploring new research topics, including theapplication of spatial information sciences on healthsciences, the roles of gut microbiota in human nutrition,
mitigation/alleviation strategies of depopulation andaging in human populations, and medical anthropology.
Professor Chiho Watanabe was transferred from the
University of Tokyo to the National Institute ofEnvironmental Studies as of April 1, 2017. Masahiro
Umezaki was appointed as a professor as of January 1,
2018. Shoko Konishi was appointed as an associate

325

professor as of June 1, 2018. Dr. Konishi has been
studying the associations between fecundity and fertility
and environmental factors from the perspectives of
population studies, environmental sciences, anthropology,
and sociology.
In fiscal year 2019, the Departmentt had four faculty
members: Drs. Umezaki, Konishi, Kosaka, and Takayasu.
The Department also had 14 extra-university lecturersdelivering lectures in either graduate or undergraduate
courses. Professor Umezaki held additional roles in the
Network for Education and Research in Asia (ASNET) as
well as in the Earth Observation Data Integration and
Fusion Research Initiative (EDITORIA) at the Universityof Tokyo.

Teaching activities
The Department is one of the six Departments of the
School of International Health. Human Ecology Special
Lecture I focuses on the basic components of humanecology, such as demography, nutrition, and environment,
and introduces the notion of human ecosystems. In
Human Ecology Special Lecture II, the emphasis is on
recent topics and ongoing research in the field of humanecology and related areas. With these classes for graduate
students, we attempt to describe human ecology as a basic
component of international health, and provide examplesof the recent issues that have been dealt with andapproaches used in this field. Graduate course lectures are
given in English.
The Department is in charge of a part of the School ofIntegrated Health Sciences, providing undergraduate
course lectures on Human Ecology, Environment and
Health, Demography, International Health, and Medical
Anthropology. We are also responsible for organizing
Pharmacology and Toxicology, Physiology, andEnvironmental Engineering/Human Engineering. At theundergraduate level, our emphasis is on introducing
global-scale issues, such as population explosion, foodsecurity, and environmental issues, in relation to the
problems that the Asia-Pacific region (including Japan)
has been facing. Another emphasis is on the relation
between human activities and chemical contamination of
the environment.

Research activities
Human ecology is the understanding of the humanpopulation in the context of their respective ecology as
well as in the global context. Most of our research tackles
the tasks in the field of Environmental Health and/or
Population Ecology [of humans], but with a morecomprehensive and broader context. Therefore, we needto adopt different approaches, including fieldwork,
experimentation, and GIS (Geographic Information
System)/GPS (Global Positioning System) analyses. Our
study fields include Asian-Oceanian (including Japan)
rural and urban communities, focusing on population,
nutrition, growth, environment, and sustainability.
Experimental studies on the effects of perinatal exposure
to heavy metals have been conducted, emphasizing thefactors that modify these effects. Almost all our studies
require a transdisciplinary approach. As such, we arecollaborating with various local and international research
institutes. The following is a list of major activities
conducted in the past year.
1. Adaptation to low-protein diet
The inconsistency between Papua New Guinea
highlanders’ protein-deficient diet and their muscularphysique is well known. Moreover, although theirprotein intake is less than biologically adequate,
disorders related to protein deficiency have rarely beenreported in this setting. We have speculated that the
population has adapted to a low-protein diet by utilizing
air nitrogen fixed by intestinal bacteria and/or byintensive “recycling” of the urea that passes into thegastrointestinal tract. Recent advances in sequencing
techniques have enabled us to examine the unsolved
question of Papua New Guinea highlanders’ adaptation
to a low-protein diet in a more direct way. In our
project, we evaluated the gut microbiota of healthy
individuals in four Papua New Guinea communities
with different degrees of protein deficiency. The
association between gut microbiota and variation inprotein intake and nutritional biomarkers wasinvestigated. Shotgun metagenomic analysis further
demonstrated that some genes related to nitrogen
fixation and urease are enriched in Papua New Guinea
communities compared with other countries.
Gnotobiotic animal experiments revealed different
nutritional responses to a low-protein diet depending on

326

the type of gut microbiota transplanted.
2. Adaptive strategy to aging and depopulation
Japan is one of the countries experiencing postdemographic transition (i.e., low fertility, aging, andpopulation decrease). Targeting Japanese ruralcommunities, the front-runners of this global issue, we
conducted population projection and studies on theirfood habits, nutritional intake, and subjective
perceptions of health. We also conducted a study toidentify mitigation and alleviation strategies against
aging and depopulation that have been formulated inlocal communities.
3. Nutrition and eating behaviors in Indonesia
We have been conducting field surveys every year in
the same villages in West Java, Indonesia. In 2019, we
conducted an interview survey with a questionnaire on
food insecurity, as well as updated the basic
information of the households in the village. In
addition, we obtained the growth records of children
and analyzed them.
4. Interdisciplinary Investigation on the Technology, theEnvironment, and Fertility
Japan has the highest number of assisted
reproductive technology use in the world. Our ongoingproject is testing a hypothesis that exposure totechnology and environmental chemicals are both linked
to increasing infertility in the country.
5. Health transition in Lao People’s Democratic
Republic
Diet in the northern parts of Laos has beencharacterized by consumption of large amounts of ricewith dishes made of wild plants. Wild plants of bitterand even astringent taste, which are supposed tocontain more phytochemicals, are preferred overdomesticated vegetables. It has been suspected thatphytochemicals have roles in nutritional adaptation
among the local people through interactions withintestinal bacteria. As the people have gradually been
involved in the market economy, their diet has changed
toward more consumption of animal meat and oil andless consumption of phytochemicals. We initiated a
research project to investigate the potential healthimpact of such dietary changes in Northern Laos. The

questionnaire survey and sampling of biological
specimens were conducted in three communities in
Oudomxay Province (one peri-urban and two farming
communities). By evaluating biomarkers of oxidative
stress, chronic inflammation, and gut microbiota
composition in three communities at different levels ofmodernization, we sought to clarify the biological link
between dietary transition and the recent emergence of
non-communicable diseases in rural Laos.
6. Potential fetal microbiome transfer from intrauterine
exposure
Mounting evidence of bacteria in fertilization
products analyzed using DNA-based technologies ischallenging the sterile womb hypothesis. We conducted
cultivation-based and 16S rRNA sequence analyses
using a mouse model in mid and late gestation thatsuggested the presence of bacteria in fetal, placental,
and uterine tissues. This low-abundance fetal
microbiome appears to be volatile and transient innature, in contrast to the relatively stable bacterial
composition that matures during infancy. The similarity
between the bacterial compositions of maternal andfetal tissues suggests a vertical transmission that has
also been previously described in other animals andgerm-free animal models. The existence of this fetal
microbiome is hypothesized to be associated withimmunocompetence in the mother and development of
immunity in the fetus.
7. Child undernutrition in Cebu, Philippines
Focusing on school children in vulnerable
communities, we investigated factors associated with
the nutritional status of children in a rural municipality
in Cebu, Philippines. Children aged 6–12 years and theirparents were asked to participate. The results showeda high prevalence of stunting and underweight in thiscommunity. Children’s nutritional status was associatedwith household income and size, parents’ nutritional
status, and severe food insecurity.
8. Mouse gut microbiome transitions
Gut microbiome and aging have been discussed
based on the average flora of people of different ages.
Meanwhile, few studies have been conducted on the
microbiome of the same individual over a long period oftime. We conducted experiments on mice from shortly

327

after birth to just before death to determine the changes
in gut microbiome related to pregnancy and lifespan.

References
1. Horwood PF, Tarantola A, Navarro S,Goarant C,
Matsui M, Klement E et al. Health challenges of the
Pacific region: Insights from history, geography,social determinants, genetics and the microbiome.
Front Immunol. 1999. doi: 10.3389/fimmu.2019.
02184
2. Wai KM, Umezaki M, Mar O, Umemura M, Chiho
Watanabe. Arsenic exposure through drinking waterand oxidative stress status: A cross-sectional study in
Ayeyarwaddy region, Myanmar. J Trace Elem Med
Biol. 2019;54:103-9.
3. Wai KM, Ser PH, Ahmad SA, Yasmin R, Ito Y,
Konishi S et al. In-utero arsenic exposure and growthof infants from birth to 6 months of age: a prospective
cohort study in rural Bangladesh. Int J Environ HealthRes. 2019;1-14.
4. Mizuno Y, Konishi S, Imai H, Fujimori E, Kojima N,
Yoshinaga J. Cadmium exposure and blood telomere
length in female university students in Japan. Biol
Trace Elem Res. 2019;192:98-105.
5. Khan R, Konishi S, Ng CFS, Umezaki M, Kabir AF,
Tasmin S, Watanabe C. Association between shortterm exposure to fine particulate matter and daily
emergency room visits at a cardiovascular hospital in
Dhaka, Bangladesh. Sci Total Environ. 2019;646:
1030-6.

328

Department of
Biomedical Chemistry
Professor
Tomoyoshi Nozaki, Ph.D., MD

Associate Professor
Yoh-ichi Watanabe, Ph.D.

Assistant Professor
Jeelani Ghulam, Ph.D., Santos Herbert Jimenez, Ph.D.

Homepage

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

Introduction and Organization
Aim of our department is to contribute to global
health and welfare from basic research. Our department, formerly named Biochemistry and Nutrition
was renamed on April 1st, 1996 to The Department of
Biomedical Chemistry as newly affiliating with
Biomedical Science Division of International Health,Graduate School of Medicine, The University ofTokyo. Former Prof. Kiyoshi Kita (Professor
Emeritus) has been retired in March 2016, and Dr.
Tomoyoshi Nozaki, National Institute of Infectious
Diseases, has been assigned as a new professor in
October, 2016, and became a full-time processor in
August, 2017.

Teaching activities
Teaching activities in our department cover a broad
spectrum of biochemistry-oriented life sciences frompremise to frontiers and in either conceptual orexperimental point of view
Graduate Course: Biomedical Chemistry I, IIThis course is comprised of lectures and seminars toprovide basic concepts and newer vistas for understanding biomedical chemistry with special reference
to biochemistry and molecular biology. These include
the structure and function of biomolecules, metabo-lism, its regulation, and underlying mechanism ateither molecular, cellular and systemic level.
Undergraduate Course: Basic Life Science, Life
Science and Genome Science I & II, Nutrition,
Laboratory Practice for Life Science Ⅰ& II, Seminarin Environmental and Human Life Sciences,
Microbiology II (Parasitology).

Research activities
Our major research interests include virulencemechanisms and metabolism of protozoa, particularly
Plasmodium spp. causing malaria and Entamoeba
histolytica causing amebic dysentery. We mainly focus
on vesicular trafficking, phagocytosis, autophagy,proteases, amino acid metabolisms, RNA maturation,translation, drug development, and organellogenesis.
Our research approaches are very robust, and include
biochemistry, molecular and cell biology, live imaging,
multi-omics including metabolomics, and reverse
genetics. Our present research themes include: Molecular elucidation of pathogenesis of parasites
 Biochemical and biological analyses of metabolism and organelles unique to parasites
 Analysis of vesicular traffic, protein secretion, andphagocytosis/trogocytosis in parasites
 Genome wide analysis and comparison of parasite
strains

329

 Drug discovery and development against protozoan
infections such as malaria and amebiasis
 Elucidation of divergence of RNA maturation andtranslation

References
1. Nakada-Tsukui K, Watanabe N, Maehama T,
Nozaki T. Phosphatidylinositol Kinases and Phosphatases in Entamoeba histolytica. Front Cell InfectMicrobiol. 2019 Jun 6;9:150. doi: 10.3389/fcimb.
2019.00150. PMID: 31245297; PMCID: PMC
6563779.
2. Wang X, Miyazaki Y, Inaoka DK, Hartuti ED,
Watanabe YI, Shiba T, Harada S, Saimoto H,
Burrows JN, Benito FJG, Nozaki T, Kita K.
Identification of Plasmodium falciparum Mitochondrial Malate: Quinone Oxidoreductase Inhibitorsfrom the Pathogen Box. Genes (Basel). 2019 Jun 21;
10(6):471. doi: 10.3390/genes10060471. PMID:
31234346; PMCID: PMC6627850.
3. Araki T, Kawai S, Kakuta S, Kobayashi H, Umeki
Y, Saito-Nakano Y, Sasaki T, Nagamune K,
Yasutomi Y, Nozaki T, Franke-Fayard B, Khan SM,
Hisaeda H, Annoura T. Three-dimensional electron
microscopy analysis reveals endopolygeny-like
nuclear architecture segregation in Plasmodium
oocyst development. Parasitol Int. 2020 Jun;76:102034. doi: 10.1016/j.parint.2019.102034. Epub
2019 Dec 2. PMID: 31805442.
4. Watanabe N, Nakada-Tsukui K, Nozaki T. Twoisotypes of phosphatidylinositol 3-phosphatebinding sorting nexins play distinct roles introgocytosis in Entamoeba histolytica. Cell
Microbiol. 2020 Mar;22(3):e13144. doi: 10.1111/
cmi.13144. Epub 2019 Dec 1. PMID: 31713312;
PMCID: PMC7027479.
5. Yanagawa Y, Arisaka T, Kawai S, Nakada-Tsukui
K, Fukushima A, Hiraishi H, Chigusa Y, Gatanaga
H, Oka S, Nozaki T, Watanabe K. Case Report:
Acute Amebic Colitis Triggered by Colonoscopy:
Exacerbation of Asymptomatic Chronic Infection
with Entamoeba histolytica Accompanied by
Dysbiosis. Am J Trop Med Hyg. 2019 Dec;101(6):1384-1387. doi: 10.4269/ajtmh.19-0396. PMID:
31595870; PMCID: PMC6896890.

6. Tomii K, Santos HJ, Nozaki T. Genome-WideAnalysis of Known and Potential Tetraspanins in
Entamoeba histolytica. Genes (Basel). 2019 Nov 3;
10(11):885. doi: 10.3390/genes10110885. PMID:
31684194; PMCID: PMC6895871.
7. Ozaki K, Iwasaki A, Sezawa D, Fujimura H, Nozaki
T, Saito-Nakano Y, Suenaga K, Teruya T. Isolation
and Total Synthesis of Mabuniamide, a Lipopeptide
from an Okeania sp. Marine Cyanobacterium. J Nat
Prod. 2019 Oct 25;82(10):2907-2915. doi: 10.1021/
acs.jnatprod.9b00749. Epub 2019 Sep 24. PMID:
31549837.
8. Santos HJ, Hanadate Y, Imai K, Nozaki T. An
Entamoeba-Specific Mitosomal Membrane Proteinwith Potential Association to the Golgi Apparatus.
Genes (Basel). 2019 May 13;10(5):367. doi: 10.
3390/genes10050367. PMID: 31086122; PMCID:
PMC6563013.
9. Santos HJ, Imai K, Makiuchi T, Tomii K, Horton P,
Nozawa A, Okada K, Tozawa Y, Nozaki T. Novellineage-specific transmembrane β-barrel proteins in
the endoplasmic reticulum of Entamoeba histolytica.
FEBS J. 2019 Sep;286(17):3416-3432. doi: 10.
1111/febs.14870. Epub 2019 May 20. PMID:
31045303.
10. Balogun EO, Inaoka DK, Shiba T, Tsuge C, May B,
Sato T, Kido Y, Nara T, Aoki T, Honma T, Tanaka
A, Inoue M, Matsuoka S, Michels PAM, Watanabe
YI, Moore AL, Harada S, Kita K. Discovery oftrypanocidal coumarins with dual inhibition of both
the glycerol kinase and alternative oxidase of
Trypanosoma brucei brucei. FASEB J. 2019 Nov;
33(11):13002-13013. doi: 10.1096/fj.201901342R.
Epub 2019 Sep 16. PMID: 31525300.

School of Public Health
1. Epidemiology and Health Sciences

331

Department of Social andPreventive Epidemiology
Professor
Satoshi Sasaki, M.D., Ph.D.

Associate
Kentaro Murakami, Ph.D.

Homepage

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

Introduction and Organization
The Department of Social and Preventive Epidemiology is a new department which was established at
the same time of the establishment of the School of
Public Health, the University of Tokyo (April 2007).
Epidemiology is a study of quantitatively assessing
health status and disease development in populations
and statistically analyzing the relationship of risk
factors with the development of certain disease. In
addition to traditional risk factors including alcohol
drinking, smoking, nutrition, and physical activity,
gene and factors controlling gene and socioeconomic
factors are also important topics in epidemiologic
research. Epidemiologic data are needed for
conducting the assessment of certain treatment
including medicine and estimating situation of diseasedevelopment.
Epidemiology not only provides research methodology in the field of public health but also is
considered a practical study for public health and thus
a central field of health science. However, botheducation and research systems have long been
insufficient in Japan.
Social and preventive epidemiology is a study of
epidemiologically clarifying the relationship between
various phenomena in human society (including
individual lifestyle) and certain disease.
The Department of Social and Preventive Epidemiology particularly focuses on nutrition, which isessential for individual and population health, as amain research topic and epidemiologically researches
various issues related to nutrition (nutritional epidemiology), playing a central role in this research field inJapan.
The Department currently consists of one professor
and one associate.

Teaching activities
We have the following two lectures in the School of
Public Health.
Epidemiological research and practice
Practice and assessment in public health
Both are strongly associated with practical tasks inpublic health field, aiming at giving students opportunities for acquiring abilities of conducting publichealth activities and tasks based on theory of
epidemiology.
We have also several lectures for students in otherschools.

Research activities
Our main topic is basic research for development andapplication of research methodology in the field of
nutritional epidemiology. Based on this basic research,
we also conduct a wide range of epidemiologic
research for investigating the relationship of nutrition
with health and disease. As a characteristic of thisresearch field, we conduct many multi-center studies

332with various kinds of disease.
Another characteristic is collection of researchfindings (scientific papers) derived from epidemiologic research all over the world on the association ofnutrition with health and disease, which is applied for
health control through nutrition improvement anddisease control.

References
1. Murakami K, Livingstone MB, Sasaki S. Diet
quality scores in relation to metabolic risk factors inJapanese adults: a cross-sectional analysis from the2012 National Health and Nutrition Survey, Japan.
Eur J Nutr 2019; 58(5): 2037-50.
2. Murakami K, Livingstone MB, Sasaki S. Mealspecific dietary patterns and their contribution to
overall dietary patterns in the Japanese context:
findings from the 2012 National Health andNutrition Survey, Japan. Nutrition 2019; 59: 108115.
3. Kobayashi S, Yuan X, Sasaki S, Osawa Y, Hirata T,
Abe Y, Takayama M, Arai Y, Masui Y, Ishizaki T.
Relative validity of brief-type self-administered diethistory questionnaire among very old Japanese aged
80 years or older. Public Health Nutr 2019; 22:212-22.
4. Fujiwara A, Murakami K, Asakura K, Uechi K,
Sugimoto M, Wang H, Masayasu S, Sasaki S.
Association of free sugar intake estimated using a
newly-developed food composition database withlifestyles and parental characteristics among
Japanese children aged 3-6 years: DONGuRI study.
J Epidemiol 2019; 29(11): 414-23.
5. Murakami K, Shinozaki N, Fujiwara A, Yuan X,
Hashimoto A, Fujihashi H, Wang H, Livingstone
MBE, Sasaki S. A systematic review of principal
component analysis-derived dietary patterns inJapanese adults: are major dietary patterns
reproducible within a country? Adv Nutr 2019;10(2): 237-49.
6. Shinozaki N, Wang HC, Yuan X, Li T, Asano K,
Kobayashi S, Sasaki S. Current status of education
and research on public health nutrition in Japan:
comparison with South Korea, Taiwan, andmainland China. BMC Nutrition 2019; 5: 10.
7. Shinozaki N, Murakami K, Masayasu S, Sasaki S.

Development and simulated validation of a dishcomposition database for estimating food group andnutrient intakes in Japan. Public Health Nutr 2019;22(13): 2367-80.
8. Sugimoto M, Murakami K, Fujitani S, Matsumoto H,
Sasaki S. Dietary free glutamate comes from avariety of food products in the United States. Nutr
Res 2019; 67: 67-77.
9. Murakami K, Livingstone MBE, Fujiwara A, Sasaki
S. Reproducibility and relative validity of the
Healthy Eating Index-2015 and Nutrient-Rich Food
Index 9.3 estimated by comprehensive and brief diethistory questionnaires in Japanese adults. Nutrients
2019; 11(10): 2540.
10. Sasaki S. Rice and Prevention of Type 2 Diabetes:
Narrative Review of Epidemiologic Evidene. J Nutr
Sci Vitaminol (Tokyo) 2019; 65(Supplement): S38S41.
11. Tajima R,Sasaki S. Estimation of habitual nutrient
intakes in Japanese adults based on 16-day dietary
records: Reference data for the comparison. Jpn J
Nutr Diet 2019; 77(6): 176-182.
12. Kobayashi Y, Ohfuji S, Kondo K, Fukushima W,
Sasaki S, Kamata N, Yamagami H, Fujiwara Y,
Suzuki Y, Hirota Y; Japanese Case-Control Study
Group for Ulcerative Colitis. Association between
dietary iron and zinc intake and development ofulcerative colitis: A case-control study in Japan. J
Gastroenterol Hepatol 2019; 34(10): 1703-10.
13. Nishida Y, Nakae S, Yamada Y, Kondo E,
Yamaguchi M, Shirato H, Hirano H, Sasaki S,
Tanaka S, Katsukawa F. Validity of one-day physicalactivity recall for estimating total energy expenditure in elderly residents at long-term care facilities:
CLinical EValuation of Energy Requirements Study(CLEVER Study) . J Nutr Sci Vitaminol (Tokyo)
2019; 65(2): 148-56.
14. Takahashi K, Tanaka K, Nakamura Y, Okubo H,
Sasaki S, Arakawa M, Miyake Y. Calcium intake
during pregnancy is associated with decreased riskof emotional and hyperactivity problems infive-year-old Japanese children. Nutr Neurosci
2019: 1-8 (Online ahead of print).

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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.
The Department accepted 12 master students for the
fiscal years of 2019.

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 the334

Patient Survey, and Hospital Census.

References
1. Aso S, Matsui H, Fushimi K, Yasunaga H.
Systemic glucocorticoids plus cyclophosphamide
for acute exacerbation of idiopathic pulmonary
fibrosis: A retrospective nationwide study.
Sarcoidosis Vasculitis and Diffuse Lung Disease.
2019 36 (2); 116-123
2. Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Outcomes following
laparoscopic versus open surgery for pediatricinguinal hernia repair: analysis using a national
inpatient database in Japan. Journal of PediatricSurgery. 2019;54(3):577-581
3. Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Early outcomes oflaparoscopic versus open surgery for urachal
remnant resection in children: a retrospective
analysis using a nationwide inpatient database inJapan. Journal of Laparoendoscopic & Advanced
Surgical Techniques. 2019;29(8):1067-1072
4. Fujiogi M, Goto T, Yasunaga H, Fujishiro J,
Mansbach JM, Camargo CA Jr., Hasegawa K.
Trends in bronchiolitis hospitalizations in the
United States, 2000-2016. Pediatrics 2019;144(6):e20192614.
5. Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Ishimaru T, Fujishiro J. Factors
affecting successful atropine therapy for infantile
hypertrophic pyloric stenosis: a retrospective
analysis using a nationwide database in Japan.
Annals of Clinical Epidemiology. 2019;1:4-10.
6. Goto T, Jo T, Matsui H, Fushimi K, Hayashi H,
Yasunaga H. Machine learning-based prediction
models for 30-day readmission after hospitalization for chronic obstructive pulmonary disease.
COPD 2019;16(5-6):338-343.
7. Hatakeyama S, Hashimoto H, Matsui H,
Sasabuchi Y, Yasunaga H, Kotani K, Nagai R.
Antibiotic prescription among outpatients in aprefecture of Japan, 2012–2013: A retrospective
claims database study. BMJ Open. 2019;9(4):e026251
8. Hiraishi Y, Jo T, Michihata N, Hasegawa W,
Sakamoto Y, Urushiyama H, Matusi H, Fushimi K,

Nagase T, Yasunaga H, Yamauchi Y. Hospital
volume and mortality following diagnostic
bronchoscopy in lung cancer patients: Data from anational inpatient database in Japan. Respiration.
2019;97(3):264-272
9. Hoshina K, Ishimaru S, Sasabuchi Y, Yasunaga H,
Komori K; Japan Committee for StentgraftManagement (JACSM). Outcomes of Endovascular Repair for Abdominal Aortic Aneurysms:
A Nationwide Survey in Japan. Ann Surg. 2019;269(3):564-573.
10. Ikawa F, Hidaka T, Yoshiyama M, Ohba H,
Matsuda S, Ozono I, Iihara K, Kinouchi H,
Nozaki K, Kato Y, Morita A, Michihata N,
Yasunaga H, Kurisu K. Characteristics ofCerebral Aneurysms in Japan. Neurol Med Chir.
2019;59(11):399-406.
11. Ishimaru M, Ono S, Matsui H, Yasunaga H.
Association between perioperative oral care andpostoperative pneumonia after cancer resection:
Conventional versus high-dimensional propensity
score matching analysis. Clinical Oral Investigations. 2019 ;23(9):3581-3588
12. Ishimaru M, Ono S, Matsui H, Yasunaga H.
Domiciliary dental care among homebound older
adults: a nested case-control study in Japan.
Geriatrics & Gerontology International. 2019;19(7):679-683
13. Ishimaru T, Fujiogi M, Michihata N, Matsui H,
Fushimi K, Kawashima H, Fujishiro J, Yasunaga
H. Impact of congenital heart disease on
outcomes after primary repair of esophageal
atresia: a retrospective observational study using anationwide database in Japan. Pediatric Surgery
International 2019 ;35(10):1077-1083.
14. Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. In-hospital Takotsubo syndrome
versus in-hospital acute myocardial infarction
among patients admitted for non-cardiac diseases:
a nationwide inpatient database study. Heart andVessels. 2019;34(9):1479-1490
15. Jo T, Michihata N, Yamana H, Sasabuchi Y,
Matsui H, Urushiyama H, Mitani A, Yamauchi Y,
Fushimi K, Nagase T, Yasunaga H. Reduction in
exacerbation of COPD in patients of advanced age
using the Japanese Kampo medicine Dai-kenchuto: a retrospective cohort study. International

335

Journal of Chronic Obstructive Pulmonary
Disease. 2019:14 129–139
16. Kawamura I, Nakajima M, Kitamura T, Kaszynski
RH, Hojo R, Ohbe H, Sasabuchi Y, Matsui H,
Fushimi K, Fukamizu S, Yasunaga H. Patient
Characteristics and In-hospital Complications of
Subcutaneous Implantable Cardioverter Defibrillator for Brugada Syndrome in Japan. Journal of
Arrhythmia 2019;35(6):842-847
17. Kinoshita T, Ohbe H, Matsui H, Fushimi K,
Ogura H, Yasunaga H. Effect of tranexamic acidon mortality in patients with haemoptysis: anationwide study. Crit Care 2019;23:347.
18. Koizumi M, Ishimaru M, Matsui H, Fushimi K,
Yamasoba T, Yasunaga H. Tranexamic acid andpost-tonsillectomy hemorrhage: propensity score
and instrumental variable analyses. European
Archives of Oto-Rhino-Laryngology. 2019;276(1):249-254
19. Koizumi M, Ishimaru M, Matsui H, Fushimi K,
Yamasoba T, Yasunaga H. Outcomes ofendoscopic sinus surgery for sinusitis-induced
intracranial abscess in patients undergoingneurosurgery. Neurosurgical Focus 2019;47(2):E12.
20. Kondo Y, Matsui H, Yasunaga H. Characteristics,
treatments, and outcomes among patients withabdominal aortic injury in Japan: A nationwide
cohort study. World Journal of Emergency
Surgery 2019;14:43.
21. Kumazawa R, Jo T, Matsui H, Fushimi K,
Yasunaga H. Association between angiotensinconverting enzyme inhibitors and post-stroke
aspiration pneumonia. Journal of Stroke andCerebrovascular Diseases 2019;28(12):104444.
22. Matsui H, Koike S, Fushimi K, Wada T,
Yasunaga H. Effect of neurologic specialist
staffing on 30-day in-hospital mortality after
cerebral infarction. Annals of Clinical Epidemiology 2019;1(3):86-94
23. Michihata N, Shigemi D, Sasabuchi Y, Matsui H,
Jo T, Yasunaga H. Safety and effectiveness ofJapanese herbal Kampo medicines for treatmentof hyperemesis gravidarum. International Journalof Gynecology & Obstetrics. 2019;145(2):182186.
24. Minami T, Yamana H, Shigemi D, Matsui H,

Fushimi K, Yasunaga H. Artificial colloids versus
human albumin for treatment of ovarian hyperstimulation syndrome: a retrospective cohort study.
International Journal of Reproductive Bio
Medicine 2019; 17: 709–716.
25. Miyamoto Y, Iwagami M, Aso S, Yasunaga H,
Matsui H, Fushimi K, Hamasaki Y, Nangaku M,
Doi K. Association between intravenous contrast
media exposure and non-recovery from dialysisrequiring septic acute kidney injury: a nationwide
observational study. Intensive Care Medicine
2019;45(11):1570-1579.
26. Morita K, Matsui H, Michihata N, Fushimi K,
Yasunaga H. Association of Early Systemic
Corticosteroid Therapy with Mortality in Patientswith Stevens–Johnson Syndrome or Toxic
Epidermal Necrosis: A Retrospective Cohort
Study Using a Nationwide Claims Database.
American Journal of Clinical Dermatology. 2019;20(4):579-592.
27. Mouri H, Jo T, Michihata N, Matsui H, Fushimi K,
Yasunaga H. Continuous Neuromuscular
Blockade and Mortality in Patients with Exacerbation of Idiopathic Interstitial Pneumonias: A
Propensity-matched Analysis. Respiratory Care.
2019;64(1):34-39.
28. Nakajima M, Aso S, Yasunaga H, Shirokawa M,
Nakano T, Goto H, Yamaguchi Y. Body
temperature change and outcomes in patients
undergoing long-distance air medical transport.
Am J Emerg Med. 2019;37(1):89-93.
29. Nakajima M, Aso S, Matsui H, Fushimi K,
Yasunaga H. Disaster-related carbon monoxide
poisoning after the Great East Japan Earthquake,
2011: a nationwide observational study. Acute
Medicine & Surgery 2019;6(3):294-300
30. Nakajima M, Kojiro M, Aso S, Matsui H, Fushimi
K, Kaita Y, Goto H, Yamaguchi Y, Yasunaga H.
Effect of high-dose vitamin C therapy on severeburn patients: A nationwide retrospective cohort
study. Crit Care 2019;23(1):407
31. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Early enteral nutrition in patients undergoingsustained neuromuscular blockade: a propensitymatched analysis using a nationwide inpatient
database. Critical Care Medicine. 2019;47(8):1072-1080

336

32. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Treatment with antithrombin or thrombomodulin
and mortality from heatstroke-induced disseminated intravascular coagulation: a nationwide
observational study. Seminars in Thrombosis andHemostasis 2019;45(8):760-766.
33. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Intravenous albumin for initial resuscitation andmortality in septic shock patients: propensity
score analyses using a nationwide inpatient
database. Annals of Clinical Epidemiology 2019;
1:45–55
34. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Extracorporeal membrane oxygenation improves
outcomes of accidental hypothermia without vital
signs: a nationwide observational study. Resuscitation 2019;144:27-32.
35. Oichi T, Oshima Y, Matsui H, Fushimi K, Tanaka
S, Yasunaga H. Can elective spine surgery be
performed safely among nonagenarians? Analysis
of a national inpatient database in Japan. Spine.
2019;44(5):E273-E281
36. Okubo Y, Miyairi I, Michihata N, Morisaki N,
Kinoshita N, Urayama KY, Yasunaga H. Recent
prescription patterns for children with acuteinfectious diarrhea. Journal of Pediatric Gastroenterology & Nutrition. 2019;68(1):13-16.
37. Okubo Y, Hayakawa I, Nariai H, Michihata N,
Matsui H, Fushimi K, Yasunaga H. Recent
practice patterns in diagnostic procedures anticonvulsants, and antibiotics for children hospitalized with febrile seizure. Seizure: European
Journal of Epilepsy. 2019; 67:52–56
38. Ota K, Sasabuchi Y, Matsui H, Jo T, Fushimi K,
Yasunaga H. Age distribution and seasonality inacute eosinophilic pneumonia: analysis using anational inpatient database. BMC Pulmonary
Medicine. BMC Pulmonary Medicine 2019;19:38
39. Sadamatsu Y, Hiratsuka Y, Michihata N, Jo T,
Matsui H, Murakami A, Fushimi K, Yasunaga H.
Activity of daily living improvement after cataract
surgery for patients in nursing care facilities.
Annals of Clinical Epidemiology 2019;1(3):80-85
40. Sekimizu M, Ogura K, Yasunaga H, Matsui H,
Tanaka S, Inagaki K, Kawai A. Development of
nomograms for prognostication of patients withprimary soft tissue sarcomas of the trunk andextremity: report from the Bone and Soft Tissue
Tumor Registry in Japan. BMC Cancer 2019;19:
657
41. Shigemi D, Yasunaga H. Antenatal corticosteroid
administration in women undergoing tocolytic
treatment who delivered before 34 weeks ofgestation: a retrospective cohort study using anational inpatient database. BMC Pregnancy andChildbirth. 2019;19(1):17
42. Shigemi D, Yamaguchi S, Aso S, Yasunaga H.
Predictive model for macrosomia using maternalparameters without sonography information.
Journal of Maternal-Fetal and Neonatal Medicine.
2019;32(22):3859-3863
43. Shigemi D, Aso S, Matsui H, Fushimi K,
Yasunaga H. Safety of laparoscopic surgery for
benign diseases during pregnancy: a nationwide
retrospective cohort study. Journal of Minimally
Invasive Gynecology. 2019;26(3):501-506
44. Shigemi D, Matsui H, Fushimi K, Yasunaga H.
Therapeutic impact of initial treatment for
Chlamydia trachomatis among patients withpelvic inflammatory disease: a retrospective
cohort study using a national inpatient database inJapan. Clinical Infectious Diseases. 2019;69(2):316-322
45. Shigemi D, Matsui H, Fushimi K, Yasunaga H.
Laparoscopic Compared With Open Surgery for
Severe Pelvic Inflammatory Disease and TuboOvarian Abscess. Obstetrics & Gynecology 2019;
133(6):1224-1230
46. Shigemi D, Aso S, Yasunaga H. Inappropriate
use of ritodrine hydrochloride for threatened
preterm birth in Japan: a retrospective cohort
study using a national inpatient database. BMC
Pregnancy and Childbirth 2019;19(1):204
47. Shigemi D, Matsui H, Fushimi K, Yasunaga H.
Recent overview of patients with anti-N-methylD-aspartate receptor encephalitis using a national
inpatient database in Japan. Annals of Clinical
Epidemiology. 2019;1:11-17.
48. Shinkawa H, Yasunaga H, Hasegawa K, Matsui
H, Michihata N, Fushimi K, Kokudo N. Mortality
and morbidity after pancreatoduodenectomy inpatients undergoing hemodialysis: analysis usinga national inpatient database. Surgery. 2019;
165(4):747-750

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49. Sugihara T, Yasunaga H, Matsui H, Kamei J,
Fujimura T, Kume H. Regional clinical practicevariation in Urology: Usage Example of the Open
Data of National Database of Health Insurance
Claims and Specific Health Checkups of Japan.
Int J Urol Int J Urol. 2019;26(2):303-305.
50. Suzuki J, Sasabuchi Y, Hatakeyama S, Matsui H,
Sasahara T, Morisawa Y, Yamada T, Yasunaga H.
Azithromycin plus β-lactam versus levofloxacin
plus β-lactam for severe community-acquired
pneumonia: a retrospective nationwide database
analysis. Journal of Infection and Chemotherapy
2019;25(12):1012-1018.
51. Tagami T, Matsui H, Ong M, Kuno M, Kaneko J,
Tanaka C, Unemoto K, Fushimi K, Yasunaga H.
Haptoglobin use and acute kidney injury requiring
renal replacement therapy among patients withsevere burn injury: a nationwide database study.
Annals of Clinical Epidemiology 2019;1:69–75
52. Takano A, Ono S, Yamana H, Matsui H,
Matsumoto T, Yasunaga H, Kawakami N. Factors
associated with the long-term prescription of
benzodiazepines: a retrospective cohort study
using a health insurance database in Japan. BMJ
Open 2019;9:e029641.
53. Takeshima T, Jo T, Yasunaga H, Morita K,
Yamauchi Y, Hasegawa W, Sakamoto Y,
Urushiyama H, Matsui H, Fushimi K, Nagase T.
Factors Associated with Severe Postoperative
Acute Respiratory Failure Requiring High Dose
Corticosteroid Therapy. Annals of Clinical
Epidemiology 2019;1:31–44
54. Tsuchiya A, Yasunaga H, Tsutsumi Y, Kawahara
T, Matsui H, Fushimi K. Nationwide
observational study of mortality from complicatedintra-abdominal infections and the role ofbacterial cultures. Br J Surg. 2019;106(5):606615.
55. Uda K, Matsui H, Fushimi K, Yasunaga H.
Intensive in-hospital rehabilitation after hip
fracture surgery and activities of daily living inpatients with dementia: Retrospective analysis ofa nationwide inpatient database. Archives ofPhysical Medicine and Rehabilitation 2019;100:2301-2307
56. Usui T, Hanafusa N, Yasunaga H, Nangaku M.
Association of dialysis with in-hospital disability

progression and mortality in community-onset
stroke. Nephrology (Carlton). 2019;24(7):737-743
57. Winburn I, Ishii T, Sumikawa T, Togo K,
Yasunaga H. Estimating the Prevalence ofTransthyretin Amyloid Cardiomyopathy in a
Large In-Hospital Database in Japan. Cardiol Ther
2019;8(2):297-316
58. Yasunaga H. How to review manuscripts. Annalsof Clinical Epidemiology. 2019;1:2-3
59. Yasunaga H. Real World Data in Japan: Chapter I
NDB. Annals of Clinical Epidemiology 2019;
1(2):28-30.
60. Yasunaga H. Real World Data in Japan: Chapter
II The Diagnosis Procedure Combination
Database. Annals of Clinical Epidemiology 2019;
1(3):76-79.

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Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Tsuyoshi Okuhara, Ph.D.

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. Interpersonal communication skills for behavioral
changes
4. Public health communication skills for behavioral
changes
5. Communicating for policy and advocacy
6. Communication in group and organization
7. Patient and public education
8. Communication with foreign patients
9. Entertainment education
10. Visual communication
11. Media and communication (1): Television
12. Media and communication (2): News paper
13. Media and communication (3): Internet
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 CDISC standards
2. Introduction to data management in clinical

339

3.
4.
5.
6.
7.

research
Data and metadata – Define.xml
Standardization of case report form – CDASH
Standardization of data format – SDTM
Standardization of dataset for analysis – AdaM
Electronic application by CDISC standards

In the undergraduate program, we present lectures
entitled “Medical Literature Informatics” and “healthcommunication.”

Research Activities
The followings are two distinguishing characteristicsof the research conducted in our Department of HealthCommunication, as compared to the research at othermedical informatics programs in Japan:(1) 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.
(2) 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.
The following are current research topics at the
Department of Health Communication:(1) 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.”(2) 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
characteristics with their communication behaviors,
and impacts of the communication on patient
outcomes.
(3) 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.
(4) 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 presents challenges.
We also conduct researches to increase influence ofsmall media such as leaflets, and held seminars forhealth professionals.

(5) Research Related to UMIN Activities
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.
(6) 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

340

attained by the medical research data center at the
UMIN.
(7) 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.

References
1. Haragi M, Yamaguchi R, Okuhara T, Kiuchi T.
Interviewing forensic specialists regarding
medical-legal illustration methods to replace
gruesome graphic evidence. Journal of Visual
Communication in Medicine. 2019; 43(1):27-34.
2. Ishikawa H., Kiuchi T. Association of healthliteracy levels between family members. Frontiersin Public Health. 2019;7:169.
3. Okuhara T, Ishikawa H, Okada M, Kato M,
Kiuchi T. Newspaper coverage before and after
the HPV vaccination crisis began in Japan: A text
mining analysis. BMC Public Health. 2019;19:770.
4. Goto E, Ishikawa H, Okuhara T, Kiuchi T.
Relationship of health literacy with utilization ofhealth-care services in a general Japanese
population. Preventive Medicine Reports. 2019;14:100811.

School of Public Health
2. Behavioral Health Sciences

342

Departments ofHealth and Social Behavior &Health Education and HealthSociology
Professor in health and social behavior
Hideki Hashimoto, M.D., D.PH.

Associate Professor in health education and health sociology
Naoki Kondo, M.D., Ph.D.

Lecturer
Daisuke Takagi, Ph. D.

Associate
Masamitsu Kamada, Ph. D.

Homepage http://webpark1166.sakura.ne.jp/
Introduction and Organization
The department originated as one of the firstdepartments dedicated to health education andbehavioral science in Japan, led by former Prof.
Emeritus Tadao Miyasaka, who had double degrees of
M.D. from the University of Tokyo and MPH in healtheducation from Harvard School of Public Health in1950s. He was succeeded by a sociologist, former
Prof. Kyoichi Sonoda who founded the first healthsociology department affiliated with the medical
school in Japan. Since then, the program has beenleading research focusing on socio-behavioral aspectsof health in this country. The legend was extended byformer Prof. Chieko Kawada who raised academic andpractical attention on the concept of empowerment
and adult pedagogy in health education. Since 1997,
the department was further evolved by Prof. Ichiro
Kai who integrated diverse health and social science
disciplines into social gerontology program, and by
Associate Prof. Yoshihiko Yamazaki who ledsociological research projects on salutogenesis, social
stigma, power, and agency in health settings. The
departments were reorganized under the newly
established School of Public Health since 2007. In
2012, the Department of Social Gerontology has beenrenamed as the Department of Health and Social
Behavior to apply a life-course perspective to a wider
range of social conditions and human well-being.
The new department intends to further integrate
health science (medicine and public health) and social
science (economics, sociology, and psychology) toreveal a causal mechanism linking social structure andindividual health for realizing health equity as afundamental goal to human security.

Teaching activities
The departments offer four courses in the master
degree program for public health, and seven courses
in the undergraduate program for the Integrated
Health Sciences track.

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1. Graduate Courses, School of Public Health
1) Health and Society I & II: The course highlights
the significance of social determinants of health(SDH) as a key exposure causing social gradientof health. A series of omnibus lectures, eachfocusing a specific topic of SDH (e.g. income
distribution,
gender,job
stress,anddiscrimination), are provided by invitedlecturers specialized in the field. The course isfollowed by course II which offers application ofconcepts into practice through in-classdiscussion and group works.
2) Health Education: The course provides basic
knowledge on relevant behavioral theories forhealth promotion and behavioral modification,
followed by case method learning on healtheducational intervention in community, school,
and work places. The case discussion was
facilitated by invited lecturers to reach practicallessons for effective communication.
3) Health Sociology: Sociology in medicine andsociology applied to health issues are treated in
the systemic course of lectures, covering social
model of health, medical gaze and socializationof health professionals, phenomenology ofchronic ills, and culture and health.
2. Undergraduate Courses, School of Integrated
Health Sciences
1) Introduction to social survey and practice;
Provides introductory lecture on sampling,
psychometrics, design of social survey andquestionnaires. Students are asked to conduct amini social survey within class on the theme theychoose as relevant in their class experience.
2) Health and Society (former Health sociology);
Lecture series on social model of healthgeneration, social relationship and health,chronic illness experience, and social stigma.
3) Health education
Case scenario based practicum and lectures on
health promotion intervention in clinical, school,
and worksite settings.
4) Social security and welfare program: Lecture
series on the history and the current systems ofhealth care security and welfare policies in thiscountry.

5) Integrated Lectures of Public Health Sciences I(jointly offered by the faculty of Health
Sciences)
6) Scientific writing
7) Critical reading/writing of epidemiologicalstudies8) Integrated Practicum of Public Health Sciences
II (jointly offered with Department of Medical
Ethics).
The department contributed to extend educational
environment in the new frame of School curriculum
policy, and management of educational duties withlimited resources became a challenge.

Research activities
The Department has contributed to an ongoing
research of socioeconomic status and health/functions
among elderly population in the collaboration with the
School of Economics of the University of Tokyo andthe Research Institute of Economic, Industry, andTechnology. The Japanese Study of Ageing andRetirement (J-STAR) is a sister study with the U.S.
Health and Retirement Study, Study of Health,Ageing, and Retirement in Europe (SHARE), EnglandLongitudinal Survey of Ageing (ELSA), and theirglobal sisters in Asian countries. The scope of JSTAR
is diverse; contribution of health for successful ageing,social economic conditions and access to health care,household economy and its impact on life styles suchas eating habits and nutrition, impact of retirement
onto cognitive function, etc..
Since 2010, the Department has launched anotherpanel study of younger generation, the Japanese studyof Stratification, Health, Income, and Neighborhood(J-SHINE) in collaboration with researcher groups on
neuroscience, economics, sociology, and social
psychology. The aim of this comprehensive panel
study is to identify a mechanism how socio-economic
environments get to “under-skin” to cause social
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344

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.
The department also joined with Departments of
Public Health, Medical Informatics, and Health
Economics and Clinical Epidemiology the management of National claim Data Base and onsite research
center under the contract with the Ministry of Health,Welfare, and Labour to extend empirical healthcare
research using a representative big administrative data.
Dr. Kondo also is an active and leading coreresearcher in another large cohort for social epidemiology in gerontology, called Japan Gerontological
Evaluation Study (JAGES) that covers more than 30
municipalities and approximately 200,000 participating old people in the community. The project purports
to reveal social relationship and its impact on healthin later life. The team has been developing community
diagnosis tool using JAGES data to support
participating municipalities to effectively findleverage population for policy intervention. The
developed tools have been disseminated andstandardized for wider use in municipalities.
Dr. Takagi, in collaboration with Niigata University,
is preparing for a social epidemiological survey ofcommunity-dwelling older adults in Myanmar andMalaysia. In these countries that have distinctive
stage of economic development, culture, and ageing
rate, this study aims at verifying applicability of theexisting social models of health and building new
theories based on each country’s context. A
probability proportionate sampling of sites andselection of local investigators have been completed
in 2017, and interview surveys will be conducted in
2018.
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.

Publications
1. Li T, Hashimoto H. Household dietary salt
consumption and mortality from cardiovasculardiseases: an ecological panel analysis in Japan.
Eur J Public Health. 2019 ckz038, https://doi.org/
10.1093/eurpub/ckz038.
2. Yokouchi N, Hashimoto H. Association Between
Deviation of Fairness Perceptions from Group
Average and Serious Psychological Distress inJapanese Worksites: a Cross-Sectional Study. Int
J Behav Med. 2019 Mar 14. doi:10.1007/s12529019-09781-8.
3. Fujii T, Ikari Y, Hashimoto H, Kadota K, Amano
T, Uemura S, Takashima H, Nakamura M, for the
J-PCI Investigators. Post-interventional adverse
event risk by vascular access site among patientswith acute coronary syndrome in Japan:
observational analysis with a national registry JPCI database. Cardiovasc Interv and Ther (2019).
https://doi.org/10.1007/s12928-019-00582-0.
4. Murakami K, Hashimoto H. Associations ofeducation and income with heavy drinking andproblem drinking among men: evidence from a
population-based study in Japan. BMC publichealth, 19(1), 420. doi:10.1186/s12889-0196790-5.
5. Amano H, Shirakawa Y, Hashimoto H.
Adiponectin levels among individuals with varied
employment status in Japan: a cross-sectional
analysis of the J-SHINE study. Sci Rep. 2019 Jul
29;9(1):10936.doi: 10.1038/s41598-019-47448-2.
6. Murakami K, Aida J, Hashimoto H. Associationsof social relationships with curative andpreventive dental care use among young andmiddle-aged adults:Evidence from a populationbased study in Japan. Community Dent Oral
Epidemiol.2019 Jul 23. doi: 10.1111/cdoe.12487.
7. Hashimoto, H. Social Determinants of Health andDiabetes Outcomes. In; Rodriquez-Saldana J, eds.
The Diabetes Textbook; Clinical Principles,Patient Management and Public Health Issues.
Springer. pp61-69. DOI:10.1007/978-3-03011815-0_5.
8. Chao D, Hashimoto H, Kondo N Social influenceof e-cigarette smoking prevalence on smoking
behaviours among high-school teenagers:

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Microsimulation experiments Plos One August29, 2019 https://doi.org/10.1371/journal.pone.
0221557
9. Ogasawara H, Hashimoto H. Relationshipbetween maternal communicative/criticalhealthliteracy and child’s asthma symptoms: Resultsfrom a population-basedsurvey in metropolitan
Japan. Patient Educ Couns. 2019 Nov 28. pii:
S0738-3991(19)30538-5. doi: 10.1016/j.pec.2019.
11.026.
10. Direito A, Murphy J, Mclaughlin M, Mair J,
Mackenzie K, Kamada M, Sutherland R,
Montgomery S, Shilton T, Milton K. Early career
professionals’ (researchers, practitioners andpolicy-makers) role in advocating, disseminating
and implementing The Global Action Plan on
Physical Activity: ISPAH Early Career Network
view. J Phys Act Health, 16(11), 940-944, 2019.
11. Abe T, Kitayuguchi J, Okada S, Okuyama K,
Gomi T, Kamada M, Ueta K, Nabika T, Tanaka C.
Prevalence and correlates of physical activity
among children and adolescents: a cross-sectional
population-based study of a rural city in Japan. J
Epidemiol (epub ahead of print, Aug 2019)https://doi.org/10.2188/jea.JE20190047
12. Lee IM, Shiroma EJ, Kamada M, Bassett DR,
Matthews CE, Buring JE. Association of step
volume and intensity with all-cause mortality inolder women. JAMA Intern Med. 179(8):11051112, 2019. doi:10.1001/jamainternmed.2019.
0899. (Altmetric score: 3054 on Dec 18, 2019.
13. Matoba T, Kohro T, Fujita H, Nakayama M,
Kiyosue A, Miyamoto Y, Nishimura K,
Hashimoto H, Antoku Y, Nakashima N, Ohe K,
Ogawa H, Tsutsui H, Nagai R. Architecture of
the Japan Ischemic Heart Disease Multimodal
Prospective Data Acquisition for Precision
Treatment (J-IMPACT) System. Int Heart J.
2019 Mar20;60(2):264-270. doi: 10.1536/ihj.18113.
14. Yasukawa K, Sawada T, Hashimoto H, Jimba M.
Health-care disparities for foreign residents inJapan. Lancet. 2019 Mar 2;393(10174):873-874.
doi:10.1016/S0140-6736(19)30215-6.
15. Zhao Z, Jinde S, Koike S, Tada M, Satomura Y,
Yoshikawa A, Nishimura Y, Takizawa R,
Kinoshita A, Sakakibara E, Sakurada H,

Yamagishi M, Nishimura F, Inai A, Nishioka M,
Eriguchi Y, Araki T, Takaya A, Kan C, Umeda M,
Shimazu A, Hashimoto H, Bundo M, Iwamoto K,
Kakiuchi C, Kasai K. Altered expression of
microRNA-223 in the plasma of patients with
first-episode schizophrenia and its possible
relation to neuronal migration-related genes.
Transl Psychiatry. 2019Nov 11;9(1):289. doi: 10.
1038/s41398-019-0609-0.
16. Tomotaki A, Kumamaru H, Hashimoto H,
Takahashi A, Ono M, Iwanaka T, Miyata H.
Evaluating the quality of data from the Japanese
National Clinical Database 2011 via a comparison
with regional government report data and medical
charts. Surg Today. 2019 Jan;49(1):65-71. doi:
10.1007/s00595-018-1700-5.
17. 佐野隆一郎 橋本英樹 井元清哉 労働時間
種別による病院勤務医の夜間休日労働の勤務意欲にもたらす影響の検討 医療経済研究
Vol.30 No.2 2018 pp68-79
18. 鎌田真光 身体活動促進のポピュレーション
戦略─エビデンスとその実際．医学のあゆみ
Vol 271, No. 2: 211-216, 2019.
19. 鎌田真光 身体活動を促進する地域普及戦略
─島根県雲南市の成功事例と世界の最新エビ
デンス．都市計画 Vol 68, No. 5 (340 号): 6265, 2019.
20. Tomoki Nakaya, Keisuke Fukui, Yuri Ito, Keiji
Yano, Yuzuru Isoda, Naoki Kondo, Kazumasa
Hanaoka, Yoshikazu Nishino, Seiki Kanemura,
Ryozo Matsuda, Shigeru Inoue, Hiroyuki Kikuchi,
Takahiro Tabuchi, Mayuko Yonejima, Tomoya
Hanibuchi. The Atlas of Health Inequalities inJapan. Springer Nature 2019. 2019/08/07
21. Kondo K, Rosenberg M, Kondo N, Cable N.
Advancing universal health coverage throughknowledge translation for healthy ageing:
Lessons learnt from the Japan Gerontological
Evaluation Study. In: Kondo K, Rosenberg M, eds.
Kobe: World Health Organization 2019.
22. Isumi A*, Fujiwara T, Kato H, Tsuji T, Takagi D,
Kondo N, Kondo K. Medical costs associatedwith childhood maltreatment history among
Japanese older people. European Journal of
Public Health. 2019;29. Epub ahead of print
23. Kondo N*. Call for papers – Journal of
Epidemiology Reprints of Pioneering Papers

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series: Spotlighting little-known non-English
language research papers from Japan and aroundthe world. J Epidemiol 2019; 30:1-2.
24. Yamada K*, Kubota Y, Tabuchi T, Shirai K, Iso
H, Kondo N, Kondo K. A prospective study ofknee pain, low back pain, and risk of dementia:
the JAGES project. Sci Rep. 2019;9(1):10690.
25. Sato K*, Kondo N, Kondo K. Rotating savingsand credit association, its members' diversity, andhigher-level functional capacity: A 3-year
prospective study from the Japan Gerontological
Evaluation Study. Geriatrics & Gerontology
International. 2019;19(12):1268-74.
26. Hirai H*, Ichikawa M, Kondo N, Kondo K. The
risk of functional limitations after driving
cessation among older Japanese adults: the
JAGES cohort study. J Epidemiol. 2019:advpub.
27. Sato K*, Ikeda T, Watanabe R, Kondo N,
Kawachi I, Kondo K. Intensity of communitybased programs by long-term care insurers andthe likelihood of frailty: Multilevel analysis ofolder Japanese adults. Soc Sci Med 2020;245:
112701.
28. Nansai K*, Fry J, Malik A, Takayanagi W, Kondo
N. Carbon footprint of Japanese health careservices from 2011 to 2015. Resources
Conservation and Recycling 2020;152:104525.
29. Nagatomo W, Saito J, Kondo N*. Effectivenessof a low-value financial-incentive program forincreasing vegetable-rich restaurant meal selection and reducing socioeconomic inequality: acluster crossover trial. Int J Behav Nutr Phys Act
2019;16:81.
30. Sampei M, Kato T, Piedvache A, Morisaki N,
Saito J, Akiyama Y, Shinohara R, Yamagata Z,
Urayama KY*, Kondo N. Municipality-level
checklist to promote parental behaviors related toprevention of unintentional injury in young
children: a multilevel analysis of national data. J
Epidemiol 2019;29:65-72.
31. Haseda M, Takagi D, Kondo K, Kondo N*.
Effectivenessofcommunityorganizing
interventions on social activities among older
residents in Japan: A JAGES quasi-experimental
study. Soc Sci Med 2019;240:112527.
32. Saito J, Haseda M, Amemiya A, Takagi D, Kondo
K, Kondo N*. Community-based care for healthy

ageing: lessons from Japan, Bull World HealthOrgan 2019; 97(8):570-574
33. Yokomichi H*, Kondo K, Nagamine Y,
Yamagata Z, Kondo N. Dementia risk by
combinations of metabolic diseases and bodymass index: Japan Gerontological Evaluation
Study (JAGES) Cohort Study. Journal of diabetes
investigation 2019;11(1):206-215.
34. Kanamori M, Kondo N*. Suicide and Types ofAgriculture: A Time-Series Analysis in Japan.
Suicide & life-threatening behavior 2019;Suicideand Life-Threatening Behavior, 50(1):122-137
35. Saito M*, Aida J, Kondo N, Saito J, Kato H, Ota
Y, Amemiya A, Kondo K. Reduced long-termcare cost by social participation among older
Japanese adults: a prospective follow-up study in
JAGES. BMJ Open 2019;9:e024439.
36. Kobayashi Y, Kondo N*. Organizational justice,
psychological distress, and stress-related
behaviors by occupational class in female
Japanese employees. PLoS One 2019;14:e0214393.
37. Inoue Y*, Howard AG, Yazawa A, Kondo N,
Gordon-Larsen P. Relative deprivation of assets
defined at multiple geographic scales, perceived
stress and self-rated health in China. Health &Place 2019;58:102117.
38. Yamaguchi M*, Takahashi K, Hanazato M,
Suzuki N, Kondo K, Kondo N. Comparison of
Objective and Perceived Access to Food Stores
Associated with Intake Frequencies of
Vegetables/Fruits
andMeat/Fishamong
Community-Dwelling Older Japanese. Int J
Environ Res Public Health 2019;16:772.
39. Amemiya A, Kondo N*, Saito J, Saito M, Takagi
D, Haseda M, Tani Y, Kondo K. Socioeconomic
status and improvement in functional ability
among older adults in Japan: a longitudinal study.
BMC Public Health 2019;19:209.
40. Amemiya A, Saito J, Saito M, Takagi D, Haseda
M, Tani Y, Kondo K, Kondo N*. Social Capitaland the Improvement in Functional Ability amongOlder People in Japan: A Multilevel Survival
Analysis Using JAGES Data. Int J Environ Res
Public Health 2019;16:1310.
41. Shiba K, Kondo N*. The Global Financial Crisis
and Overweight among Children of Single

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Parents: A Nationwide 10-Year Birth Cohort
Study in Japan. Int J Environ Res Public Health
2019;16. (6)42. Saito M*, Kondo N, Oshio T, Tabuchi T, Kondo
K. Relative Deprivation, Poverty, and Mortality
in Japanese Older Adults: A Six-Year Follow-Upof the JAGES Cohort Survey. International
Journal of Environmental Research and Public
Health 2019;16(2):182.
43. Shimoda A*, Hayashi H, Sussman D, Nansai K,
Fukuba I, Kawachi I, Kondo N. Our health, ourplanet: a cross-sectional analysis on theassociation between health consciousness andpro-environmental behavior among healthprofessionals. Int J Environ Health Research
2019: 08 Feb 2019,30(1):63-74.
44. Hayashi H*, Tan ASL, Kawachi I, Ishikawa Y,
Kondo K, Kondo N, Tsuboya T, Viswanath K.
Interpersonal Diffusion of Health Information:
Health Information Mavenism among People Age
65 and over in Japan. Health Communication
2019;23:1-11.
45. Sato K*, Viswanath K, Hayashi H, Ishikawa Y,
Kondo K, Shirai K, Kondo N, Nakagawa K,
Kawachi I. Association between exposure to
health information and mortality: Reduced
mortality among women exposed to information
via TV programs. Soc Sci Med 2019;221:124-31.
46. Nagamine Y, Kondo N*, Yokobayashi K, Ota A,
Miyaguni Y, Sasaki Y, Tani Y, Kondo K.
Socioeconomic Disparity in the Prevalence of
Objectively Evaluated Diabetes Among Older
Japanese Adults: JAGES Cross-Sectional Data in2010. J Epidemiol. 2019;29(8):295-301.
47. Saito J*, Kondo N, Saito M, Takagi D, Tani Y,
Haseda M, Tabuchi T, Kondo K. Exploring 2.5Year Trajectories of Functional Decline in Older
Adults by Applying a Growth Mixture Model and
Frequency of Outings as a Predictor: A 2010-2013
JAGES Longitudinal Study. J Epidemiol 2019;29:65-72.

School of Public Health
3. Health Services Sciences

349

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Research Associate
Ayako Kohyama-Koganeya, Ph.D.
Toki Saito, Ph.D.

Homepage:

http://webpark1893.sakura.ne.jp/wp/

Introduction and Organization
Information engineering in Japan places a great dealof weight on computer hardware, software, and dataprocessing. It is a discipline that seeks objective dataand emphasizes the conception of new methods ofdata transfer, storage, processing, and input/output. It
also targets research on developing computer devices
and systems.
Reviewing the history of the application ofcomputers in medicine, calculating machines forsupporting scientists and technologists first appearedin the 1950s. In the 1960s, computers were used foraccounting and various statistics. The personal
computer appeared in the 1980s and was adopted for
personal use in many professions. The systematizationof large hospitals, such as university hospitals, pushedahead rapidly.
In the 1990s, the computer began to be used as atool to help human thinking, such as in presentations,design, and discovery. When computers became
connected to each other through the internet, thedistribution of information became very easy andrapid, not only within organizations, but alsointernationally.
In 2003, a high-quality, "finished" sequence of thehuman genome was completed. At the dawn of thetwenty-first century, bioinformatics appeared as a new
discipline, one that uses applied mathematics,
informatics, statistics, computer science, and bio-chemistry to solve biological problems. In medicine,advanced information technologies have been applied
to health information infrastructures, electrical clinicalguidelines, and knowledge navigation systems.
In response to the needs of the time, the Departmentof Clinical Information Engineering (CIE) wasestablished at the School of Public Health in April
2007. Its predecessor was the clinical informationengineering division of clinical bioinformatics, using
Special Coordination Funds for Promoting Scienceand Technology from the Ministry of Education,
Culture, Sports, Science, and Technology, of Japan.

Teaching activities
The purpose of the Department of Clinical
Information Engineering is to nurture talented people
who have special knowledge and skills at aninternational level in order to apply advanced
information technologies to practical projects inclinical medicine and the health sciences. It offers
courses on information system design, development
methodology, evaluation and project management inbiomedicine, health care and public health in the
School of Public Health, and data mining and virtual
reality for clinical decision-making in social medicine.
Famous visiting lecturers and researchers from the
National Cancer Center and other universities havegiven lectures here, furthering our hope of becoming aworld leader in this field.

350

The education of graduate students is based on
weekly conferences at which the students present the
progress on their own research projects and discuss
their future directions.

Research activities
Our research covers the biomedical computer
applications that focus on biomedical data (collection,
analysis, and representation). It constitutes a
combination of information science, computer science,and clinical science designed to assist in the
management and processing of data, information, andknowledge to support the practice and delivery ofclinical care. Our laboratory is engaged in thefollowing research activities:(1) Computer Graphics & Virtual Reality (VR) for
Medical Science: Our research has three goals:(1) to improve the living conditions of in-patientswith limited physical activity by providing virtual
experiences; (2) to develop new diagnostic
methods using medical imaging; and (3) todevelop a surgical edutainment and preoperative
surgical planning support system in virtual space.
The advantages of simulating surgical procedures
using VR techniques include: (1) practicing thesurgical procedure and image-based training; (2)planning the surgical procedure for individual
patients preoperatively using VR images modeledfrom the patient's preoperative computed tomography (CT) or magnetic resonance (MR) images,
in collaboration with the Department of Neurosurgery; (3) allowing supervisors to evaluate aprocedure objectively; and (4) helping patientsand their families to better understand the surgicalprocedure before and after the operation.
(2) Social Information Engineering for Public Health(Public Health Informatics): Our laboratory
researches new tools and methodologies for
applying information and computer science andtechnology to public health practice, research,and learning.
At present, we are studying
differences in the computerization of publichealth in the US and Japan.

References
1. Yukihiro Yoshida, Toshiki Manaka, Jun-Ichi
Nitadori, Aya Shinozaki-Ushiku, Takehito Doke,
Toki Saito, Jiro Sato, Tempei Miyaji, Takuhiro
Yamaguchi, Hiroshi Oyama, Masashi Fukayama,
Yoshikazu Nakajima, Jun Nakajima. A
comparison between 2- and 3-dimensional
approaches to solid component measurement asradiological criteria for sublobar resection in lungadenocarcinoma ≤ 2 cm in size. Surgery today
49(10) 828 - 835 2019.
2. Kumiko T Kanatani, Takeo Nakayama, Yuichi
Adachi, Kei Hamazaki, Kazunari Onishi, Yukuo
Konishi, Yasuyuki Kawanishi, Tohshin Go, KeikoSato, Youichi Kurozawa, Hidekuni Inadera, Ikuo
Konishi, Satoshi Sasaki, Hiroshi Oyama. Highfrequency of vitamin D deficiency in current
pregnant Japanese women associated with UV
avoidance and hypo-vitamin D diet. PloS one
14(3) e0213264 2019.
3. Kumiko T Kanatani, Yuichi Adachi, Kei
Hamazaki, Kazunari Onishi, Tohshin Go, Kyoko
Hirabayashi, Motonobu Watanabe, Keiko Sato,
Youichi Kurozawa, Hidekuni Inadera, Hiroshi
Oyama, Takeo Nakayama. Association between
vitamin D deficiency and allergic symptom inpregnant women. PloS one 14(4) e0214797 2019.

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Department of Global
Environmental Health
Associate Professor
Yoonhee Kim, Ph.D.

Homepage https://sites.google.com/m.u-tokyo.ac.jp/envhealth/Introduction and Organization
The Department of Global Environmental Health(GEH) started under the School of Public Health(SPH), Graduate School of Medicine since April 2018,
and affiliated with the School of International Health(SIH), Graduate School of Medicine since July 2018as an Associate Department. GEH aims:
1. To study relationships between environmental
exposure and human health
2. To produce well-educated professionals with theacademic knowledge and ability to undertake
environmental epidemiological research

Teaching activities
This department provides two postgraduate courses
under SPH: 1) Environmental Health and 2) Methods
for Environmental Health Research. The former is an
introductory course in environmental epidemiologythat introduces basic concepts and methods to assess a
potential relationship between environmental stressors
and health outcomes at both individual and populationlevels. It also provides state-of-the-art scientificknowledge and interpretation for health risk/impact
assessment in environmental health perspectives. The
latter is an advanced course dealing with statisticaland epidemiological methodologies in environmental
epidemiology, that provides the theory and practice ofa specific method to estimate a short-term effect ofenvironmental risk factors on human health.
In this year, we also provided a special lecture entitled“Air pollution, climate change and human health” toundergraduate students from three schools (Peking
University, Seoul National University, and The
University of Tokyo) in the 2019 CAMPUS Asia
Summer Program, hosted by East Asian Academy for
New Liberal Arts (EAA), The University of Tokyo.
GEH journal club
GEH has participated in a weekly conference call withmultiple schools/institutes* to read and discuss articles
in environmental epidemiology.
*

Seoul National University, Korea Advanced Institute of Science &Technology (KAIST), National Institute for Environmental Studies,
University of Tsukuba, Kyoto University, and Nagasaki University

Research activities
Our research interests particularly focus on climatechange and air pollution in human populations in thefield of environmental epidemiology. We address thescientific questions of how they link, quantify thehealth risks of a specific environmental factor, andfurther investigate social determinants that could
potentially modify the exposure-response relationships.
Our research collaborations include:
1. Global perspectives of seasonal variability ofsuicide and the short-term associations between
suicide and ambient temperature and air pollution
including daily time-series database across 19
countries, as a part of the Multi-Country
Multi-City Collaborative Research Network
2. Health risk assessment of climate change and air
pollution in northeast Asian countries

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3. Establishment of an early warning system for
malaria incidence in southern Africa

References
1. Kim Y, Kim H, Gasparrini A, Armstrong B,
Honda Y, Chung Y, Ng CFS, Tobias A, Íñiguez C,
Lavigne E, Sera F, Vicedo-Cabrera AM, Ragettli
MS, Scovronick N, Acquaotta F, Chen BY, Guo
YLL, Seposo X, Dang TN, Coelho MSZS, Saldiva
PHN, Kosheleva A, Zanobetti A, Schwartz J, BellML, Hashizume M. Suicide and Ambient
Temperature: A Multi-Country Multi-City Study.
Environmental Health Perspectives 2019:127(11):117007.
2. Kim Y, Ratnam JV, Doi T, Morioka Y, Behera S,
Tsuzuki A, Minakawa N, Sweijd N, Kruger P,
Maharaj R, Imai CC, Ng CFN, Chung Y,
Hashizume M. Malaria predictions based on
seasonal climate forecasts in South Africa: A timeseries distributed lag nonlinear model. Scientific
Reports 2019:9:17882.
3. Matsushita N, Kim Y, Ng CFS, Moriyama M,
Igarashi T, Yamamoto K, Otieno W, Minakawa M,
Hashizume M. Differences of rainfall-malaria
associations in lowland and highland in Western
Kenya. International Journal of Environmental
Research and Public Health 2019:16:3693.
4. Ng CFS, Hashizume M, Obase Y, Doi M, Tamura
K, Tomari S, Kawano T, Fukushima C, Matsuse
H, Chung Y, Kim Y, Kunimitsu K, Kohno S,
Mukae H. Associations of chemical compositionand sources of PM2.5 with lung function of severe
asthmatic adults in a low air pollution environment of urban Nagasaki, Japan. Environmental
pollution 2019:252:599–606.

Endowed Department

354

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
Ryohei Yamaguchi, M.D., Ph.D.

Project Researcher
Kiminori Shimamoto, M.E.

Homepagehttps://ai-health.m.u-tokyo.ac.jp/

Introduction and Organization

Teaching activities

The transformation of industrial structures has
become inevitable in many fields with the arrival of
the practical application of artificial intelligence (AI).
Healthcare is not exempt from this trend, and thedevelopment of services based on AI and informationand communications technology (ICT) are anticipated.
The present program was inaugurated in August 2018
sponsored by the Hanshin Dispensing Holding Co.,
Ltd. and Em Systems Co., Ltd. and with thecooperation of the Department of Biomedical
Informatics, Division of Social Medicine, Graduate
School of Medicine, The University of Tokyo, which
has been involved in the development of hospital datasystems and standardization of medical data, and theDepartment of Healthcare Information Management of
The University of Tokyo Hospital. At the time of its
inauguration, the activities of the program consisted of
1) defining the form of new medical services utilizing
AI and ICT, 2) developing the technologicalgroundwork and 3) establishing a center to provide
support for researchers involved in the project,
thereby 4) educating and training competentcandidates in this field.

We are promoting activities to cultivate researchers
in this field by educating and training internal andexternal graduate students. In 2018, we advised
doctorate students in the joint program, theDepartment of Biomedical Informatics, and offeredcourses for the School of Public Health (SPH). In
2019, we plan to accept graduate students from otherprograms and students from other universities forpractical training, and we also hope to improve the AI
and IT skills of hospital staff by hosting internalseminars.

Research activities
In the present program, we seek to apply dataprimarily obtained from electronic medical records
using information processing technology and machinelearning technology to develop technologies that assist
diagnosis. The main research themes of the present
program are listed below.
1.

Development of information extraction andprocessing infrastructure from medical records

It is difficult even to determine which disease apatient is receiving treatment for by computer

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processing alone based on records in the current
electronic medical record system. For example,
disease names inputted for the purpose of healthinsurance claims do not reflect actual disease names.
There are also only few diseases that can be
determined based on medication or biopsy testing
results. Therefore, it is anticipated that the utilizationof natural language processing technology will makeit possible to extract data from records of treatment
and test reports. Examples may include basic tasks,
such as creating written summaries based on apatient’s symptomatic and clinical data, to more
complex tasks, such as discovery of new clinicalknowledge. To date, we have developed a term
database to provide solutions for non-standardized
terms and abbreviations of symptoms and disease
nomenclature characteristic of medical documents,
funded by the Ministry of Health, Labour and Welfare(MHLF) Grants-in-Aid for Scientific Research(Kakenhi) in a joint research with the MEDNLP(Manbyo Dictionary) of the Nara Institute of Scienceand Technology. We are also developing a method of
obtaining the semantic representation of a text by
extracting terms constituting the text and mappingthem onto concepts defined by clinical ontology andrepeated synthesis of adjacent concepts. This process
allows “reading between the lines” to infer otherconcepts based on explicitly written concepts.
2.

Automatic diagnostic classifications based on
histopathological images of kidney disease

The widespread use of AI technology has seen an
unprecedented advancement in automation ofdiagnostic classification based on medical images.
The present program is funded by the MHLW Kakenhi
and seeks to build a database of pathology images ofkidney disease biopsies in a multicenter joint research.
It has also been working on developing methods ofdiagnoses on glomerular histological images applying
Convolutional Neural Networks (CNN). Our achievements to date are summarized as follows.
1) A facility participating in the study built a database
based on the 112,210 fluorescent antibody images and7,123 Whole Slide Image (WSI) that were provided toit. 2) A CNN assessment of estimated accuracy offluorescence intensity in images of glomeruli stainedby IgG fluorescent antibodies (F1) showed
fluorescence intensity in the mesangial, loop wall, andother regions were 75.6%, 67.9% and 60.5%,
respectively. 3) A method using Faster R-CNN on
pathologic optic microscopy images to detectmicroscopic glomeruli from high-resolution WSI wasdeveloped, achieving a higher detection accuracy thanprevious studies. 4) Twelve items in findings in PAS
staining were identified through discussion between
the five study group member experts in renal
pathology. Assessment of the degree of coincidence
indicated that there was a spread between the findings,
with kappa indices of 0.04 - 0.43. 5) The accuracy
according to CNN, which classifies glomerular
findings based on one glomerular image, resulted in a
ROC-AUC exceeding 0.9 for Extracellular matrix
sclerosis / Collapsing obsolete and Crescent. The focal
points of the CNN were also visualized to analyzeerrors in the analysis. 6) The outcomes of this study
were applied to the development of a WEB
application system that detects the glomerular region
from WSI. We plan to publish the results as a datasetwith annotations in the future.
3.

Prediction of clinical events from composite
chronological medical data

AI for medical images and videos have beendeveloped for each imaging modality, and practicalimplementation is likely to happen soon. Meanwhile,
there is also a flourishing body of research on models
applying data other than images, such as electronic
medical records including medication and testing
result data to predict clinical events. Electronic
medical records contain a lot of longitudinal data; thatis, data on one subject that is followed up andcollected over multiple points in time. However, thismakes it difficult to develop prediction models. For
example, results of sampling tests such as blood andurine test are typical types of longitudinal data. They
are also chronological data on multiple variablesconsidering the many parameters examined insampling tests. However, not all parameters aremeasured at the same time, and they are also taken at
irregular intervals, which means that missing values
make it difficult to be handled as chronological data

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and cause problems when attempting to analyze them.
Similar problems also occur in using data collectedfrom sources other than sampling test results, such as
medication orders and disease names entered for
insurance purposes. The present program aims todevelop methods that apply multiple types of medical
data as chronological order. In the past, we havereported the application of a method using
convolutional encoder for interpolation of missing
data from blood tests that are taken at irregularintervals for higher accuracy of data compared tolinear interpolation. In another study, we reported on
the efficacy of a neural network model that classifies
prognosis based on low level feature values extractedwith an anti-encoder that accounts for missing values
from a series of diabetes test items.

2.

3.

Appointed a member of the Japanese Medical
Association Gakujutsu suishinkaigi (Academic
Promotion Committee), we have been involved indefining the status quo and establishing thechallenges in AI application in health care.
Member of the ICD10 Hyoujun byoumei masuta
kentou iinkai sagyouhan [Working Group to the
Master Committee of Standard Disease
Nomenclature: 10th revision of the International
Statistical Classification of Diseases and Related
Health Problems]: Promoting standardization of
disease names and relevant codes on theelectronic medical record system as well as theconsistent and widespread use of such names andcodes.

References
4.

Research and development of a hospital datasystem for cancer genetic panel testingWith the budding application of clinical genome
sequencing, the genetic panel testing TodaiOncoPanelproject was established in Tokyo University Hospitalin 2018 under the field of advanced medical care. In
2019, genetic panel testing NCC OncoPanel, F1CDX
was started as part of insured health service. What isnotable among these cancer genomic panel studies isthat the three parties: the core and cooperative
hospitals, the Center for Cancer Genomics andAdvanced Therapeutics (C-CAT) and testing
companies are connected by a network to send clinicaldata and genomic sequencing data collected
throughout the nation to C-CAT. Program chairman
Kawazoe has been a member of the Working group for
the Core Hospitals and Cooperative Hospitals forCancer Genomic Medicine and has been conducting
research on information related to the applications ofgenomic data through developing an information
system for genomic medicine. We are alsocollaborating with the Department of Genomic
Medicine in The Tokyo University Hospital to
improve in-hospital application systems.

Social activities
1.

We have clarified the challenges for applying AI
in health care by giving presentations at various
conferences.

1. Hayakawa M, Imai T, Kawazoe Y, Kozaki K, Ohe
K. Auto-Generated Physiological Chain Data for
an Ontological Framework for Pharmacology andMechanism of Action to Determine Suspected
Drugs in Cases of Dysuria. Drug Safety. 2019,42:
1055–1069.
2. Kagawa R, Shinohara E, Imai T, Kawazoe Y, Ohe
K. Bias of Inaccurate Disease Mentions inElectronic Health Record-based Phenotyping. Int
J Med Inform. 2019 Apr;124:90-96.

357

Health Economy and Society
PolicyProject Professor
Tomoyuki Takura, Ph.D, MEng.

Project Lecturer
Project Lecturer: Seika Horiuchi, MD
Project Lecturer: Mariko Tsuji, MD
Project Lecturer: Aya Nagahata, BA
Project Lecturer: Masataka, Hasegawa, MD

Homepage

http://plaza.umin.ac.jp/hehp/

Introduction and Organization
Health Economy and Society policy is a donatedfund course established in 22nd Century Medical andResearch Center in February 2017, which is donated by
10 companies, Development Bank of Japan Inc.,
Chugai Pharmaceutical Co., Ltd., Baxter Limited,
Nihon Medi-Physics Co., Ltd., Medibrain Corporation,
Asahi Kasei Medical Co., Ltd., NIPRO Corporation,
Toray Medical Co., Ltd., JMS Co., Ltd., and Terumo
Corporation, and is cooperating with Department of
Cardiac Surgery, Division of Nephrology and Endocrinology, and Department of Clinical Epidemiology &Health Economics as cooperating course.
The social structure has been changing over recent
years and it can be assumed that policies related to the
medical system and medical industry are at a
crossroads in Japan and may undergo dramatic changes
in the future. Our department was established to discuss
future healthcare systems (medical practices andsystems, economy and industry), particularly in termsof theory construction and validation studies pertaining
to the "evaluation of the value of the healthcare field"
and other topics. Concretely, we promote theoreticaland methodological research on health technology
assessment, cost effectiveness analysis, and thehealthcare industry structure, and aim to evaluate thevalue of healthcare technologies and healthcare
systems. We also promote manpower training programs(Program for “The movements of medical value“) inhealth technology assessment with collaboration
departments.

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 painon the disease burden in Japan.
3) Testing and developing methods for evaluating laborproductivity (e.g., the productivity of cardiology
doctors) by applying data envelopment analysis(DEA) techniques.
Moreover, we are also working on a project todevelop a forecasting model for health technology
assessment (HTA) that makes use of big data. We also
have a plan to start a study that applies computational
finance to forecast the market value of research and358

development projects.

References
1. Tomoyuki Takura, Nozomi Ebata-Kogure, Yoichi
Goto, Masahiro Kohzuki, Masatoshi Nagayama,
Keiko Oikawa, Teruyuki Koyama, Haruki Itoh.
Cost-effectiveness of cardiac rehabilitation inpatients with coronary artery disease: a metaanalysis. Cardiol Res Pract. 2019; 1840894.
2. Imagama Shiro, Murakami Hideki, Kaito Takashi,
Matsuyama Yukihiro, Yamashita Toshihiko,
Kawakami Mamoru, Takahashi Kazuhisa, Yoshida
Munehito, Ohtori Seiji, Taguchi Toshihiko, Haro
Hirotaka, Taneichi Hiroshi, Yamazaki Masashi,
Inoue Gen, Nishida Kotaro, Yamada Hiroshi,
Kabata Daijiro, Shintani Ayumi, Iwasaki Motoki,
Ito Manabu, Miyakoshi Naohisa, Yonenobu Kazuo,
Takura Tomoyuki, Mochida Joji. Impact ofbackground factors on outcomes of pharmacological therapy for chronic low back pain: A
nationwide multicenter prospective study. J Orthop
Sci. 2020; 2658(20): 30051-8.
3. Ueda Kaname, Takura Tomoyuki, Fujikoshi Shinji,
Meyers Juliana, Nagar Saurabh P, Enomoto
Hiroyuki. Longitudinal Assessment of PainManagement Among the Employed Japanese
Population with Knee Osteoarthritis. Clinicalinterventions in aging. 2020; 15: 1003-1012.
4. Tomoyuki Takura, Makoto Hiramatsu, Hidetomo
Nakamoto, Takahiro Kuragano, Jun Minakuchi,
Hironori Ishida, Masaaki Nakayama, Susumu
Takahashi, Hideki Kawanishi.. Health economic
evaluation of peritoneal dialysis based on costeffectiveness in Japan: a preliminary study.
Clinicoecon Outcomes Res. 2019; 11:579-590.
5. Takashi Kaito, Yukihiro Matsuyama, Toshihiko
Yamashita, Mamoru Kawakami, Kazuhisa
Takahashi, Munehito Yoshida, Shiro Imagama,
Seiji Ohtori, Toshihiko Taguchi, Hirotaka Haro,
Hiroshi Taneichi, Masashi Yamazaki, Gen Inoue,
Kotaro Nishida, Hiroshi Yamada, Daijiro Kabata,
Ayumi Shintani, Motoki Iwasaki, Manabu Ito,
Naohisa Miyakoshi, Hideki Murakami, Kazuo
Yonenobu, Tomoyuki Takura, Joji Mochida, The
Project Committee of the Japanese Society for
Spine Surgery and Related Research (JSSR). Cost-

effectiveness analysis of the pharmacologicalmanagement of chronic low back pain with four
leading drugs. J Orthop Sci. 2019; 24(5):805-811.
6. Tomoyuki Takura, Hideki Kawanishi. Health
Economic Evaluation of Peritoneal Dialysis Basedon Cost-Effectiveness in Japan. ISPD Asia-Pacific
Chapter Newsletter. 2020; 18 (1): 18-21.
7. Tomoyuki Takura. Health Economics ― Effect ofElectronic Medical Record Systems on
Cardiovascular Disease Outpatient Consultation
Time ―. Circulation Reports. 2019; 1 (9): 355360.
8. Tomoyuki Takura. Current Trends in Medical
Economics in the Circulatory Field ―Socioeconomics Background and Research Issue―. Circulation Reports. 2019; 1 (8): 342-346.

359

Department of medical researchand the management ofmusculoskeletal pain
Professor
Koh Matsudaira, M.D,Ph.D.

Associate Professor
Hiroyuki Oka, M.D,Ph.D.

Assistant professor
Tomoko Fujii, M.D,Ph.D

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/undouki_toutu.html

Introduction and Organization
The department of medical research and the
management of musculoskeletal pain was establishedat the 22nd Century Medical and Research Centre
thanks to donations from Nippon Zoki Pharmaceutical,
AYUMI Pharmaceutical, Ono Pharmaceutical, Sompo
Holdings,Inc., NuVasive Japan, Inc, Promotion of
Practical Use of AI Medical Diagnosis Support
Equipment, MTG Co., Ltd., Shionogi & Co., Ltd. The
department is a collaboration among the Departmentof Orthopaedics, the Department of Rehabilitation
Medicine. Currently, our aims are to design analgorithm for diagnosing and treating most types ofmusculoskeletal pain that do not have establishedtreatment guidelines and to elucidate evidence for the
possibility of developing causal therapies.
In the “Comprehensive Survey of Living Conditions”
and the “Survey on the Status of Occurrence of
Diseases at Work,” which were published by the
Health, Labour, and Welfare Ministry, the issues
affecting the locomotive apparatus over the years,
particularly low back pain and joint pain, have beenranked as the top complaints among citizens and as acause of absence from work. Musculoskeletal pain,
mainly low back pain and joint pain, is an issue with ahigh complaint rate that causes tremendous social
loss.
The course on medical research and the
management of musculoskeletal pain was madeavailable to provide more knowledge on highly
prevalent musculoskeletal pain and to become a coreprogramme in leading multidisciplinary clinicalresearch.
To achieve these goals, we will closely collaborate
with the Department of Orthopaedics, Department of
Spinal Surgery, Department of Rehabilitation. On thebasis of an extensive epidemiological survey, we will
identify risk factors that contribute to determining thetherapeutic strategy for treating musculoskeletal pain
as well as the prognosis. In addition, on the basis ofthese determined risk factors, we will develop andpropose diagnostic tools/algorithms as well as
prevention and treatment programmes. Then we willcollect and analyse clinical data and systematise thediagnosis, prevention, and treatment of chronic pain –mainly musculoskeletal pain.

Research activities
We will explore the risk factors that contribute todetermining the therapeutic strategy for treating

360

musculoskeletal pain and the prognosis.

Prospects for future research
1) Systematization of chronic pain, mainly motororgan pain (collection and analysis of clinical data)
A manual that can realize back pain prevention in thefield of industrial health, treatment and work balance
support for workers who have diseases that cause
motor pain, such as cancer patients, support forbalancing chronic pain and work/reducing healthcosts.
2) Development of diagnostic tools and treatment
programs for musculoskeletal pain
Development of back pain preventive exercise,development of sensor for presenting posture toprevent back pain, development of quantitativeevaluation system for knee oseteoarthritis X-ray basedon a large database, clinical information, and medical
images of musculoskeletal diseases. Developed asystem that predicts sarcopenia and muscle weakness
with high accuracy by using medical equipment(non-invasive and simple ultrasound and artificial
intelligence), spinal canal and paraspinal muscle oflumbar spine for quantitative evaluation of fatty
degeneration in humans (joint research with Dr.
Jeremy Fairbank, University of Oxford).
3) Fostering clinicians who are familiar withmusculoskeletal pain assessment and treatment,
and enlightening the general public withevidence-based knowledge about musculoskeletal
pain

3.

4.

5.

6.

References
1. Ishimoto Y, Jamaludin A, Cooper C, Walker-BoneK, Yamada H, Hashizume H, Oka H, Tanaka S,
Yoshimura N, Yoshida M, Urban J, Kadir T,
Fairbank J. Could automated machine-learned
MRI grading aid epidemiological studies oflumbar spinal stenosis? Validation within the
Wakayama spine study. BMC Musculoskelet
Disord. 2020 Mar 12;21(1):158. doi: 10.1186/
s12891-020-3164-1. PMID: 32164627; PMCID:
PMC7066833.
2. Oshima Y, Doi T, Kato S, Taniguchi Y,

7.

Matsubayashi Y, Nakajima K, Oguchi F, Oka H,
Hayashi N, Tanaka S. Association between
ossification of the longitudinal ligament of thecervical spine and arteriosclerosis in the carotid
artery. Sci Rep. 2020 Feb 25;10(1):3369. doi:
10.1038/s41598-020-60248-3. PMID: 32098972;
PMCID: PMC7042362.
Ishii K, Iwai H, Oka H, Otomo K, Inanami H. A
protective method to reduce radiation exposure to
the surgeon during endoscopic lumbar spine
surgery. J Spine Surg. 2019 Dec;5(4):529-534.
doi: 10.21037/jss.2019.09.17. PMID: 32043003;
PMCID: PMC6989937.
Shinto K, Minamide A, Hashizume H, Oka H,
Matsudaira K, Iwahashi H, Ishimoto Y, Teraguchi
M, Kagotani R, Asai Y, Muraki S, Akune T,
Tanaka S, Kawaguchi H, Nakamura K, Yoshida M,
Yoshimura N, Yamada H. Prevalence of Facet
Effusion and Its Relationship with Lumbar
Spondylolisthesis and Low Back Pain: The
Wakayama Spine Study. J Pain Res. 2019 Dec 31;
12:3521-3528. doi: 10.2147/JPR.S227153. PMID:
32021388; PMCID: PMC6946631.
Nagata K, Oshima Y, Nakamoto H, Sakamoto R,
Ohtomo N, Izuka M, Nakajima K, Yoshimoto T,
Fujii T, Matsudaira K, Tanaka S, Oka H. Validityof the Japanese Core Outcome Measures Index(COMI)-Back for thoracic and lumbar spine
surgery: a prospective cohort study. Eur Spine J.
2020 Jun;29(6):1435-1444. doi: 10.1007/s00586019-06249-x. Epub 2019 Dec 16. PMID:
31845032.
Kobayashi H, Iwata S, Wakamatsu T, Hayakawa
K, Yonemoto T, Wasa J, Oka H, Ueda T, Tanaka S.
Efficacy and safety of trabectedin for patientswith unresectable and relapsed soft-tissue
sarcoma in Japan: A Japanese Musculoskeletal
Oncology Group study. Cancer. 2020 Mar 15;
126(6):1253-1263. doi: 10.1002/cncr.32661. Epub
2019 Dec 11. PMID: 31825533.
Fujii T, Oka H, Takano K, Asada F, Nomura T,
Kawamata K, Okazaki H, Tanaka S, Matsudaira K.
Association between high fear-avoidance beliefs
about physical activity and chronic disabling low
back pain in nurses in Japan. BMC Musculoskelet
Disord. 2019 Nov 28;20(1):572. doi: 10.1186/
s12891-019-2965-6. PMID: 31779617; PMCID:

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PMC6883590.
8. Nagata K, Yamada K, Shinozaki T, Miyazaki T,
Tokimura F, Oka H, Tajiri Y, Tanaka S, Okazaki H.
Non-inferior comparative study comparing one or
two day antimicrobial prophylaxis after clean
orthopaedic surgery (NOCOTA study): a study
protocol for a cluster pseudo-randomized
controlled trial comparing duration of antibiotic
prophylaxis. BMC Musculoskelet Disord. 2019
Nov 13;20(1):533. doi: 10.1186/s12891-0192879-3. PMID: 31722700; PMCID: PMC
6854781.
9. Iidaka T, Muraki S, Oka H, Horii C, Kawaguchi H,
Nakamura K, Akune T, Tanaka S, Yoshimura N.
Incidence rate and risk factors for radiographic
hip osteoarthritis in Japanese men and women: a
10-year follow-up of the ROAD study.
Osteoarthritis Cartilage. 2020 Feb;28(2):182-188.
doi: 10.1016/j.joca.2019.09.006. Epub 2019 Oct
16. PMID: 31629024.
10. Yoshimoto T, Oka H, Ishikawa S, Kokaze A,
Muranaga S, Matsudaira K. Factors associatedwith disabling low back pain among nursing
personnel at a medical centre in Japan: acomparative cross-sectional survey. BMJ Open.
2019 Sep 27; 9(9): e032297. doi: 10.1136/
bmjopen-2019-032297.
PMID:
31562162;
PMCID: PMC6773308.
11. 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. 2019 Nov;24(6):1074-1080.
doi:10.1016/j.jos.2019.08.014. Epub 2019 Sep 11.
PMID: 31521453.
12. Uehara K, Akai M, Doi T, Oka H, Iwaya T.
Relationship between X-ray findings of lumbar
spondylosis and knee pain. BMC Musculoskelet
Disord. 2019 Aug 17;20(1):379. doi: 10.1186/
s12891-019-2755-1. PMID: 31421680; PMCID:
PMC6698333.
13. 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.
2019
Oct;36(5):441-448.
doi:
10.1007/s10585-019-09983-0. Epub 2019 Jul 18.
PMID: 31321589.
14. Soma K, Kato S,
Oka H, Matsudaira K,
Fukushima M, Oshina M, Koga H, Takano Y, Iwai
H, Ganau M, Tanaka S, Inanami H, Oshima Y.
Influence of incidental dural tears and theirprimary microendoscopic repairs on surgicaloutcomes in patients undergoing microendoscopic
lumbar surgery. Spine J. 2019 Sep;19(9):15591565. doi: 10.1016/j.spinee.2019.04.015. Epub
2019 Apr 19. PMID: 31009767.
15. Yamada K, Nakajima K, Nakamoto H, Kohata K,
Shinozaki T, Oka H, Yamakawa K, Matsumoto T,
Tokimura F, Kanai H, Takeshita Y, Karita T, Tajiri
Y, Okazaki H, Tanaka S. Association Between
Normothermia at the End of Surgery andPostoperative
Complications
Following
Orthopedic Surgery. Clin Infect Dis. 2020 Jan 16;70(3):474-482. doi: 10.1093/cid/ciz213. PMID:
30863863.
16. Horii C, Asai Y, Iidaka T, Muraki S, Oka H,
Tsutsui S, Hashizume H, Yamada H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Tanaka S,
Yoshimura N. Differences in prevalence andassociated factors between mild and severe
vertebral fractures in Japanese men and women:
the third survey of the ROAD study. J Bone Miner
Metab. 2019 Sep;37(5):844-853. doi: 10.1007/
s00774-018-0981-5. Epub 2019 Jan 3. PMID:
30607619.
17. Fujimoto Y, Fujii T, Oshima Y, Oka H, Tanaka S,
Matsudaira K. The association between neck andshoulderdiscomfort-Katakori-andhighsomatizing tendency. Mod Rheumatol. 2020 Jan;30(1):191-196. doi: 10.1080/14397595.2018.
1551177. Epub 2019 Jan 3. PMID: 30482076.
18. Oka H, Nomura T, Asada F, Takano K, Nitta Y,
Uchima Y, Sato T, Kawase M, Sawada S,
Sakamoto K, Yasue M, Arima S, Katsuhira J,
Kawamata K, Fujii T, Tanaka S, Konishi H,
Okazaki H, Miyoshi K, Watanabe J, Matsudaira K.
The effect of the 'One Stretch' exercise on the
improvement of low back pain in Japanese nurses:
A large-scale, randomized, controlled trial. Mod
Rheumatol. 2019 Sep;29(5):861-866. doi: 10.

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1080/14397595.2018.1514998. Epub 2019 Jan 3.
PMID: 30130991.

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Department of Medical Genomics
Project Associate Professor
Noriko Hosoya, M.D., Ph.D. (~April, 2019).

Project Assistant Professor
Satoshi Inoue, Ph.D.

Introduction and organization
Department of Medical Genomics was establishedwith Project Professor Hiroyuki Mano in September
2009 with the goal to identify essential growth drivers
in every cancer, by taking advantage of our functional
screening system coupled with the next generation
sequencing technologies. Department of Medical
Genomics had been settled by the tight support from
Department of Molecular Pathology (Professor Kohei
Miyazono) and by the donation from Astellas Pharma
Inc. and Illumina, Inc. Starting as of September 2012,
Department of Medical Genomics had been run onlyby the donation from Astellas Pharma Inc. In April
2013, Project Professor Hiroyuki Mano was promoted
to be the Professor of Department of Cellular
Signaling which then co-supported this department.
Instead, Project Associate Professor Yoshihiro
Yamashita led this department. Starting from
September 2014, Department of Medical Genomics
has entered the second 5-year term by the support
from Eisai Co., Ltd. In September 2014, Dr. Yoshihiro
Yamashita was promoted to become Associate
Professor at Department of Cellular Signaling, andthis department was run by the leadership of Project
Associate Professor Eirin Sai. After the retirement of
Dr. Sai in March 2017, Dr. Masahito Kawazu
managed this department as Project Associate
Professor from April 2017 until March 2018. From
April 2018, Dr. Shogo Ehata took his position as
Project Associate Professor of this department until
August 2018, and was then promoted to become
Associate Professor of Environmental Science Centerof The University of Tokyo. From September 2018,
this department has been co-supported by Laboratoryof Molecular Radiology (Professor Kiyoshi
Miyagawa). From November 2018, Dr. Noriko
Hosoya served as Project Associate Professor of thisdepartment until April 2019, and then was promoted
to become Associate Professor of Laboratory of
Molecular Radiology in May 2019.
Department of Medical Genomics enjoyed a wide
range of research collaboration with many academic
institutes within Japan and also from abroad.
Especially, this department was under an intimate
collaboration with Department of MolecularPathology and Laboratory of Molecular Radiology.
We also supported cancer genomic medicine using a
multiplex genome sequencing, named "Todai
OncoPanel” at the University of Tokyo Hospital. This
department ended in August 2019.

Teaching activities
We took the responsibility for the lectures of generalpathology and basic radiation medicine as well as thetraining of handling radioactive materials for theundergraduate students of School of Medicine. We
also accepted undergraduate students taking “Free
Quarter” and “Early-Exposure-to-Medicine” courses.
We also took part in the education of radiation healthscience for the 3rd year students of School ofIntegrated Health Sciences and the lectures ofmolecular biology for graduate students of the
Graduate School of Medicine. We also delivered
training on basic medical research for bothundergraduate students and graduate students.

364

Research activities
Department of Medical Genomics tried to fulfill ourgoals mainly through the following approaches.
(1) Functional screening with the use of retroviral
cDNA expression libraries.
The focus formation assay had been widely used in
1980s and 1990s to identify oncogenes from humancancer. However, since this technology directly usescancer genome to transfer oncogenes into recipient
cells, expression of each gene is regulated by its own
promoter/enhancer fragments. Therefore, suchtechnology is theoretically unable to capture
oncogenes whose promoter/enhancer is silent inrecipient cells. To make every gene expressedsufficiently in recipient cells, we here developed ahighly efficient retrovirus–mediated cDNA expression
library system. Our system enables to make a librarywith high complexity (containing millions of
independent cDNA clones) even from < 104 of cells.
Application of this technology to a lung cancer
specimen led to the discovery of a novel fusion-type
oncogene EML4-ALK (Nature 448:561). A tiny
chromosomal inversion, inv(2)(p21p23), within lungcancer cells fuses EML4 (Echinoderm microtubule
associated protein like 4) to ALK (anaplastic
lymphoma kinase), resulting in the production of aconstitutively active tyrosine kinase EML4-ALK.
Many pharmaceutical companies are currently
developing ALK inhibitors, and more than six ofdifferent inhibitors are under clinical trials to treat
EML4-ALK-positive lung cancer. The efficacy of oneof such compounds, crizotinib, has been publishedalready, and, surprisingly treatment with crizotinib
resulted in ~90% of response rate plus the presence of
patients under complete remission. Crizotinib wasapproved as a therapeutic drug against lung cancer asof August 2011, which is the record-breaking speed in
the history of cancer drug development.
We examined gene copy number of EML4-ALK–
positive tumors in a genome-wide manner, and foundthat copy number alterations in oncogenes andtumor-suppressor genes are significantly less frequentin tumors harboring EML4-ALK than those without it.
(2) Cancer genome resequencing
In addition to the functional screening shown above,
we also tried to search for somatically mutated genes

in human cancers with the use of “the next generation
sequencers (NGS)”. While development of NGS has
enabled us to determine the full genome sequence of acancer specimen even in private laboratories, it is stilla demanding task to conduct full-genome sequencing
for a large number of samples. Therefore, manylaboratories now purify exonic fragments from asample genome, and determine their sequences.
However, since gene fusions usually take place at
intronic regions, such sequencing approach with
captured exons fails to discover fusion genes.
Thus, we have developed a “cDNA-capturesystem”, in which exon capture is conducted on cDNA,
not genomic DNA. With this technology, a single
NGS experiment can detect point mutations,insertions/deletions and gene fusions simultaneously(Cancer Sci 103:131)
We applied this technology to a humanfibrosarcoma cell line, HT1080, leading to thediscovery of oncogenic mutants among small GTPases,
NRAS(Q61K) and RAC1(N92I) (PNAS 110:3029).
Interestingly, RAC1(N92I), but not NRAS(Q61K),
was shown to be an essential growth driver to whichcancer cells are addicted.
(3) High-throughput functional evaluation method
Numerous variants of unknown significance (VUS)
have been identified through large-scale cancer
genome projects, although their functional relevanceremains uninvestigated. The L858R substitution orexon 19 deletions are, for instance, known to confer
activation of epidermal growth factor receptor (EGFR)
kinase, but there are more than one thousand of
nonsynonymous mutations within EGFR reported in
the COSMIC database. It is still obscure whether suchmutations have some relevance to EGFR kinase
activity or are merely passenger mutations. To
drastically increase the speed of functional annotation,
here we have developed a mixed-all-nominatedmutants-in-one (MANO) method to evaluate thetransforming potential and drug sensitivity of
oncogene VUS in a high-throughput manner. To
validate its usefulness, we applied this method to 101
nonsynonymous EGFR mutants, and successfully
evaluated clinical relevance of each mutations. Also,
we assessed functional relevance of 55 VUSs in the
ERBB2 gene, revealing that many VUSs have distinct
sensitivity to different ERBB2 inhibitors.

365(4) Comparative analysis of TTF-1-binding DNA
regions in SCLC and non-SCLC
In collaboration with a group at the Department of
Molecular Pathology, we have conducted genomewide comparative analysis of thyroid transcription
factor-1 (TTF-1, encoded by the NKX2-1 gene)binding DNA regions in small-cell lung carcinoma(SCLC) and non-small-cell lung carcinoma (NSCLC).
TTF-1 is highly expressed in both SCLC and NSCLC.
TTF-1 antagonizes the effect of TGF-β in the
induction of epithelial-mesenchymal transition (EMT)in NSCLC, and functions as an anti-tumorigenic factor.
We compared the genome-wide distributions of TTF-1
binding regions and the transcriptional programs
regulated by TTF-1 using a human SCLC cell line
NCI-H209 (H209) and a human lung adenocarcinoma(NSCLC) cell line NCI-H441 (H441), by ChIP-seq
and RNA-seq analyses. TTF-1 binding regions in
H209 and H441 cells differed by 75.0%. ASCL1 (alsoknown as ASH1) is an E-box binding basic helix-loophelix transcription factor, and a lineage-survival
oncogene of SCLC. We found that TTF-1 and ASCL1
were coexpressed and bound to adjacent sites on target
genes in SCLC, and cooperatively regulate transcripttion of them. Moreover, TTF-1 regulated expressionof the Bcl-2 gene family and showed anti-apoptotic
function in SCLC. Thus, TTF-1 promotes SCLC
growth by partly coordinating with ASCL1 and serves
as a pro-tumorigenic factor in SCLC (also see theSection of “Department of Molecular Pathology”).
(5) Molecular mechanisms underlying DNA repair andits regulation
Genomic instability describes a state in which there isan increased tendency to acquire genetic alterations
and is a hallmark of cancer. Aberrations in DNA repair
machinery in cancer cells not only cause genomic
instability but also provide promising biomarkers or
targets for cancer therapy. While both activation andinactivation of DNA repair are observed in various
sporadic cancers, the molecular mechanisms
underlying aberrations in DNA repair machinery are
not fully understood. We recently focus on the roles of“cancer-testis antigens”, which are normally expressed
only in the germ cells but are also expressed atvarying levels in cancer. We have reported that theseantigens can modulate DNA repair in cancer invarious manners. For example, the cancer-testis

antigen SYCP3 impairs mitotic DNA double-strand
break repair by interfering with the homologous
recombination protein BRCA2 (Hosoya et al, EMBO
Rep 2012). Another cancer-testis antigen SYCE2
constitutively insulates the chromatin-related protein
HP1α from heterochromatin and potentiates DNA
double-strand break repair, inducing radioresistance(Hosoya et al, Life Science Alliance 2018). Based onthese achievements, we are now investigating the rolesof other cancer-testis antigens in regulating genomic
stability and also trying to clarify the functional links
between the nuclear microenvironment and DNA
repair or between cell cycle regulation and DNA repair.
Recently, we have found that another cancer-testis
antigen SYCE3 does not affect DNA repair but
promotes cancer cell survival by regulating cell
division throughout mitosis, indicating that cancertestis antigens can induce genomic instability throughvarious mechanisms.

References
1. Namba, S., Sato, K., Kojima, S., Ueno, T.,
Yamamoto, Y., Tanaka, Y., Inoue, S., Nagae, G.,
Iinuma, H., Hazama, S., Ishihara, S., Aburatani,
H., Mano, H., and Kawazu M. (2019) Differential
regulation of CpG island methylation withindivergent and unidirectional promoters incolorectal cancer. Cancer Science 110 (3), 10961104. doi: 10.1111/cas.13937.
2. Kohsaka, S., Tatsuno, K., Ueno, T., Nagano, M.,
Shinozaki-Ushiku, A., Ushiku, T., Takai, D.,
Ikegami, M., Kobayashi, H., Kage, H., Ando, M.,
Hata, K., Ueda, H., Yamamoto, S., Kojima, S.,
Oseto, K., Akaike, K., Suehara, Y., Hayashi, T.,
Saito, T., Takahashi, F., Takahashi, K., Takamochi,
K., Suzuki, K., Nagayama, S., Oda, Y., Mimori,K., Ishihara, S., Yatomi, Y., Nagase, T., Nakajima,J., Tanaka, S., Fukayama, M., Oda, K., Nangaku,M., Miyazono, K., Miyagawa, K., Aburatani, H.,
and Mano, H. (2019) Comprehensive assay for themolecular profiling of cancer by target enrichmentfrom formalin-fixed paraffin-embedded specimens. Cancer Science 110 (4), 1464-1479. doi:
10.1111/cas.13968.
3. Taguchi, L., Miyakuni, K., Morishita, Y.,
Morikawa, T., Fukayama, M., Miyazono, K., and

366

4.

5.

6.

7.

Ehata, S. (2019) c-Ski accelerates renal cancer
progression by attenuating transforming growth
factor-β signaling. Cancer Science 110 (6), 20632074. doi: 10.1111/cas.14018.
Nakai, Y., Okamoto, K., Terashima, A., Ehata, S.,
Nishida, J., Imamura, T., Ono, T., and Takayanagi,
H. (2019) Efficacy of an orally active smallmolecule inhibitor of RANKL in bone metastasis.
Bone Research 7, 1. doi: 10.1038/ s41413-0180036-5.
Sato, K., Kawazu, M., Yamamoto, Y., Ueno, T.,
Kojima, S., Nagae, G., Abe, H., Soda, M., Oga, T.,
Kohsaka, S., Sai, E., Yamashita, Y., Iinuma, H.,
Fukayama, M., Aburatani, H., Watanabe, T., andMano, H. (2019) Fusion kinases identified bygenomic analyses of sporadic microsatellite
instability-high colorectal cancers. ClinicalCancer Research 25 (1), 378-389. doi: 10.1158/
1078-0432.CCR-18-1574.
Hokari, S., Tamura, Y., Kaneda, A., Katsura, A.,
Morikawa, M., Murai, F., Ehata, S., Tsutsumi, S.,
Ishikawa, Y., Aburatani, H., Kikuchi, T.,
Miyazono, K., and Koinuma, D. (2019)
Comparative analysis of TTF-1-binding DNA
regions in small cell lung cancer and non-small
cell lung cancer. Molecular Oncology 14 (2), 277293. doi: 10.1002/1878-0261.12608.
Inoue, S., Hirota, Y., Ueno, T., Fukui, Y., Yoshida,E., Hayashi, T., Kojima, S., Takeyama, R.,
Hashimoto, T., Kiyono, T., Ikemura, M., Taguchi,A., Tanaka, T., Tanaka, Y., Sakata, S., Takeuchi,K., Muraoka, A., Osuka, S., Saito, T., Oda, K.,
Osuga, Y., Terao, Y., Kawazu, M., and Mano, H.
(2019) Uterine adenomyosis is an oligoclonal
disorder associated with KRAS mutations. Nature
Communications 10 (1), 5785. doi: 10.1038/
s41467-019-13708-y.

367

Department of Osteoimmunology
Project Associate Professor
Kazuo Okamoto, Ph.D.

Project Assistant Professor
Asuka Terashima, Ph.D.

Homepage

http://www.osteoimmunology.com/kifu.html

Introduction and Organization
Bone is a key component of the skeletal-locomotor
system and serves as a calcium reservoir regulated by
the endocrine system in vertebrates. Bone also acts
as the “primary lymphoid organ” that harbors andmobilizes hematopoietic stem cells (HSCs) andimmune progenitor cells. Furthermore, the bone andimmune systems are closely related through a numberof shared regulatory molecules including cytokines,
receptors and signaling molecules.
Osteoimmunology is an interdisciplinary research field thatinvestigates the shared mechanisms and crosstalks
between the bone and the immune systems. Studies
on bone destruction associated rheumatoid arthritis(RA) have highlighted regulation of bone by the
immune cells and promoted this field. As seen in theclinical benefits of anti-TNF antibody, anti-IL-6
antibody and CTLA4-Ig on inflammation andosteoclast differentiation for the treatment of RA, theosteoimmunological insight is now of growing
importance in clinical applications. It is necessary tocomprehensively understand the interplay betweenbone and immune systems for elucidation of themolecular mechanisms underlying the pathogenesis ofvarious bone diseases (osteoporosis, osteoarthritis,
periodontal disease etc.) and immune diseases(autoimmune diseases, infectious diseases etc.).
Osteoimmunology is now emphasized by not only
the academic but also clinical sides, and theinternational competition has intensified in both basic
and pharmaceutical researches. This department was
founded as a new department focusing on the osteo-

immunology in May 2016, with the support of Noevir
Co., Ltd., Chugai Pharmaceutical Co., Ltd. andAYUMI Pharmaceutical Corporation. 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.
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

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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).
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 ovariectomy-

induced osteoporosis.
Thus, membrane-boundRANKL mainly functions in osteoclast differentiationin vivo Furthermore, unlike RANKL-null mice,soluble RANKL-deficient mice had normal
development of the immune organs, including lymph
node development, thymic medullary epithelial celldifferentiation and M cell differentiation. Collectively,
we demonstrated that soluble RANKL is dispensablefor physiological regulation of bone and immune
systems (Asano et al, Nat Metab, 2019).
RANKL also deeply contributes to the pathogenesisof bone metastasis. In bone, tumor cells induce theRANKL expression in osteoblasts through the
production of PTHrP and IL-6. RANKL promotes
osteoclastic bone resorption, which provides space fortumor expansion and releases certain growth factors
from the degraded bone matrices to stimulate tumor
growth, forming a vicious cycle. In addition, RANK
is expressed at high levels on many different epithelial
tumor cells that preferentially metastasize to bone.
RANKL acts directly on RANK-expressing tumor
cells to increase tumor migration to bone. Notably,soluble RANKL contributes to bone metastasis byexerting a chemotactic activity in tumor cells
expressing RANK (Asano et al, Nat Metab, 2019).
Soluble RANKL deficiency in mice markedly
suppressed the metastasis of murine melanoma cellline B16F10 and breast cancer cell line EO771, bothof which express RANK, to bone. Interestingly, therecent human study indicates that breast cancer
patients with high levels of serum RANKL had anincreased risk of developing bone metastases. Thus,
to measure the serum RANKL level may help identify
the patients who have a high risk of development ofbone metastasis.
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).

369

Roles of T cells in bone destruction associated with
inflammation
The bone destruction in RA is the result of theenhanced osteoclast activity due to the inflammatory
responses triggered by the activation of pathogenic
helper T cells. We previously reported using amouse model of autoimmune arthritis that a subset of
Foxp3+ T cells loses Foxp3 expression under arthritic
conditions and converts into IL-17-prodcing T cells(called exFoxp3Th17 cells).
exFoxp3Th17 cells
display a greater capacity for inducing both synovitis
and osteoclastic bone resorption (Komatsu et al, Nat
Med, 2014). The conversion of Foxp3+ T cells into
effector T cells has also been observed in various
diseases such as diabetes and multiple sclerosis. We
have recently demonstrated that exFoxp3Th17 cells
also act as osteoclastogenic T cells in alveolar bone
destruction in periodontitis.
exFoxp3Th17 cells
accumulate in periodontitis tissues in response to oral
bacteria, and stimulate mesenchymal cells including
osteoblastic cells and periodontal ligament cells to
induce RANKL. We found that exFoxp3Th17 cells
protect against bacteria by evoking mucosal immune
responses as well as removing the tooth (Tsukasaki etal, Nat Commun, 2018). Our findings introduce a
new concept that bone destruction contributes to thehost defense against oral bacteria in periodontitis.
In recent years, Jak inhibitors have attracted
attention as potential agents for the autoimmune
diseases such as rheumatoid arthritis. We haverecently found that protein arginine methylation, a
post-translational modification, is critically involvedin the regulation of the Jak signaling pathway. T
cell-specific deficiency of the arginine methyltransferase PRMT5 led to a decrease in the number of
peripheral CD4, CD8 and regulatory T cells, and analmost complete loss of iNKT cells.
PRMT5mediated arginine methylation was essential for the
expression of the cytokine-signal-transducing components, the common cytokine receptor γ-chain (γc)
and JAK3, which are required for the development of
iNKT cells and the proliferation and survival of
peripheral T cells. PRMT5 induced the arginine
methylation of the spliceosomal component SmD3
that promoted the splicing of pre-mRNA encoding γc
and JAK3 (Inoue et al, Nature Immunol, 2018). This
study presented a novel regulatory mechanism

governing γc family cytokine-Jak3 signaling in T
cells.
Immune regulation by osteoblast in the bone marrow
HSCs have the capacity to differentiate into all
immune cells, and their activities require extrinsic
signals from the microenvironments (niches) in thebone marrow. Various cell types including CXCL12abundant reticular (CAR) cells, leptin receptorexpressing perivascular stromal cells, Nestin+
perivascular cells and neural cells have been shown to
be important for HSC maintenance. Although osteoblasts were first reported to function as the HSC niche
about 10 years ago, the significance of the osteoblastic
niche has 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. Asano T, Okamoto K*, Nakai Y, Tsutsumi M,
Muro R, Suematsu A, Hashimoto K, Okamura T,
Ehata S, Nitta T, Takayanagi H*. (*corresponding
authors) Soluble RANKL is physiologicallydispensable but accelerates tumour metastasis tobone. Nature Metabolism, 1:868–875, 2019
2. Terashima A, Takayanagi H. The role of bonecells in immune regulation during the course of
infection. Semin Immunopathol. 41: 619-626,
2019
3. Hayashi M, Nakashima T, Yoshimura N, Okamoto
K, Tanaka S, Takayanagi H. Autoregulation of
osteocyte Sema3A orchestrates estrogen action
and counteracts bone aging. Cell Metabolism, 29:
1-11, 2019

370

4. Nakai Y, Okamoto K*, Terashima A, Ehata S,
Nishida J, Imamura T, Ono T, Takayanagi H.* (*:corresponding authors) Efficacy of an orally
active small-molecule inhibitor of RANKL inbone metastasis. Bone Research, 7: 1, 2019
5. Okamoto K, Takayanagi H. Osteoimmunology.
Cold Spring Harbor Perspectives in Medicine, 9:
1, 2019

371

Department of Continence
Medicine
Project Professor
Yasuhiko Igawa, M.D.,Ph.D.

Project Assistant Professor
Naoki Aizawa, Ph.D.

Homepage: http://cont-med.umin.jp/
Introduction and Organization

Clinical activities

Our department has been established as anendowment department supported by Astellas Pharma
Inc. in close collaboration with the Department ofUrology on July 1st 2010 to facilitate researches
specially focusing on continence medicine. Since July,
2013, this department has been received kind
donations from six pharmaceutical companies(Astellas Pharma Inc., Asahi-kasei Pharma Corp., Ono
Pharmaceutical Co., Ltd, Kissei Pharmaceutical Co.,
Ltd, Kyorin Pharmaceutical Co., Ltd, and Taiho
Pharmaceutical Co., Ltd).
The aim of our department is to contribute to theadvancement of continence medicine through basic
and clinical researches on regulation mechanisms oflower urinary tract (LUT) function and pathphysiology of LUT dysfunction, as well as function/
dysfunction of lower bowel and pelvic floor.
We believe that a multi-disciplinary professionalteam consisted of physicians, surgeons, nurses,
physiotherapists, bio-engineers, social workers andscientists is necessary to achieve greater advancementof continence medicine and care. We hope many
researchers with different specialties are interested inour research themes and collaborate with us for the
purpose of supporting patients with continence
problems by providing them better treatment andmanagement strategies.

Professor Igawa offers clinical services specialized
for patients with intractable lower urinary tract
dysfunction as well as for children with urogenital
disorders in conjunction with the Department ofUrology.

Teaching activities
We take part in providing systematic urologicallectures for second year medical students, and bed
side teaching for third and fourth year medical
students.

Research activities
We are currently investigating regulation mechanisms of lower urinary tract (LUT) function, andpathophysiological mechanisms of various LUT dysfunction, including overactive bladder (OAB), bladderoutlet obstruction (BOO), interstitial cystitis/bladderpain syndrome(IC/BPS), and underactive bladderdysfunction, especially focusing on:
1. To elucidate bladder sensory transduction mechanisms
2. To disclose pathophysiology of development of
detrusor overactivity/OAB
3. To find useful biomarkers for IC/BPS
4. To evaluate the effects of metabolic syndrome on
LUT function

372

5. To develop novel pharmacological treatment forrefractory LUT dysfunction
6. To establish continence-care system consisted ofmulti-disciplinary professionals to contribute to
the advancement of continence medicine

Publications
1. Igawa Y, Aizawa N, Michel MC. β(3)Adrenoceptors in the normal and diseased urinary
bladder - what are the open questions? Br J
Pharmacol. 2019 Mar 14. doi: 10.1111/bph.14658.
[Epub ahead of print] Review
2. Akiyama Y, Maeda D, Katoh H, Morikawa T,
Niimi A, Nomiya A, Sato Y, Kawai T, Goto A,
Fujimura T, Fukuhara H, Nakagawa T, Igawa Y,
Ishikawa S, Fukayama M, Kume H, Homma Y.
Molecular Taxonomy of Interstitial Cystitis/
Bladder Pain Syndrome Based on Whole
Transcriptome Profiling by Next-Generation RNA
Sequencing of Bladder Mucosal Biopsies. J Urol.
2019 Mar 13:101097JU0000000000000234. doi:
10.1097/JU.0000000000000234. [Epub ahead ofprint]
3. Kamei J, Watanabe D, Homma Y, Kume H, Igawa
Y. Feasibility of approximate measurement of
bladder volume in male patients using the Lilium
α-200 portable ultrasound bladder scanner. Low
Urin Tract Symptoms. 2019 Mar 10. doi:10.1111/
luts.12258. [Epub ahead of print]
4. Suzuki M, Miyazaki H, Kamei J, Yoshida M,
Taniguchi T, Nishimura K, Igawa Y, Sanada H,
Homma Y. Ultrasound-assisted prompted voiding
care for managing urinary incontinence in nursing
homes: A randomized clinical trial. Neurourol
Urodyn. 2019 Feb;38(2):757-763.
5. Aizawa N, Ohshiro H, Watanabe S, Kume H,
Homma Y, Igawa Y. RQ-00434739, a novel
TRPM8 antagonist, inhibits prostaglandin E2induced hyperactivity of the primary bladderafferent nerves in rats. Life Sci. 2019 Feb 1;218:
89-95
6. Yamaguchi O, Kakizaki H, Homma Y, Igawa Y,
Takeda M, Nishizawa O, Gotoh M, Yoshida M,
Yokoyama O, Seki N, Okitsu A, Hamada T,
Kobayashi A, Kuroishi K. Long-term safety andefficacy of antimuscarinic add-on therapy inpatients with overactive bladder who had asuboptimal response to mirabegron monotherapy:
A multicenter, randomized study in Japan (MILAI
II study). Int J Urol. 2019 Mar;26(3):342-352
7. Yoshida M, Matsunaga A, Igawa Y, Fujimura T,
Shinoda Y, Aizawa N, Sato Y, Kume H, Homma Y,
Haga N, Sanada H. May perioperative ultrasoundguided pelvic floor muscle training promote earlyrecovery of urinary continence after robot-assisted
radical prostatectomy? Neurourol Urodyn. 2019
Jan;38(1):158-164.
8. Kamei J, Aizawa N, Nakagawa T, Kaneko S,
Kume H, Homma Y, Igawa Y. AttenuatedLipopolysaccharide-induced inflammatory bladder hypersensitivity in mice deficient of transient
receptor potential ankilin1. Sci Rep. 2018 Oct 23;
8(1):15622. doi: 10.1038/s41598-018-33967-x.
9. Aizawa N, Watanabe D, Fukuhara H, Fujimura T,
Kume H, Homma Y, Igawa Y. Inhibitory effects ofsilodosin on the bladder mechanosensitiveafferent activities and their relation with bladder
myogenic contractions in male rats with bladderoutlet obstruction. Neurourol Urodyn. 2018 Aug;37(6):1897-1903
10. Aizawa N, Fujimori Y, Kobayashi JI, Nakanishi O,
Hirasawa H, Kume H, Homma Y, Igawa Y. KPR2579, a novel TRPM8 antagonist, inhibits acetic
acid-induced bladder afferent hyperactivity in rats.
Neurourol Urodyn. 2018 Jun;37(5):1633-1640
11. Akiyama Y, Niimi A, Nomiya A, Yamada Y,
Nakagawa T, Fujimura T, Fukuhara H, Kume H,
Igawa Y, Homma Y. Extent of Hunner lesions:
The relationships with symptom severity andclinical parameters in Hunner type interstitial
cystitis patients. Neurourol Urodyn. 2018 Apr;
37(4):1441-1447
12. Yamada Y, Fujimura T, Fukuhara H, Sugihara T,
Nakagawa T, Kume H, Igawa Y, Homma Y.
Predictors of Early Continence after Robotassisted Radical Prostatectomy. Low Urin Tract
Symptoms. 2018 Sep;10(3):287-291

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Department of Computational
Diagnostic Radiology andPreventive Medicine
Project Professor
Naoto Hayashi, M.D.,Ph.D.

Project Associate Professor
Kansei Uno, M.D.,Ph.D., Takeharu Yoshikawa, M.D.,Ph.D.

Project Assistant Professor
Yukihiro Nomura, Ph.D., R.T.

Project Research Associate
Kensuke Asaba, M.D.,Ph.D., Eriko Maeda, M.D.,Ph.D., Soichiro Miki, M.D., Ph.D.,
Aya Watanabe, M.D.,Ph.D., Katsura Soma, M.D.,Ph.D., Katsuhiro Koyama, M.D., Ph.D.

Project researcher
Masaya Akiyama, M.S., Hisaichi Shibata, Ph.D., Tomomi Takenaga, Ph.D., R.T.,
Quing Chang, Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/computer.html

Introduction and Organization
The Department of Computational Diagnostic
Radiology and Preventive Medicine (CDRPM) wasestablished in May 2005. It is under the supervision of
the Department of Radiology.
The aim of our research project is as follows: (1) tocreate a large database of health screening clinical data
including medical images, (2) to develop methods toanalyze large volumes of medical images and to search
for algorithms to detect subtle abnormal findings inthese images, and (3) to evaluate the clinical usefulnessof such image processing methods and to apply thesystem in clinical settings.
The department comprises three project associate
professors, five project research associates and two
project researchers, along with a medical staff ofapproximately 50 employees in the health-screening

center.

Clinical Activities
CDRPM is responsible for the clinical activities in
the CDRPM Health Screening Center. The following
diagnostic imaging modalities are installed to facilitatehigh level of diagnostic accuracy: positron emission
computed tomography (PET), 3-tesla magnetic
resonance imaging (3T-MRI) system, multidetector CT(MDCT), ultrasound imaging system, and digital
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

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themes include image analysis such as computerassisted detection, or epidemiologic studies employing
health-screening data.
3)

Research Activities
1) Health screening database
We have developed a unique health screening information system to facilitate daily management of thehealth screening activities and to input health screening
data. This information system is still under constantrevision. The medical images acquired in the healthscreenings are stored in the hospital picture archiving
and communication system (PACS) for clinical use.
Medical images used solely for research purposes are
stored in an independent PACS installed inside 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 forsoftware development, and clinical application of thedeveloped software. The research part consists of aninterface to obtain images of the representative cases todevelop the software, and an interface to test thedeveloped 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) Abe H, Takeda N, Isagawa T, Semba H, Nishimura
S, Morioka M,S., NakagamaY, Sato T, Soma K,
Koyama K, et al. Macrophage hypoxia signaling
regulates cardiac fibrosis via Oncostatin M. Naturecommunications 2019;10(1):1; 1.
2) Hanaoka S, Nomura Y, Takenaga T, Murata M,
Nakao T, Miki S, et al. HoTPiG: a novel graphbased 3-D image feature set and its applications tocomputer-assisted detection of cerebral aneurysms

4)

5)

6)

7)

8)

and lung nodules. International journal forcomputer assisted radiology and surgery 2019;14(12):2095; 2095-2107; 2107.
Hoshiai S, Masumoto T, Hanaoka S, Nomura Y,
Mori K, Hara T, et al. Clinical usefulness of
temporal subtraction CT in detecting vertebral
bone metastases. Eur J Radiol 2019;118:175; 175180; 180.
Nomura Y, Miki S, Hayashi N, Hanaoka S, Sato I,
Yoshikawa T, et al. Novel platform for development, training, and validation of computer-assisted
detection/diagnosis software. International journal
for computer assisted radiology and surgery 2020;
15(4):661; 661-672; 672.
Nomura Y, Nemoto M, Hayashi N, Hanaoka S,
Murata M, Yoshikawa T, et al. Pilot study oferuption forecasting with muography using
convolutional neural network. Scientific reports
2020;10(1):-.
Okamura K, Nakagama Y, Takeda N, Soma K,
Sato T, Isagawa T, et al. Therapeutic targeting of
mitochondrial ROS ameliorates murine model ofvolume overload cardiomyopathy. Journal ofpharmacological sciences 2019;141(1):56; 56-63;
63.
Sassa T, Nakayama A, Saito A, Soma K, Inuzuka
R, Hirata Y, et al. Combination Therapy ofFenestrated-Fontan Procedure with Medication
Improved Double-outlet Right Ventricle in
Adulthood. J Cardiovasc Imaging 2019 Oct;27(4):288-289.
Takenaga T, Hanaoka S, Nomura Y, Nemoto M,
Murata M, Nakao T, et al. Four-dimensional fully
convolutional residual network-based liver
segmentation in Gd-EOB-DTPA-enhanced MRI.
International journal for computer assisted
radiology and surgery 2019;14(8):1259; 12591266; 1266.

375

Department of Home Care
Medicine
Project Associate Professor
Takashi Yamanaka, M.D., Ph.D.

Project Lecturer
Jiro Okochi, M.D., Ph.D.

Project Assistant Professor
Kiwami Kidana, M.D., Ph.D., Bo-Kyung Son, Ph.D.

Project Researcher
Shigemasa Katayama, M.D., Ph.D., Tatsuya Kurokawa, M.D., Ph.D.,
Maiko Mizuki, MPH., Shota Hamada, R.Ph., Dr.P.H.

Project Academic Support Staff
Satomi Kudo

Homepage

http://chcm.umin.jp/

Introduction and Organization
Department of Home Care Medicine was establishedin 2018 at the 22nd Century Medical and ResearchCenter in the University of Tokyo Hospital based upon
contributions by Mr. Kazuteru Noguchi, JSH Co., Ltd.,
Japan Home Medical Care Inc., Towa Pharmaceutical
Co. Ltd., Sawai Pharmaceutical Co. Ltd., AKTIO
Corporation and Ain Pharmaciez. Our department
collaborates with Department of Geriatric Medicine.
We have taken over educational activities and research
activities from Center for Home Care Medicine,
Faculty of Medicine.
With the increase in the elderly population, home care
medicine is more needed compared with the past. We
teach home care medicine to medical students andtrainee doctors along with studying the topics of homecare medicine to systematize it.

Education
Clinical education of home care medicine is provided
for fifth and sixth year medical students. We create apersonalized mandatory program of home care
medicine and give an orientation of the program. Then
medical students learn about home care medicine withphysicians, nurses, medical social workers or caremanagers in the community. We got the third prize forthe best clinical department in clinical clerkshipprogram, Faculty of Medicine rated by medical
students in 2018.
We also create a program of home care medicine fortrainee doctors who wish to learn about it.

Research
The main themes of our study were as follows.
1) Educational program development of home care
medicine and studying the educational effectiveness of the program2) Building a database of patients who receive home
medical care
3) Follow-up study on QOL or prognosis of patients
who receive home medical care and their caregivers3764) Drug treatment in home medical care5) Skills of medical therapeutics and care in homecare medicine

Publications
English Article
1. Noguchi-Watanabe M, Maruyama-Sakurai K,
Yamamoto-Mitani N, Matsumoto Y, Yoshie S,
Iijima K, Yamanaka T, Akishita M.
Community-based program promotes interprofessional collaboration among home healthcare
professionals: A non-randomized controlled study.
Geriatr Gerontol Int. 2019;19(7):660-666.
2. Kidana, K, Ishii, S, Osawa, I, Yoneda A,
Yamaguchi K, Yamaguchi Y, Tsuji K, Akishita M,
Yamanaka T. Medication prescription in older
people receiving home medical care services.
Geriatr. Gerontol. Int. 2019;19(12):1292–1293.
Conference Presentations
1. Yamanaka T (Lecture): Current Status andProspect of Home Care Medicine in Japan:
Homeward Medical Services. Parallel Session1
Integrated Healthcare and Community Care. The
10th Korea Healthcare Congress. Seoul, Korea,
2019.4.4.
2. Yamanaka T (Lecture): The Role of Home Care
Medicine in Aging Society. 30th Anniversary
symposium of Department of Family Medicine,
Asan Medical Center. Seoul, Korea, 2019.6.14.
3. Yamanaka T (Lecture): Home Care Medicine inJapan. China international health care industry
EXPO (Jinan) and medical care high-level summit.
Jinan, Shandong, China, 2019.6.16.
4. Yamanaka T (Lecture): Comprehensive Geriatric
Assessment and Nutritional Management in Home
Care Medicine. International Training Workshopof Home Care. Tai'an, Shandong, China, 2019.
6.17.
5. Yamanaka T (Lecture): Diagnostic devices used inhome medical care and medical therapeutic
management at home. International Training
Workshop of Home Care. Tai'an, Shandong, China,
2019.6.17.
6. Yamanaka T (Lecture): Chronic heart failuremanagement at home. International Training

Workshop of Home Care. Tai'an, Shandong, China,
2019.6.18.
7. Yamanaka T, Kidana K, Osawa I, Yoneda A, Tsuji
K, Yamaguchi K, Yamaguchi Y, Akishita M.
Medication prescription in older people receiving
home visiting services. The 11th International
Association of Gerontology and Geriatrics Asia/
Oceania Regional congress. Taipei, Taiwan, 2019.
10.26.
8. Yamanaka T. Home Care Medicine Education in
Japan. Gerontological Society of America 2019
Annual Scientific Meeting. International Workshop on Home Care Medicine. Austin, USA, 2019.
11.15.
9. Noguchi-Watanabe M, Yamamoto-Mitani N,
Yamanaka T. Service delivery and interprofessional care in Japan. Gerontological Societyof America 2019 Annual Scientific Meeting.
International Workshop on Home Care Medicine.
Austin, USA, 2019.11.15.

377

Department of
Therapeutic Strategy forHeart Failure
Research Associate Professor
Masaru Hatano, M.D., Ph.D

Research Lecturer
Eisuke Amiya, M.D., Ph.D
Yumiko Hosoya, M.D., Ph.D

Research Assistant Professor
Seitaro Nomura, M.D., Ph.D

Project Researcher
Naoko Kato, Ph.D

Homepage

http://plaza.umin.ac.jp/~heart-f/

Introduction and Organization
The Department of Therapeutic Strategy for Heart
Failure (TSHF) in the University of Tokyo Hospital
was established by the support of the Department of
Cardiac Surgery and the Department of Cardiovascular
Medicine of the University of Tokyo Hospital in May
2008. The purpose to establish the department of TSHF
is to promote surgical and medical innovative treatment
for end-stage heart failure in the University of Tokyo
Hospital, which includes heart transplant, pediatricheart transplant, ventricular assist device, andregenerative therapy. The Department has been also
supported by nine 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
remains to be elucidated. Pulmonary hypertension (PH)is also an important cause of RHF. Now a lot of patientswith severe PH are referred to our hospital because theUniversity of Tokyo Hospital has been approved as alung transplantation center since 2014. 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. When some
symptom or findings which suggest rejection aredetected, patients will undergo 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 and378

clinical status).
3. Treatment of PH
Although pulmonary arterial hypertension (PAH)
was a disease of poor prognosis, the treatment outcomeof PAH significantly improved in this decade attributed
to a number of newly approved drugs. Now we can use
ten agents for PAH including oral, inhaled, subcutaneous and intravenous drugs. Combination therapyof these drugs is increasingly prevalent for the management of PAH. We join the nationwide PH registry toestablish optimal treatment strategy for PAH .

Teaching Activities
We have the chair of systematic review of cardiovascular surgery in the spring term at the 2nd grade of
medical course. We also take charge in clinical practiceon diagnosis of cardiovascular disease in the autumn
term at the 2nd grade. We expose the students to dailyclinical works as well as research works during thecourse of “Free Quarter” and “Research Lab Visit”,
which are scheduled in the summer and springvacations at 1st and 2nd grade. Joint lectures with the
Cardiology Department are scheduled 3rd through 4th
grades. Each student is assigned one or two
cardiovascular surgical cases in the Bed Side Learning,in which he/she is required to learn preoperative patient
evaluation and management, surgical treatment andpostoperative care, based on participatory practice.
There are also twelve small key-lectures on
cardiovascular surgery. Hands-on practice is provided
during the “Clinical clerkship” one-month course in thelast months of 3rd grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/ subspecialty training
programs to allow the residents to pass Cardiovascular
Board Examination by 10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments forheart failure, it is essential for our department of the
University to have active research programs in clinicaland basic subjects related to assisted circulations andheart transplantation. We created highly active research
programs in the every field of medical and surgicalheart failure treatment, played an internationallyleading role and contributed to its development. A
research meeting is held every Saturday on a research
project with 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. Minatsuki S, Kiyosue A, Kodera S, Hara T, Saito
A, Maki H, Hatano M, Takimoto E, Ando M,
Komuro I. Effectiveness of balloon pulmonary
angioplasty in patients with inoperable chronic
thromboembolic pulmonary hypertension despite
having lesion types suitable for surgical treatment.
J Cardiol. 2020 Feb;75(2):182-188.
2. Tahara N, Dobashi H, Fukuda K, Funauchi M,
Hatano M, Ikeda S, Joho S, Kihara Y, Kondo T,
Matsushita M, Minamino T, Nakanishi N, Okano
Y, Ozaki Y, Saji T, Sakai S, Tanabe N, Watanabe
H, Yamada H, Yoshioka K, Hatta M, Sasayama S.
Long-term treatment of pulmonary arterial
hypertension with macitentan in Japanese patients.
Curr Med Res Opin. 2020 Jun;36(6):921-928.
3. Sugihara T, Hasegawa H, Uchida HA, Yoshifuji H,
Watanabe Y, Amiya E, Maejima Y, Konishi M,
Murakawa Y, Ogawa N, Furuta S, Katsumata Y,
Komagata Y, Naniwa T, Okazaki T, Tanaka Y,
Takeuchi T, Nakaoka Y, Arimura Y, Harigai M,
Isobe M; Japan Research Committee of the
Ministry of Health, Labour, and Welfare for
Intractable Vasculitis (JPVAS). Associated factorsof poor treatment outcomes in patients with giant
cell arteritis: clinical implication of large vessel
lesions. Arthritis Res Ther. 2020 Apr 7;22(1):72.
4. Maki H, Hara T, Tsuji M, Saito A, Minatsuki S,

379

Inaba T, Amiya E, Hosoya Y, Hatano M, Morita
H, Yao A, Kinugawa K, Komuro I. The Clinical
Efficacy of Endothelin Receptor Antagonists inPatients with Pulmonary Arterial Hypertension. Int
Heart J. 2020;61(4): 799-805.
5. Watanabe A, Amiya E, Hatano M, Watanabe M,
Ozeki A, Nitta D, Maki H, Hosoya Y, Tsuji M,
Bujo C, Saito A, Endo M, Kagami Y, Nemoto M,
Nawata K, Kinoshita O, Kimura M, Ono M,
Komuro I. Significant impact of left ventricularassist device models on the value of flow-mediateddilation: effects of LVAD on endothelial function.
Heart Vessels. 2020 Feb;35(2): 207-213.
6. Aozasa N, Hatano M, Saigusa R, Nakamura K,Takahashi T, Toyama T, Sumida H, Tamaki Z,
Maki H, Minatsuki S, Komuro I, Sato S, Asano Y.
Clinical significance of endothelial vasodilatory
function evaluated by EndoPAT in patients withsystemic sclerosis. J Dermatol. 2020 Jun;47(6):609-614.
7. Shiraishi Y, Amiya E, Hatano M, Katsuki T, Bujo
C, Tsuji M, Nitta D, Maki H, Ishida J, Kagami Y,
Endo M, Kimura M, Ando M, Shimada S,
Kinoshita O, Ono M, Komuro I. Impact oftacrolimus versus cyclosporin A on renal function
during the first year after heart transplant. ESC
Heart Fail. 2020 Aug;7(4):1842-1849.
8. Amiya E. Nrf-2: The Target of Vascular
Dysfunction in Diabetes. Am J Hypertens. 2020 Jul
18;33(7):597-598.
9. Saito A, Soma K, Masuzawa A, Hatsuse S,
Nakayama Y, Amiya E, Yao A, Hirata Y, Komuro
I. Symptomatic Right Ventricular Outflow Tract
Obstruction Due to Sinus of Valsalva Aneurysm.
Circ J. 2020 Oct 10. doi: 10.1253/circj.CJ-20-0554.
10. Kawakubo Y, Uehara M, Minatsuki S, Amiya E,
Komuro I. Multiple coronary aneurysms
characterized by cobblestone-like appearance withsilent ischaemia in a patient with neurofibromatosis type 1. Eur Heart J Cardiovasc
Imaging. 2020 May 28:jeaa127. doi: 10.1093/
ehjci/jeaa127.
11. Amiya E. MicroRNA-17: A Modulator of Interferon Regulatory Factor 9-Induced Phenotypic
Switching in Vascular Smooth Muscle Cells. Am J
Hypertens. 2020 Sep 8:hpaa147. doi: 10.1093/ajh/
hpaa147.

12. Minatsuki S, Kodera S, Kiyosue A, Saito A, Maki
H, Hatano M, Takimoto E, Komuro I. Balloon
pulmonary angioplasty improves quality of life inJapanese patients with chronic thromboembolic
pulmonary hypertension. J Cardiol. 2020 Aug;76(2):205-210.
13. Narita K, Amiya E, Kakuda N, Kaneko H, Hatano
M, Komuro I. The Efficacy of Lactulose for theTreatment of Hyperammonemic Encephalopathy
Due to Severe Heart Failure. Diagnostics (Basel).
2020 Jan 27;10(2):70.
14. Saito A, Amiya E, Soma K, Inaba T, Maki H,
Hatano M, Yao A, Morita H, Komuro I. Fractional
exhaled nitric oxide in adult congenital heartdisease. Nitric Oxide. 2020 Aug 1;100-101:45-49.
15. Taya M, Amiya E, Hatano M, Saito A, Nitta D,
Maki H, Hosoya Y, Minatsuki S, Tsuji M, Sato T,
Murakami H, Narita K, Konishi Y, Watanabe S,
Yokota K, Haga N, Komuro I. Clinical importanceof respiratory muscle fatigue in patients withcardiovascular disease. Medicine (Baltimore).
2020 Aug 21;99(34):e21794.
16. Minatsuki S, Kiyosue A, Kodera S, Hirose K, Saito
A, Maki H, Hatano M, Takimoto E, Ando J,
Komuro I. Novel Balloon Pulmonary Angioplasty
Technique for Chronic Thromboembolic Pulmonary Hypertension. Int Heart J. 2020;61(5): 9991004.
17. Tsuji M, Amiya E, Bujo C, Maki H, Ishida J,
Hatano M, Ono M, Komuro I. Takotsubo
syndrome in the same heart before and after hearttransplantation. ESC Heart Fail. 2020 Sep 10.
18. Yasunaga M, Yasuda Y, Honda A, Maki H,
Toyama K, Masamoto Y, Bujo C, Amiya E,
Hatano M, Ono M, Komuro I, Kurokawa M.
Successful treatment of EBV-related lymphoproliferative disease after heart transplantation
with autologous hematopoietic stem cell transplantation despite transient heart failure associated withengraftment syndrome. Ann Hematol. 2020 Aug
6.doi:10.1007/s00277-020-04198-w.
19. Saito A, Amiya E, Hatano M, Shiraishi Y, Nitta
D, Minatsuki S, Maki H, Hosoya Y, Tsuji M, Bujo
C, Nawata K, Kinoshita O, Kimura M, Endo M,
Kagami Y, Nemoto M, Ikeda Y, Morita H, Ono M,
Komuro I. Controlling Nutritional Status Score As
a Predictive Marker for Patients With Implantable

380

Left Ventricular Assist Device. ASAIO J. 2020
Feb;66(2):166-172.
20. Atsukawa M, Tsubota A, Hatano M, Kondo C,
Shioda K, Ohno H, Kawano T, Hayama K, Arai T,
Nakagawa-Iwashita A, Itokawa N, Kaneko K,
Yoshida Y, Koeda M, Okubo T, Yamamoto T,
Yamamoto T, Taniai N, Yoshida H, Kanazawa H,
Shimizu W, Iwakiri K. Prevalence and characteristics of portopulmonary hypertension in cirrhotic
patients who underwent both hepatic vein andpulmonary artery catheterization. Hepatol Res.
2020 Aug 21. doi: 10.1111/hepr.13560.
21. Tanabe N, Ogo T, Hatano M, Kigawa A, Sunaya
T, Sato S. Safety and effectiveness of riociguat forchronic thromboembolic pulmonary hypertension
in real-world clinical practice: interim data frompost-marketing surveillance in Japan. Pulm Circ.
2020 Jul 23;10(3): 2045894020938986. doi: 10.
1177/ 2045894020938986.
22. Narita K, Amiya E, Komuro I. Efficacy and Safetyof Direct Oral Anticoagulant for Treatment of
Atrial Fibrillation in Cerebral Amyloid
Angiopathy. Cureus. 2020 Aug 30;12(8): e10143.
23. Nomura S. Single-cell genomics to understanddisease pathogenesis. J Hum Genet. 2020 Sep 19.
doi: 10.1038/s10038-020-00844-3.
24. Yamaguchi T, Sumida TS, Nomura S, Satoh M,
Higo T, Ito M, Ko T, Fujita K, Sweet ME, Sanbe
A, Yoshimi K, Manabe I, Sasaoka T, Taylor MRG,
Toko H, Takimoto E, Naito AT, Komuro I. Cardiac
dopamine D1 receptor triggers ventriculararrhythmia in chronic heart failure. Nat Commun.
2020 Aug 31;11(1):4364.
25. Koyama S, Ito K, Terao C, Akiyama M, Horikoshi
M, Momozawa Y, Matsunaga H, Ieki H, Ozaki K,
Onouchi Y, Takahashi A, Nomura S, Morita H,
Akazawa H, Kim C, Seo JS, Higasa K, Iwasaki M,
Yamaji T, Sawada N, Tsugane S, Koyama T,
Ikezaki H, Takashima N, Tanaka K, Arisawa K,
Kuriki K, Naito M, Wakai K, Suna S, Sakata Y,
Sato H, Hori M, Sakata Y, Matsuda K, Murakami
Y, Aburatani H, Kubo M, Matsuda F, Kamatani Y,
Komuro I. Population-specific and trans-ancestry
genome-wide analyses identify distinct and shared
genetic risk loci for coronary artery disease. Nat
Genet. 2020 Oct 5. doi: 10.1038/s41588-020-07053.

26. Matsunaga H, Ito K, Akiyama M, Takahashi A,
Koyama S, Nomura S, Ieki H, Ozaki K, Onouchi
Y, Sakaue S, Suna S, Ogishima S, Yamamoto M,
Hozawa A, Satoh M, Sasaki M, Yamaji T, Sawada
N, Iwasaki M, Tsugane S, Tanaka K, Arisawa K,
Ikezaki H, Takashima N, Naito M, Wakai K,
Tanaka H, Sakata Y, Morita H, Sakata Y, Matsuda
K, Murakami Y, Akazawa H, Kubo M, Kamatani
Y, Komuro I. Transethnic Meta-Analysis of
Genome-Wide Association Studies Identifies
Three New Loci and Characterizes PopulationSpecific Differences for Coronary Artery Disease.
Circ Genom Precis Med. 2020 Jun;13(3):e002670.

381

Department of Biostatistics andBioinformatics
Project Professor
Daisuke Koide, R.Ph., HIM, Ph.D.

Project Associate Professor
Akihiro Hirakawa, Ph.D.

Project Assistant Professor
Sachiko Ono, DDS, MPH.

Homepage

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

Introduction and Organization
Biostatistics is an applied statistics in the fields of
medical and health sciences and contributes to thesefields through developments of statistical methodologies for clinical trials and epidemiological researches.
Biostatisticians who work at an organization for
conducting and coordinating clinical researches (e.g.,
academic research organization) in hospitals andinstitutions are few in Japan. To this end, the Japanfunding agency, Agency for Medical Research andDevelopment (AMED), started the Support Programfor Biostatisticians from 2016.
The AMED selected the Graduate School of the
University of Tokyo and the Graduate school of the
Kyoto University, as 2 centers for training biostatisticians, which function as core facilities, respectively.
Each graduate school establishes a new biostatistics
course, forms a training center upon collaboration
with a hospital, and performs on-the-job training.
This program improves the environment that leads
to higher quality in clinical research and trials, withthe collaboration of industry, academia, and thegovernment, based upon the donations from drug
companies and national research funding. Collaborative projects of industry, academia, and the government through the flow of funds in this program, arethe first of their kind in Japan.
On March 1, 2017, the Department of Biostatistics

and Bioinformation was established in the Graduate
School of Medicine. In the Graduate School ofInterdisciplinary Information Studies in the Universityof Tokyo, the Biostatistics and Bioinformatics course
also started on April 1, 2018. This course provides
specialized education to acquire not only statisticalmethodologies, but also practical skills (e.g., design
and analysis of clinical research, programming,
reporting) for conducting clinical research. We train
biostatisticians with high communication skill andethics that can promote high quality research incollaboration with health care professionals byteaching and on-the-job -training (OJT).

Teaching activities
1) Education in the Biostatistics and Bioinformatics
courseIn the Biostatistics and Bioinformatics course,
through the following teachings, we educate a wide
range of knowledge and skills required to biostatisticians. Its curriculum is made up of 28 subjects
including 42 credits. For students who have taken over
38 credits, we issue a certificate along with the Master
degree.
Biostatistics
Statistical inference, categorical data analysis,
survival analysis, longitudinal data analysis, Bayesian382

statistics, multiple comparison procedure, multivariate
analysis, causal inference, missing data analysis,
stochastic process and time series analysis, pharmacometrics, statistical programming, genomic data
analysis
Clinical research and epidemiology
Clinical trial methodology, design and analysis of
epidemiological research, research ethics andguidelines, medical research and CDISC standards,
general clinical medicine, regulatory science, medical
writing, medical technology evaluation exercises
In addition, the students receive the OJT at
University of Tokyo Hospital and the National Cancer
Center. The OJT programs are developed by thebiostatisticians of each institution. In the first year of
master's program, the students learn the basic practiceof biostatistician through the training at the Universityof Tokyo Hospital. In the second year, at the National
Cancer Research Center, students receive advanced
training in how to plan the design and analysis ofclinical researches.
2) Seminars and symposiums for the healthcare
professionals and biostatisticians
We give seminars about clinical trial methodologies
and biostatistics for physician, nurse, clinical researchcoordinator, monitor, and other healthcare professionals. We also hold symposia for biostatisticians inacademia and pharmaceutical companies in order toshare and discuss the “state-of-the-arts” of statisticalmethodologies.

Research activities
In the department of biostatistics and bioinformatics,
the main research areas are as follows:
1) Statistical methodology and design of clinical trials
and epidemiology
We study on the statistical methodologies and design
for streamlining clinical trial and estimating treatment
effect precisely. The research area includes Bayesian
design in oncology, clinical trial design using
biomarkers, adaptive design, study on the use ofBayesian statistics in clinical trials, causal inference,and multiple comparison method.
2) Epidemiological methodology
Epidemiology deals with health or disease related
incidence quantitatively in large populations,evaluates cause and effective factors, and ultimately
finds the measures of prevention. It starts fromepidemics (such as infectious diseases) and now its
focus is on lifestyle related diseases, such as cardiovascular disorders. Also, several kinds of medical
databases are developed rapidly in Japan. It is
important to conduct epidemiological, pharmacoepidemiological and clinical epidemiological studies
using such databases.
3) Pharmacoepidemiology
Pharmacoepidemiology is a study to investigate drug
use and its effects in a population. We are engaged inresearch on effectiveness, risk, and cost using dataobtained from hospital information system andelectronic medical record.
4) Clinical Epidemiology
Clinical epidemiology is the application of theprinciples and methods of epidemiology to conductclinical research studies focusing on prevention,
diagnosis, prognosis, and treatment of disease. As thebasic science of Evidence-based Medicine, the importance of clinical epidemiology has been increasing.
5) Medical informatics
Medical informatics is a science of studying how to
use data, information and knowledge in the all
medical fields, such as clinical, medical studies,
education and government. Recently, the area of
medical informatics is much expanding because of the
progress of genomic studies or bioinformatics, andintroduction of new technologies, such as virtual
reality and artificial intelligence (AI).
6) Algebraic statistics
The focus of research is on developing and applying
methods of algebraic statistics to specific statisticalproblems. In statistical inference, the computation ofcomplicated integrals or summation sometimes makes
the problem intractable. When a statistical model
has algebraic structure, techniques from algebraic

383

statistics are useful. I currently work on the topics
related to Groebner basis theory and the holonomic
gradient method.

References
1. Ono S, Ono Y, Koide D, Yasunaga H: Association
between routine nephropathy monitoring andsubsequent change in estimated glomerular
filtration rate in patients with diabetes mellitus: aJapanese non-elderly cohort study. J Epidemiol.
2019 Jun 15. doi: 10.2188/jea.JE20180255.
2. Hirakawa A, Sudo K, Yonemori K, Sadachi R,
Kinoshita F, Kobayashi Y, Okuma SH, Kawachi A,
Tamura K, Fujiwara Y, Rubinstein L, Takebe N. A
comparative study of longitudinal toxicities ofcytotoxic drugs, molecularly targeted agents,
immunomodulatory drugs, and cancer vaccines.
Clinical Pharmacology & Therapeutics. 106:803809, 2019.
3. Kakurai Y, Kaneko S, Hamada C, Hirakawa A(corresponding author). Dose individualizationand variable selection using Bayesian Lasso inearly phase dose-finding trials. Applied Statistics.
68:445-460, 2019.
4. Kada A, Hirakawa A (co-first author), Kinoshita F,
Kobayashi Y, Hatakeyama T, Kobayashi D,
Nishiyama C, Iwami T. Sample size estimation
and re-estimation of cluster randomized
controlled trials for real-time feedback, debriefing,
and retraining system of cardiopulmonary
resuscitation for out-of-hospital cardiac arrests.
Contemporary Clinical Trials Communications.
14: 100316, 2019.
5. Hirakawa A, Tanaka Y, Kaneko S. Pragmatic
dose-escalation methods incorporating relative
dose intensity assessment for molecularly targeted
agents in phase I trials. Contemporary Clinical
Trial Communications. https://doi.org/10.1016/j.
conctc.2019.100489, 2019.
6. Ito D, Hashizume A, Hijikata Y, Yamada S, Iguchi
Y, Iida M, Kishimoto Y, Moriyoshi H, Hirakawa A,
Katsuno M. Elevated serum creatine kinase in theearly stage of sporadic amyotrophic lateralsclerosis. Journal of Neurology, doi: 10.1007/
s00415-019-09507-6.2019
7. Hirata T, Tanigaki T, Kawase Y, Hirakawa A,

Omori H, Okamoto S, Ota H, Sobue Y, Kikuchi J,
Okubo M, Kamiya H, Kawasaki M, Suzuki T,
Pijls NHJ, Matsuo H. Post-occlusional hyperemia
for fractional flow reserve assessment and pullback curve analysis. Cardiovascular Intervention
and Therapeutics, doi: 10.1007/s12928-01900579-9, 2019.
8. Hashizume A, Katsuno M, Suzuki K, Banno H,
Takeuchi Y, Kawashima M, Suga N, Mano T,
Araki A, Hijikata Y, Hirakawa A, Sobue G;
JASMITT study group. Efficacy and safety ofleuprorelin acetate for subjects with spinal andbulbar muscular atrophy: pooled analyses of two
randomized-controlled
trials.
Journalof
Neurology, 266:1211-1221, 2019.
9. Yoshimi A, Yamada S, Kunimoto S, Aleksic B,
Hirakawa A, Ohashi M, Matsumoto Y, Hada K,
Itoh N, Arioka Y, Kimura H, Kushima I,
Nakamura Y, Shiino T, Mori D, Tanaka S,
Hamada S, Noda Y, Nagai T, Yamada K, Ozaki N.
Proteomic analysis of lymphoblastoid cell lines
from schizophrenic patients. Translational
Psychiatry, 9: 126, 2019.
10. Shimizu S, Tsuchiya S, Hirakawa A, Kato K,
Ando M, Mizuno M, Osugi M, Okabe K, Katagiri
W, Hibi H.. Design of a Randomized Controlled
Clinical Study of tissue-engineered osteogenic
materials using bone marrow-derived mesenchymal cells for Maxillomandibular bone defects inJapan: the TEOM study protocol. BMC Oral
Health, 19:69, 2019.
11. Kato M, Hirakawa A, Kobayashi Y, Yamamoto A,
Ishida R, Sano T, Kimura T, Majima T, Ishida S,
Funahashi Y, Sassa N, Fujita T, Matsukawa Y,
Yamamoto T, Hattori R, Gotoh M, Tsuzuki T. The
influence of the presence of intraductal carcinomaof the prostate on the grade group system's
prognostic performance. Prostate, doi:10.1002/
pros.23818, 2019.
12. Takano N, Yamada S, Hirakawa A, Yokoyama Y,
Kawashima H, Maeda O, Okada T, Ohno E,
Yamaguchi J, Ishikawa T, Sonohara F, Suenaga M,
Takami H, Hayashi M, Niwa Y, Hirooka Y, Ito Y,
Naganawa S, Ando Y, Nagino M, Goto H, Fujii T,
Kodera Y. Phase II study of chemoradiotherapy
combined with gemcitabine plus nab-paclitaxel
for unresectable locally advanced pancreatic384

ductal adenocarcinoma (NUPAT 05 Trial): study
protocol for a single arm phase II study. Nagoya
Journal of Medical Science, 81:233-239, 2019.
13. Yokoyama T, Miyahara R, Funasaka K, Furukawa
K, Yamamura T, Ohno E, Nakamura M,
Kawashima H, Watanabe O, Hirooka Y, Hirakawa
A, Goto H. The utility of ultrathin endoscopy withflexible spectral imaging color enhancement forearly gastric cancer. Nagoya Journal of Medical
Science, 81:241-248, 2019.
14. Taniguchi A, Kawada JI, Go K, Fujishiro N,
Hosokawa Y, Maki Y, Sugiyama Y, Suzuki M,
Tsuji T, Hoshino S, Muramatsu H, Kidokoro H,
Kinoshita F, Hirakawa A, Takahashi Y, Sato Y,
Natsume J. Comparison of clinical characteristics
of human metapneumovirus and respiratorysyncytial virus infection in hospitalized young
children. Japanese Journal of Infectious Diseases,
72: 237-242, 2019.
15. Ikenaka K, Atsuta N, Maeda Y, Hotta Y,
Nakamura R, Kawai K, Yokoi D, Hirakawa A,
Taniguchi A, Morita M, Mizoguchi K, Mochizuki
H, Kimura K, Katsuno M, Sobue G. Increase ofarginine dimethylation correlates with the progression and prognosis of ALS. Neurology, 92:
e1868-e1877, 2019.
16. Maeda T, Sato Y, Hirakawa A, Nakatochi M,
Kinoshita F, Suzuki T, Ichimura S, Ito R, Kudo R,
Suzuki M, Hoshino S, Sugiyama Y, Muramatsu H,
Kidokoro H, Kawada JI, Takahashi Y. Design of aprospective multicenter randomized controlled
trial evaluating the effects of gastric lavage on
coffee-ground emesis in neonates: study protocol.
Nagoya Journal of Medical Science, 81:227-232,
2019.
17. Yonemori K, Shimomura A, Yasojima H, Masuda
N, Aogi K, Takahashi M, Naito Y, Shimizu S,
Nakamura R, Hashimoto J, Yamamoto H,
Hirakawa A, Michimae H, Hamada A, Yoshida T,
Sukigara T, Tamura K, Fujiwara Y. A phase I/II
trial of olaparib tablet in combination witheribulin in Japanese patients with advanced ormetastatic triple-negative breast cancer previously
treated with anthracyclines and taxanes. European
Journal of Cancer, 109: 84-91, 2019.

385

Department of Advanced
Cardiology
Project Associate Professor
Katsuhito Fujiu, M.D., Ph.D.

Project Assistant Professor
Hidehiro Kaneko, M.D., Ph.D.

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

Introduction and Organization
This course is an endowed chair established on April 1,
2018, under the donations of Medtronic Japan Co.,
Ltd., St. Jude Medical Co., Ltd., Boston ScientificJapan Co., Ltd., and Fukuda Denshi Tokyo Central
Sales Co., Ltd.
In conjunction with the department ofcardiovascular medicine, this course develops
leading-edge medical care. It elucidates thepathogenesis of unresolved heart failure andcardiovascular disease and analyzes the pathologicalcondition using cultured cells, experimental animals,
and patient specimens. By clarifying the new disease
pathogenesis mechanism and pathogenesis mechanism,
it
aims
at
elucidatingthefundamental
pathophysiology of cardiovascular disease anddeveloping development prevention methods, newdiagnostic methods, and new therapeutic methods.
In Japan, cardiovascular death is the leading
cause of death in the elderly and is the leading causeof shortening a healthy lifespan. Despite theemergence of various new drugs, new devices, andnew treatments, we have not succeeded in reducing
cardiovascular death for the last 20 years. We havefound that it is important not to study cardiomyocytes
alone, but to examine non-cardiomyocytes to consider
heart disease (Nature 2007, Circulation Research 2005,
Nature Medicine 2017). We also hypothesized thatcooperation between the brain and heart maintains
cardiac homeostasis, and that failure leads to the onsetof cardiovascular disease and cardiovascular death(Nature Medicine 2017). The idea that the brain
regulates the heart is understandable in common sense.
Since ancient times, it has been considered, but
analysis using current molecular biological techniques
has hardly been conducted. We find that the brain
controls the heart, and the heart controls the brain andchanges each other, mainly through animal experiments. Such a molecular biological approach to brainheart linkage will understand new cardiac control
mechanisms and novel therapeutic targets. Besides, asa therapeutic development, we are promoting researchthat will develop new clinical approaches such as drugintervention approaches to non-cardiomyocytes, brain
imaging diagnosis, and brain stimulation therapy.

Teaching activities
The above research results are presented at theuniversity and academic conferences, the importanceof this field is well known and widely presented bydissertation. Also, we are actively engaged in outreachactivities for society.

Research activities
The heart and blood vessels maintain homeostasis incooperation with organs throughout the body. The
failure of this cooperation is considered to cause theonset of heart failure and sudden death. The therapy
that improved cardiovascular death prognosis is a drug

386that acts on the whole body, not on the heart alone,
except for cardiac resynchronization therapy andimplantable defibrillator. From this point of view, as a
research to improve the prognosis of cardiovasculardeath, we will proceed with the investigation,
considering that poor coordination among multiple
organs is involved in the onset of heart disease.
Furthermore, about half of the cells that make up theheart are cardiomyocytes. In contrast, the other half
are non-cardiomyocytes. In this study, we focus on
non-cardiomyocytes and how non-cardiomyocytesinteract with cardiomyocytes. The aim is to find newtherapeutic targets for heart disease by clarifying
whether it is acting, maintaining homeostasis of theheart, and elucidating the pathogenesis of heart failurethat is its failure.
Furthermore, the relationship between theheart and the brain has been examined in detail as astudy of inter-organ cooperation.

References
1. Maladaptive Alterations of Autonomic Nerve
System in Cardiovascular Disorders. Nakayama Y,
Fujiu K Int Heart J 2019;60(1):4-6
2. Interleukin-13 receptor α2 is a novel marker andpotential therapeutic target for human melanoma
Okamoto H, Yoshimatsu Y, Tomizawa T, Kunita A,
Takayama R, Morikawa T, Komura D, Takahashi
K, Oshima T, Sato M, Komai M, Podyma-Inoue
KA, Uchida H, Hamada H, Fujiu K, Ishikawa S,
Fukayama M, Fukuhara T, Watabe T Sci Rep 2019Feb 4;9(1):1281
3. Predictors of permanent pacemaker implantation
after transcatheter aortic valve implantation for
aortic stenosis using Medtronic new generation
self-expanding CoreValve Evolut R. Kaneko H,
Hoelschermann F, Seifert M, Tambor G, Okamoto
M, Moeller V, Neuss M, Butter C.
Heart Vessels. 2019 Feb;34(2):360-367.
4. C-Reactive Protein and Chronic Inflammation - Is
It a Novel Therapeutic Target for Subsequent
Cancer Death in Patients With Coronary Artery
Disease? Kaneko H, Komuro I.Circ J. 2019 Feb
25;83(3):513-514.

5. Clinicalutilityofintraprocedural

three-

dimensional integrated image guided transcatheter
aortic valve implantation using novel automatedcomputed tomography software: A single-center
preliminary experience. Butter C, Kaneko H,
Tambor G, Hara M, Neuss M, Hoelschermann F.
Catheter Cardiovasc Interv. 2019 Mar 1;93(4):722-728.
6. Pulseless Electric Activity with pre-excitation:
Idiopathic Ventricular Fibrillation and Fasciculoventricular Accessory Pathway. Oshima T, Fujiu
K, Matsuda J, Matsubara T, Hasumi, E, Oguri G,
Kojima T, Komuro I Int Heart J 2019 Mar 20;
60(2):470-473
7. Predictors of mortality in ischaemic versus
non-ischaemic functional mitral regurgitation
after successful transcatheter mitral valve repair
using MitraClip: results from two high-volume
centres. Kitamura M, Kaneko H, Schlüter M,
Schewel D, Schmidt T, Alessandrini H, Kreidel F,
Neuss M, Butter C, Kuck KH, Frerker C.Clin Res
Cardiol. 2019 Mar;108(3):264-272.
8. Use of Ghost Cytometry to Differentiate Cells
with Similar Gross Morphologic Characteristics
Adachi H, Kawamura Y, Nakagawa K, Horisaki R,
Sato I, Yamaguchi S, Fujiu K, Waki K, Noji H,
Ota S arXiv:1903.09538 [q-bio.QM]
9. Endothelin-1

andAtrialCardiomyopathy

Matsubara TJ, Fujiu K. Int Heart J 2019;60(2):238-240.
10. Impact of N-terminal pro-B-type natriuretic
peptide response on long-term prognosis after
transcatheter aortic valve implantation for severe
aortic stenosis and heart failure. Kaneko H,
Hoelschermann F, Tambor G, Okamoto M, Neuss
M, Butter C. Heart Vessels. 2019 May;34(5):777783.
11. Left Main Coronary Artery Obstruction by Huge
Noncoronary Cusp Calcification After Transcatheter Aortic Valve Replacement. Kiriyama H,
Kaneko H, Itoh H, Uehara M, Kodera S, Kiyosue
A, Yamauchi H, Daimon M, Ando J, Morita H,
Ono M, Komuro I. JACC Cardiovasc Interv. 2019

387

Jul 8;12(13):1285-1287.

of the Japanese Circulation Society- Renaissance

12. JCS 2017 Guideline on Prevention and Treatment
of Infective Endocarditis.

of Cardiology for the Creation of Future Medicine.

Nakatani S, Ohara T,

Akazawa H, Toko H, Harada M, Ueda K, Kodera

Ashihara K, Izumi C, Iwanaga S, Eishi K, Okita Y,

S, Kiyosue A, Fujiu K, Hatano M, Daimon M,

Daimon M, Kimura T, Toyoda K, Nakase H,

Ando J, Takimoto E, Morita H, Komuro I. Circ J.

Nakano K, Higashi M, Mitsutake K, Murakami T,2019 Aug 23;83(9):1829-1835.

Yasukochi S, Okazaki S, Sakamoto H, Tanaka H,

20. Impacts of Left Bundle/Peri-Left Bundle Pacing

Nakagawa I, Nomura R, Fujiu K, Miura T,

on Left Ventricular Contraction.

Morizane T; Japanese Circulation Society Joint

Fujiu K, Nakanishi K, Komuro I. Circ J. 2019

Working Group. Circ J. 2019 Jul 25;83(8):1767-

Aug 23;83(9):1965-1967.

1809.

Hasumi E,

21. Cell Cycle Arrest-Driven Fibrosis. Oshima T,

13. Response to Comment on “Ghost cytometry” Ota

Fujiu K. Int Heart J. 2019;60(4):785-787.

S, Horisaki R, Kawamura Y, Ugawa M, Sato I,

22. Short-Term and Long-Term Efficacy of Drug-

Adachi H, Yamaguchi S, Fujiu K, Waki K, Noji H

Coated Balloon for In-Stent Restenosis in

Science 2019, Vol. 364, Issue 6437

Hemodialysis Patients with Coronary Artery

14. Effects of Adipocyte Expansion on Cardio-

Disease. Kiriyama H, Kodera S, Minatsuki S,

vascular System and Ongoing Debate over

Kaneko H, Kikuchi H, Kiyosue A, Toko H,

Obesity Paradox.

Daimon M, Ando J, Morita H, Komuro I. Int

Nakayama Y, Fujiu K. Int

Heart J. 2019;60(3):499-502.

Heart J. 2019 Sep 27;60(5):1070-1076.

15. Relation between the Updated Blood Pressure

23. Roleofanemiaandproteinuria

inClassification according to the American College

developmentofsubsequent

renal

of

deteriorationinapopulation

Cardiology/American

Heart

Association

generalthefunction
with

Guidelines and Carotid Intima-Media Thickness.

preserved glomerular filtration rate: a community-

Itoh H, Kaneko H, Kiriyama H, Yoshida Y,

based cohort study. Kiriyama H, Kaneko H, Itoh

Nakanishi K, Mizuno Y, Daimon M, Morita H,

H, Yoshida Y, Nakanishi K, Mizuno Y, Daimon M,

Yatomi Y, Komuro I. Am J Cardiol. 2019 Aug 1;

Morita H, Yatomi Y, Komuro I. J Nephrol. 2019

124(3):396-401.

Oct;32(5):775-781.

16. Feasibility of a T-Shirt-Type Wearable Electro-

24. Correction to: Role of anemia and proteinuria in

cardiography Monitor for Detection of Covert

the development of subsequent renal function

Atrial Fibrillation in Young Healthy Adults.

deterioration

Fukuma N, Hasumi E, Fujiu K, Waki K, Toyooka

preserved glomerular filtration rate: a community-

T, Komuro I, Ohe K. Sci Rep. 2019 Aug 13;9(1):based cohort study. Kiriyama H, Kaneko H, Itoh11768.

H, Yoshida Y, Nakanishi K, Mizuno Y, Daimon M,

17. Asymptomatic Long-term Cardiac Perforation bya Pacemaker Lead. Nakao T, Fujiu K, Uehara M,
Komuro I. Intern Med. 2019 Aug 15;58(16):24092410.
18. Nationwide

inageneralpopulation

withMorita H, Yatomi Y, Komuro I. J Nephrol. 2019
Oct;32(5):843-846.
25. Alteration of Cardiac Performance and Serum
B-Type Natriuretic Peptide Level in Healthy

Actions

AgainstHeart

FailureAging. Yoshida Y, Nakanishi K, Daimon M,

Pandemic in Japan - What Should We Do From

Ishiwata J, Sawada N, Hirokawa M, Kaneko H,

Academia? Komuro I, Kaneko H, Morita H, Isobe

Nakao T, Mizuno Y, Morita H, Di Tullio MR,

M, Nakayama H, Minematsu K, Yamaguchi T,

Homma S, Komuro I.J Am Coll Cardiol. 2019 Oct

Yazaki Y.Circ J. 2019 Aug 23;83(9):1819-1821.

8;74(14):1789-1800.

19. Overview of the 83rd Annual Scientific Meeting

26. Longitudinaldissociationandtransition

in

388

thickness of the His-Purkinje system cause
various QRS waveforms of surface ECG underHis bundle pacing: A simulation study based onclinical observations. Okada JI, Fujiu K, Washio T,
Sugiura S, Hisada T, Hasumi E, Komuro I. J
Cardiovasc Electrophysiol. 2019 Nov;30(11):2582-2590.
27. Effect of Body Weight Change on Blood Pressure
in a Japanese General Population with a Body
Mass Index ≥ 22 kg/m2. Itoh H, Kaneko H,
Kiriyama H, Nakanishi K, Mizuno Y, Daimon M,
Morita H, Yamamichi N, Komuro I. Int Heart J.
2019 Nov 30;60(6):1381-1386.
28. Frozen Heart and Arrhythmia. Yuxiang L, Fujiu K.
Int Heart J. 2019;60(5):1019-1021.
29. Relationship Between Brain Hemodynamic State,
Autonomic Nerve Input, and Symptoms of Atrial
Fibrillation. Matsubara TJ, Fujiu K. Int Heart J.
2019;60(6):1233-1235
30. Antithrombotic Therapy for Atrial Fibrillation
With Stable Coronary Disease Yasuda S, Kaikita
K, Akao M, Ako J, Matoba T, Nakamura M,
Miyauchi K, Hagiwara N, Kimura K, Hirayama A,
Matsui K, Ogawa H, Collaborators AFIRE
Investigators; Fujiu K＜290 人中 112 番目＞N
Engl J Med. 2019 Dec 19;381(25):2481
31. Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of
non-alcoholic steatohepatitis. Asakawa M, Itoh M,
Suganami T, Sakai T, Kanai S, Shirakawa I, Yuan
X, Hatayama T, Shimada S, Akiyama Y, Fujiu K,
Inagaki Y, Manabe I, Yamaoka S, Yamada T,
Tanaka S, Ogawa Y. Sci Rep. 2019 Dec 20;9(1):19601.
32. Appetite Status After Transcatheter Aortic Valve
Implantation. Itoh H, Kaneko H. Int Heart J.
2019;60(6):1236-1237

389

Laboratory for Advanced Researchon Pathophysiology of Metabolic
Diseases
Project Associate Professor
Miki Okada-Iwabu, Ph.D.

Project Associate Professor
Masato Iwabu, M.D., Ph.D.

Introduction and Organization
Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases was launched in2017 to promote cutting-edge research aimed at
unraveling the underlying pathophysiology of diabetes
and related metabolic diseases thereby contributing to
the development of effective preventive measuresagainst 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 andencompasses a wide disease spectrum from such rare
conditions as mitochondrial diabetes and lipoatrophic
diabetes to diabetes 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 andobesity. Therefore, the Laboratory is intended topromote wide-ranging research into human tissues
from patients with diabetes mellitus as a common
disease but from those with rare forms of diabetes bydrawing on state-of-the-art genomic, epigenomic,

metabolomic, metagenomic and iPS-cell technologies
and to bring resulting research insights to bear on thedevelopment of innovative diagnostic, preventive andtherapeutic modalities for diabetes.
Within the research milieu that theLaboratory offers, therefore, the research currently
being promoted is expected to lead to the elucidationof the pathophysiology of diabetes and related
metabolic diseases, where rare disease-derived tissueand iPS cell-based investigations are expected toprovide invaluable insights into the pathophysiology
of diabetes as a common disease. Thus, the Laboratory
is devoted to promoting relevant research leading to
the development of innovative diagnostic, preventive
and therapeutic 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 sensewith the 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 rolein the clinical researcher development program by the390

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
and clinical researchers in training. As part ofMetabolism Research Course on the clinicalresearcher development program, the Course holds up
and pursues, as its research theme, exploration of key
molecules involved in the onset/progression ofobesity/ type 2 diabetes, given that radical preventive/
therapeutic modalities remain yet to be established forthe so-called lifestyle-related diseases, which include
the metabolic syndrome, type 2 diabetes, obesity,
dementia, and frailty, as well as for age-relateddiseases, all of which are known to occur and progress
through interactions between individuals’ genetic andenvironmental factors. Thus, the aim of the program is
to explore these key molecules by drawing on theanalysis 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 inJapan and overseas as well as their publication as
peer-reviewed 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 onstate-of-the-art omic (genomic, epigenomic, metabolomic, and metagenomic) and iPS-cell technologies
and genetic 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 andinsights.

References
1. Okada-Iwabu M, Iwabu M, Yamauchi T and
Kadowaki T. Drug development research fornovel adiponectin receptor-targeted antidiabetic
drugs contributing to healthy longevity. Diabetol.
Int. 10, 237-244, 2019
2. Iwabu M, Okada-Iwabu M, Yamauchi T and
Kadowaki T. Adiponectin/AdipoR Research and
Its Implications for Lifestyle-Related Diseases.
Front. Cardiovasc. Med. 6, 116, 2019
3. Caterson ID, Alfadda AA, Auerbach P, Coutinho
W, Cuevas A, Dicker D, Hughes C, Iwabu M,
Kang JH, Nawar R, Reynoso R, Rhee N, Rigas G,
Salvador J, Sbraccia P, Vázquez-Velázquez V and
Halford JCG. Gaps to bridge: misalignment
between perception, reality and actions in obesity.
Diabetes Obes Metab. 21, 1914-1924, 2019

391

Department of Advanced Clinical
Science and Therapeutics
Project Associate Professor
Mutsuo Harada, M.D., Ph.D.

Project Assistant Professor
Masamichi Ito, M.D., Ph.D.

Project Researcher
Yusuke Adachi, M.D., Ph.D.

Project Academic Support Staff
Kanako Ikeya,
Yuko Ishiyama

Homepage

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

Introduction and Organization
The Department of Advanced Clinical Science andTherapeutics, established at the University of Tokyo in
2004, aims to develop new clinical strategies andtherapy in cardiovascular medicine and other areas.
The laboratory location was moved to the brand new
research building called Clinical Research Center-A in
January 2020. This department hopes to develop not
only basic research, but also applications to devise
new clinical strategies.

Research activities
Followings are our recent basic and clinical research
activities.
• New strategies to regulate acute/chronic myocarditis.
• New strategies to regulate acute myocardial infarction and ischemia/reperfusion injury.
• New strategies to regulate atherosclerosis andaneurism.
• New strategies to regulate systolic/diastolic heart
failure.
• New strategies to regulate cardio-kidney syndrome.

• Development of gene therapies with AAV vectors(anti-inflammation etc.).
• Development of new growth factor treatments(hepatocyte growth factor, etc.).
• Development of new anti-adhesion molecule
treatments (anti-inflammation, etc.).
• Development of new anti-extracellular treatments(anti-inflammation, anti-oxidation, etc.).
• Development of new chemical compounds (antiinflammation, anti-coagulation, etc.).
• Development of drug screening for heart failureusing iPS cell-derived cardiomyocytes.
• Expanding the use of foods and natural extracts.
• Expanding the application of existing drugs anddevices.
• Analysis of angiogenesis using in situ hybridization.

References
1. Fukuma N, Takimoto E, Ueda K, Liu P, Tajima M,
Otsu Y, Kariya T, Harada M, Toko H, Koga K,
Blanton RM Jr, Karas RH, Komuro I. Estrogen
Receptor-α Non-Nuclear Signaling Confers

392

2.

3.

4.

5.

6.

Cardioprotection and Is Essential to cGMP-PDE5
Inhibition Efficacy. JACC Basic Transl Sci. 2020
Mar 4;5(3):282-295.
Akazawa H, Toko H, Harada M, Ueda K, Kodera
S, Kiyosue A, Fujiu K, Hatano M, Daimon M,
Ando J, Takimoto E, Morita H, Komuro I.
Overview of the 83rd Annual Scientific Meetingof the Japanese Circulation Society - Renaissanceof Cardiology for the Creation of Future Medicine.
Circ J. 2019 Aug 23;83(9):1829-1835.
Satoh M, Nomura S, Harada M, Yamaguchi T, Ko
T, Sumida T, Toko H, Naito AT, Takeda N, Tobita
T, Fujita T, Ito M, Fujita K, Ishizuka M, Kariya T,
Akazawa H, Kobayashi Y, Morita H, Takimoto E,
Aburatani H, Komuro I. High-throughput singlemolecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload. J Mol Cell Cardiol. 2019 Mar;
128:77-89.
Shibamoto M, Higo T, Naito AT, Nakagawa A,
Sumida T, Okada K, Sakai T, Kuramoto Y,
Yamaguchi T, Ito M, Masumura Y, Higo S, Lee JK,
Hikoso S, Komuro I, Sakata Y. Activation of DNA
Damage Response and Cellular Senescence in
Cardiac Fibroblasts Limit Cardiac Fibrosis After
Myocardial Infarction. Int Heart J. 2019 Jul 27;
60(4):944-957.
Ko T, Fujita K, Nomura S, Uemura Y, Yamada S,
Tobita T, Katoh M, Satoh M, Ito M, Domoto Y,
Hosoya Y, Amiya E, Hatano M, Morita H,
Fukayama M, Aburatani H, Komuro I.
Quantification of DNA Damage in Heart Tissue asa Novel Prediction Tool for Therapeutic Prognosis
of Patients With Dilated Cardiomyopathy. JACC
Basic Transl Sci. 2019 Sep 25;4(6):670-680.
Ueda K, Adachi Y, Liu P, Fukuma N, Takimoto E.
Regulatory Actions of Estrogen Receptor
Signaling in the Cardiovascular System. Front
Endocrinol (Lausanne). 2020 Jan 10;10:909.

393

Department of Medical andPharmaceutical Community
Healthcare
Project Professor
Hirohisa Imai, M.D., Ph.D.

History and Organization Overview
Although the average person may not know about therevolutionary changes that are currently taking place,
we have entered the dawn of a new age in which drugs
are utilized more efficiently and delivered morereliably in regional health care, leading to improved
patient outcomes. Regional formularies are being
established, combatting polypharmacy has become thebiggest issue confronting clinicians (as revealed by the
results of a questionnaire survey), methodologies for
implementing refillable prescriptions in Japan arebeing put in place, and the Law for Ensuring the
Quality, Efficacy, and Safety of Drugs and Medical
Devices has come fully into effect. A major
rearrangement of the medical device landscape isunderway, and collaboration between physicians andpharmacists is becoming more important in regional
health care.
In health care today, there needs to be morecooperation among doctors and other medical
professionals in order to provide patients with an
optimal level of care. In particular, if doctors andpharmacists are able to reach a common
understanding of a patient’s illness, this will allow
them to administer an appropriate drug treatment
regimen, to perform continuous patient follow-up, andto evaluate the administered treatment accurately. The
delivery of optimal drug therapy involves multiple
interconnected processes, from investigating whatdrugs should be used to planning the treatment
regimen, assessing treatment compliance andeffectiveness, and managing adverse reactions, andonly a multidisciplinary, team-oriented approach tohealth care will make it possible to provide patientswith efficient, effective drug therapy. Unfortunately,
there are currently few examples of such
“multidisciplinary approaches to delivering optimal
drug therapy.” Japan is a “super-aging” society andthe rapidly increasing number of elderly patients who
are taking multiple medications has become an issueof significant concern. Because optimal drug therapy
delivery cannot be accomplished through thetraditional health care system or through regional
health care systems, the construction of a new healthcare system for the delivery of drug therapy isrequired.
The interfaces between the systems used in the fieldsof medicine and pharmacology, and the working
relationships between doctors and pharmacists, havegaps; these systems function independently of eachother, rendering the design of the overall systeminefficient. To date, it has not been possible toformulate measures for solving these problems
because of a lack of evidence.
For example, although dispensing limits for patientswith long-term prescriptions have been discussed incancer therapy and primary care settings, notheoretical or empirical research has been conductedto study this issue. Nor have any systems been put inplace to manage drug therapies based on
predetermined protocols for patients with chronic
diseases who are in stable condition. In addition, notenough empirical research has been conducted on thedevelopment of optimal treatment methods (e.g.,394

optimal patient selection, efficient treatment
procedures) based on postmarketing surveillance ofexpensive drug products.
Against the aforementioned background, the objectiveof this program is to conduct theoretical and empiricalresearch on the development of new regional healthcare and collaborative systems for doctors (hospitals/
clinics) and pharmacists (both hospital and nonhospital pharmacists) in order to try to construct a newcollaborative system for doctors and pharmacists tooptimize the drug therapies that are provided topatients.
In this program, we will plan theoretical research toformulate measures that will support the constructionof efficient and effective regional medical care andempirical research using large-scale data, and we will
use statistical and epidemiological procedures toanalyze medical record data and prescription drug(including medical history) data as well as data fromour own epidemiological research in order toinvestigate systems for delivering effective drug
therapy through a multidisciplinary approach, startingwith the attending physician and the pharmacist, andfocusing specifically on dispensing limits for patientswith long-term prescriptions, the introduction ofregional formularies, and the introduction ofmultidisciplinary interventions in the treatment ofcancer and cognitive disorders.
This program consists of 1 program professor and 1
assistant program professor. The former is Hirohisa
Imai, a specialist in public health and epidemiology
who also teaches these subjects, and the latter is
Takuya Hirai, Ph.D., a graduate of the University ofTokyo's Graduate School of Public Health and a
specialist in collagen disease. The program also has 2
full-time administrative staff. In addition, graduate
students in the professional degree course of the
School of Public Health have been involved in thisprogram’s research activities and providing teachingsupport.

a single patient is over. The coming age will see
physicians, pharmacists, nurses, public health andwelfare workers, etc. use a multidisciplinary approach,and collaborate with the government as well, toimplement regional, comprehensive health caresystems. This program will train the health carespecialists that will be needed for this coming age. In
addition, in order to help train the next generation ofresearchers, this program will be responsible forteaching courses and seminars at the School of
Medicine. the Epidemiology courses and seminars
will focus on pharmacoepidemiological and pharmacoeconomic issues, and provide instruction on how toapply epidemiological approaches to identify
problems and formulate responses in regional healthcare. We will attempt to convey the significance andfundamentals of epidemiology to students with nofield experience by exposing them to common
scenarios in regional health care.
In the School of Public Health (professional degree
course), this program will offer courses in connection
with the School of Medicine in, for example,
Pharmaceutical Epidemiology, Drug Product Delivery
Systems, Adverse Reactions, and the Behavior of
Pharmaceutical Companies. As part of their MPH
degree research, this program has teached graduate
students in the School of Public Health, andperformed interventional research on polypharmacy
patients until now. Graduate students in the latterstages of obtaining their doctorate degrees, who will
be expected to perform their own, independent
research in the future, will receive instruction increating themes for research papers, analyzing data,
the handling of literature references, and other basic
and critical skills, and will also receive guidance whenwriting their dissertations on how to develop a
consistently logical argument throughout theirdissertation as well as on how to properly cite
literature references.

Research
Education
The objective of this program is to develop health carespecialists who can implement medical collaborations
that are suited to a super-aging society. The era when asingle doctor is capable of handling all of the care forThis program will utilize primarily prescription drug
data (including prescribing histories) and medical
record data to conduct theoretical and empiricalresearch focusing on the biostatistical and epidemiological methodologies involved in “the development of395

new methods of multidisciplinary collaboration for
optimizing physician-directed drug therapies.”
1.

Research on prescription drug dispensing limits
for patients with long-term prescriptions
1) “Dispensing limits for patients with long-termprescriptions” refers to the practice of having
patients who have, for example, received a90-day prescription go to the pharmacy every 30
days to receive 30 days’ worth of medicine. The
pharmacist submits a tracking report to theprescribing doctor when the patient picks up his
medicine. This has many benefits in the case ofpatients with chronic conditions, including
making it possible to manage the patient’s drug
therapy appropriately, reducing the physician’s
workload, managing the quantity of drug
remaining, controlling health care costs more
appropriately. This program will conduct
theoretical and empirical research aimed at
establishing a model system that doctors andpharmacists can use in both primary care andoncology to implement dispensing limits forpatients with long-term prescriptions.
2) A pilot study on dispensing limits for patientswith long-term prescriptions is currently
underway (in hypertension, diabetes, dyslipidemia, osteoporosis, breast cancer hormone therapy,
and rheumatism). In the future, this programplans to conduct a larger-scale research study
with the help of the Ministry of Health, Labourand Welfare.

2.

Research on multidisciplinary interventions in
drug therapy in regional health care1) This program will cooperate with regional
metropolitan doctors’ and pharmacists’ associations, national health insurance regional branch
offices, Japan Health Association branch offices,prefectural health and welfare agency pharmaceutical affairs bureaus, and the like to conduct
research on optimal drug therapy interventions
for elderly patients. The patients who should
receive interventions will be identified by apatient selection board comprised of doctors andpharmacists, and said interventions will be
implemented.

2) This program will use prescribing data fromhealth insurance societies to conduct research on
implementing notification interventions for
optimizing drug therapy in the elderly. The
program is conducting research on interventions
that attempt to improve drug therapies by sending
prescribing physicians and compounding
pharmacists written notices informing them of
inappropriate prescriptions. The results of such
notification interventions will be evaluated after
half a year.
3.

Research on the development of methodologies
for implementing regional formularies
1) The cost effectiveness of the use of drug products
has been called into serious question in recent
years, and the efficient use of drug products isbeing required within the framework of regional
comprehensive health care systems. Althoughformularies may be one effective method ofaccomplishing this, “Hospital Formularies” and“Regional Formularies” are very different,
although they may appear alike, because thelatter have many stakeholders, and theimplementation of such formularies is therefore
extremely
difficult.
Althoughregional
formularies have not yet been implemented inJapan, this program is conducting research into
how they can be developed. This program will
investigate, in a quantitative scientific manner,incentives and inducements for promoting datacollection and analysis and the screening and useof listed drug products.
2) This program has started to conduct research toassess the effects of introducing regional
formularies using certain government-approved“Regional Health Care Collaboration Promotion
Foundations.” This program will collect data
provided by prefectural health insurance andJapan Health Association offices on patientcharacteristics,
diseasenames,
medicalinstitutions, drugs, etc. and perform an impact
assessment on the introduction of regional
formularies.

4.

The development of systems for optimizing drug
therapies that utilize artificial intelligence396

Adverse reactions have many causes, includinginteractions between different drugs andinteractions with the metabolites of certain drugs,
and the identification and prevention of adverse
reactions requires tremendous effort. Because atremendous amount of work is required toinvestigate the causes of adverse reactions andprevent them from occurring, systems are being
developed that utilize artificial intelligence toidentify safer and more effective drug therapies.
A research team is in the process of collecting
and managing a vast amount of data, and working
to develop innovative interfaces that will allow
doctors andpharmacists to easily make use of
artificial intelligence.

Publication
1. Watanabe T, Yagata H, Saito M, Okada H,
Yajima T, Tamai N, Yoshida Y, Takayama T,
Imai H, Nozawa K, Sangai T, Yoshimura A,
Hasegawa Y, Yamaguchi T, Shimozuma K,
Ohashi Y. A multicenter survey of temporalchanges in chemotherapy-induced hair loss inbreast cancer patients. PLoS ONE 14(1):e0208118, 2019.
2. Sato H, Tomioka Y, Nakamura T, Oda S, Oki T,
Imai H. Factors Affecting the Submission ofReports of Test Results to Pharmacies by Patients.
Japanese Journal of Pharmaceutical Health Careand Sciences, 45(3):164-170, 2019.
3. Imai H. Elimination of polypharmacy and thecalculation of the medication adjustment support
fee. Sun Life Planning, 1-233, 2019.

397

Department of Molecular Structure
and Dynamics
Project Professor
Nobutaka Hirokawa, M. D.

Home page

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

Teaching activities
We are involved in teaching medical students andMaster course and Ph. D. course students in thefollowing lectures and laboratory courses together
with the Department of Cell Biology and Anatomy.
I.
1) Lecture on Cell Bilogy, Developmental Biology,
Histology and Neurocytology.
2) Lecture on Gross Anatomy and Neuroanatomy. to
medical students and students of other facultiesII.
1) Laboratory course of Gross Anatomy and
Neuroanatomy.
2) Laboratory course of Histology and Histology of
the Cenrtral Nervous System.
to medical students and students of other faculties.
In addition we offer a special training course (freequarter) of various kinds of molecular cell biology
techniques such as immunocytochemistry, electron
microscopy, biochemistry, molecular biology, biophysics, and cellular and molecular neurobiology
technique to medical students.
Especially we devote ourselves for the teaching of the
cutting edge approaches of new light microscopy suchas the Photoactivated Localization Microscopy (PALM),
cryo-electron microscopy and X-ray crystallography.

Research activities
Our laboratory studies molecular motors and rail
microtubules and the mechanisms of intracellulartransport. To study these molecular mechanisms we
use new molecular cell biological approaches

including cutting edge light microscopies, cryo
electron microscopy of molecular resolution, X-ray
crystallography, biophysics, molecular biology andmolecular genetics. We aim to study the structure anddynamics of the molecular motors in vitro and in vivo
at the highest special and temporal resolution and onthese bases try to elucidate functions of molecularmotors in vivo combining molecular genetics.

References
1. Ichinose, S., T. Ogawa, X. Jiang, and N.
Hirokawa. The Spatiotemporal Construction of
the Axon Initial Segment via KIF3/KAP3/
TRIM46 Transport under MARK2 Signaling.
Cell Reports 28 (9): 2413-2426. 2019.
(Published
Online:August27,2019).
https://doi.org/10.1016/j.celrep.2019.07.093
2. Toyoshima M., Jiang X., Ogawa T., Ohnishi T.,
Yoshihara S., Balan S., Yoshikawa T., and N.
Hirokawa. Enhanced carbonyl stress induces
irreversible multimerization of CRMP2 inschizophrenia pathogenesis. Life Sci Alliance.
2019 Oct 7;2(5). pii: e201900478. doi: 10.26508/
lsa.201900478. Print 2019 Oct.
3. Alsabban AH., Morikawa M., Tanaka Y., Takei
Y., and N. Hirokawa. Kinesin Kif3b mutation
reduces NMDAR subunit NR2A trafficking andcauses schizophrenia-like phenotypes in mice.
EMBO Journal . 2019 Nov 20:e101090. doi:
10.15252/embj.2018101090. [Epub ahead ofprint]
4. Yoshihara S., Jiang X., Morikawa M., Ogawa T.,
Ichinose S., Yabe H., Kakita A., Toyoshima M.,

398

Kunii Ya, Yoshikawa T., Tanaka Y., and N.
Hirokawa. Betaine ameliorates schizophrenic
traits by functionally compaensating KIF3-based
CRMP2 transport. Cell Reports in press
5. Iwata S., Morikawa M., Takei, Y., and N.
Hirokawa. An activity-dependent local transport
regulation via degradation and synthesis of KIF17
underlying
cognitive
flexibility.
Science
Advances. 2020 6 : eabc8355

399

Department of Molecular
Neurology
Professor
Shoji Tsuji, M.D., Ph.D.

Associate Professor
Jun Mitsui, M.D., Ph.D.

Assistant professor
Takashi Matsukawa, M.D., Ph.D.

Homepagehttps://molecular-nuerology.org/

Introduction and Organization
Department of Molecular Neurology was established on April 1, 2017 to elucidate the molecularmechanisms based on detailed clinical information
and research that integrates comprehensive genome
analysis, furthermore, to develop new therapies that
can intervene in pathophysiological mechanisms ofthe neurological diseases and to conduct new clinical
trials for the neurological diseases.

Clinical activities
We have outpatient clinic specialized in multiple
system atrophy (MSA) cooperating with Departmentof Neurology. We have started a registry for MSA toestablish the natural history of MSA, and, furthermore,
to recruit patients to the clinical trial which we arepreparing. We also take care of patients in theinpatient’s’ ward cooperating with Department of
Neurology. We provide clinical sequencing forpatients with neurological diseases to help clinicaldiagnosis of these patients. We also provide clinicalsequencing on referral basis from other hospitals.

Teaching activities
In under-graduate education, we offer opportunities of research experience on molecular genetics

of neurological disorders during the period of the“free–quarter program”. In the post-graduate
education, we offer programs for graduate students
including molecular genetics, neurobiology andtranslational researches.

Research activities
Multiple system atrophy (MSA) is a progressive
neurodegenerative disease which is characterized byvarious combinations of cerebellar ataxia andparkinsonism in addition to autonomic failure. No
effective therapeutic measures are available. We havebeen conducting extensive researches on MSA
including comprehensive genome analysis on familial
as well as sporadic MSA. We have found that a
homozygous mutation and compound heterozygous
mutations of COQ2 gene are associated with anincreased risk of MSA in multiplex families, andheterozygous mutations of COQ2 gene are associatedwith an increased risk of MSA in patients withsporadic disease (Mitsui J, et al. N Engl J Med. 2013;
369:233-44). Based on these findings, we consideredthat supplementation of coenzyme Q10 to patients with
MSA could benefit patients because COQ2 encodes
the enzyme essential for the biosynthesis of coenzyme
Q10. Recent studies have reported decreased coenzyme
Q10 levels in blood, cerebral spinal fluid, and the
cerebellum even in MSA patients without COQ2

400

mutations. Based on these studies, we started amulticenter-based (13 institutions) phase II clinical
trial (UMIN000031771) to evaluate the clinicalefficacy of a high-dose ubiquinol (reduced form ofcoenzyme Q10) supplementation for suppressing
progression of symptoms of patients with MSA in2013.
To facilitate recruitment of MSA patients into theclinical trial, as well as to establish a detailed natural
history of MSA, we started a registry for MSA. To
standardize the rating of patients based on Unified
Multiple System Atrophy Rating Scale (UMSARS)
among the 13 institutions in the phase II clinical trial,
we translated the original UMSARS into Japanesewith generous help by Dr. Gregor Wenning, theoriginal author of UMSARS. We have also establisheda method for more sensitive evaluation of the
enzymatic activity of COQ2 mutations (Yasuda T, et al.
Neurogenetics. 2019 Mar;20(1):51-5).

3.

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Fujigasaki H, Tamaki H, Tamaki R, Kito S,
Taguchi Y, Tanaka K, Atsuta N, Sobue G, Kondo
T, Inoue H, Tsuji S, Hozumi I. Functional
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17. Naruse H, Matsukawa T, Ishiura H, Mitsui J,
Takahashi Y, Takano H, Goto J, Toda T, Tsuji S.
Association of ATXN2 intermediate-length CAG
repeats with amyotrophic lateral sclerosis
correlates with the distributions of normal CAG
repeat alleles among individual ethnic populations.
Neurogenetics. 2019 May; 20(2):65-71. doi: 10.
1007/s10048-019-00570-9.
18. Bannai T, Mano T, Chen X, Ohtomo G, Ohtomo R,
Tsuchida T, Koshi-Mano K, Hashimoto T,
Okazawa H, Iwatsubo T, Tsuji S, Toda T, Iwata A.
Chronic cerebral hypoperfusion shifts the equilibrium of amyloid β oligomers to aggregation-prone
species with higher molecular weight. Sci Rep.
2019 Feb 26;9(1):2827. doi: 10.1038/s41598-01939494-7.
19. Yasuda T, Matsukawa T, Mitsui J, Tsuji S. Oxygen
consumption rate for evaluation of COQ2 variants
associated with multiple system atrophy.
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1007/s10048-018-0563-7.
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Doi K, Umeda T, Yamauchi H, Tsuchiya M, Koh
K, Yamashiro N, Mitsui J, Goto J, Onishi H,
Ohtsuka T, Shindo K, Morishita S, Tsuji S,
Takiyama Y. Neuroimaging, genetic, andenzymatic study in a Japanese family with a GBA
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21. Miyabayashi T, Ochiai T, Suzuki N, Aoki M, Inui
T, Okubo Y, Sato R, Togashi N, Takashima H,
Ishiura H, Tsuji S, Koh K, Takiyama Y, Haginoya
K. A novel homozygous mutation of the TFG
gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. J Hum Genet. 2019 Feb;64(2):171-176.
doi: 10.1038/s10038-018-0538-4.
22. Naruse H, Ishiura H, Mitsui J, Takahashi Y,
Matsukawa T, Tanaka M, Doi K, Yoshimura J,
Morishita S, Goto J, Toda T, Tsuji S. Burden ofrare variants in causative genes for amyotrophic
lateral sclerosis (ALS) accelerates age at onset of
ALS. J Neurol Neurosurg Psychiatry. 2019 May;
90(5):537-542. doi: 10.1136/jnnp-2018-318568.
23. Koh K, Ichinose Y, Ishiura H, Nan H, Mitsui J,
Takahashi J, Sato W, Itoh Y, Hoshino K, Tsuji S,

Takiyama Y; Japan Spastic Paraplegia ResearchConsotium. PLA2G6-associated neurodegeneration presenting as a complicated form ofhereditary spastic paraplegia. J Hum Genet. 2019
Jan; 64(1):55-59. doi: 10.1038/s10038-018-05197.
24. Nakano Y, Tsunoda K, Yamashita T, Mitsui J, Sato
K, Takemoto M, Hishikawa N, Ohta Y, Toda T,
Tsuji S, Abe K. Late presented congenital
myasthenic syndrome with novel compound
heterozygous CHRNE mutations mimicking
seronegative myasthenia gravis. Neurol Clin
Neurosci. 2019 June; 7(5): 288-290. doi.org/10.
1111/ncn3.12317
25. Taminato T, Araki M, Sato N, Ishiura H,
Yoshimura J, Doi K, Morishita S, Tsuji S,
Takahashi Y. Sporadic progressive myoclonic
epilepsy with early‐onset dementia caused by a denovo mutation in PSEN1. Neurol Clin Neurosci.
2019 June; 7(5): 294-296. doi.org/10.1111/ncn3.
12319

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Department of Molecular Sciences
on Diabetes
Project Associate Professor
Hironori Waki, M.D.,Ph.D.

Project Research Associate
Masatoshi Kobayashi, M.D.,Ph.D., Takayoshi Sasako, M.D., Ph.D.

Introduction and Organization
The prevalence of diabetes is rising to epidemic
proportions worldwide. There is urgent need fordevelopment of the treatment for diabetes and relateddiseases.
Advances in molecular biology had
successfully led to elucidation of various mechanisms
at a cellular level and at a tissue level in thephysiological condition and in the disease states. In
order to understand the precise mechanism underlying
the development of diabetes, it is critical to reveal
systemic connections between the cells and the tissues
in the body.
The specific aims of our department are (1) todeepen and expand the investigations on metabolic
tissues involved in glucose and lipid homeostasis,such as pancreatic endocrine cells, skeletal muscle,
liver and adipose tissue and (2) to reveal the essential
causes of diabetes from the perspective of thesystemic network among the metabolic tissues.

Teaching activities
As for the under-graduate education, ourdepartment takes a part in systemic lectures. We train
graduate and post-graduate students in Nutrition andMetabolism, Internal Medicine, Graduate School of
Medicine, The University of Tokyo.

Research activities
Adipocyte and Energy Metabolism
Brown fat dissipates energy in the form of heat.

Increasing the mass or activity of brown fat is an
attracting strategy for the treatment of obesity. We
analyzed open chromatin genomic regions in brown
fat and identified NFIA as a new transcription factor
that controls brown-fat-specific gene program. NFIA
binds to enhancers near brown-fat-specific genes andfacilitates the binding of PPARγ—the adipocyte
master regulator—to these enhancers. We further
demonstrated its role by conducting experiments using
culture cells, gene knock out animals, and epigenetic
analysis using next generation sequencer. We also
elucidated multiple activities and the roles of NFIA in
the body by analyzing the effect of artificial mutationsof NFIA and genetically engineered mice.
We also found that RNA N6-adenosine methyltransferase complex consisting of Wilms’ tumor
1-associating protein (WTAP), methyltransferase like3 (METTL3), and METTL14 positively controls
adipogenesis by promoting cell cycle transition in the
mitotic clonal expansion phase during adipogenesis.
WTAP heterozygous knockout mice exhibited smaller
adipocytes and were resistant to diet-induced obesity.
CDK5 Regulatory Subunit-Associated Protein
1-like 1 (CDKAL1) was identified as a susceptibility
gene for type 2 diabetes and body mass index ingenome-wide association studies. We found that
CDKAL1 is expressed in adipose tissue and its
expression is increased during differentiation. Stable
overexpression of CDKAL1, however, inhibited
adipocyte differentiation of 3T3-L1 cells, whereas
knockdown of CDKAL1 promoted differentiation.
CDKAL1 increased protein levels of β-catenin and its

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active unphosphorylated form in the nucleus, thereby
promoting Wnt target gene expression, suggesting that
CDKAL1 activated the Wnt/β-catenin pathway—a
well-characterized inhibitory regulator of adipocyte
differentiation Our results identify CDKAL1 as novel
negative regulator of adipocyte differentiation andprovide insights into the link between CDKAL1 andmetabolic diseases such as type 2 diabetes and obesity.
We generated mice overexpressing CDKAL1 in
adipose tissue and showed that these mice areprotected from obesity under a high-fat diet.
Liver and Energy Homeostasis
Dynamic metabolic changes occur in the liver
during the transition between fasting and feeding,which contributes to the maintenance of systemic
homeostasis of glucose and lipid metabolism.
We have found that transient endoplasmic reticulum(ER) stress responses in the liver following feedingterminated by stromal cell-derived factor 2 like 1(Sdf2l1) are essential for normal glucose and lipid
homeostasis. In obese and diabetic mice, however,Sdf2l1 is downregulated, whereas restoration of
Sdf2l1 expression ameliorates glucose intolerance andfatty liver with decreased ER stress. In diabetic
patients, insufficient induction of Sdf2l1 correlateswith progression of insulin resistance andsteatohepatitis. Therefore, failure to build an ER stressresponse in the liver may be a causal factor in
obesity-related
diabetes
andnonalcoholicsteatohepatitis, for which Sdf2l1 could serve as atherapeutic target and sensitive biomarker.

References
1. Kobayashi M, Ohsugi M, Sasako T, Awazawa M,
Umehara T, Iwane A, Kobayashi N, Okazaki Y,
Kubota N, Suzuki R, Waki H, Horiuchi K,
Hamakubo T, Kodama T, Aoe S, Tobe K,
Kadowaki T, Ueki K. The RNA Methyltransferase
Complex of WTAP, METTL3, and METTL14
Regulates Mitotic Clonal Expansion in
Adipogenesis. Mol. Cell Biol. Aug 15:38:e0011600118, 2018.
2. Enooku K, Kondo M, Fujiwara N, Sasako T,
Shibahara J, Kado A, Okushin K, Fujinaga H,
Tsutsumi T, Nakagomi R, Minami T, Sato M,

Nakagawa H, Kondo Y, Asaoka Y, Tateishi R,
Ueki K, Ikeda H, Yoshida H, Moriya K,
Yotsuyanagi H, Kadowaki T, Fukayama M, Koike
K: Hepatic IRS1 and beta-catenin expression isassociated with histological progression and overt
diabetes emergence in NAFLD patients. J
Gastroenterol 53(12): 1261-1275, December
2018.
3. Sasako T, Ohsugi M, Kubota N, Itoh S, Okazaki Y,
Terai A, Kubota T, Yamashita S, Nakatsukasa K,
Kamura T, Iwayama K, Tokuyama K, Kiyonari H,
Furuta Y, Shibahara J, Fukayama M, Enooku K,
Okushin K, Tsutsumi T, Tateishi R, Tobe K,
Asahara H, Koike K, Kadowaki T, Ueki K.
Hepatic Sdf2l1 controls feeding-induced ER stressand regulates metabolism.Nat. Commun. Feb 27;
10(1):947. 2019.

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Department of
Immunotherapeutics
Project Professor
Kazuhiro Kakimi, M.D., Ph.D.

Project Assistant Professor
Koji Nagaoka, Ph.D.

Homepage http://immunoth.umin.jp/
Introduction and Organization
Since immune checkpoint blockade therapies wereapproved for the treatment of many cancer types,
remarkable clinical responses have been achieved in acertain proportion of patients. Nonetheless, many
patients are unresponsive, and there remain several
tumor types that are refractory to immunotherapy.
Multiple immunosuppressive mechanisms operate in
the tumor microenvironment (TME), and any
anti-tumor immune cells that might be present areoften impaired in the TME.
Thus, effective immunotherapy requires a
combination of potent stimulation of anti-tumor
immune responses and, additionally, manipulation of
the immunosuppressive environment to prevent tumor
escape. Therefore, elucidating the mechanisms of
responsiveness or refractoriness and the moleculardeterminants thereof is required to improve cancer
immunotherapy.
The objective of our department is to demonstrate
the feasibility of an immunological data-guided
personalized adaptive approach to immunotherapy,
whereby immunomodulatory strategies are tailored tothe patient’s specific TME.

Clinical activities
We provide outpatient services for cancer patients.
All interventions performed in the department are
defined by the protocols based on the Act on
Securement of Safety of Regenerative Medicine(Approved on Nov 20, 2013). The following clinical
trials were conducted in our department:γδ T cell therapy for advanced cancer
1. UMIN registration number ： UMIN000006128
active, recruiting. Adoptive immunotherapy using
zoledronate-expanded autologous γδ T cells forpatients with non-small cell lung cancer refractory
to standard treatment.
Immunomodulator(anti-CCR4 mAb+anti-PD-1mAb)
1. UMIN-CTR Clinical Trial ID：UMIN000021480.
ClinicalTrials.gov ID ： NCT02946671. Study ofPre-operative
Combination
Therapy
with
Mogamulizumab and Nivolumab Against Solid
Cancer Patients

Teaching activities
Research guidance in molecular immunology isprovided to postgraduate students. Because knowledge
and techniques for evaluation of immune response areimportant for clinicians and medical researchers, we
also provide many opportunities to postgraduate
students to learn how to analyze in vivo immune
responses through experiments using animal models
and by the immunological monitoring of the patientsthemselves in clinical research.

406

Research activities
Immunotherapy with immune checkpoint inhibitors(ICIs) has completely changed the therapeutic
landscape for many types of solid tumors. Several
combinations of immunotherapy with chemotherapy,
molecular targeted drugs, or combinations of different
ICIs are now approved for the first-line treatment ofvarious cancers. However, not all types of cancer
respond equally well to ICIs, and even in responsive
cancers, only a subset of patients experiences durable
responses and favorable long-term outcomes. This isbecause primary and acquired resistance occurs in aconsiderable proportion of patients across different
cancer types.
Therefore, it is crucial to establish reliablepredictive biomarkers to distinguish ICI responders
from non-responders, who may suffer unnecessary
costs and toxicities, and to identify candidates forrational combination therapies. Currently, tumor
mutational burden and PD-L1 expression are the two
major variables used as biomarkers that have beenvalidated in phase III clinical trials. Additionally,
several other factors associated with response or
resistance to ICIs across cancer types have been
proposed as biomarkers, based on molecular profilingof cancers treated with different immunotherapies.
These include an immune-inflamed phenotype,
expression of T cell signaling pathway genes such as
IFNγ, microsatellite instability, somatic copy-number
alterations, HLA class I diversity, T cell repertoire
clonality change, WNT-β-catenin signaling, TGF
expression and even commensal microbiota.
However, as single biomarkers, none of the above issufficient to identify individual patients who will
likely benefit from immunotherapy. Unlike conventional cancer therapies, immunotherapies, including
ICIs, do not directly target tumor cells; instead, theyaffect tumor cells through the patient’s immune
system or the tumor microenvironment (TME).
Therefore, the different components that affecttumor-immune interactions need to be taken into
account when developing predictive biomarkers for
immunotherapy. Comprehensive analysis of multiple
different functional pathways and molecular networks
that reveal integrated mechanisms of tumor-immune
interactions are crucial for this purpose. General andlocal cancer immunity status in each patient needs tobe taken into consideration.
To this end, Blank et al. proposed the concept of thecancer immunogram that integrates multiparameterbiomarkers to visualize the immunological status of anindividual patient. We have applied this concept tolung cancer patients and developed an immunogram
reflecting the cancer-immunity cycle. Since then, van
Dijk et al. have reported an immunogram informative
specifically for urothelial cancer patients. Althoughimmunograms may be useful for visualizing thelandscape of the tumor microenvironment and thecompromised steps of anti-tumor immunity in eachpatient, both Blank et al. and van Dijk et al. had only
theorized that they could be useful to patients but had
not tested the concept in clinical practice. In contrast,
we analyzed real-world lung cancer patient data to
generate immunograms with potential applications for
personalized immunotherapy. We utilized RNA-Seq
data from the TCGA cohort as a standard and set up ascoring scale to quantify parameters incorporated in
the immunogram. We propose a novel versatilescoring method for constructing such individual
immunograms.

List of Publications
1) Ohue Y, Kurose K, Karasaki T, Isobe M, Yamaoka
T, Futami J, Irei I, Masuda T,Fukuda M, Kinoshita
A, Matsushita H, Shimizu K, Nakata M, Hattori N,
Yamaguchi H, Fukuda M, Nozawa R, Kakimi K,
Oka M. Serum Antibody Against NY-ESO-1
andXAGE1 Antigens Potentially Predicts Clinical
Responses to Anti-Programmed Cell Death-1
Therapy in NSCLC. J Thorac Oncol. 2019 Dec;
14(12):2071-2083.
2) Nejo T, Matsushita H, Karasaki T, Nomura M,
Saito K, Tanaka S, Takayanagi S,Hana T,
Takahashi S, Kitagawa Y, Koike T, Kobayashi Y,
Nagae G, Yamamoto S, Ueda H, Tatsuno K,
Narita Y, Nagane M, Ueki K, Nishikawa R,
Aburatani H, Mukasa A, Saito N, Kakimi K.
Reduced Neoantigen Expression Revealed byLongitudinal Multiomics as a Possible Immune
Evasion Mechanism in Glioma. Cancer Immunol
Res.2019 Jul;7(7):1148-1161.
3) Sugimoto K, Kakimi K, Takeuchi H, Fujieda N,

407

Saito K, Sato E, Sakamaki K,Moriyasu F, Itoi T.
Irreversible Electroporation versus Radiofrequency Ablation:Comparison of Systemic
Immune Responses in Patients with Hepatocellular Carcinoma. J Vasc Interv Radiol. 2019
Jun;30(6):845-853.e6.
4) Aoki H, Ueha S, Shichino S, Ogiwara H,
Hashimoto SI, Kakimi K, Ito S,Matsushima K.
TCR Repertoire Analysis Reveals Mobilization ofNovel CD8+ T Cell Clones Into the CancerImmunity Cycle Following Anti-CD4 Antibody
Administration. Front Immunol. 2019 Jan 24; 9:3185.

Presentation at International
conference
1) 2019/6/6-7. The 26th International Symposium on
Molecular Cell Biology of Macrophages
MMCB2019. Tokyo. Koji Nagaoka, Akihiro
Hosoi, Changbo Sun, Kiyomi Taniguchi,
Masataka Shirai, Kazuhiro Kakimi. Early
activation of myeloid cells is required for theCD8+ T-cell dependent anti-tumor immunity
2) 2019/9/9. 2019 World Conference Lung Cancer(IASLC). Barcelona, Spain. T. Karasaki, Y.
Kobayashi, A. Shinozaki- Ushiku, C. Konoeda, K.
Kitano, K. Nagayama, M. Sato, A. Hosoi, K.
Kakimi, J. Nakajima. TUMOR SPPEAD
THROUGH AIR SPACES IS ASSOCIATED
WITH THE NON-INFLAMED IMMUNEMICROENVIRONMENTINLUNGSQUAMOUS CELL CARCINOMA

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Department of Immunotherapy
Management
Project Associate Professor
Hiroko Kanda, M.D., Ph.D.

Project Associate
Mariko Inoue, M.D., PhD, Shoko Tateishi, M.D., PhD

Homepage

http://ryumachi.umin.jp/immu.html

Introduction and Organization
Recently, biologic agents targeting cytokines or cellsurface molecules and small molecules targeting
intracellular pathways relevant to cytokine production
or cytokine signaling, play an important role in thetreatment of autoimmune diseases. Both of them are
named as molecularly targeted drugs. In Japan, thesemolecularly targeted drugs are available for thetreatment of rheumatoid arthritis, psoriasis, Behcet
disease and inflammatory bowel diseases. Thesediseases are treated in the Department of Allergy &Rheumatology, Dermatology, Orthopedics Gastroenterology, Surgical oncology & vascular surgery, andOphthalmology. The Department of Immunotherapy
Management was established in April 2013, andrenewed through donations from new seven pharmaceutical companies (Mitsubishi-Tanabe, Chugai,
Ayumi, Taishotoyama, Nipponkayaku, UCB Japan,
Abbvie) in June 2016. The Department of Allergy &Rheumatology, Dermatology and Orthopedics work incollaboration.
Biologics agents include infliximab, infliximab BS,
adalimumab, golimumab, certolizumab pegol,etanercept, tocilizumab, abatacept, ustekinumab,
secukinumab, ixelizumb, brodulumab, guselkumab,
rituximab, mepolizumab and belimumab. The Jakkinase inhibitors include tofacitinib and baricitinib.
These molecularly targeted drugs have beendeveloped in succession. However, it is difficult topredict the efficacy and toxicity of these agents by the

background characteristics of patients withrheumatoid arthritis. The aims of this department are
to propose an optimal treatment strategy for eachpatient and to establish a platform to investigate novel
biologics through analyses of immunological changes
by molecularly targeted therapy and the relationshipbetween biologics response and biomarkers or genetic
information.

Clinical activities
We established a new booth for outpatients withrheumatoid arthritis who are receiving molecularly
targeted drugs which is available every morning from
Monday to Friday. We focus on total rheumatoid
arthritis care with molecularly targeted drugs.
Moreover, we examine outpatients with psoriasis,
spodyloarthritis and Behcet’s disease before
molecularly targeted therapy and judge whether thesetreatments can be used safely. In every Friday
afternoons, we evaluate for outpatient with psoriatic
arthritis including accurate diagnosis and monitoringdisease activity by clinical and imaging examinations.

Teaching activities
As for education, we take part in providing
information of molecularly targeted drugs for patients
who are the candidates to receive biologics, including
necessity, benefits, safety, complications, procedures
and costs. Every time when a new molecularly
targeted drug becomes available for prescription, we409

provide information of the agent for medical staffs.
Moreover, we are giving lectures about molecularly
targeted therapy for medical students at bed-side
learning programs or at systematic lecture courses.

Research activities
As for research, we are investigating novel
molecularly targeted drugs through analyses of
immunological changes by molecularly targeted
therapy and the relationship between biologics
response and biomarkers or genetic information.

References
1. Kato R, Sumitomo S, Tsuchida Y, Tsuchiya H,
Nakachi S, Sakurai K, Hanata N, Nagafuchi Y,
Kubo K, Tateishi S, Kanda H, Okamura T,
Yamamoto K, Fujio K: CD4+CD25+LAG3+ T
Cells With a Feature of Th17 Cells AssociatedWith Systemic Lupus Erythematosus Disease
Activity. Front Immunol 10:1619-28, 2019

410

Department of Ubiquitous
Preventive Medicine
Associate Professor
Yuichi Ikeda, M.D., Ph.D.

Assistant Professor
Kazutaka Ueda, M.D., Ph.D.

Introduction and Organization
As an official department in the Graduate School of
Medicine of the University of Tokyo, the Departmentof Ubiquitous Preventive Medicine was established inAugust 1st, 2007, with a donation from three pharmaceutical companies, Toa-Eiyo Ltd., Shionogi & Co.,
Ltd. and NEC Corporation to the University. Its
predecessor is the Clinical Bio-Informatics Research
Unit, which was established in 2002 as a governmentfunded program (Bio-Informatics Training Programsupported by the Ministry of Education, Culture,
Sports, Science and Technology [MEXT] throughSpecial Coordination Funds for Promoting Scienceand Technology). When the Clinical Bio-Informatics
Research Unit completed its program tenure in 2007,
its academic services were succeeded by our department and the Department of Clinical Epidemiology
and Systems, both affiliated with the Department of
Cardiovascular Medicine in the Graduate School of
Medicine of the University of Tokyo.
Our department provides clinical as well as
academic support for the Department of Epidemiology
and Preventive Medicine, which was established in2007 within the University of Tokyo Hospital. In
collaboration with our department, the Department ofClinical Epidemiology and Systems also support the
management of the Department of Epidemiology andPreventive Medicine.

Research Activities
Our goal is to create diagnostic and therapeuticbasis for prevention and early detection ofcardiovascular diseases by utilizing advanced
techniquesofbiochemistryandmolecular
pharmacology. We especially focus on the discoveryof bioactive molecules and diagnostic biomarkers inorder to promote translational research, whichconnects basic scientific findings to tangible clinicalapplication.
One of our achievements is the establishment of anovel technique for detecting post-translational
modification and degradation of B-type natriuretic
peptide, one of the most important biomarkers in
cardiovascular pathologies such as ischemic heartdisease and heart failure. This unique technique wasdevelopedincollaboration
withShimadzu
Corporation.
We have already confirmed andpublished its utility in clinical practice (Clin Chem, inpress), further, issued press-release from the
University of Tokyo Hospital.
In addition to the development of diagnostic
techniques, we have also established several screening
systems towards the discovery of bioactive substancesthat are involved in the pathogenesis of cardiovasculardiseases. Utilizing these newly developed systems,
we will screen tissue extracts and a small-moleculecompound library to identify novel bioactive
molecules.
In this way, Ubiquitous Preventive Medicine is anapplied science, based on which a comprehensive
system is to be developed in an effort to promote
preventive medicine for health promotion.

411

Clinical activities
The Department of Ubiquitous Preventive Medicine
is involved in the management of the Department of
Epidemiology and Preventive Medicine in the
University of Tokyo Hospital and provides clinical aswell as academic support for the department.

Teaching activities
The Department of Ubiquitous Preventive Medicine
offers education and research supervision to graduate
students and post-doctoral fellows in the affiliate
Department of Cardiovascular Medicine.

Publications
1. Takanashi M, Kimura T, Li C, Tanaka M,
Matsuhashi A, Yoshida H, Noda A, Xu P, Takase
S, Okazaki S, Iizuka Y, Kumagai H, Ikeda Y,
Gotoda T, Takahashi M, Yagyu H, Ishibashi S,
Yamauchi T, Kadowaki T, Liang G, Okazaki H.
Critical Role of SREBP-1c large-VLDL pathway
in environment-induced hypertriglyceridemia of
APO AV deficiency. Arterioscular Thromb Vasc
Biol. 39:373-386,2019
2. Ueda K, Toko H, Komuro I. Endothelial cellderiverd angiocrines elicit physiological cardiomyocyte hypertrophy. Circulation. 139:25852587,2019
3. Akazawa H, Toko H, Harada M, Ueda K, Kodera
S, Kiyosue A, Fujiu K, Hatano M, Daimon M,
Ando J, Takimoto E, Morita H, Komuro I.
Overview of the 83rd annual scientific meeting of
the Japanese circulation society -Renaissance of
cardiology for the creation of future medicine.
Circ J. 83:1829-35,2019

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Department of Life Support
Technology (Molten)
Project Professor
Taketoshi Mori, Ph.D.

Project Lecturer
Hiroshi Noguchi, Ph.D.

Project Assistant Professor
Toshiaki Takahashi, Ph.D.

Homepage http://www.lifesupport.m.u-tokyo.ac.jp/
Introduction and Organization
Department of Life Support Technology (Molten) was
founded Oct. 1, 2010 as a laboratory in Graduate
School of Medicine of the University of Tokyo.
The aim of the department is to establish life support
technology, which include not only pathophysiology
investigation of diseases and symptoms caused bydaily life activities but also development of directintervention method based on nursing approach andmethodology establishment for supporting daily life
widely.
First, Prof. Hiromi Sanada, who drives translational
research in nursing research area, and Molten Corp.,
which is one of Japanese welfare device development
companies, planned to establish this department. After
planned, Prof. Takeyoshi Dohi, leading person in
welfare and medical device engineering, recommended Taketoshi Mori, Ph.D. as a leader of thedepartment. He arrived at his post and the department
was established.
From Oct 1, 2015, the second term of the department
started. On Feb 20, 2016, the celebration party for
department continuation and promotion of Prof. Mori
was held at Gakushi-Kaikan, which is the same placeas the celebration party for department establishment.

Many people including president of Molten Corp.
Kiyoshi Tamiaki, Prof. Noriko Yamamoto and Prof.
Takeyoshi Dohi attended the party. Both nursing
researchers and engineering researches congratulate
the department continuation and promotion of Prof.
Mori.
Our department contributed to establishment of thesociety for nursing science and engineering from 2012.
The first annual meeting of nursing science andengineering was hold at 5th Oct 2013. Our department
played a great important role for management of themeeting as a host.
From Apr 1, 2017, global nursing research center was
established in Graduate School of Medicine of the
University of Tokyo. In the center, Project Prof. Mori
held the addition concurrent post of Robotic Nursing
in Division of Care innovation.
Current members include a project professor, a project
lecturer and a project assistant professor. We accept
students from Division of Health Science and Nursing.
Accepted two master course students were graduatedat the end of 2013. The supportive department is the
Department of Gerontological Nursing / Wound CareManagement. We also accept foreign students. In 2013,
we accepted a Ph.D. student from Mexico. In 2017,

413

we accepted a research student from Korea. The
student was a 2nd year student of Division of Health
Science and Nursing.

naturally, 2) understanding the typical behaviors, and
3) predicting diseases, injuries, and accidents using
various sensing technology.

Teaching activities

Main themes of our department are the following:a) Development of monitoring systems for patient on
a bed and vital sign measurement system using
mattressb) Construction of behavior measurement in dailyliving environment using simple sensors andalgorithm for typical behavior pattern extraction
and transition estimation of human behavior
patternc) Three-dimensional leg movement measurement
and spatiotemporal 3D leg state measurement for
prevention of foot ulcerd) Clinical research and image processing technology
development for current status and management ofincontinencee) Human position measurement and behavior
estimation using laser range scannersf) Design and construction of human behavior
database

As for lectures, our department assisted the lectures ofthe supportive department, the Department ofGerontological Nursing/Wound Care Management. In
a part of Wound Care Management I for graduate
course, Taketoshi Mori taught electric engineering,which is closely related to development of medical
and nursing devices. Hiroshi Noguchi taught
measurement engineering. We invited engineering
professors outside the university for GerontologicalNursing II for graduate course. In a part ofGerontological Nursing I for graduate course, themembers in the department lectured the features andreading method of journal papers of engineeringresearch based on typical publications.
As for the other education activity, our department
supported management of the seventh seminar for
nursing science and engineering, which was organizedby global nursing research center. The staffs in our
department had engineering-related lectures.
From establishment of global nursing research center,the laboratory have accepted training or visitation in
our laboratory 15 times (7 from foreigners, and 8 fromdomestic visitors)

Research activities
Our research themes are to investigate causes of
diseases and/or wounds due to daily life activity, andto develop instrument for effective monitoring andpreventing diseases and/or wounds. We study scienceand technology of natural human monitoring, nursing
engineering, and human behavior sensing thoroughly.
We are seeking a new interdisciplinary researchdomain between engineering and nursing, and willing
to realize comfortable daily life through theseresearches.
We are developing the methodology to support healthy
and comfortable daily life by 1) monitoring daily life

As for the clinical field, we started the research at the
University hospital using communication robots from2017. From 2018, we extended the robot research field
to another facility with Department of GerontologicalNursing/Wound Care Management.
The master course student, who was belonging to ourdepartment, developed a new non-invasive device toestimate skin condition online and onsite using
electric-impedance tomography for assessment ofpressure ulcer healing condition. He wrote mastercourse thesis “Developing a pressure ulcer monitoring
tool using electrical impedance tomography andspectroscopy: Phantom study and preliminary humantrial” and graduated.
We achieved the following award in this year.
1. Presentation award of Japanese Society of Wound,
Ostomy, and Continence Management (domestic
conference)．Takeo Minematsu, Michitaka Ogata, Nao
Tamai, Koichi Yabunaka, Tomonori Maeda, Gojiro
Nakagami, Hiroshi Noguchi, Hiromi Sanada “Deeptissue injury actual situation among wheel chair basket

414

athletes: skin properties related to deep tissue injury”.
Proceedings of the 28th annual conference of JapaneseSociety of Wound, Ostomy, and ContinenceManagement. Vol.23, No. 2, pp. 242, 2019.
2. Presentation award of Japanese Society of Pressure
Ulcer (domestic conference)．Tomonori Maeda, Nao
Tamai, Takeo Minematsu, Hiroshi Noguchi, Goijro
Nakagami, Koichi Yabunaka, Hiromi Sanada.
“Relationship between hip pressure during playing
and pressure ulcer occurrence among wheel chairbasketball athlete”, Proceedings of Japanese Societyof Pressure Ulcer. Vol.21, No. 3, pp. 309, 2019.

References
1. Takahashi T, Murayama R, Abe-Doi M,
Miyahara-Kaneko M, Kanno C, Nakamura M,
Mizuno M, Komiyama C, Sanada H. Preventing
peripheral intravenous catheter failure by
reducing mechanical irritation. Scientific Reports.
2020;10(1550).
2. Kanno C, Murayama R, Abe-Doi M, Takahashi T,
Shintani Y, Nogami J, Komiyama C, Sanada H.
Developmentofanalgorithm
using
ultrasonography-assisted peripheral intravenous
catheter placement for reducing catheter failure.
Drug Discoveries ＆ Therapeutics. 2020;14(1):27-34.
3. Oe M, Tsuruoka K, Ohashi Y, Takehara K,
Noguchi H, Mori T, Yamauchi T, Sanada H.
Prevention of diabetic foot ulcers using aself-monitoring device smartphone and mobile
thermography：Case study. Journal of Wound Care.
2020.
4. Noguchi H, Oe M, Takehara K, Mori T, Sanada H.
Onsite visualization of shoe fitting for educationof the people with diabetes using 3D scanner: A
pilot study. Journal of Nursing Science andEngineering. 2020;7:162-169.
5. Noyori S, Nakagami G, Noguchi H, Mori T,
Sanada H. Unintentional body movement
parameters and pulse rate variability parameters
are associated with the desire to void. Medical
Engineering ＆ Physics. 2019;68:116-121.
6. Takahashi T, Minematsu T, Murayama R,
Nakagami G, Mori T, Sanada H. Catheter tips area possible resource for biological study oncatheter
failure.
Drug
Discoveries＆
Therapeutics. 2019;13(5):280-287.
7. Noguchi H, Koyano Y, Mori H, Komiyama C,
Sanada H, Mori T. Exploration of communication
robot use for older patients in an acute hospital
based on case trials. Journal of Nursing Scienceand Engineering. 2019;6(2):70-82.
8. Takahashi T, Murayama R, Yabunaka K, Tanabe H,
Sanada H. Using Tablet-Type Ultrasonography toAssess Peripheral Veins for Intravenous
Catheterization: A Pilot Study. Journal of the
Association for Vascular Access. 2019;24(3):1-6.
9. Takahashi T, Minematsu T, Murayama R,
Nakagami G, Mori T, Sanada H. Catheter tips area possible resource for biological study oncatheter
failure.
Drug
Discoveries＆
Therapeutics. 2019;13(5):280-287

415

Department of Clinical Trial DataManagement
Project Assistant Professor
Tempei Miyaji, M.Sc.

Project Researcher
Takuhiro Yamaguchi, Ph.D.

Registered Researcher
Satoru Fukimbara, Ph.D.
Hideki Suganami, Ph.D.
Yukikazu Hayashi, M.Sc.

Project Academic Support Staff
Miyuki Kurosaki
Kumiko Seike

Homepage

http://ctdm.umin.jp/

Introduction and Organization
Why we discuss Clinical Data Management (CDM)?
The reason why the concept of CDM is important has
not been fully discussed and educated in Japan. Our
department was established to answer this question.
The Department of Clinical Trial Data Management
was established in 2007 and carried out educationaland research activities on CDM in collaboration withThe Department of Biostatistics, The ClinicalResearch Support Center and Department of HealthCommunication in University of Tokyo.
As compared to the situation of CDM in the UnitedStates and Europe, technical aspects (data collection,
entry, check…) have been mainly focused in Japan but
the essence of CDM is to ensure quality of clinicaldata to appropriate level for fair and scientificevaluation. This has not been recognized in manyeducational activities. CDM should be defined as atechnical system to conduct clinical trials scientifically,
ethically and efficiently and to draw correctconclusion and also as a research discipline withtheory and practice that applies statistics, quality
control and clinical knowledge. It can optimize thewhole clinical trial process, keep the level of data
quality appropriately and calculate the trial cost.
One of our missions is to promote researches on CDM
aimed at improving the quality of clinical trials. The
other is to provide training for data managers with the
new education system which can look around all theclinical trial process to adapt rapid change of medical
environment and recent increase of e-clinical trials in
the world.

Teaching activities
1. Development of systematic educational programsof CDM and holding of seminars, which include; Design of clinical trials
 CDM
 Risk-based Monitoring Patient-reported Outcome
 Mobile Helath Safety information and PMS

416

 Translational research methodology
2. Acceptance of clinical trial staffs from other sites,that is, conducting an on-the-job training (OJT)
3. Support to clinical researchers, especially those in
the University of Tokyo Hospital, in collaboration
with the Clinical Research Support Center and theDepartment of Clinical Epidemiology and Systems;
 Consultation works on medical statistics andresearch methodology
 Functioning as a data center and stuffs
participate in projects as biostatisticians or
clinical data managers.

4.

5.

Research activities
In addition to activities described above, we areconducting the research on methodology of Riskbased monitoring, mobile Health (mHealth) anddeveloping ePRO in collaboration with otheruniversities, pharmaceutical industries, CRO andvenders.
We are also supporting several clinical studies which
are conducted in the University of Tokyo Hospital.
Moreover, we also have collaborative works outsideof University of Tokyo Hospital for several clinicalresearches.

References
1. Miyaji T, Kawaguchi T, Azuma K, Suzuki S, Sano Y,
Akatsu M, Torii A, Kamimura T, Ozawa Y, Tsuchida
A, Eriguchi D, Hashiguchi M, Nishino M, Nishi M,
Inadome Y, Yamazaki T, Kiuchi T, Yamaguchi T:
Patient-generated health data collection using awearable activity tracker in cancer patients—a
feasibility study. Support Care Cancer (2020).
2. Tanaka R, Kaburaki T, Yoshida A, Takamoto M,
Miyaji T, Yamaguchi T: Fluorescein Angiography
Scoring System Using Ultra-Wide-Field Fluorescein
Angiography Versus Standard Fluorescein Angiography in Patients with Sarcoid Uveitis. Ocul
Immunol Inflamm. 2020 Mar 12, 1-5. doi: 10.1080/
09273948.2020.1737141. [Epub ahead of print]
PMID: 32162984
3. Hashimoto H, Yamaguchi T, Abe M: A new standard
prophylaxis for emesis caused by cisplatin? Authors' reply. Lancet Oncol. 2020 Mar, 21(3):e129.

6.

7.

8.

doi:
10.1016/S1470-2045(20)30100-5.
PMID:
32135113
Tagami K, Kawaguchi T, Miura T, Yamaguchi T,
Matsumoto Y, Watanabe YS, Uehara Y, Okizaki A,
Inoue A, Morita T, Kinoshita H: The association
between health-related quality of life and achievement of personalized symptom goal. Support Care
Cancer. 2020 Jan 22, doi: 10.1007/s00520-02005316-0. [Epub ahead of print] PMID: 31970517
Hirota S, Yamaguchi T: Timing of Pediatric DrugApproval and Clinical Evidence Submitted toRegulatory Authorities: International Comparison
Among Japan, the United States, and the European
Union. Clin Pharmacol Ther. 2019 Dec 23, doi: 10.
1002/cpt.1757. [Epub ahead of print] PMID:
31933395
Hashimoto H, Abe M, Tokuyama O, Mizutani H,
Uchitomi Y, Yamaguchi T, Hoshina Y, Sakata Y,
Takahashi TY, Nakashima K, Nakao M, Takei D,
Zenda S, Mizukami K, Iwasa S, Sakurai M,
Yamamoto N, Ohe Y: Olanzapine 5 mg plus
standard antiemetic therapy for the prevention ofchemotherapy-induced nausea and vomiting(J-FORCE): a multicentre, randomised, double-blind,placebo-controlled, phase 3 trial. Lancet Oncol.
2020 Feb, 21(2):242-249. doi: 10.1016/S1470-2045(19)30678-3. Epub 2019 Dec 11. PMID:31838011
Matsuoka H, Iwase S, Miyaji T, Kawaguchi T,
Ariyoshi K, Oyamada S, Satomi E, Ishiki H,
Hasuo H, Sakuma H, Tokoro A, Matsuda Y,
Tahara K, Otani H, Ohtake Y, Tsukuura H,
Matsumoto Y, Hasegawa Y, Kataoka Y, Otsuka M,
Sakai K, Nakura M, Morita T, Yamaguchi T,
Koyama A: Predictors of duloxetine response inpatients with neuropathic cancer pain: a secondary
analysis of a randomized controlled trial-JORTCPAL08 (DIRECT) study. Support Care Cancer. 2019
Nov 25, doi: 10.1007/s00520-019-05138-9. [Epubahead of print] PMID: 31761974
Matsuda Y, Morita T, Matsumoto H, Hosoi K,
Kusama K, Kohashi Y, Morishita H, Kaku S,
Ariyoshi K, Oyamada S, Inoue Y, Iwase S,
Yamaguchi T, Nishikawa M: Morphine for dyspnoea
in chronic obstructive pulmonary disease: abefore-after efficacy study. BMJ Support Palliat
Care. 2019 Nov 15, pii: bmjspcare-2019-001929.

417

doi: 10.1136/bmjspcare-2019-001929. [Epub aheadof print] PMID: 31732660
9. Fuji S, Kurosawa S, Inamoto Y, Murata T,
Utsunomiya A, Uchimaru K, Yamasaki S, Inoue Y,
Moriuchi Y, Choi I, Ogata M, Hidaka M, Yamaguchi
T, Fukuda T: A decision analysis comparing
unrelated bone marrow transplantation and cord
blood transplantation in patients with aggressive
adult T-cell leukemia-lymphoma. Int J Hematol.
2019 Nov 7, doi: 10.1007/s12185-019-02777-w.
[Epub ahead of print] PMID: 31701480
10. Ban K, Tsunoda H, Watanabe T, Kaoku S,
Yamaguchi T, Ueno E, Hirokaga K, Tanaka K:
Characteristics of ultrasonographic images of ductal
carcinoma in situ with abnormalities of the ducts. J
Med Ultrason (2001). 2019 Oct 26, doi: 10.1007/
s10396-019-00981-z. [Epub ahead of print]. PMID:
31655940
11. Tanaka H, Chiu SW, Watanabe T, Kaoku S,
Yamaguchi T: Computer-aided diagnosis system forbreast ultrasound images using deep learning. Phys
Med Biol. 2019 Oct 23, doi: 10.1088/1361-6560/
ab5093. [Epub ahead of print] PMID: 31645021
12. Mori M, Morita T, Matsuda Y, Yamada H, Kaneishi
K, Matsumoto Y, Matsuo N, Odagiri T, Aruga E,
Watanabe H, Tatara R, Sakurai H, Kimura A,
Katayama H, Suga A, Nishi T, Shirado AN,
Watanabe T, Kuchiba A, Yamaguchi T, Iwase S:
How successful are we in relieving terminal dyspnea
in cancer patients? A real-world multicenter prospective observational study. Support Care Cancer.
2019 Oct 19, doi: 10.1007/s00520-019-05081-9.
[Epub ahead of print] PMID: 31630256
13. Yamaguchi T, Kawaguchi T, Miyaji T: [Patient
Reported Outcome (PRO) in Oncology]. Gan To
Kagaku Ryoho. 2019 Sep, 46(9):1345-1356. PMID:
31530769
14. Ikeda R, Oshima T, Mizuta K, Arai M, Endo S, Hirai
R, Ikeda K, Kadota S, Otsuka Y, Yamaguchi T,
Kawase T, Kobayashi T: Efficacy of a silicone plugfor patulous eustachian tube: A prospective,
multicenter case series. Laryngoscope. 2019 Aug 10,
doi: 10.1002/lary.28229. [Epub ahead of print]
PMID: 31400157.
15. Sato H, Taguchi A, Yamaguchi T, Omori J: [Factors
related to support provided by preschool personnel
for parents rearing children with special needs:

Focus on communicating about the child'sdevelopmental problems]. Nihon Koshu Eisei
Zasshi. 2019, 66(7):356-369. doi: 10.11236/jph.66.
7_356. Japanese. PMID: 31341141.
16. Matsuoka H, Iwase S, Miyaji T, Kawaguchi T,
Ariyoshi K, Oyamada S, Satomi E, Ishiki H, Hasuo
H, Sakuma H, Tokoro A, Shinomiya T, Otani H,
Ohtake Y, Tsukuura H, Matsumoto Y, Hasegawa Y,
Kataoka Y, Otsuka M, Sakai K, Matsuda Y, Morita T,
Koyama A, Yamaguchi T: Additive Duloxetine forCancer-Related Neuropathic Pain Nonresponsive or
Intolerant to Opioid-Pregabalin Therapy: A
Randomized Controlled Trial (JORTC-PAL08). J
Pain Symptom Manage. 2019 Jun 26, pii: S08853924(19)30364-1. doi: 10.1016/j.jpainsymman.2019.
06.020. [Epub ahead of print]. PMID: 31254640
17. Mori M, Fujimori M, van Vliet LM, Yamaguchi T,
Shimizu C, Kinoshita T, Morishita-Kawahara M,
Inoue A, Inoguchi H, Matsuoka Y, Bruera E, Morita
T, Uchitomi Y: Explicit prognostic disclosure to
Asian women with breast cancer: A randomized,
scripted video-vignette study (J-SUPPORT1601).
Cancer. 2019 Jun 17, doi: 10.1002/cncr.32327.
[Epub ahead of print]. PMID: 31206639
18. Kurosawa S, Yamaguchi T, Oshima K, Yanagisawa
A, Fukuda T, Kanamori H, Mori T, Takahashi S,
Kondo T, Kohno A, Miyamura K, Umemoto Y,
Teshima T, Taniguchi S, Yamashita T, Inamoto Y,
Kanda Y, Okamoto S, Atsuta Y: Resolved versus
Active Chronic Graft-versus-Host Disease: Impact
on Post-Transplantation Quality of Life. Biol Blood
Marrow Transplant. 2019 May 24, pii: S10838791(19)30327-1. doi: 10.1016/j.bbmt.2019.05.016.
[Epub ahead of print]. PMID: 31129353
19. Akizawa T, Nangaku M, Yamaguchi T, Arai M,
Koretomo R, Maeda K, Miyazawa Y, Hirakata H:
Enarodustat, Conversion and Maintenance Therapy
for Anemia in Hemodialysis Patients: A
Randomized, Placebo-Controlled Phase 2b Trial
Followed by Long-Term Trial. Nephron. 2019 May
22, 1-9. doi: 10.1159/000500487. [Epub ahead ofprint]. PMID: 31117088
20. Yoshida Y, Manaka T, Nitadori JI, Shinozaki-Ushiku
A, Doke T, Saito T, Sato J, Miyaji T, Yamaguchi T,
Oyama H, Fukayama M, Nakajima Y, Nakajima J:
A comparison between 2- and 3-dimensional
approaches to solid component measurement as418

radiological criteria for sublobar resection in lungadenocarcinoma ≤ 2 cm in size. Surg Today. 2019
Apr 9, doi: 10.1007/s00595-019-01806-9. [Epubahead of print]. PMID: 30968225
21. Fujiwara M, Inagaki M, Shimazu T, Kodama M, So
R, Matsushita T, Yoshimura Y, Horii S, Fujimori M,
Takahashi H, Nakaya N, Kakeda K, Miyaji T,
Hinotsu S, Harada K, Okada H, Uchitomi Y,
Yamada N. A randomised controlled trial of a casemanagement approach to encourage participation incolorectal cancer screening for people withschizophrenia in psychiatric outpatient clinics: study
protocol for the J-SUPPORT 1901 (ACCESS) study.
BMJ Open 2019;9:e032955. doi: 10.1136/bmjopen2019-032955

419

Department of Preventive Medicine
for Locomotive Organ Disorders
Project Professor
Noriko Yoshimura, M.D., Ph.D.

Project Research Associate
Toshiko Iidaka, M.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 March 1st, 2017, which is anendowment department supported by Chugai
Pharmaceutical Co., Ltd., Fujifilm Corporation,
Ajinomoto Co., Inc., ASAHI KASEI PHARMACORPORATION, ALCARE Co., Ltd., Inter Reha
Co.,Ltd., Anima Corporation, TEIJIN PHARMALIMITED, Suntory Holdings Limited, Hisamitsu
Pharmaceutical Co., Inc., and in close collaboration
with departments of Orthopaedic Surgery andRehabilitation Medicine in the hospital. Our
department has been established to clarify the
epidemiological profiles of locomotive organ
disorders, such as, osteoarthritis (OA), osteoporosis(OP) and sarcopenia (SP). Further, we also try to
elucidate the frequencied and risk factors forlocomotive syndrome, which was defined by theJapanese Orthopaedic Association (JOA) in 2014.

environmental 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
further follow-up surveys.

References
1.

Research activities
Although locomotive organ disorders are major causesof disability and require support, little information isavailable regarding their epidemiology. The Research
on Osteoarthritis/Osteoporosis Against Disability(ROAD) study, which started in 2005-7, is a
prospective cohort study that aims to elucidate the2.

3.

Yamada K, Satoh S, Hashizume H, Yoshimura N,
Kagotani R, Ishimoto Y, Abe Y, Toyoda H, Terai
H, Masuda T, Muraki S, Nakamura H, Yoshida
M: Diffuse idiopathic skeletal hyperostosis isassociated with lumbar spinal stenosis requiring
surgery. J Bone Miner Metab 37(1): 118-124,
2019
Hayashi M, Nakashima T, Yoshimura N,
Okamoto K, Tanaka S, Takayanagi H:
Autoregulation of osteocyte Sema3A orchestrates
estrogen action and prevents bone ageing. Cell
Metab 29(3): 627-637.e5, 2019
Nagata K, Yoshimura N, Hashizume H, Yamada

420

4.

5.

6.

7.

8.

9.

H, Ishimoto Y, Muraki S, Nakagawa Y, Minamide
A, Oka H, Kawaguchi H, Tanaka S, Nakamura K,
Yoshida M: Physical performance decreases inthe early stage of cervical myelopathy before the
myelopathic signs appear: the Wakayama Spine
Study. Eur Spine J 28(5): 1217-1224, 2019
Ishimoto Y, Cooper C, Ntani G, Yamada,Hashizume H, Nagata K, Muraki S, Tanaka S,
Yoshimura N, Yoshida M, Walker-Bone K:
Factory and construction work is associated withan increased risk of severe lumbar spinal stenosis
on MRI: A case control analysis within the
wakayama spine study. Am J Ind Med 62(5):430-438, 2019
Horii C, Asai Y, Iidaka T, Muraki S, Oka H,
Tsutsui S, Hashizume H, Yamada H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Tanaka S,
Yoshimura N: Differences in prevalence andassociated factors between mild and severe
vertebral fractures in Japanese men and women:
the third survey of the ROAD study. J Bone
Miner Metab 37(5): 844-853, 2019
Deguchi T, Hashizume H, Nakajima M,
Teraguchi M, Akune T, Yamada H, Tanaka S,
Yoshimura N, Nojima M, Yoshida M, Ikegawa S:
A population-based study identifies anassociation of THBS2 with intervertebral discdegeneration. Osteoarthritis Cartilage 27(10):1501-1507, 2019
Nishizawa Y, Miura M, Ichimura S, Inaba M,
Imanishi Y, Shiraki M, Takada J, Chaki O,
Hagino H, Fukunaga M, Fujiwara S, Miki T,
Yoshimura N, Ohta H; from the Japan
Osteoporosis Society Bone Turnover Marker
Investigation Committee: Executive summary of
the Japan Osteoporosis Society Guide for the Useof Bone Turnover Markers in the Diagnosis andTreatment of Osteoporosis (2018 Edition). Clin
Chim Acta 498: 101-107, 2019
Yoshimura N, Muraki S, Iidaka T, Oka H, Horii
C, Kawaguchi H, Akune T, Nakamura K, Tanaka
S: Prevalence and co-existence of locomotive
syndrome, sarcopenia, and frailty: the thirdsurveyofResearchon
Osteoarthritis/
Osteoporosis Against Disability (ROAD) study. J
Bone Miner Metab 37(6): 1058-1066, 2019
Ishimoto Y, Cooper C, Ntani G, Yamada H,

10.

11.

12.

13.

Hashizume H, Nagata K, Muraki S, Tanaka S,
Yoshida M, Yoshimura N, Walker-Bone K: Is
radiographic lumbar spondylolisthesis associatedwith occupational exposures? Findings from anested case control study within the Wakayama
spine study. BMC Musculoskelet Disord 20(1):618, 2019
Shinto K, Minamide A, Hashizume H, Oka H,
Matsudaira K, Iwahashi H, Ishimoto Y, Teraguchi
M, Kagotani R, Asai Y, Muraki S, Akune T,
Tanaka S, Kawaguchi H, Nakamura K, Yoshida
M, Yoshimura N, Yamada H: Prevalence of Facet
Effusion and Its Relationship with Lumbar
Spondylolisthesis and Low Back Pain: The
Wakayama Spine Study. J Pain Res 12: 35213528, 2019
Iidaka T, Muraki S, Oka H, Horii C, Kawaguchi
H, Nakamura K, Akune T, Tanaka S, Yoshimura
N: Incidence rate and risk factors forradiographic hip osteoarthritis in Japanese men
and women: a 10-year follow-up of the ROAD
study. Osteoarthritis Cartilage 28(2): 182-188,
2020
Ishimoto Y, Jamaludin A, Cooper C,
Walker-Bone K, Yamada H, Hashizume H, Oka H,
Tanaka S, Yoshimura N, Yoshida M, Urban J,
Kadir T, Fairbank J: Could automated machinelearned MRI grading and epidemiological studies
of lumbar spinal stenosis? Validation within the
Wakayama Spine Study. BMC Musculoskelet
Disord 21(1):158, 2020
Matsui T, Hara K, Kayama T, Iwata M, Shitara N,
Hojo S, Endo Y, Fukuoka H, Yoshimura N,
Kawaguchi H: Cervical muscle diseases areassociated with indefinite and various symptoms
in the whole body. Eur Spine J, in pressSocial Cooperation Program422

Department ofAdvanced Nursing Technology
Project Associate Professor
Ryoko Murayama, Ph.D., R.N.M.

Project Assistant Professor
Mari Abe, MHS, R.N.

Visiting Researcher
Hidenori Tanabe, MS.

Homepage http://ant.m.u-tokyo.ac.jp/index.html
Introduction and Organization
The Department of Advanced Nursing Technology
was established in December 2012 with the aim ofdeveloping new academic fields in order to create
advanced nursing technology based on clinicalevidences. The primary aim is to “Never let patientsendure suffering in healthcare;” therefore, ouractivities aimed to directly assist patients to live
longer and have healthier lives.
To date, significant challenges in creating advanced
nursing technology have resulted in a gap between
academic research and clinical setting requirements.
Therefore, strategies of advanced nursing technology
have not been applied in hospitals due to its unsuitability in the clinical setting, despite being beneficial
to academic nursing researchers at universities.
In contrast, new nursing technologies are often
developed by nurses’ experiences in clinical settings;
however, they have certain limitations such as
unavailability of scientific processes. Furthermore,
systems to promote and support nurses who wish to
conduct research in the clinical setting are insufficient.
The Department of Advanced Nursing Technology
was established at the University of Tokyo Hospital(Tokyo, Japan), with the support of Terumo Corp.
(Tokyo, Japan), as a social cooperation program. The
social cooperation program at the University of Tokyo
was established to address the abovementioned

challenges and further development of nursing
technology. The Department of Advanced Nursing
Technology (since in March 2018) now comprises the
Department of Gerontological Nursing/Wound CareManagement, Department of Nursing, and Department
of Hematology and Oncology. This program aimed todevelop a new research model through a collaborative
research with the Departments of Nursing andMedical Examination of the University of Tokyo
Hospital and the Division of Health Sciences andNursing of the University of Tokyo. In addition, thisprogram aimed to disseminate advances in nursing
technology based on the needs of clinical practices
worldwide.
The team included the following members fromvarious departments at the University of Tokyo:
Ryoko Murayama (Project Associate Professor) andMari Abe (Project Assistant Professor), as well as
Hidenori Tanabe (Visiting Researcher; from Terumo
Corp.).
Furthermore, the Global Nursing Research Center(GNRC), Graduate School of Medicine, the Universityof Tokyo, has been established in April 2017. Thiscenter was in charge of the department of ClinicalNursing Technology, Division of Care Innovation of
GNRC, and contributed to promote research on
innovative nursing science and to create an inter-423

disciplinary research and educational environment that
fosters young leaders in nursing research.

Teaching activities
This program guided Master’s and Ph.D. students
from the Department of Gerontological Nursing/
Wound Care management on matters concerning
research planning and practical work. Furthermore, wehave been involved in providing lectures on topics,
such as gerontological nursing and wound carenursing, for undergraduates, master’s and Ph.D.
students within the Department of GerontologicalNursing/Wound Care management.
The primary master thesis in 2019 was titled“Incidence, characteristics and timing of peripheral
intravenous catheter failure in patients receiving
chemotherapy with hematological malignancy; aprospective descriptive study.”
We were in charge of lectures on nursing
translational research at the seminar hosted by GNRC
for post-doctoral fellows and other researchers.
(Introduction seminar to Nursing Science andEngineering)Research activities
1. Activity policy
A new nursing research scheme aimed at
identifying clinical needs related to our primary belief
will be developed, i.e., “Never let patients endure
suffering in healthcare.” Solutions to clinical issues innursing will be determined using multidisciplinary
studies and research. Regarding our scientificapproach, epidemiologic surveys and genetic research
will be conducted, followed by evaluation oftechnologies/devices developed in collaboration withcompanies, endeavoring to provide epoch-making
technologies that meet clinical needs utilizing the
Nursing Translational Research system.
Several research projects are also ongoing in our
department, such as development of nursing technology for the early detection of extravasation, clarification of infiltration, identification of mechanisms,
development of a new intravenous catheter to prevent
catheter failures, and a proposal or new program on
infusion therapy management. These projects arebeing conducted in collaboration with nurses at the
University of Tokyo Hospital.
We offer lectures and consultations on researchmatters and provide guidance on article writing topromote nursing research in the clinical setting. We
are planning and running an annual symposium known
as “UTokyo nursing research” in order to promotejoint research with the Departments of Nursing andMedical Examination and School of Health Science at
the University of Tokyo Hospital.
2. Research fields and themes in 2019 Understanding the mechanisms that lead toperipheral intravenous catheter failures: PIV-CF.
 Development of a new intravenous catheter toprevent PIV-CF.
 Development of a thermo-film for the early
detection of extravasation.
 Development of a training program for thetechnical improvement of peripheral venous
catheter placement using ultrasonography.

References
1. Takahashi T, Minematsu T, Murayama R,
Nakagami G, Mori T, Sanada H. Cathetertips are apossible resource for biological study on catheter
failure. Drug Discoveries & Therapeutics. 2019;13(5):280-287.
2. Murayama R, Oya M, Abe-Doi M, Oe M,
Komiyama C, Sanada H. Characteristics ofsubcutaneous tissues at the site of insertion of
peripheral infusion in patients undergoing
paclitaxel and carboplatin chemotherapy. Drug
Discoveries & Therapeutics. 2019;13(5):288-293.
3. Tanabe H, Takemura N, Terao H, Hagiwara H,
Zushi Y, Murayama R, et al. Vascular endothelium
damage from catheter-induced mechanicalstimulation causes catheter sleeve formation in a
rabbit model. The Journal of Vascular Access.
2019; 21(3):379-386.
4. Takahashi T, Murayama R, Yabunaka K, Tanabe H,
Sanada H. Using Tablet-Type Ultrasonography toassess peripheral veins for intravenous
catheterization: A pilot study. Journal of the
Association for Vascular Access. 2019; 24(3): 1-6.

424

5. Abe-Doi M, Murayama R, Yabunaka K, Tanabe H,
Komiyama C, Sanada H. Ultrasonographic assessment of an induration caused by extravasation of anon-vesicant anti-cancer drug: A case report.
Medicine. 2019;98(14): e15043. doi: 10.1097/
MD.0000000000015043.

425

Department of
Imaging Nursing Science
Project Associate Professor
Nao Tamai, Ph.D

Project Lecturer
Masaru Matsumoto, Ph.D

Project Assistant Professor
Yuka Miura, Ph.D

Collaborative Researchers
Mayumi Handa and Mikihiko Karube

Homepage

http://www.imagingnursing.m.u-tokyo.ac.jp/index.html

Organization history and overview
The Department of Imaging Nursing Science wasfounded as part of the Corporate Sponsored Research
Programs offered by the Graduate School of Medicine,
The University of Tokyo, in April 2017. It aims torealize “a safe, secure, and comfortable medical careexperience” through visualized nursing technology.
The department conducts translational researchthrough surveys on actual nursing care conditions
based on imaging technology and propose nursing
techniques and their evaluation, with the goal ofdeveloping care systems and applying these in clinicalsettings.
Specific plans include developing (1) an ultrasoundtechnology support system for nursing care, (2) aremote support system using imaging technology toassist nursing care, and (3) innovative technologies
using new imaging techniques in nursing.
This Social Cooperation Program was establishedwith the cooperation of FUJIFILM Corp. and with the
Department of Gerontological Nursing / Wound CareManagement as partner departments aiming to findsolutions to these challenges and to further the
progress in nursing technologies. It aspires to establish
imaging nursing technologies in clinical nursing

settings in Japan, as a forerunner in shifting towards a
globally unprecedented super-aging society, and to
become the first transmitter of new discoveries to theworld.
Department members are Project Associate
Professor Nao Tamai, Project Lecturer Masaru
Matsumoto, Project Assistant Professor Yuka Mirura,and Visiting Researchers Mayumi Handa and
Mikihiko Karube (FUJIFILM Corp.). The Project
Associate Professor concurrently served as a member
at a visualized nursing field of Division of Care
Innovation, the Medical Graduate School of Global
Nursing Research Center and now strives to establish
and disseminate imaging nursing skills in nursing
research.

Education
In 2019, we provided the following lectures forundergraduate and postgraduate students.
a) Human Anatomy (A1 in 3rd yr.)b) Bioengineering Nursing (S2 in 4th yr.)c) Laboratory Practice for Life Science Ⅱ (S2 in
3rd yr.)d) Practicum in Human Health Support (W in 2nd
yr.)

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e) Gerontological Nursing (A2 in 4th yr.)f) Special Lecture in Gerontological Nursing I (S1)g) Special Lecture in Wound Care Nursing I (S2)h) Special Lecture in Wound Care Nursing II (A)We instructed and cooperated with graduate
students of the Department of Gerontological Nursing/ Wound Care Management regarding their researchplans through seminars and practical training.
Through external lectures and workshops toincrease awareness, we have held lectures on skin andelimination care at levels equivalent to curricula for
Certified Nurses in Wound, Ostomy and Continence
Nursing course at the Nurse Training Center of the
Kyoto Tachibana University. We have also held
lectures on training for nurse-designated procedures in
the Nursing Training School of the Japanese Nursing
Association as well as on skin tears in the Adachi
Community Health Center and Keiyu Hospitals.
At the seminar on nursing science and engineering,sponsored by the Global Nursing Research Center, we
lectured on imaging nursing skills to many nursing
researchers and clinical nurses. In addition, we gavehands-on training in ultrasound technology andqualitative sketching techniques useful for nursing tointerested participants.

Research
This course seeks to develop nursing assessment
skills using ultrasonography and to promote research
in imaging nursing that directly contributes to clinicalsettings. We are developing a versatile portableultrasound device that is ultralight-weight, produceshigh image quality, and operates on a wide range of
frequencies. Furthermore, a nursing assessment
coaching software is being developed using imaging
analysis, which does not require special techniques, tosupport assessment by nurses.
Specifically,weundertook
researchanddevelopment on the following topics in our Japan
Agency for Medical Research and Developmentfunded study titled, “Constructing a multidisciplinary
system implementing advanced nursing techniques tosupport eating and defecating in patients receiving
home and facility care.” We have developed the
support systems of “eating,” “elimination,” and“skin/wound care” using ultrasound devices:

1)

2)

3)

Development
andassessmentofahome/long-term care facility multidisciplinary
system to support eating and swallowing.
Development
andassessmentofahome/long-term care facility multidisciplinary
information and communication technology
system to support bowel elimination.
Development of an educational program for deep
tissue injury using artificial intelligence.

With these research activities, we have received thefollowing awards:
・Best Moderated Poster Award from the 8th Asia
Pacific Enterostomal Therapy Nurse Association(2019, Nov)．Ayano Nakai, Toshihiro Tsukatani,
Nao Tamai, Tamae Urai, Yukie Mori, Kuang Weijie,
Takeo Minematsu, Chika Takada, Hiromi Sanada.
Relationship between type IV collagen positivity
via skin blotting and conventional risk factors ofskin tears.
・ Best Presentation Award from the 21st Annual
Congress of Japanese Society of Pressure Ulcers(2019, Aug). Tomonori Maeda, Nao Tamai, Takeo
Minematsu, Hiroshi Noguchi, Gojiro Nakagami,
Koichi Yabunaka, Hiromi Sanada. Relationshipbetween pressure ulcers and dynamic buttock
pressure distributions during performance inwheelchair basketball athletes.
・Best Presentation Award from the 28th JapaneseSociety of Wound, Ostomy & ContinenceManagement (2019, May). Takeo Minematsu,
Michitaka Ogata, Nao Tamai, Koichi Yabunaka,
Tomonori Maeda, Gojiro Nakagami, Hiroshi
Noguchi, Hiromi Sanada. Skin properties related todeep tissue damage in wheelchair basketballathletes.

References
1. Nakai A, Minematsu T, Tamai N, Sugama J, Urai
T, Sanada H. Prediction of healing in category I
pressure ulcers by skin blotting with plasminogenactivator inhibitor 1, interleukin-1α, vascularendothelial growth factor C, and heat shockprotein 90α: A pilot study. Journal of Tissue
Viability. 2019;28(2):87-93.
2. Matsumoto M, Yabunaka K, Yoshida M,

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3.

4.

5.

6.

Nakagami G, Sanada H. Validity assessment of
two bladder volume estimation methods using
hand-held ultrasonography devices: verification
with a small amount of bladder urine. Journal of
Nursing Science and Engineering. 2019;6(1):2232.
Matsumoto M, Tsutaoka T, Yabunaka K, Handa M,
Yoshida M, Nakagami G, et al. Development andevaluation of automated ultrosonographic
detection of bladder diameter for estimation of
bladder urine volume. PLOS ONE. 2019;14(9).
Hase T, Miura Y, Nakagami G, Okamoto S,
Sanada H, Sugama J. Food bolus-forming ability
predicts incidence of aspiration pneumonia in
nursing home older adults: a prospective
observational study. Journal of Oral Rehabilitation.
2019;47(1):53-60.
Miura Y, Yabunaka K, Karube M, Tsutaoka T,
Yoshida M, Matsumoto M, et al. Establishing a
Methodology for Ultrasound Evaluation ofPharyngeal Residue in the Pyriform Sinus andEpiglottic Vallecula. Respiratory Care. Epub 2019Oct 29.
Tamai N, Miura Y, Matsumoto M, Takada C,
Sanada H. Evaluation of urinary bladder imagesby a nurse who received an education program forurinary continence care using ultrasound devices:inter-rater reliability. Japanese Journal of GeriatricUrology. 2019;32(2):46-51. [in Japanese]428

Department of Healthcare Quality
Assessment
Project Professor
Hiroaki Miyata, Ph.D.

Project Associate Professor
Hiraku Kumamaru, M.D., Sc.D.

Project Assistant Professor
Naoaki Ichihara, M.D., Ph.D., M.P.H.

Researcher
Shun Kosaka, M.D., Ph.D.

Adjunct Researcher
Norimichi Hirahara, Ph.D.
Kan Nawata, M.D., Ph.D.
Hiroyuki Yamamoto, M.D., Ph.D., M.P.H.
Arata Takahashi, HIM, M.S.
Eriko Fukuchi, M.S.

Registered Researcher
Hideki Endo, M.D.
Chieko Fujimura.
Shiori Nishimura, M.S.

Clerical Staff
Urara Isozumi, M.S.

Clerical Staff (Secretary)
Takayo Nakamura.

Homepage

http://hqa.umin.jp/

Introduction and Organization
The Department of Healthcare Quality Assessment(HQA) was established in 2006 and has been engaging
in research on healthcare quality improvement incollaboration with the Department of Cardiothoracic
Surgery in University of Tokyo.

The objective of providing healthcare is to provide
high quality healthcare services to all patients.
Institute of Medicine states that health care reform
should focus on improving the patients’ health as wellas health care values that they think are important.
In the 21st century, this viewpoint, together withinsight from health economics, has been the first429

priority in the field of medicine and healthcare.
“Quality improvement initiative,” therefore, needs toadjust the healthcare systems to accommodate thefee-for-service perspectives while improving theclinical environment for both patients and providers.

Research activities
Department of Healthcare Quality Assessment (HQA)
has been actively collaborating with healthcare
professionals and various clinical committees as theyplay key roles in the quality improvement initiatives
in the field. In such positive environment driven by
the patient-centered philosophy, the patients receive
more satisfying care, physicians are rewarded for their
excellence, and healthcare costs are sustained. To
accomplish this goal, there are 3 principles thatnavigate us through the journey: (a) the topmost value
should always be on that of patients, (b) all medical
practices should be organized around medical
conditions as well as the care cycles of the patients,and (c) the results---risk-adjusted outcomes andmedical costs spent---must be scientifically measured
and evaluated.
In April 2010, the Japan Society of Surgery and 10
related surgical societies founded the National
Clinical Database (NCD), which is an all-Japanendeavor that aims to build a large-scale,comprehensive clinical registry that utilize the “bigdata” to improve the quality of surgery as well as
surgical sciences in Japan. HQA has been playing
important academic roles in the project since its birth.
The actual data entry started from January 1st, 2011,
and since then NCD has been collecting approximately 95% of all surgical operations across Japan in
the collaboration with the clinical societies. NCD is
also connected with the participating societies’ boardof certification systems, which makes it unique among
other large-scale clinical registries in the world. Today
more than 5,300 hospitals and clinics are participatingin NCD with the accumulated data of 10 million cases(approximately 1.5 million each year).
HQA has developed risk models for different groupsof surgical procedures that help us implement several
practical tools aimed for medical professionals in the
joint research activity with Japan Cardiovascular
Surgery Database (JCVSD). One of those tools is

JapanSCORE, which allows a user to calculate apatient’s post-operative risk of mortality andmorbidities.
Another tool called RiskCalculator
returns a medical professional the calculated risk ofmortality and morbidity in a real-time manner afters/he inputs a minimum number of pre-operative risk
information. Both tools can be used in medical teammeetings as well as in sessions with patients to reachbetter informed consent. Just like JCVSD’s
JapanSCORE and RiskCalculator, feedback tools
based on the NCD data have been provided todifferent subspecialty areas. All of these activities
help Japan’s healthcare quality initiatives in various
places, and HQA is proud of being part of it.
HQA also has conducted evidence-based policy
analysis to help federal and local government todevelop better healthcare policy-making. It is anacademic activity that contributes in a different angle
to the endeavor of healthcare quality improvement
than those with healthcare professionals in the field,
described above. In 2012, HQA started participating
in a series of research to evaluate the validity ofJapan’s cancer control policy framework using various
stakeholders’ perspectives. Interview as well as
questionnaire studies were conducted in accordancewith the Basic Plan for Implementing Cancer Control
administered by the Japanese Government.
Clinical databases like NCD are the core componentsof quality improvement initiative in many health careservices such as in the field of thoracic surgery.
HQA supports NCD’s systematic data collection, data
management, data analyses, and the development of
useful feedback systems. Non-surgical fields such as
clinical oncology are also joining NCD and this trend
is becoming stronger. Our benchmarking projects
backed up by NCD’s big data will keep driving thequality improvement activities in many healthcare
fields.
Increasing number of clinical researches, conducted incollaboration with the professional societies, has comeout based on detailed analyses of various registry datacollected by NCD. Also, in collaboration with
Pharmaceuticals and Medical Devices Agency as well
as device manufacturers, new registries have workedonacademia-government-industry
collaboration
projects using NCD registry data. One example is theresearch project based on the registry for transcatheter

430

valve therapy which also supported the manufacturers’
post-marketing surveillance activities. HQA has also
been involved in international research collaborations
with major registries abroad, including American
College of Surgeon’s NSQIP, Asian Cardiac Databaseand The Society of Thoracic Surgeons National
Database, aiming to participate in quality
improvement activities in different regions of theworld.

References
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William E Boden, Bernard R Chaitman, Roxy
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Goodman, Witold Ruzyllo, Gilbert Gosselin, Aldo
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Jesus Peteiro, Todd D Miller, Hanna Szwed, Rolf
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Gabriel Steg, Claes Held, Shun Kohsaka,
Stavroula Mavromichalis, Ruth Kirby, Neal O
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Stable Coronary Disease. N Engl J Med.
382(15):1395-1407. 2020 Apr 9.
2. Inohara T, Vemulapalli S, Kohsaka S, Yashima F,
Watanabe Y, Shirai S, Tada N, Araki M,
Naganuma T, Yamanaka F, Ueno H, Tabata M,
Mizutani K, Higashimori A, Takagi K, Yamamoto
M, Shimizu H, Fukuda K, Hayashida K;
OCEAN-TAVI Investigators. Appropriateness ofTranscatheter Aortic Valve Replacement: Insight
From the OCEAN-TAVI Registry. Circ
Cardiovasc Qual Outcomes. 13(4):e006146. 2020
Mar 26.

3. Izumisawa Y, Endo H, Ichihara N, Takahashi A,
Nawata K, Shiraishi H, Miyata H, Motomura N.
Association between prehospital transfer distanceand surgical mortality in emergency thoracic
aortic surgery. J Thorac Cardiovasc Surg. S00225223(20)30709-1. 2020 Mar 23.
4. Ban D, Tanabe M, Kumamaru H, Nitta H, Otsuka
Y, Miyata H, Kakeji Y, Kitagawa Y, Kaneko H,
Wakabayashi G, Yamaue H, Yamamoto M. Safe
Dissemination of Laparoscopic Liver Resection in
27,146 Cases Between 2011 and 2017 From the
National Clinical Database of Japan. Ann Surg.
2020 Mar 20.
5. Shoji S, Kohsaka S, Sawano M, Okamura T,
Hirata A, Sugiyama D, Ohkubo T, Nakamura Y,
Watanabe M, Kadota A, Ueshima H, Okayama A,
Miura K; NIPPON DATA2010 Research Group.
Electrocardiographic Left Atrial Abnormality and
B-Type Natriuretic Peptide in a General Japanese
Population: NIPPON DATA2010. J Atheroscler
Thromb. 2020 Mar 19.
6. Nakamura M, Kimura K, Kimura T, Ishihara M,
Otsuka F, Kozuma K, Kosuge M, Shinke T,
Nakagawa Y, Natsuaki M, Yasuda S, Akasaka T,
Kohsaka S, Haze K, Hirayama A. JCS 2020
Guideline Focused Update on Antithrombotic
Therapy in Patients With Coronary Artery Disease.
Circ J. 84(5):831-865.2020 Mar 13.
7. Miura S, Inoue K, Kumamaru H, Yamashita T,
Hanyu M, Shirai S, Ando K. Clinical impact ofpathology-proven etiology of severely stenotic
aortic valves on mid-term outcomes in patients
undergoing surgical aortic valve replacement.
PLoS One. 15(3):e0229721. 2020 Mar 10.
8. Sawano M, Yuan Y, Kohsaka S, Inohara T, Suzuki
T, Okamura T, Howard G, Howard VJ, Judd S,
Soliman EZ, Cushman M. Electrocardiographic
ST-T Abnormities Are Associated With Stroke
Risk in the REGARDS Study. Stroke. 51(4):11001106. 2020 Mar 4.
9. Fujishiro J, Watanabe E, Hirahara N, Terui K,
Tomita H, Ishimaru T, Miyata H. Laparoscopic
Versus Open Appendectomy for AcuteAppendicitis in Children: a Nationwide Retrospective Study on Postoperative Outcomes. J
Gastrointest Surg. 2020 Mar 3.
10. Kameda T, Kumamaru H, Nishimura S, Kohsaka

431

S, Miyata H. Use of oral antidiabetic drugs inJapanese working-age patients with type 2
diabetes mellitus: dosing pattern for metformin
initiators. Curr Med Res Opin. 2020 Feb 27:1-8.
11. Yashima F, Inohara T, Numasawa Y, Kuno T,
Sawano M, Ueno K, Shimoji K, Noma S, Fukuda
K, Kohsaka S. Transradial percutaneous coronary
intervention in patients with advanced chronic
kidney disease. Cardiovasc Revasc Med. 2020
Feb 12.
12. Kawakami T, Matsubara H, Abe K, Kataoka M,
Kohsaka S, Sato Y, Shinke T, Fukuda K.
Multicentre randomised controlled trial of balloon
pulmonary angioplasty and riociguat in patientswith chronic thromboembolic pulmonary hypertension: protocol for the MR BPA study. BMJ
Open. 10(2):e028831. 2020 Feb 6.
13. Nakata K, Yamamoto H, Miyata H, Kakeji Y, Seto
Y, Yamaue H, Yamamoto M, Nakamura M.
Definition of the objective threshold ofpancreatoduodenectomy with nationwide datasystems. J Hepatobiliary Pancreat Sci. 27(3):107113. Epub 2020 Feb 3.
14. Saito A, Amiya E, Hatano M, Shiraishi Y, Nitta D,
Minatsuki S, Maki H, Hosoya Y, Tsuji M, Bujo C,
Nawata K, Kinoshita O, Kimura M, Endo M,
Kagami Y, Nemoto M, Ikeda Y, Morita H, Ono M,
Komuro I. Controlling Nutritional Status Score As
a Predictive Marker for Patients With Implantable
Left Ventricular Assist Device. ASAIO J. 66(2):166-172. 2020 Feb.
15. Mizuno S, Ono K, Mikami Y, Naganuma M,
Fukuda T, Minami K, Masaoka T, Terada S,
Yoshida T, Saigusa K, Hirahara N, Miyata H,
Suda W, Hattori M, Kanai T. 5-Aminosalicylic
acid intolerance is associated with a risk ofadverse clinical outcomes and dysbiosis inpatients with ulcerative colitis. Intest Res. 18(1):69-78. Epub 2020 Jan 30.
16. Iwakami N, Nagai T, Furukawa TA, Tajika A,
Onishi A, Nishimura K, Ogata S, Nakai M,
Takegami M, Nakano H, Kawasaki Y, Alba AC,
Guyatt GH, Shiraishi Y, Kohsaka S, Kohno T,
Goda A, Mizuno A, Yoshikawa T, Anzai T;
investigators for the WET-NaDEF Collaboration
Project. Optimal sampling in derivation studies
was associated with improved discrimination inexternal validation for heart failure prognostic
models. J Clin Epidemiol. 121:71-80. Epub 2020
Jan 29.
17. Shiraishi Y, Kohsaka S, Katsuki T, Harada K,
Miyazaki T, Miyamoto T, Matsushita K, Iida K,
Takei M, Yamamoto Y, Shindo A, Kitano D,
Nagatomo Y, Jimba T, Yamamoto T, Nagao K,
Takayama M; for Tokyo CCU Network ScientificCommittee.. Benefit and harm of intravenous
vasodilators across the clinical profile spectrum inacute cardiogenic pulmonary oedema patients.
Eur Heart J Acute Cardiovasc Care. 2020 Jan 29:
2048872619891075.
18. Miura K, Ikemura N, Kimura T, Katsumata Y,
Ueda I, Tanimoto K, Ohki T, Shinmura D, Negishi
K, Fukuda K, Takatsuki S, Kohsaka S. Treatment
strategies and subsequent changes in thepatient-reported quality-of-life among elderly
patients with atrial fibrillation. Am Heart J. 222:
83-92. Epub 2020 Jan 21.
19. Fujishiro J, Fujiogi M, Hirahara N, Terui K,
Okamoto T, Watanabe E, Ishimaru T, Miyata H.
Abdominal Drainage at Appendectomy forComplicated Appendicitis in Children: A
Propensity-matched Comparative Study. Ann Surg.
2020 Jan 21
20. Tokuda Y, Yamamoto H, Miyata H, Usui A,
Motomura N; Japan Cardiovascular Surgery
Database Organization. Contemporary Outcomesof Surgical Aortic Valve Replacement in Japan.
Circ J. 84(2):277-282. Epub 2020 Jan 11
21. Shoji S, Shiraishi Y, Kohsaka S, Fukuda K,
Yoshikawa T. Long-Term Outcomes According to
Etiology May Alter Under Different Circumstances. JACC Heart Fail. 8(1):83-84. 2020 Jan.
22. Heerspink HJL, Karasik A, Thuresson M,
Melzer-Cohen C, Chodick G, Khunti K, Wilding
JPH, Garcia Rodriguez LA, Cea-Soriano L,
Kohsaka S, Nicolucci A, Lucisano G, Lin FJ,
Wang CY, Wittbrodt E, Fenici P, Kosiborod M.
Kidney outcomes associated with use of SGLT2
inhibitors in real-world clinical practice (CVDREAL 3): a multinational observational cohort
study. Lancet Diabetes Endocrinol. 8(1):27-35.
2020 Jan
23. Tani H, Sawano M, Numasawa Y, Kobayashi Y,
Suzuki M, Noma S, Shiraishi Y, Ueda I, Fukuda K,

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Kohsaka S. In-hospital outcome in patients
presenting with acute coronary syndrome with left
main coronary artery disease: A report fromJapanese prospective multicenter percutaneous
coronary intervention registry. J Cardiol. 2019
Dec 30.
24. Nakata K, Yamamoto H, Miyata H, Kakeji Y, Seto
Y, Yamaue H, Yamamoto M, Nakamura M.
Definition of the objective threshold ofpancreatoduodenectomy with nationwide datasystems. J Hepatobiliary Pancreat Sci. 2019 Dec
26.
25. Aizawa Y, Tanimoto Y, Hirata Y, Fujisawa T,
Fukuoka R, Nakajima K, Katsumata Y, Nishiyama
T, Kimura T, Yuasa S, Kohno T, Kohsaka S,
Murata M, Maekawa Y, Furukawa Y, Takatsuki S,
Fukuda K. Incidence, Clinical Characteristics, andLong-term Outcome of the Dilated Phase ofHypertrophic Cardiomyopathy. Keio J Med.
68(4):87-94.2019 Dec 25.
26. Matsushita K, Harada K, Miyazaki T, Miyamoto T,
Kohsaka S, Iida K, Yamamoto Y, Nagatomo Y,
Yoshino H, Yamamoto T, Nagao K, Takayama M.
Reply to: Heart Failure With Preserved Ejection
Fraction in Older Adults. J Am Geriatr Soc. 2019
Dec 20.
27. Ohkura Y, Miyata H, Konno H, Udagawa H, Ueno
M, Shindoh J, Kumamaru H, Wakabayashi G,
Gotoh M, Mori M. Development of a Model
Predicting the Risk of Eight Major Postoperative
Complications After Esophagectomy Based on
10,826 Cases in the Japan National Clinical
Database. J Surg Oncol. 2019 Dec 10.
28. Sujino Y, Nakano S, Tanno J, Shiraishi Y, Goda A,
Mizuno A, Nagatomo Y, Kohno T, Muramatsu T,
Nishimura S, Kohsaka S, Yoshikawa T; WestTokyo Heart Failure Registry Investigators.
Clinical implications of the blood urea
nitrogen/creatinine ratio in heart failure are andtheir association with haemoconcentration. ESC
Heart Fail. 2019 Dec 9.
29. Ohno Y, Yamaji K, Kohsaka S, Inohara T, Amano
T, Ishii H, Kadota K, Nakamura M, Nakazawa G,
Yoshimachi F, Ikari Y; J-PCI Registry Investigators. Incidence and In-Hospital Outcomes ofPatients Presenting With Stent Thrombosis (fromthe Japanese Nationwide Percutaneous Coronary

Intervention Registry). Am J Cardiol. 125(5):7207262020. Epub 2019 Dec 9.
30. Yoshida N, Yamamoto H, Miyata H, Baba H.
Response to Comment on "Can Minimally
Invasive Esophagectomy Replace Open Esophagectomy for Esophageal Cancer? Latest Analysis of
24,233 Esophagectomies From the Japanese
National Clinical Database". Ann Surg 270(6):e110-e111. 2019 Dec.
31. Yamamoto H, Miyata H, Tanemoto K, Saiki Y,
Yokoyama H, Fukuchi E, Motomura N, Ueda Y,
Takamoto S. Quality improvement in cardiovascular surgery: results of a surgical quality
improvement programme using a nationwide
clinical database and database-driven site visits inJapan. BMJ Qual Saf. 2019 Nov 20.
32. Takahara M, Iida O, Kohsaka S, Soga Y, Fujihara
M, Shinke T, Amano T, Ikari Y; J-EVT and J-PCI
investigators. Presentation Pattern of Lower
Extremity Endovascular Intervention versus
PercutaneousCoronary
Intervention.
J
Atheroscler Thromb. 2019 Nov 21.
33. Takahara M, Iida O, Kohsaka S, Soga Y, Fujihara
M, Shinke T, Amano T, Ikari Y; J-EVT and J-PCI
investigators. Diabetes mellitus and othercardiovascular risk factors in lower-extremity
peripheral artery disease versus coronary arterydisease: an analysis of 1,121,359 cases from thenationwide databases. Cardiovasc Diabetol. 18(1):155. 2019 Nov 15.
34. Tsuji S, Nawata K, Shimada S, Hirata Y, Ono M.
A superior vena cava to right pulmonary arteryshunt for severe right ventricular outflow tract
stenosis caused by an unresectable cardiac tumor.
J Cardiol Cases. 21(3):97-100. 2019 Nov 13.
35. Irie H, Okamoto H, Uchino S, Endo H, Uchida M,
Kawasaki T, Kumasawa J, Tagami T, Shigemitsu
H, Hashiba E, Aoki Y, Kurosawa H, Hatakeyama J,
Ichihara N, Hashimoto S, Nishimura M; JIPAD
Working Group in the Japanese Society of
Intensive Care Medicine. The Japanese Intensive
care PAtient Database (JIPAD): A national
intensive care unit registry in Japan. J Crit Care.
55:86-94. 2019 Oct 25.
36. Kudo M, Izumi N, Kubo S, Kokudo N, Sakamoto
M, Shiina S, Tateishi R, Nakashima O, Murakami
T, Matsuyama Y, Takahashi A, Miyata H,

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Takayama T. Report of the 20th Nationwide
Follow-up Survey of Primary Liver Cancer inJapan. Hepatol Res. 2019 Oct 26.
37. Kodaira M, Sawano M, Kuno T, Numasawa Y,
Noma S, Suzuki M, Imaeda S, Ueda I, Fukuda K,
Kohsaka S. Outcomes of acute coronary
syndrome patients with concurrent extra-cardiac
vascular disease in the era of transradial coronary
intervention: A retrospective multicenter cohort
study. PLoS One. 14(10):e0223215. 2019 Oct 16.
38. Akita K, Inohara T, Yamaji K, Kohsaka S,
Numasawa Y, Ishii H, Amano T, Kadota K,
Nakamura M, Maekawa Y. Impact ofReduced-Dose Prasugrel vs. Standard-Dose
Clopidogrel on In-Hospital Outcomes of
Percutaneous Coronary Intervention in 62,737
Patients with Acute Coronary Syndromes: A
Nationwide Registry Study in Japan. Eur Heart J
Cardiovasc Pharmacother. 2019 Oct 8
39. Motoyama S, Yamamoto H, Miyata H, Yano M,
Yasuda T, Ohira M, Kajiyama Y, Toh Y, Watanabe
M, Kakeji Y, Seto Y, Doki Y, Matsubara H. Impactof certification status of the institute and surgeon
on short-term outcomes after surgery for thoracic
esophageal cancer: evaluation using data on
16,752 patients from the National Clinical
Database in Japan. Esophagus. 2019 Oct 3.
40. Endo S, Ikeda N, Kondo T, Nakajima J, Kondo H,
Shimada Y, Sato M, Toyooka S, Okada Y, Sato Y,
Yoshino I, Okada M, Okumura M, Chida M,
Fukuchi E, Miyata H. Correction to: Risk
assessments for broncho-pleural fistula andrespiratory failure after lung cancer surgery by
National Clinical Database Japan. Gen Thorac
Cardiovasc Surg. 67(10):904-906. 2019 Oct.
41. Nishioka N, Ichihara N, Bando K, Motomura N,
Koyama N, Miyata H, Kohsaka S, Takamoto S,
Hashimoto K. Body mass index as a tool for
optimizing surgical care in coronary artery bypass
grafting through understanding risks of specificcomplications. J Thorac Cardiovasc Surg. 2019
Sep 28.
42. Sandhu AT, Kohsaka S, Bhattacharya J, Fearon
WF, Harrington RA, Heidenreich PA. Association
Between Current and Future Annual Hospital
Percutaneous Coronary Intervention Mortality
Rates. JAMA Cardiol. 2019 Sep 18:1-8.

43. Ko S, Uno S, Kohsaka S. Author reply: Early
Operation and Establishment of Endocarditis
Team. Intern Med. 2019 Sep 18.
44. Nawata K, D'Agostino RS, Habib RH, Kumamaru
H, Hirahara N, Miyata H, Motomura N, Takamoto
S, Shahian DM, Grover FL. First Database
Comparison Between the United States and Japan:
Coronary Artery Bypass Grafting. Ann Thorac
Surg. 109(4):1159-1164. Epub 2019 Sep 17.
45. Sakaguchi G, Miyata H, Motomura N, Ueki C,
Fukuchi E, Yamamoto H, Takamoto S, Marui A.
Surgical Repair of Post-Infarction Ventricular
Septal Defect - Findings From a Japanese
National Database. Circ J. 83(11):2229-2235.
Epub 2019 Sep 11.
46. Tsutsui H, Isobe M, Ito H, Ito H, Okumura K,
Ono M, Kitakaze M, Kinugawa K, Kihara Y, Goto
Y, Komuro I, Saiki Y, Saito Y, Sakata Y, Sato N,
Sawa Y, Shiose A, Shimizu W, Shimokawa H,
Seino Y, Node K, Higo T, et al. JCS 2017/JHFS
2017 Guideline on Diagnosis and Treatment of
Acute and Chronic Heart Failure - Digest Version.
Circ J. 83(10):2084-2184. Epub 2019 Sep 10.
47. Katsumata Y, Tamura Y, Kimura T, Kohsaka S,
Sadahiro T, Nishiyama T, Aizawa Y, Azuma K,
Fukuda K, Takatsuki S. A high BNP level predicts
an improvement in exercise tolerance after asuccessful catheter ablation of persistent atrial
fibrillation. J Cardiovasc Electrophysiol. 30(11):2283-2290. Epub 2019 Sep 8.
48. Abe T, Nakano K, Hirahara N, Motomura N,
Miyata H, Takamoto S. Correction to: Current
status of cardiovascular surgery in Japan, 2015
and 2016, a report based on the Japan
Cardiovascular Surgery Database. 3-Valvular
heart surgery. Gen Thorac Cardiovasc Surg. 67(9):750. 2019 Sep.
49. Saito A, Hirahara N, Motomura N, Miyata H,
Takamoto S. Current Status of cardiovascularsurgery in Japan, 2015 and 2016: a report basedon the Japan Cardiovascular Surgery Database.
2-Isolated coronary artery bypass grafting surgery.
Gen Thorac Cardiovasc Surg 67(9):736-741. 2019Sep.
50. Kubo M, Kawai M, Kumamaru H, Miyata H,
Tamura K, Yoshida M, Ogo E, Nagahashi M,
Asaga S, Kojima Y, Kadoya T, Aogi K, Niikura N,434

Miyashita M, Iijima K, Hayashi N, Yamamoto Y,
Imoto S, Jinno H. A Population-Based Recurrence
Risk Management Study of Patients With pT1
Node-Negative HER2+ Breast Cancer: A National
Clinical Database Study. Breast Cancer Res Treat.
178(3):647-656. Epub 2019 Aug 26.
51. Shimada S, Nawata K, Kinoshita O, Ono M.
Mechanical circulatory support for the rightventricle in combination with a left ventricularassist device. Expert Rev Med Devices. 16(8):663-673. 2019 Aug.
52. Kato M, Tanaka K, Kida M, Ryozawa S, Matsuda
K, Fujishiro M, Saito Y, Ohtsuka K, Oda I, KatadaC, Kobayashi K, Hoteya S, Horimatsu T,
Kodashima S, Matsuda T, Muto M, Yamamoto H,
Iwakiri R, Kutsumi H, Miyata H, Kato M,
Haruma K, et al. Multicenter database registry forendoscopic retrograde cholangiopancreatography:
Japan Endoscopic Database Project. Dig Endosc.
2019 Jul 30.
53. Hata T, Ikeda M, Miyata H, Nomura M, Gotoh M,
Sakon M, Yamamoto K, Wakabayashi G, Seto Y,
Mori M, Doki Y. Frequency and Risk Factors for
Venous Thromboembolism After Gastroenterological Surgery Based on the Japanese National
Clinical Database (516 217 Cases). Ann
Gastroenterol Surg. 3(5):534-543. 2019 Jul 22.
54. Inokuchi M, Kumamaru H, Nakagawa M, Miyata
H, Kakeji Y, Seto Y, Kojima K. Feasibility oflaparoscopic gastrectomy for patients with poor
physical status: a retrospective cohort study basedon a nationwide registry database in Japan.
Gastric Cancer. 2019 Jul 22
55. Hirahara N, Miyata H, Motomura N, Kohsaka S,
Nishimura T, Takamoto S. Procedure- andHospital-Level Variation of Deep Sternal WoundInfection From All-Japan Registry. Ann Thorac
Surg. 109(2):547-554. Epub 2019 Jul 20.
56. Watanabe A, Amiya E, Hatano M, Watanabe M,
Ozeki A, Nitta D, Maki H, Hosoya Y, Tsuji M,
Bujo C, Saito A, Endo M, Kagami Y, Nemoto M,
Nawata K, Kinoshita O, Kimura M, Ono M,
Komuro I. Significant impact of left ventricularassist device models on the value of flowmediated dilation: effects of LVAD on endothelial
function. Heart Vessels. 35(2):207-213. Epub
2019 Jul 20

57. Hojo T, Masuda N, Iwamoto T, Niikura N, Anan
K, Aogi K, Ohnishi T, Yamauchi C, Yoshida M,
Kinoshita T, Masuoka H, Sagara Y, Sakatani T,
Kojima Y, Tsuda H, Kumamaru H, Miyata H,
Nakamura S. Taxane-based combinations asadjuvant chemotherapy for node-positive ERpositive breast cancer based on 2004-2009 datafrom the Breast Cancer Registry of the Japanese
Breast Cancer Society. Breast Cancer. 2019 Jul
20.
58. Hirata Y, Hirahara N, Murakami A, Motomura N,
Miyata H, Takamoto S. Current status ofcardiovascular surgery in Japan, 2015 and 2016: areport based on the Japan Cardiovascular Surgery
Database. 1-congenital heart surgery. Gen Thorac
Cardiovasc Surg 67(9):731-735. Epub 2019 Jul
20.
59. Shimizu H, Hirahara N, Motomura N, Miyata H,
Takamoto S. Current status of cardiovascularsurgery in Japan, 2015 and 2016: analysis of datafrom Japan Cardiovascular Surgery Database.
4-Thoracic aortic surgery. Gen Thorac Cardiovasc
Surg. 67(9):751-757. Epub 2019 Jul 16.
60. Kubota K, Aoki T, Kumamaru H, Shiraki T,
Miyata H, Seto Y, Kakeji Y, Yamamoto M. Use of
the National Clinical Database to evaluate theassociation between preoperative liver function
and postoperative complications among patients
undergoing hepatectomy. J Hepatobiliary Pancreat
Sci. 26(8):331-340. Epub 2019 Jul 15.
61. Ko S, Uno S, Kohsaka S. Prosthetic Aortic Valve
Endocarditis. Intern Med 58(21):3201. Epub 2019
Jul 10.
62. Abe T, Nakano K, Hirahara N, Motomura N,
Miyata H, Takamoto S. Current status ofcardiovascular surgery in Japan, 2015 and 2016, areport based on the Japan Cardiovascular Surgery
Database. 3-Valvular heart surgery. Gen Thorac
Cardiovasc Surg. 67(9):742-749. Epub 2019 Jul 3.
63. Matsushita K, Harada K, Miyazaki T, Miyamoto T,
Kohsaka S, Iida K, Yamamoto Y, Nagatomo Y,
Yoshino H, Yamamoto T, Nagao K, Takayama M.
Younger- vs Older-Old Patients with Heart Failure
with Preserved Ejection Fraction. J Am Geriatr
Soc. 67(10):2123-2128. Epub 2019 Jul 1.
64. Nishi H, Miyata H, Motomura N, Takahashi T,
Sawa Y, Takamoto S; Japan Cardiovascular435

Surgery Database Organization. Which Patients
Are Candidates for Minimally Invasive Mitral
Valve Surgery? - Establishment of Risk
Calculators Using National Clinical Database.
Circ J. 83(8):1674-1681. Epub 2019 Jun 29.
65. Inohara T, Piccini JP, Mahaffey KW, Kimura T,
Katsumata Y, Tanimoto K, Inagawa K, Ikemura N,
Ueda I, Fukuda K, Takatsuki S, Kohsaka S. A
Cluster Analysis of the Japanese Multicenter
Outpatient Registry of Patients With Atrial
Fibrillation. Am J Cardiol. 124(6):871-878. Epub
2019 Jun 25.
66. Bujo C, Amiya E, Hatano M, Tsuji M, Maki H,
Hosoya Y, Fujii E, Kamon T, Kojima T, Nawata K,
Kinoshita O, Kimura M, Ono M, Komuro I.
Clinical impact of newly developed atrial
fibrillation complicated with longstanding
ventricular fibrillation during left ventricularassist device support: A case report. BMC
Cardiovasc Disord. 19(1):151 2019 Jun 21.
67. Haga Y, Miyata H, Tsuburaya A, Gotoh M,
Yoshida K, Konno H, Seto Y, Fujiwara Y, Baba H.
Development and validation of grade-based
prediction models for postoperative morbidity ingastric cancer resection using a Japanese webbased nationwide registry. Ann Gastroenterol Surg
3(5):544-551. 2019 Jun 20.
68. Kamiya K, Yamamoto T, Tsuchihashi-Makaya M,
Ikegame T, Takahashi T, Sato Y, Kotooka N, Saito
Y, Tsutsui H, Miyata H, Isobe M. Nationwide
Survey of Multidisciplinary Care and Cardiac
Rehabilitation for Patients With Heart Failure in
Japan 縲- An Analysis of the AMED-CHF Study.
Circ J. 83(7):1546-1552. Epub 2019 Jun 11.
69. Kashihara N, Kohsaka S, Kanda E, Okami S,
Yajima T. Hyperkalemia in Real-World Patients
Under Continuous Medical Care in Japan. Kidney
Int Rep. 4(9):1248-1260. 2019 May 30.
70. Takei M, Kohsaka S, Shiraishi Y, Goda A,
Nagatomo Y, Mizuno A, Suzino Y, Kohno T,
Fukuda K, Yoshikawa T. Heart Failure With
Midrange Ejection Fraction in Patients Admitted
for Acute Decompensation: A Report from theJapanese Multicenter Registry. J Card Fail. 25(8):666-673. Epub 2019 May 23.
71. Moriyama H, Kohno T, Kohsaka S, Shiraishi Y,
Fukuoka R, Nagatomo Y, Goda A, Mizuno A,

Fukuda K, Yoshikawa T; West Tokyo Heart
Failure Registry Investigators. Length of hospital
stay and its impact on subsequent earlyreadmission in patients with acute heart failure: areport from the WET-HF Registry. Heart Vessels.
34(11):1777-1788. Epub 2019 May 27.
72. Kuno T, Numasawa Y, Sawano M, Abe T, Ueda I,
Kodaira M, Suzuki M, Noma S, Nakamura I,
Negishi K, Ishikawa S, Fukuda K, Kohsaka S.
Real-world use of intravascular ultrasound inJapan: a report from contemporary multicenter
PCI registry. Heart Vessels. 34(11):1728-1739.
Epub 2019 May 25.
73. Inohara T, Kohsaka S, Yamaji K, Ishii H, Amano
T, Uemura S, Kadota K, Kumamaru H, Miyata H,
Nakamura M. Risk stratification model for
in-hospital death in patients undergoing
percutaneous coronary intervention: a nationwide
retrospective cohort study in Japan. BMJ Open.
9(5):e026683. 2019 May 22.
74. Miura S, Yamashita T, Hanyu M, Kumamaru H,
Shirai S, Ando K. Propensity score-matchedanalysis of patients with severe aortic stenosis
undergoing surgical aortic valve replacement.
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75. Hasegawa H, Takahashi A, Kakeji Y, Ueno H,
Eguchi S, Endo I, Sasaki A, Takiguchi S,
Takeuchi H, Hashimoto M, Horiguchi A, Masaki
T, Marubashi S, Yoshida K, Konno H, Gotoh M,
Miyata H, Seto Y. Surgical outcomes ofgastroenterological surgery in Japan: Report of
the National Clinical Database 2011-2017. Ann
Gastroenterol Surg. 3(4):426-450. 2019 May 20.
76. Miyashita M, Niikura N, Kumamaru H, Miyata H,
Iwamoto T, Kawai M, Anan K, Hayashi N, Aogi
K, Ishida T, Masuoka H, Iijima K, Masuda S,
Tsugawa K, Kinoshita T, Tsuda H, Nakamura S,
Tokuda Y. Role of Postmastectomy Radiotherapy
After Neoadjuvant Chemotherapy in Breast
Cancer Patients: A Study from the Japanese Breast
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77. Harada S, Aoki K, Okamoto K, Kinoshita O,
Nawata K, Ishii Y, Tateda K, Sasaki M, Saga T,
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80. Uemura S, Okamoto H, Nakai M, Nishimura K,
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81. Takesue Y, Miyata H, Gotoh M, Wakabayashi G,
Konno H, Mori M, Kumamaru H, Ueda T,
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for predicting postoperative pneumonia after
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82. Marubashi S, Liu JY, Miyata H, Cohen ME, Ko
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83. Hirata K, Imamura M, Fujiwara T, Fukui T,
Furukawa T, Gotoh M, Hakamada K, Ishiguro M,
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Sato M, Shibata A, Takemasa I, Unno M, Yokoi K,
Nishidate T, Nishiyama M. Current status ofsite-specific cancer registry system for the clinicalresearches: aiming for future contribution by theassessment of present medical care. Int J Clin
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Watanabe M, Matsubara H, Kakeji Y, Seto Y.
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systems and clinical practice guideline adherence
to surgical treatment of esophageal cancer inJapan: a questionnaire survey of departments
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85. Fujinami-Yokokawa Y, Pontikos N, Yang L,
Tsunoda K, Yoshitake K, Iwata T, Miyata H,
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87. Akita K, Kohno T, Kohsaka S, Shiraishi Y,
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3.

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Voice Analysis of Pathophysiology
Project Associate Professor
Shinichi TOKUNO, M.D.,Ph.D.

Project Assistant Professor
Mitsuteru NAKAMURA, Ph.D.

Websitehttp://www.univ.tokyo/

Introduction and Organization

Teaching activities

Department of Voice Analysis of Pathophysiology
was established as a Social Cooperation Program on
September 2014, funded by Mazda Co., Ltd. and MKI(Mitsui Knowledge Industry) Co., Ltd. Professor
Yahagi, Emergency and Critical Care Medicine,
assisted us at that time. From September 2017, We
funded by Mazda Co., Ltd. and PST Inc. Professor
Yamada, Anesthesiology, assisted us at that time.
Purpose of our department is “to establish Verbal
Analysis of Pathophysiology as academic In order tobuild a safe and secure society in which those whoneed emergency medical care can reach timely andappropriate emergency medical care. That is followed
to build a system to support an approach to emergency
medical care not only after onset of the disease but
also before onset of the disease in daily life”.
In general, the physician discerns a qualitativechange in the patient's voice and inferred his/her
medical condition. Verbal Analysis of Pathophysiology Technology is to visualize the condition of
the patients from his /her voice, to assist in the
diagnosis, treatment and prevention. Verbal Analysis
of Pathophysiology academically organized thistechnology, and visualizes the disease by using thebiometric information of the voice which has not been
so far utilized
Faculties were Shinichi TOKUNO, M.D.,Ph.D.,
Project Associate Professor, Mitsuteru NAKAMURA,
Ph.D., Project Assistant Professor and one project
researchers. Additionally, two guest researchers willattend our department.

Shunji MITSUYOSHI, Project Lecturer was
performing a lecture about overview of the verbal
analysis of pathophysiology technology (PST:
Psychoanalysis System Technology) and the voice
emotion recognition technology (ST: Sensibility
Technology) underlying PST in the department ofengineering.

Research activities
It includes voluntary component such as language
and involuntary component which is mainly derived
from the autonomic nervous in voice. Voice emotion
recognition technology which recognizes an emotionof the speaker by assessing patterning the involuntarycomponent has already been established. Our research
forces on the assessment of the medical validity of theverbal analysis of pathophysiology technology (PST:
Psychoanalysis System Technology) which measure
the health of mind (depressive or manic) from thevoice, and the research for the society implementationof this technology. Additionally, we will further
develop this technology, and try to applicate it to theother diseases.
 Research for medical verification and social
implementation of depression evaluation by voice
1) Voice comparison of healthy subjects and patients
Currently, by analyzing the voice for long term
about two weeks, it was possible to substantially
identify the voice of patients and healthy subjects.
In the future, to increase the accuracy, we will
increase the number of cases.

438

2)

3)

4)

5)



1)

2)



A study on the monitoring of health status byvoice using a smartphone
As a social implementation research, we areconducting prospective research on long-term use
by volunteers.
Use in industrial hygiene field of stress check byvoice
As research for social implementation, we areconducting a study to use our technology in thecontext of industrial hygiene.
Verification in other languages
In order to confirm the usefulness of languages
other than Japanese, we are conducting a joint
research of the speech database of the foreign
languages and other countries.
The detailed study by multicenter study
Because of the robustness evaluation oftechnology, we are conducting joint research inthe multi-center.
Application of the verbal analysis ofpathophysiology technology to other than the
stress-depression
We perform the joint research with Mazda Co.,
Ltd., which our investment company.
sleep apnea syndrome
By the analysis of voice in the awakening andsnoring in falling asleep of the patients who have
sleep apnea syndrome, we have done research on
the measurement of the quality of sleep.
Application to other diseases
We are currently conducting research on
psychiatric disorders (major depression, bipolar
disorder), neurological disorders (Parkinson's
disease), dementia (including Alzheimer's
disease), oral surgery diseases (tongue adhesions)and so on.
A study for the effects of driving a car on thehealth of maind
We perform the joint research with Mazda Co.,
Ltd., which our investment company.

References
1. Omiya Y, Hagiwara N, Takano T, Shinohara S,
Nakamura M, Higuchi M, Mitsuyoshi S, Toda H,
Tokuno S, Difference in Speech Analysis Resultsby Coding, Advances in Science, Technology andEngineering Systems Journal 3(5), 488-491(2018.10)
2. Higuchi M, Shinohara S, Nakamura M, Omiya Y,
Hagiwara N, Takano T, Mitsuyoshi S, Tokuno S,
Study on Indicators for Depression in the Elderly
Using Voice and Attribute Information. Communications in Computer and Information Science,
869, 127-146, (2018.6)
3. Higuchi M, Shinohara S, Nakamura M, Omiya Y,
Hagiwara N, Takano T, Mitsuyoshi S, Tokuno S,
Accuracy Evaluation for Mental Health Indicator
Based on Vocal Analysis in Noisy Environments.
Journal of Information and Communication
Engineering (JICE), 4(1), 217-222, (2018.04)
4. Higuchi M, Tokuno S, Nakamura M, Shinohara S,
Mitsuyoshi S, Omiya Y, Hagiwara N, Takano T,
Toda H, Saito T, Terashi H, Mitoma H,
Classification of Bipolar Disorder, Major
Depressive Disorder and Healthy State Using
Voice, Asian J Pharm Clin Res, Vol 11, Special
issue 3, 89-93, 2018

439

Department of Ubiquitous
Health Informatics
Associate Professor
Waki Kayo, M.D., M.P.H., Ph.D.

Researcher
Aki Hayashi, M.D., Ph.D., Kana Miyake, M.D., Ph.D., Akiko Sankoda, M.D., Ph.D.

Homepage http://uhi.umin.jp
Introduction and Organization
Our mission is to promote research and development of anovel integration system in which pieces of patients’
healthcare information are virtually combined and stored
separately in diverse medical/ healthcare facilities.
Recently developed mobile information communication
technologies (ICT)—in conjunction with cloudcomputing—provide a sturdy environment in which tobuild a “virtual ubiquitous health information space.” Weparticularly focus on better clinical outcomes in various
medical/healthcare fields, as well as the efficacy, safety,
and security achieved by these innovative systems. This
department has finished in August 2019. The following
researches are taken over by Department of Healthcare
Information Management, The University of Tokyo
Hospital.

Research activities● DialBetics: A novel smartphone-based selfmanagement support system for type 2 diabetes
patients
Patients with diabetes are expected to have access to theintegral components of diabetes care. Self-management is
the core of diabetes treatment because it ties thecomponents of diabetes therapy together, enabling
patients to assess and control the interplay of nutrition,
physical activity, emotional/physical stress, andmedications that are critical with diabetes. There had long
been a need for an effective self-management tool that
could automate and standardize much of the counselingprocess, facilitating self-monitoring of blood glucose,blood pressure, body weight and lifestyle, and particularly
diet and exercise. Accordingly, we developed just such a
real-time, partially automated interactive system tointerpret patients’ data—biological information, exercise,and diet content calculated from a message sent by
patients—and respond with appropriate actionablefindings, helping the patients achieve diabetes selfmanagement. In addition, the safety and clinicaleffectiveness of the system had to be examined. A onemonth, non-blinded, non-randomized uncontrolled study
was conducted; it demonstrated that DialBetics was a
feasible and effective tool for type 2 diabetes patients who
also received insulin therapy. We conducted a 3-monthclinical trial for type 2 diabetes patients using DialBetics
in Pavia, Italy. The effectiveness of this system was also
confirmed in Italy. In our latest study, we conducted aquestionnaire survey that adopts AI technology as afunction of DialBetics for diabetic patients. Based on ourprevious findings, we started a new study—a randomized
clinical study—among patients with diabetic kidneydisease (DKD). DKD is a known risk factor for end-stage
renal disease, cardiovascular disease, and all-cause death.
One method to evaluate DKD is to identify abnormal
urinary albumin excretion. Effective intervention forearly-stage DKD is important to slow the progression of
kidney disease and improve prognoses. The purpose of thestudy is to evaluate the efficacy of the addition of a selfmanagement system, DialBeticsPlus, to a standard
conventional therapy in DKD patients with microalbuminuria. This study is a prospective, randomized,

440

open-label, multicenter clinical trial. The target
population consists of 160 patients (age ≥ 20 years)
diagnosed with DKD accompanied with microalbuminuria. We will randomize the patients between thetwo groups—the intervention group that uses
DialBeticsPlus in addition to a conventional therapy andthe control group that only receives a conventional
therapy. DialBeticsPlus is a modified version of
DialBetics. The study period is 12 months, with a followup survey at 18 months. The primary outcome for thisstudy is change in albuminuria levels measured in a firstmorning void at 12 months. Secondary outcomes include
changes in physical parameters, parameters of glycemic
control, lipid metabolism and renal function, lifestyle
habits, self-management scores, medication therapy,
adherence to oral hypoglycemic agents, and quality of life.
Additional evaluations will be made of all-cause death,composite cardiovascular outcomes, composite renal
endpoint, efficacy of “hospital-led” and “dispensingpharmacy-led” methods of deploying DialBeticsPlus,safety, and usage pattern of DialBeticsPlus. The study wasapproved in April 2018. We began recruiting patients inJuly 2018 and finished recruiting in August 2019. The
final 18-months follow-up will be done in March 2021.
The first results are expected to be published in 2021. We
predict that albuminuria levels will decrease significantlyin the intervention group. We also expect other parameters
to improve after the intervention due to improved lifestyle
habits and behaviors.
● GlucoNote: Self-management and recording application for the type 2 diabetes and diabetes spare group
We started a clinical study using a smartphone application
with ResearchKit by Apple Inc. that is called "GlucoNote"
for type 2 diabetes patients and diabetes spare group. Thisapplication continuously collects home vital data such as
blood glucose level, blood pressure, weight, active mass,
and also lifestyle data―dietary intake, exercise, and sleep.
A total of 522 patients signed up for the study for theduration of one year. It was indicated that patients who
continue to measure themselves―self-management―
resulting in weight decrease. The results are published in
the form of a refereed journal article.
● Multi-institutional joint prospective study onarrhythmia detection efficiency by wearable heart ratemonitorCardiogenic cerebral infarction has a poor prognosis inthat it leaves big sequelae, and its early detection isimportant. In order to investigate whether it is possible tocapture pulse irregularities simply and conveniently, weplanned research to monitor long-term heart rate using awearable heart rate monitor that is on the market. We
conducted clinical research for 100 workers who are at
risk of developing cerebral infarction if they have atrial
fibrillation, such as high blood pressure, diabetes, cerebral
infarction, heart failure, etc. New atrial fibrillation was
confirmed in two participants. It was suggested that atrial
fibrillation can be detected by long-term electrocardiogram monitoring. The results are published in theform of a refereed journal article.
● Inspection of the correlation of blood sugar level andexpiration acetone measurements
To diagnose ketoacidosis under diabetes mellitus requiremeasurement of blood test and urinalysis. We studied thecorrelation of expiration acetone levels using portable
expiration acetone measuring system and blood acetone
levels. We conducted a clinical trial with 120 diabetic
patients, and also investigated the variation of error within
the same participants. A patent has been applied for.
● Survey of medication, health care and intent to use
personal health record in ethical pharmacy users.
This survey was to clarify whether medication management requires PHR and what kind of items the users are
required for the management of PHR. We surveyed 3,717
people and got responses from 2,307 people. Results were
presented at the 37th joint conference on medical
informatics. The results are published in the form of arefereed journal article.

● DialBeticsLite for health guidance object persons
Health guidance is a support program for people withmetabolic syndrome to improve their lifestyle. We
conducted a clinical trial to study the effect of
DialBeticsLite and differences from type 2 diabetes
patients using DialBetics for health guidance object
persons in four companies. Notably, we (University ofTokyo hospital) made DialBeticsLite fit for practical use
in a company. DialBeticsLite was used in three companies
already.

441● DialBeticsStep for people with high risk of lifestylerelated disease
Behavioral interventions based on behavioral theory werereported to increase the amount of exercise in patientswith type 2 diabetes significantly. We incorporated
behavioral theory in DialBetics to motivate users toincrease the number of steps. A pilot study was conductedamong participants with a high risk of lifestyle-relateddiseases. Preliminary results show that the application iseffective in increasing the amount and encouragement of
exercise.
Future directions
To fulfill our mission, we plan to generalize thefindings made in several clinical studies and promote
ongoing and growing telemedicine service with the use of
ICT in the future.

Publications in English
1. Fukuma N, Hasumi E, Fujiu K, Waki K, Toyooka T,
Komuro I, Ohe K. Feasibility of a T-Shirt-Type
Wearable Electrocardiography Monitor for Detectionof Covert Atrial Fibrillation in Young Healthy Adults.
Sci Rep. 2019 Aug 13;9(1):11768. doi: 10.1038/
s41598-019-48267-1. PubMed PMID: 31409855;
PubMed Central PMCID: PMC6692346.
2. Tamura K, Waki K, Kawai Y, Ueda E, Ishii T, Wakui
H. Possible interesting link between dipping status
and morning surge for subclinical target organ
damage in hypertension. J Clin Hypertens(Greenwich). 2019 Sep;21(9):1295-1297. doi: 10.
1111/jch.13637. Epub 2019 Aug 3. PubMed PMID:
31376242.
3. Yamaguchi S, Waki K, Nannya Y, Nangaku M,
Kadowaki T, Ohe K. Usage Patterns of GlucoNote, a
Self-Management Smartphone App, Based on
ResearchKit for Patients With Type 2 Diabetes andPrediabetes. JMIR Mhealth Uhealth. 2019 Apr 24;
7(4):e13204. doi: 10.2196/13204. PubMed PMID:
31017586; PubMed Central PMCID: PMC6505564.
4. Adachi H, Kawamura Y, Nakagawa K, Horisaki R,
Sato I, Yamaguchi S, Fujiu K, Waki K, Noji H, Ota
S. Use of ghost cytometry to differentiate cells withsimilar gross morphologic characteristics. arXiv.
2019; 1903.09538

5. Ota S, Horisaki R, Kawamura Y, Ugawa M, Sato I,
Adachi H, Yamaguchi S, Fujiu K, Waki K, Noji H.
Response to Comments on “Ghost cytometry”.
Science. 2019 Apr 19;364(6437): eaav3136.

442

Department of Skincare Science
Project Associate Professor
Takeo Minematsu, Ph.D

Project Lecturer
Misako Dai, Ph.D., R.N., P.H.N., CLT.

Homepage: http://skincarescience.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Skincare Science was establishedin the Graduate School of Medicine with funding from
Saraya Co., Ltd. on February 1st, 2017. We try todevelop new nursing technologies to evaluate andimprove the physiological conditions of vulnerable
skin due to aging and diseases.
The department is currently headed by one Project
Associate Professor and assisted by one ProjectLecturer.

Teaching activities
In FY2019, we provided the following lectures forundergraduates, master course students, or Ph.D.
course students:a) Gerontological Nursing in Gerontological Nursing(A2 in 3rd yr/ S1 in 4th yr)b) Clinical Practice (S2 in 4th yr)c) Bioengineering and Nursing (S2 in 4 th yr)d) Gerontological Nursing I (S1)e) Wound Care Management I (S2)f) Wound Care Management II (S2)
We advised graduate course students belonging to
the Department of Gerontological Nursing/Wound
Care Management on matters concerning researchplanning and practice work.
The following were master’s and bachelor’s
research themes in 2019:
Master: “Polymorphism analysis of candidate risk
genes for pressure ulcers in older Japanese patients: A
cross-sectional study at a long-term care hospital”
Bachelor: “Development of the estimation method tomeasure weight and body fat percentage for basketballathletes.

Research activities
1. Activity policy
The skin is a unique organ which we can directly see
and touch. Because several sensory systems are
distributed in the skin, skin disorders have unique
physical and mental influences. Healthy skin is,therefore, a foundation of a healthy life. The
Department of Skincare Science was founded toestablish skincare for people with vulnerable skin due
to aging and dermopathy.
Our project associate professor was also in chargeof the Department of Biological Nursing, Division ofCare Innovation, Global Nursing Research Center, andworked to establish and spread methodologies to study
the biological properties of nursing problems.
We delivered lectures about analytical thinking
processes and physiological/molecular biology techniques for many nursing researchers and clinical nurses
in the bioengineering nursing research seminarorganized by Global Nursing Research Center on July
2019. We furthermore organized an advanced
hands-on seminar of bioengineering nursing researchmethodologies on February 2020.
2. Research themes in 2019
Since February 2017, we have worked with Saraya
Co., Ltd., to develop new nursing technologies using
wound blotting for application in clinical setting. Afterlaunched in 2018, this new product has been appliedin many facilities. In furtherance of this effort, we443

have also contributed to the 2020 Tokyo Paralympic
Games through pressure ulcer care for wheelchairathletes.
 Development of non-invasive skin assessment
methods using skin blotting
Evaluation of skin barrier functions
Detection of tinea pedis
Detection of dehydration
Predictive validity of skin blotting for skin teardevelopment
 Development and practical realization of woundassessment methods using wound blotting
Prediction of pressure ulcer healing
Detection of wound biofilm
Effects of medical wigs during chemotherapy
 Pressure ulcer care in wheelchair athletesSurvey of pressure ulcers
 Skin regenerative medicine
Survey of pressure ulcers
 Development of scaffold materials to regenerate
ultrastructure of epidermis Development of predictive scoring tool for skintear Development preventive care for recurrent
cellulitis with lymphoedema
Identify the biomarkers for recurrent cellulitis withlymphoedema
Development of ultrasound assessment method for
lymphoedema patients
Our research was recognized in the form of several
awards, as follows:
・The 8th Asia Pacific Enterostomal Therapy Nurse
Association, Best Moderated Poster Award.
Minematsu T, Tsukatani T, Weijie K, Nakai
A,Tomida S, Nakagami G, Sanada H. Intra-rater
reliability of albumin measurement by skin blottingin healthy volunteers. The 8th Asia PacificEnterostomal Therapy Nurse Association, Taipei(Taiwan), 2019/11/22.
・The 8th Asia Pacific Enterostomal Therapy Nurse
Association, Best oral Award. Nakagami G, Sanada
H, Mori Y, Minematsu T, Kitamura A. Biofilmbased wound care system for treating chronic
wounds. The 8th Asia Pacific Enterostomal Therapy
Nurse Association, Taipei (Taiwan), 2019/11/22.

・The 8th Asia Pacific Enterostomal Therapy Nurse
Association, Best Moderated Poster Award. Nakai
A,Tsukatani T, Tamai N, Mori Y, Weijie K,
Minematsu T, Takada C, Sanada H. Relationshipbetween type IV collagen positivity via skinblotting and conventional risk factors of skin tears.
The 8th Asia Pacific Enterostomal Therapy Nurse
Association, Taipei (Taiwan), 2019/11/22.
・2019 Skin Integrity Summer School. Best
Innovation Poster Award. ILF Japan (Sanada H,
Sugama J, Dai M, Nakagami G). LIMPRINT
reporting from ILF Japan.
・Good Design Award Office, Japan Institute of
Design Promotion. Good Design Award. Elastic
stocking for patients “Cool lala”. Batel Plus
Corporation, Yoshida Tsukasa Co., LTD., Dai M,
Murayama H.

References
1. Dai M, Nakagami G, Sugama J, Kobayashi N,
Kimura E, Arai Y, Sato A, Mercier G, Moffatt C,
Murray S, Sanada H. The prevalence andfunctional impact of chronic edema andlymphedema in Japan: LIMPRINT Study.
Lymphatic Research and Biology. 17(2): 195-201.
2019. https://doi.org/10.1089/lrb.2018.0080.
2. Kitamura A, Minematsu T, Nakagami G,
Miyagaki T, Sasaki S, Hayashi C, Sanada H.
Assessment of subclinical inflammation based on
peroxidase activity detected by wound blotting
among patients with pressure ulcers. Journal of
Wound Care. 28(9): 586-591. 2019. doi: 10.
12968/jowc.2019.28.9.586.
3. Mori Y, Nakagami G, Kitamura A, Minematsu T,
Kinoshita M, Suga H, Kurita M, Hayashi C,
Kawasaki A, Sanada H. Effectiveness of biofilmbased wound care system on wound healing inchronic wound. Wound Repair and Regeneration.
27(5): 540-547. 2019. doi: 10.1111/wrr.12738.
4. Goto T, Nakagami G, Minematsu T, Tomida S,
Shinoda M, Iwata K, Sanada H. Topically injected
adrenocorticotropic hormone induces mechanicalhypersensitivity on a full-thickness cutaneous
wound model in rats. Exp Dermatol. 28(9): 10101016. 2019. doi: 10.1111/exd.13994.2019 1.

444

5. Hirono K, Dai M, Sugama J. Influence of
subcutaneous tissue thickness and sub-bandage
pressure on grater saphenous venous blood flowin healthy adults. Lymphoedema Research andPractice.7(1): 1-10.2019. ［in Japanese］
6. Takahashi T, Minematsu T, Murayama R,
Nakagami G, Mori T, Sanada H. Catheter tips area possible resource for biological study oncatheter failure. Drug Discoveries & Therapeutics.
13(5): 280-287. 2019.
doi:10.5582/ddt.2019.010736.
7. Okida S, Kinoshita S, Dai M, Kawamura K,
Sugama J. Effect of medical compression
stockings with markers on ease of wearing,
twisting and skin. Lymphoedema Research andPractice.7(1): 20-28.2019. ［in Japanese］
8. Goto T, Nakagami G, Minematsu T, Shinoda M,
Sanada H. Measurement of mechanical withdrawal threshold on full-thickness cutaneous
wounds in rats using the von Frey test. J Wound
Care. 28: 762-772, 2019.
9. Nakagami G, Schultz G, Kitamura A, Minematsu
T, Akamata K, Suga H, Kurita M, Hayashi C,
Sanada H. Rapid detection of biofilm by woundblotting following sharp debridement of chronicpressure ulcers predicts wound healing: A
preliminary study. Int Wound J. 17(1): 191-196.
2020. doi: 10.1111/iwj.13256.
10. Kimura N, Nakagami G, Minematsu T, Sanada H.
Noninvasive detection of local tissue responses topredict pressure ulcer development in mice model.
Journal of Tissue Viability. 29(1): 51-57. 2020.
11. Tamai N, Minematsu T, Maeda T, Yabunaka K,
Sanada H. The relationship between skinultrasound images and muscle damage using skinblotting in wheelchair basketball athletes. Spinal
Cord. 2020. doi: 10.1038/s41393-020-0442-6[Epub ahead of print]

445

Department of Prevention of
Diabetes and Lifestyle-RelatedDiseases
Project Associate Professor
Satoko Yamaguchi, M.D.,Ph.D.

Project Assistant Professor
Akira Okada, M.D., Ph.D.

Homepage http://prev.umin.jp/
Introduction and Organization
The Department of Prevention of Diabetes andLifestyle-Related Diseases is a Social Cooperation
Program founded in April 2018, which is sponsoredby Asahi Mutual Life Insurance Company and iscooperating with the Department of Nephrology and
Endocrinology (Professor Masaomi Nangaku) and
Department of Diabetes and Metabolic Diseases(Professor Toshimasa Yamauchi).
The objective of our department is to undertake
research on preventing onset and progression ofdiabetes and other lifestyle-related diseases, throughanalyses of big data including medical databases andusage of information and communication technology(ICT), thereby making a contribution to improving
health of people in Japan.
Lifestyle-related diseases including diabetes
account for approximately 30% of medical expenses
and 60% of deaths. Moreover, Japan is facing an
unprecedented super aged society with aging rate of
28.1% in 2018, and an increasing number of people
require long-term care due to conditions caused bylifestyle-relateddiseases.
Analyzing
factors
associated with onset and progression of lifestylerelated diseases is expected to contribute topreventing lifestyle-related diseases and conditions
caused by them, decreasing the number of people
requiring long-term care, as well as optimizing

medical expenses.
Our department intends to conduct multidirectional
analyses of big data including medical databases andconstruct models predicting progression oflifestyle-related diseases.
We are receiving three collaborative researchers
from Asahi Mutual Life Insurance Company.

Research activities
The members of our department are working on thefollowing research topics.
1) Research on long-term care
An increasing number of people require long-termcare in recent years, and as of 2018, 6.5 million people
have been certified as being in need for long-term carein Japan. However, factors and diseases leading toconditions requiring long-term care remain largely
unknown. In order to identify factors predicting
conditions requiring long-term care, we obtained andare analyzing anonymized data of Comprehensive
Survey of Living Conditions, a nationwide survey
containing household situation and health-related
questions, from Ministry of Health, Labor andWelfare.
2) Research on discontinuation of physician visit inpatients with diabetes

446

Discontinuation of diabetes care is associated withincreased rate of complications and mortality. One of
the limitations in the previous studies is selection bias,
as the patients mostly voluntarily participated in thestudies so were more motivated than the averagepatients. In order to identify predictors of
discontinuation in patients with diabetes in real-world
data, we are analyzing the JMDC database incollaboration with the Department of Clinical
Epidemiology and Health Economics (Professor
Hideo Yasunaga).
3) Research on diabetes and cancer
Patients with diabetes have higher risks of developing
such diseases as cardiovascular diseases, cerebrovascular diseases, kidney diseases and cancer. While
improved glycemic controls is associated with areduced risk for vascular diseases and kidney diseases,
association between glycemic control and cancer risk
is unclear. In order to investigate this issue, we are
analyzing data of patients with diabetes in a medical
information database of the University of Tokyo
Hospital, in collaboration with the Department of
Biomedical Informatics (Professor Kazuhiko Ohe).
In addition to moving these projects forward, we plan
to take on new projects using databases in the future.

References
1. Yamaguchi S, Waki K, Nannya Y, Nangaku M,
Kadowaki T, Ohe K. Usage Patterns of GlucoNote,a Self-Management Smartphone App, Based on
ResearchKit for Patients With Type 2 Diabetes
andPrediabetes.

JMIR

MhealthUhealth.

2019;7(4):e13204.
2. Okada A, Higashihara T, Kusano T, Takemura K,
Saigusa H, Maruno S, et al. IL-6-producing Renal
Cell Carcinoma Causing Renal and Endocrine
Paraneoplastic

Syndromes.

InternMed.

2019;58(13):1953-60.
3. Mukaiyama Y, Okada A, Kawakatsu Y, Akuzawa
S, Suzuki K, Ishigami N, et al. Complete
post-operative

resolutionof"temporary"end-stage kidney disease secondary to aortic
dissection without static renal artery obstruction:a case study. BMC Nephrol. 2019;20(1):368.

447

Department of Innovative
Dementia Prevention
Project Associate Professor
Tadafumi Hashimoto, Ph.D.

Project Assistant Professor
Tomoko Wakabayashi, Ph.D.

Homepage

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

Department of Innovative Dementia Prevention was
launched on July 2017, through the financial supportof 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 AssistantProfessor started the research projects, with Dr.
Daisuke Izawa of Kobayashi as a collaborative
researcher. From January 2019, Dr. Tomoko
Wakabayashi joined in the department in the replace
ment of Dr. Ryoko Ihara, and Dr. Yutaro Ito of
Kobayashi also joined in the research project in thereplacement of Dr. Izawa.
The aged society in Japan urges us to challenge thedementing disorders including Alzheimer’s disease(AD), although there have emerged no effective
therapeutic strategies against AD based on its
pathomechanism. Our laboratory will conduct basic
research on the molecular mechanism of dementia anddevelopment of clinical measures for evaluation ofefficacies of the therapeutic drugs in parallel, aiming
at identifying the novel targets for prevention andearly treatment of dementia and establish methods toprevent or delay the progression of dementia by drugs
and functional foods. We also will be actively
involved in the education and outreach activities ofbasic and clinical research on AD and dementia.

Education
In 2018, Department of Innovative Dementia

Prevention was involved in the education throughresearch activities of two doctor course graduate
students of the Graduate School of Medicine, one
doctor course graduate student of the School of
Pharmaceutical Sciences, one master course graduate
students of the Graduate School of Medicine, as wellas one medical student belonging to the Medical
Scientist Training Program. In addition, TH has given
a lecture on “Special Course for Clinical Pharmacy” tostudents belonging to the Graduate School of
Pharmaceutical Sciences

Research
Department of Innovative Dementia Prevention isconducting research in the following four directions,based on the amyloid hypothesis of AD, toward thegoal of developing strategies for prevention ofdementia and AD.
① Molecular mechanism of A dynamics in thebrain
Amyloid  peptide (A), a causative protein for AD,
is produced from Aprecursor protein (APP) throughtwo-step proteolysis by - and -secretases, and thensecreted into the extracellular space. Once released
outside the neurons, A is readily cleared byproteolytic degradation or transported outside thebrains. However, A that escaped from the clearance
starts to aggregate and deposit forming amyloid fibrils.
Thus, the elucidation of the A dynamics in the brain,
comprised of the elementary processes of448“production”,“secretion”,“aggregation”
and“deposition”, is vital to the clarification of thepathogenic mechanism of AD as well as developmentof therapeutic and prevention strategies against AD.
However, to quantitatively analyze each of the process,there is a compelling need for accurate quantitation ofA that is present at picomolar levels in brains.
We have adopted the microdialysis technique using
dialysis membrane of ~1,000 kDa cut-off that enables
the recovery of brain interstitial fluids andquantitation of the levels, rates of production andclearance of A in the hippocampus and other parts ofthe brains (Yamamoto K, et al., Cell Rep., 2015). In
combination with the in vivo seeding experiments
injecting aggregation seeds for A and evaluate thefollowing A deposition (Hori Y, et al., J. Biol. Chem.,2015), we have identified a >200 kDa high molecularweight A oligomer species in the soluble fractions ofbrains of APP transgenic mice and AD brains(Hashimoto T, Soc for Neuroscience meeting 2017).
We will further identify A species that are involvedin the A dynamics in the brain, including thosespecifically involved in deposition or toxicity of A.
② Elucidation of the role of apolipoprotein E (apoE)in the pathogenesis of AD, and development ofmethod of AD prevention targeting apoE
Apolipoprotein E (apoE) is produced by astrocytes
and comprises the major lipoprotein in the central
nervous system. Human APOE gene has three genetic
polymorphisms (2, 3, 4), resulting in the
production of three protein isoforms (apoE2, apoE3,
apoE4) harboring different amino acids at two criticalresidues at positions 112 and 158. The allele
frequency of ApoE4 allele is ~8-10% in normal
population, whereas it is elevated to >30-40% in AD.
Thus, ApoE4 is a strong genetic risk factor of AD,
although the mechanism whereby ApoE4 accelerates
AD pathophysiology has remained elusive, without
any effective therapeutic strategies targeting apoE.
We have created a series of bigenic mice bycrossing 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 A dynamics in the brain. This
will lead us to the intervention into the effect of apoE
isoforms on A, toward the goal of AD prevention. In

2017, we have found a significant decrease in Adeposition in the brains of human apoE3 KI/APPtransgenic mice. In 2018, we have also found that
apoE3 reduced the deposition of A compared withmurine apoE using in vivo seeding technique. We also
found that the A levels in the interstitial fluids ofhuman apoE3 KI/APP transgenic mice are similar to
those in APP transgenic mice by in vivo microdialysis
method. We also have established a method to monitor
the interaction between A and apoE using abi-molecular complementation assay. We will use thisunique assay system to identify small molecule drugs
that modulate the interaction of apoE and A.
③ Establishment of a novel AD model using
three-dimensional culture system for thedevelopment of prevention methods targeting
brain A metabolism.
To overcome the lack of experimental paradigms
for the evaluation of aggregation and deposition invitro, we adopted 3-dimensional culture system using
Matrigel for the neuronal differentiation of human
ReNcell-VM neuronal precursor cells, to observe theprocess of A deposition and A-dependentneurotoxicity reminiscent to that in AD brains. In
2018, we found the phosphorylation of tau by the
overproduction of E22G mutant A in the
ReNcell-VM neurons. We will use this system for thedevelopment of anti-dementia drugs targeting A
production and deposition.
④ Clinical studies on the clinical and cognitive
measures in the early stages of AD.
We have set out to the systematic analysis of theclinical data on the natural course of the early stage fo
AD derived from Japanese Alzheimer’s Disease
Neuroimaging Initiative (J-ADNI), with a special
focus on the preclinical AD stage, where elderly
individuals are clinically and cognitively normal but
positive for amyloid 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 at international harmonization andcomparison of the evaluation of cognitive decline,
using US-ADNI database and other international
datasets.

449⑤ Molecular mechanisms linking between type II
diabetes mellitus and Alzheimer’s disease
Based on epidemiological and experimental
studiesd, type 2 diabetes mellitus (T2DM), especiallyinsulin resistance that comprises the core mechanismof T2DM, has been recognized as a significant risk
factor for AD. However, the molecular mechanisms
linking between T2DM and AD is not fully
understood yet. To study the causal relations andmolecular
mechanisms
underlying
insulinresistance-induced exacerbation of amyloid pathology,
we investigated the chronological changes in thedevelopment of insulin resistance and amyloid
pathology in two independent insulin-resistant AD
mouse models, i.e. long-term high-fat diet (HFD)
feeding and genetic disruption of Irs2, in combination
with dietary interventions.
In this year, we found that HFD-fed diabetic AD
model mice displayed a reduced brain response toperipheral insulin stimulation and a decrease brain toplasma ratio of insulin during the hyperinsulinemic
clamp. Diet-induced defective insulin action in thebrain was accompanied by a decreased clearance ofthe extracellular A in vivo and an exacerbation ofbrain amyloid pathology (Wakabayashi T, et al., Mol
Neurodegener, 2019).

Publications
1. Tomoko Wakabayashi, Kazuki Yamaguchi,
Kentaro Matsui, Toshiharu Sano, Tetsuya Kubota,
Tadafumi Hashimoto, Ayako Mano, Kaoru
Yamada, Yuko, Yuko Matsuo, Naoto Kubota,
Takashi Kadowaki, Takeshi Iwatsubo: Differential
effects of diet- and genetically-induced brain
insulin resistance on amyloid pathology in amouse model of Alzheimer’s disease. Molecular
Neurodegeneration, 14(1): 15, 2019
2. Miki Eto, Tadafumi Hashimoto, Takao Shimizu,
Takeshi Iwatsubo: Characterization of the uniquein vitro effects of unsaturated fatty acids on theformation of amyloid  fibrils. PLoS ONE, 14(7):e0219465, 2019
3. Sangeun Park, Sei-Kyoung Park, Naruaki
Watanabe,
Tadafumi
Hashimoto,TakeshiIwatsubo, Tatyana A. Shelkovnikova, Susan W
Liebman:Calcium-responsive
transactivator(CREST) toxicity is rescued by loss of
PBP1/ATXN2 function in a novel yeast
proteinopathy model and in transgenic flies. PLoS
Genetics 15(8), e1008308, 2019
4. Haruka Munezane, Hiroaki Oizumi, Tomoko
Wakabayashi, Shu Nishio, Tomoko Hirasawa,Takashi Sato, Akihiro Harada, Tomoyuki Yoshida,
Takahiro Eguchi, Yuji Yamanashi, Tadafumi
Hashimoto, Takeshi Iwatsubo: Roles of collagen
XXV and its putative receptors PTP / inintramuscular motor innervation and congenital
cranial dysinnervation disorder. Cell Reports,
29(13), 4362-4376, 2019
5. Yoichiro Abe, Natsumi Ikegawa, Keitaro Yoshida,
Kyosuke Muramatsu, Satoko Hattori, Kenji
Kawai, Minetaka Murakami, Takumi Tanaka,
Wakami Goda, Motohito Goto, Taichi Yamamoto,Tadafumi Hashimoto, Kaoru Yamada, Terumasa
Shibata, Hidemi Misawa, Masaru Mimura, Kenji
F. Tanaka, Tsuyoshi Miyakawa, Takeshi Iwatsubo,
Jun-ichi Hata, Takako Niikura, Masato Yasui:
Behavioral and electrophysiological evidence fora neuroprotective role of aquaporin-4 in the
5xFAD
transgenic
mice
model.
Acta
Neuropathologica Communications, 8(1), 67,
2020

450

Department of Health Services
Research
Project Associate Professor
Taisuke Jo, M.D.,Ph.D.

Project Assistant Professor
Nobuaki Michihata, M.D., PhD.

Project Assistant Professor
Hayato Yamana, M.D., PhD.

Homepage

http://webpark1902.sakura.ne.jp/wp/

Introduction and Organization
The Department of Health Services research (HSR),
a Social Cooperation Program, was founded byProfessor Hideo Yasunaga, Department of Clinical
Epidemiology & Health Economics with the supportof Professor Takahide Nagase, Department ofRespiratory Medicine in April 2016. The program wasfunded by Tsumura & Co., Tokyo, Japan.
The objective of the Department of HSR was toconvey and develop HSR, which encompasses clinicalmedicine, clinical epidemiology and health economics,
to pursue maintenance of health services particularlyin the aging society in Japan. Education and trainingof personnel to cultivate human resources such as
researchers and analysts in HSR is another importantmission of this program.
The founding staff members were Taisuke Jo(Project Associate Professor), Nobuaki Michihata(Project Assistant Professor) and Yusuke Sasabuchi(Project Assistant Professor). Hayato Yamana (Project
Assistant Professor) started to take part in thisprogram in April 2018 with the two other staff
members, Taisuke Jo and Nobuaki Michihata.

Teaching activities
All the members of HSR participated in the lecturesof Clinical Epidemiology, a curriculum of School of

Public Health (SPH) in The University of Tokyo. The
members also contributed to the education andtraining of individual students of SPH as well as
students of Graduate School of Medicine, The
University of Tokyo.
Taisuke Jo (Project Associate Professor)
participated in the series of clinical lectures in
Respiratory Medicine for students of Faculty of
Medicine, The University of Tokyo.

Research activities
Health Services Research covers a broadcross-disciplinary field involving studies of structures,processes and outcomes assessment in clinicalepidemiology and health services, studies evaluating
quality of health care and analysis of heath economics,
finance and allocation of medical resources. Utilizing
large databases, the members of HSR were working toaddress the following issue.
1) Clinical and epidemiological research questions related to various disease, including respiratory disease.
2) Outcomes and cost effectiveness in both western
medicine and eastern medicine in Japan.
3) Impact of super aging society on population
dynamics and demand of health services.
4) Efficient distribution of medical staffs, medical
institutions and armamentarium.
The followings are the examples of studies

451

conducted in 2019.
1) Hospital Volume and Mortality following
Diagnostic Bronchoscopy in Lung Cancer Patients:
Data from a National Inpatient Database in Japan
Recent advances in bronchoscopy utilizing
endobronchial ultrasound (EBUS) as well as lungcancer therapy may have driven physicians to perform
diagnostic bronchoscopy (DB) for high-risk patients.
The aim of this study was to clarify the relationshipbetween hospital volume (HV) and outcomes of DB.
We collected data on inpatients with lung cancer who
underwent DB from July 2010 to March 31, 2014. The
annual HV of DB was classified as “very low” (≤50
cases/year), “low” (51–100 cases/ year), “high” (101–300 cases/year), or “very high” (>300 cases/year). The
primary outcome was all-cause 7-day mortality after
DB. Multivariable logistic regression fitted with ageneralized estimation equation was performed toevaluate the association between HV and all-cause
7-day mortality after DB, adjusted for patient
background factors.
We identified a total of 77,755 eligible patients in
954 hospitals. All-cause 7-day mortality was 0.5%.
Compared with the lowvolume group, 7-day mortality
was significantly lower in the high-volume group(odds ratio [OR] = 0.69, 95% confidence interval [CI]:0.52–0.92, p = 0.010), and a similar trend was shownin the very-high-volume group (OR = 0.67; 95% CI:
0.43–1.05, p = 0.080). Radial EBUS with the guide
sheath method and EBUS-guided transbronchialneedle aspiration showed a significantly lower 7-day
mortality.
All-cause 7-day mortality was inversely associatedwith HV. The risk of DB in patients with lung cancer
should be recognized, and the exploitation of EBUS
may help reduce mortality after DB.
2) Reduction in exacerbation of COPD in patients ofadvanced age using the Japanese Kampo medicine
Dai-kenchu-to: a retrospective cohort study
Patients with symptomatic COPD are recommended
to use inhaled bronchodilators containing long-acting
muscarinic receptor antagonists (LAMAs). However,bronchodilators may cause gastrointestinal adverse
effects due to anticholinergic reactions, especially inadvanced-age patients with COPD. Dai-kenchu-to(TU-100, Da Jian Zhong Tang in Chinese) is the mostfrequently prescribed Japanese herbal Kampo

medicine and is often prescribed to control abdominal
bloating and constipation. The purpose of this study
was to evaluate the role of Dai-kenchu-to as asupportive therapy in advanced-age patients with
COPD.
We used the Japanese Diagnosis Procedure
Combination inpatient database and identified patients
aged ≥75 years who were hospitalized for COPD
exacerbation. We then compared the risk of
re-hospitalization for COPD exacerbation or death
between patients with and without Dai-kenchu-to
using 1-to-4 propensity score matching. A Cox
proportional hazards model was used to compare thetwo groups. We performed subgroup analyses forpatients with and without LAMA therapy.
Patients treated with Dai-kenchu-to had asignificantly lower risk of re-hospitalization or death
after discharge; the HR was 0.82 (95% CI, 0.67–0.99)
in 1-to-4 propensity score matching. Subgroup
analysis of LAMA users showed a significant
difference in re-hospitalization or death, while
subgroup analysis of LAMA non-users showed nosignificant difference.
Our findings indicate that Dai-kenchu-to may have
improved the tolerability of LAMA in advanced-age
patients with COPD and, therefore, reduced the risk of
re-hospitalization or death from COPD exacerbation.
Dai-kenchu-to may be recommended as a usefulsupportive therapy for advanced-age patients with
COPD.
3) Safety and effectiveness of Japanese herbal Kampo
medicines for treatment of hyperemesis gravidarum
To investigate whether Japanese Kampo medicines,
including Sho-hangekabukuryou-to, Touki-syakuyakusan, and Hange-kouboku-to, are safe for fetuses, andwhether these medicines reduce hospitalizations andmedical costs in pregnant women with hyperemesis
gravidarum.
We used the Japan Medical Data Center database to
extract data for pregnant women (aged ≥19 years)
admitted to obstetric clinics or hospitals for delivery
between January 1, 2005, and December 31, 2016.
Eligible patients were classified into three groups:
Kampo medicines for hyperemesis gravidarum, othermedicines for hyperemesis gravidarum, and without
hyperemesis gravidarum. Safety outcome measures
were neonatal outcomes (congenital anomalies, low452birthweight, and preterm birth), and effectivenessmeasures were mother's unplanned hospitalization for
hyperemesis gravidarum and total medical costs
within 20 weeks of gestation.
We identified 121 287 eligible mothers. No
significant differences in the safety measures wereobserved among the groups. The Kampo medicationgroup had a significantly lower proportion of motherswith unplanned hospital admission (odds ratio 0.80,
95% confidence interval [CI] 0.69–0.92) and lower
total costs (coefficient [US$] 12.8, 95% CI −23.2 to−2.4) than the other medication group.
Kampo medicines may reduce unplanned admissions and medical costs among pregnant women withhyperemesis gravidarum
The members of HSR are further mounting an effort
to accomplish the task in cooperation with the Department of Clinical Epidemiology & Health Economics
and the Department of Respiratory Medicine.

References
1. Ota K, Sasabuchi Y, Matsui H, Jo T, Fushimi K,
Yasunaga H. Age distribution and seasonality inacute eosinophilic pneumonia: analysis using anational inpatient database. BMC Pulm Med.
2019;19(1):38.
2. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Early Enteral Nutrition in Patients Undergoing
Sustained
Neuromuscular
Blockade:A
Propensity-Matched Analysis Using a Nationwide
Inpatient Database. Crit Care Med. 2019;47(8):1072-80.
3. Ohbe H, Isogai S, Nakajima M, Jo T, Matsui H,
Fushimi K, et al. Physician-manned prehospitalemergency care in tertiary emergency centers inJapan. Acute Med Surg. 2019;6(2):165-72.
4. Ohbe H, Isogai S, Jo T, Matsui H, Fushimi K,
Yasunaga H. Extracorporeal membrane oxygenation improves outcomes of accidental hypothermia without vital signs: A nationwide observational study. Resuscitation. 2019;144:27-32.
5. Ohbe H, Isogai S, Jo T, Matsui H, Fushimi K,
Yasunaga H. Treatment with Antithrombin or
Thrombomodulin and Mortality from HeatstrokeInduced Disseminated Intravascular Coagulation:
A Nationwide Observational Study. Semin

Thromb Hemost. 2019;45(8):760-6.
6. Mouri H, Jo T, Michihata N, Matsui H, Fushimi
K, Yasunaga H. Continuous Neuromuscular
Blockade and Mortality in Subjects With
Exacerbation of Idiopathic Interstitial Pneumonias.
Respir Care. 2019;64(1):34-9.
7. Michihata N, Shigemi D, Sasabuchi Y, Matsui H,
Jo T, Yasunaga H. Safety and effectiveness ofJapanese herbal Kampo medicines for treatmentof hyperemesis gravidarum. Int J Gynaecol Obstet.
2019;145(2):182-6.
8. Kumazawa R, Jo T, Matsui H, Fushimi K,
Yasunaga H. Association between AngiotensinConverting Enzyme Inhibitors and Post-Stroke
Aspiration Pneumonia. J Stroke Cerebrovasc Dis.
2019;28(12):104444.
9. Jo T, Michihata N, Yamana H, Sasabuchi Y,
Matsui H, Urushiyama H, et al. Reduction in
exacerbation of COPD in patients of advanced age
using the Japanese Kampo medicine Dai-kenchuto: a retrospective cohort study. Int J Chron
Obstruct Pulmon Dis. 2019;14:129-39.
10. Hiraishi Y, Jo T, Michihata N, Hasegawa W,
Sakamoto Y, Urushiyama H, et al. Hospital
Volume and Mortality following Diagnostic
Bronchoscopy in Lung Cancer Patients: Data
from a National Inpatient Database in Japan.
Respiration. 2019;97(3):264-72.
11. Goto T, Jo T, Matsui H, Fushimi K, Hayashi H,
Yasunaga H. Machine Learning-Based Prediction
Models for 30-Day Readmission after Hospitalization for Chronic Obstructive Pulmonary Disease.
COPD. 2019;16(5-6):338-43.
12. Minami T, Mph, Yamana H, Ph DM, Shigemi D,
Mph, et al. Artificial colloids versus humanalbumin for the treatment of ovarian hyperstimulation syndrome: A retrospective cohort
study. Int J Reprod Biomed. 2019;17(10):709-16.
13. Takano A, Ono S, Yamana H, Matsui H,
Matsumoto T, Yasunaga H, et al. Factors
associated with long-term prescription of
benzodiazepine: a retrospective cohort study
using a health insurance database in Japan. BMJ
Open. 2019;9(7):e029641.
14. Shinkawa H, Yasunaga H, Hasegawa K, Matsui H,
Michihata N, Fushimi K, et al. Mortality andmorbidity after pancreatoduodenectomy in453

patients undergoing hemodialysis: Analysis usinga national inpatient database. Surgery. 2019;
165(4):747-50.
15. Okubo Y, Miyairi I, Michihata N, Morisaki N,
Kinoshita N, Urayama KY, et al. Recent
Prescription Patterns for Children With Acute
Infectious Diarrhea. J Pediatr Gastroenterol Nutr.
2019;68(1):13-6.
16. Okubo Y, Hayakawa I, Nariai H, Michihata N,
Matsui H, Fushimi K, et al. Recent practicepatterns in diagnostic procedures anticonvulsants,
and antibiotics for children hospitalized withfebrile seizure. Seizure. 2019;67:52-6.
17. Morita K, Matsui H, Michihata N, Fushimi K,
Yasunaga H. Association of Early Systemic
Corticosteroid Therapy with Mortality in Patientswith Stevens-Johnson Syndrome or Toxic
Epidermal Necrolysis: A Retrospective Cohort
Study Using a Nationwide Claims Database. Am J
Clin Dermatol. 2019;20(4):579-92.
18. Ishimaru T, Fujiogi M, Michihata N, Matsui H,
Fushimi K, Kawashima H, et al. Impact ofcongenital heart disease on outcomes after
primary repair of esophageal atresia: a retrospective observational study using a nationwide
database in Japan. Pediatr Surg Int. 2019;35(10):1077-83.
19. Ikawa F, Michihata N, Akiyama Y, Iihara K,
Matano F, Morita A, et al. Treatment Risk for
Elderly Patients with Unruptured Cerebral
Aneurysm from a Nationwide Database in Japan.
World Neurosurg. 2019;132:e89-e98.
20. Ikawa F, Hidaka T, Yoshiyama M, Ohba H,
Matsuda S, Ozono I, et al. Characteristics ofCerebral Aneurysms in Japan. Neurol Med Chir
(Tokyo). 2019;59(11):399-406.
21. Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Outcomes following
laparoscopic versus open surgery for pediatricinguinal hernia repair: Analysis using a national
inpatient database in Japan. J Pediatr Surg. 2019;54(3):577-81.
22. Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Early Outcomes of
Laparoscopic Versus Open Surgery for Urachal
Remnant Resection in Children: A Retrospective
Analysis Using a Nationwide Inpatient Databasein Japan. J Laparoendosc Adv Surg Tech A. 2019;29(8):1067-72.

454

Division of Chronic Kidney Disease(CKD) Pathophysiology
Division Chief (Professor)
Reiko Inagi, Ph.D.

Assistant Professor
Tsuyoshi Inoue, M.D., Ph.D.

Postdoctoral fellow
Hiroshi Maekawa, M.D., Ph.D. (Division of Nephrology and Endocrinology)
Sho Hasegawa, M.D., Ph.D. JSPS Research Fellowship for Young Scientists (DC2)

PhD Students
Rie Fujii, M.D. (Division of Nephrology and Endocrinology)
Rie Uni, M.D. (Division of Nephrology and Endocrinology)
Haruki Ouchi, M.D. (Division of Nephrology and Endocrinology)

Visiting Researcher
Kenichiro Yoshioka, M.Pharm. (Kyowa Kirin Co., Ltd.)
Daichi Fukaya, M.D. (Saitama Medical University)
Wachirasek Peerapanyasut, DMV. (Mahidol University, Nakhon Sawan Campus, Thailand)

Lab Technician
Ikumi Okuaki, B.S.
Rieko Matsuda, B.S.

Homepage

http://www.todai-ckd.com

Introduction and Organization
In Japan, more than 13 million people suffer fromchronic kidney disease (CKD), or roughly one inevery eight adults. Why has the number of CKD
patients increased so remarkably? One major cause is
the sharp increase in the number of people withdiabetic nephropathy, which is a complication ofdiabetes; since 1998, this has been the most importantcause among diseases which require incipient dialysis
in Japan. Additional causes include the aging ofsociety and other social factors. The kidney is called asilent organ, and CKD progresses without subjective
symptoms. It is now evident, however, thatasymptomatic CKD which progresses over time
carries a number of risks.
One risk is the possible progression of CKD to
end-stage renal disease (ESRD), which requires renal
replacement therapy. A second risk is the development
and progression of lifestyle-related diseases, such asheart attack and arteriosclerosis. The kidneys work
closely with the heart and other organs, and a decrease
in renal function causes dysfunction of the heart and455

blood vessels. This adverse impact of the progressionof CKD on other organs underlines the importance of
the kidneys in maintaining general health. Further,many researchers have also focused on the vicious
spiral of aging and CKD: aging worsens the
progression of CKD, while CKD accelerates aging.
With our modern lifestyles and the super-aging society,
CKD cannot be separated from lifestyle-relateddiseases, and senility cannot be separated from CKD.
Creating a healthy, long-lived society full of energy
and vigor requires that the quality of life (QOL) of theelderly be improved. In turn, total medical
expenditures will also be decreased. These are important issues requiring urgent solutions. Against thisbackground, the Division of CKD Pathophysiology
was newly established in November 2013 withsupport from Kyowa Hakko Kirin Co., Ltd. The aimof the Division is to aid and support the CKD control
and the creation of a healthy and long-lived society.
The Division takes an innovative approach toidentifying the pathophysiology of CKD, and works todevelop more effective CKD preventive andtherapeutic strategies. Through these research
activities, our goal is to contribute to the creation of ahealthy, long-lived society in which the elderly canlive a happy and independent life.

Major Research Projects
The Division of CKD Pathophysiology works incollaboration with the Division of Nephrology and
Endocrinology, a part of The University of Tokyo
Graduate School of Medicine (Professor Masaomi
Nangaku) to conduct basic and clinical research on
CKD pathophysiology, including:1) Identifying the mechanism of destruction ofadaptive signals to various stresses (endoplasmic
reticulum stress, ischemia, glycative stress,
oxidative stress) in CKD; and using the findings
obtained to establish new CKD treatment
strategies.
2) Clarifying the mechanism of functional change inrenal erythropoietin (EPO)- producing cells, alongwith the mechanisms of CKD progression andidentification of the mechanism of development
and progress of renal anemia.

3) Clarifying the impact of kidney aging on CKD
progression in super-aging society4) Identifying factors in the exacerbation of CKD inpatients with diabetes, and developing diagnostic
and therapeutic drugs targeting such factors.
5) Pathophysiology of uremic toxins on organcrosstalk and impact of uremia management in
CKD
6) Elucidating the neuro-immune axis in kidney
injury7) Role of ADP-ribosyl cyclase (Bst1, CD38) inrenal injury

Research Funds (PI) Japan Society for the Promotion of Science, Grantsin-Aid for Scientific Research
18H02727 (to Reiko Inagi, Mechanisms oforganelle cross talk disorder and failure of organ
homeostasis in aging and disease),
18H06192 (to Tsuyoshi Inoue, The mechanism of
immune cell activation in the cholinergic
anti-inflammatory pathway)
 Nipro Co. Ltd, (to Reiko Inagi, Collaborative study
on metabolome of serum exosome in HD patients)
 Japan Agency for Medical Research andDevelopment (AMED)PRIME 19gm6210013h0001 (to Tsuyoshi Inoue,
Elucidation of cell interaction mechanism insuppression of chronic kidney disease progression
through nervous and immune systems
 MSD Life Science Foundation, Public Interest
Incorporated Foundation, Research Grant (toTsuyoshi Inoue, Suppressive mechanism ofatherosclerosis progression by vagus nerve
stimulation) The Kidney Foundation, Japan, Grant for
pathophysiological research conference in chronic
kidney disease (to Tsuyoshi Inoue, Elucidation oferythropoietin production regulation mechanism byvagus nerve) The Salt Science Research Foundation, Research
Grant (to Tsuyoshi Inoue, Elucidation of sodium
balance regulation mechanism through vagus
nerve)
 Smoking Research Foundation, Project Research
Grant (to Tsuyoshi Inoue, Mechanism of456

suppression/treatment of progression of chronic
kidney disease through nicotinic receptor)
 Yukiko Ishibashi Foundation, Research Grant (toTsuyoshi Inoue, Elucidation of the renal protective
effect mechanism of vagus nerve stimulation forchronic kidney injury)
 Takeda Science Foundation, Medical Research
Grant (to Tsuyoshi Inoue, Elucidation of new
anti-inflammatory
and
organ
protection
mechanisms controlled by autonomic nervous
system) Mochida Memorial Foundation for Medical andPharmaceutical Research, Research Grant (toTsuyoshi Inoue, Elucidation of the mechanism ofmacrophageanti-inflammatory
effectbysympathetic and parasympathetic stimulation)
 Astellas Foundation for Research on Metabolic
Disorders, Research Grant (to Tsuyoshi Inoue,
Anti-inflammatory mechanism of macrophages byautonomic nerve stimulation)
 Suzuken Memorial Foundation, Research Grant (toTsuyoshi Inoue, Study on therapeutic effect ofautonomic nerve stimulation in kidney disease)AwardsDr. Tsuyoshi Inoue received the Medical Research
Encouragement Prize of The Japan Medical
Association.
Dr. Hiroshi Maekawa received the Best abstract
Award at the 62nd Conference of Japanese Society ofNephrology.
Dr. Hiroshi Maekawa received the Best English
Presentation Award at the 62nd Conference of JapaneseSociety of Nephrology.
Dr. Hiroshi Maekawa received the Best Presentation
Award at the Japan Kidney Council 2019.
Dr. Sho Hasegawa received the CKD Award at the 8thChronic Kidney Disease Frontier.
Dr. Sho Hasegawa received the YIA Award at the 56th
Annual Meeting of Japanese Society of Molecular
Medicine.

Dr. Sho Hasegawa received the YIA Award at the 10th
Japanese Society of Pathophysiology in Kidney
Failure.

References
1. Inoue T, Abe C, Kohro T, Tanaka S, Huang L,
Yao J, Zheng S, Ye H, Inagi R, Stornetta RL,
Rosin DL, Nangaku M, Wada Y, Okusa MD.
Non-canonical cholinergic anti-inflammatory
pathway-mediated activation of peritoneal
macrophages induces Hes1 and blocks kidney
injury. Kidney Int. 2019 Mar;95(3):563-576. doi:
10.1016/j.kint.2018.09.020.
2. Jao TM, Nangaku M, Wu CH, Sugawara M, Saito
H, Maekawa H, Ishimoto Y, Aoe M, Inoue T,
Tanaka T, Staels B, Mori K, Inagi R. ATF6 and
PPAR crosstalk provides new insights into
lipotoxicity-induced tubulointerstitial fibrosis.
Kidney Int. 2019 Mar; 95(3): 577-589. doi:10.
1016/j.kint.2018.09.023.
3. Inoue T, Maekawa H, Inagi R. Organelle crosstalkin the kidney. Kidney Int. 2019 Jun; 95(6):1318-1325. doi:10.1016/j.kint.2018.11.035.
4. Tatsuzaki J, Ohwada T, Otani Y, Inagi R,
Ishikawa T. A simple and effective preparation ofquercetin pentamethyl ether from quercetin.
Beilstein J Org Chem. 2018 Dec 28;14:31123121. doi:10.3762/bjoc.14.291.
5. Mitrofanova A, Mallela SK, Ducasa GM, Yoo TH,
Rosenfeld-Gur E, Zelnik ID, Molina J, Varona
Santos J, Ge M, Sloan A, Kim JJ, Pedigo C, Bryn
J, Volosenco I, Faul C, Zeidan YH, Garcia
Hernandez C, Mendez AJ, Leibiger I, Burke GW,
Futerman AH, Barisoni L, Ishimoto Y, Inagi R,
Merscher S, Fornoni A. SMPDL3b modulates
insulin receptor signaling in diabetic kidneydisease. Nat Commun. 2019 Jun 19; 10(1):2692.
doi:10.1038/s41467-019-10584-4.
6. Ducasa GM, Mitrofanova A, Mallela SK, Liu X,
Molina J, Sloan A, Pedigo CE, Ge M, Santos JV,
Hernandez Y, Kim JJ, Maugeais C, Mendez AJ,
Nair V, Kretzler M, Burke GW, Nelson RG,
Ishimoto Y, Inagi R, Banerjee S, Liu S, Szeto HH,
Merscher S, Fontanesi F, Fornoni A. ATPbinding cassette A1 deficiency causes
cardiolipin-driven mitochondrial dysfunction in457

podocytes. J Clin Invest. 2019 Jul 22;129(8):3387-3400. doi:10.1172/JCI125316.
7. Nishi H, Higashihara T, Inagi R. Lipotoxicity in
Kidney, Heart, and Skeletal Muscle Dysfunction.
Nutrients. 2019 Jul 20; 11(7). pii: E1664. doi:
10.3390/nu11071664.
8. Hasegawa S, Inoue T, Inagi R. Neuroimmune
interactions and kidney disease. Kidney Res Clin
Pract. 2019 Sep 30; 38(3):282-294. doi:10.
23876/j.krcp.19.014.
9. Maekawa H, Inoue T, Ouchi H, Jao TM, Inoue R,
Nishi H, Fujii R, Ishidate F, Tanaka T, Tanaka Y,
Hirokawa N, Nangaku M, Inagi R. Mitochondrial
Damage Causes Inflammation via cGAS-STING
Signaling in Acute Kidney Injury. Cell Rep. 2019Oct 29; 29(5):1261-1273.e6. doi:10.1016/j.celrep.
2019.09.050.
10. Maekawa H, Inagi R. Pathophysiological Role ofOrganelle Stress/Crosstalk in AKI-to-CKD
Transition. Semin Nephrol. 2019 Nov; 39(6):581-588. doi:10.1016/j.semnephrol.2019.10.007.

458

Department of Lipidomics
Professor
Yoshiya Oda, Ph.D.

Assistant Professor
Suzumi Tokuoka, Ph.D.

Homepage http://lipidomics.m.u-tokyo.ac.jp/index-e.html
Introduction and Organization
The Department of Lipidomics was established in
April 2011, funded by Shimadzu Corp. and Ono
Pharmaceutical Co., Ltd. The objective of the laboratory is to establish and improve mass spectrometrybased lipidomics methodologies, and its application tobiomedical studies including basic lipid biology as
well as clinical research.
The laboratory was started with three staff scientists,
Takao Shimizu (Professor), Yoshihiro Kita (Associate
Professor. He moved to Life Science Core Facility in
Dec. 2013), and Suzumi Tokuoka (Assistant Professor). In April, 2014, Fuyuki Tokumasu joined as an
Associate Professor (he moved to Nagasaki University
in April, 2019) and in May 2018, Yoshiya Oda joined
as a professor. In 2014, we had another assistantprofessor, two guest researchers and two technicalassistants.

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,459

because changes in metabolic flux is not always
reflected to static amount of metabolites. To overcome
this situation, we are developing a flux-oriented
lipidomics analysis using stable-isotope tracers.
Lipid biomarker/lipid mediator discovery using
animal models
Appling the latest lipidomics technologies to theanalysis of specimens from the animal models forvarious diseases including metabolic disease, we aretrying to discover novel lipid biomarkers. We also
analyze various gene-deficient mice and transgenic
mice to seek important lipid markers, lipid mediators,
and lipid profiles.
Multiplex quantitation strategy for lipid mediators
Lipid mediators, including prostaglandins, leukotrienes, platelet-activating factor, and many otherbioactive lipid metabolites are attracting great
attention as disease-related or physiologically important molecules. Comprehensive analysis of known
lipid mediators is a useful, unbiased method in diseasemechanism studies, and the lipid mediator profile is a
useful parameter that characterizes disease status aswell. We have developed an original multiplex
quantification method for trace amounts of lipid
mediators using liquid chromatography-tandem mass
spectrometry (LC-MS/MS). We are developing moresensitive and rapid methods that cover more lipid
mediators, which meet the demands on various
large-scale studies and high-throughput screening
approaches.
Discovery of novel lipid mediator metabolizing
pathways
Although major biosynthetic and catabolic
pathways for classical lipid mediators have been well
documented so far, there are still possibilities for yet
unidentified lipid mediator metabolizing pathways invivo. We have obtained preliminary data for novel
lipid mediator-producing pathway using genedeficient mice. Using the latest lipidomics techniques
to the cell cultures and animal models, we will
elucidate a novel lipid mediator related pathway andits biological significance.
Expansion of proteomics based on immune-PCR
Until now, proteomics based on mass spectrometry
has been the mainstream method, but quantitative

analysis was poor and plasma proteomics could notdetect proteins such as cytokines, which are only
present in very small amounts. This is why weintroduced this method for the first time in Japan. We
have already found interesting biomarker candidates
in various diseases. We are also trying to integrate
lipidomics and proteomics.

References
1. 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.
2. 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.
3. 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)
4. 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)
5. 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)
6. Yoshida K, Kita Y, Tokuoka SM, Hamano F,
Yamazaki M, Sakimura K, Kano M, Shimizu T.
Monoacylglycerol
lipasedeficiency
affects
diet-induced obesity, fat absorption, and feeding
behavior in CB1 cannabinoid receptor-deficient

460

mice. FASEB J, 33, 2484-2497 (2019) (Published
Online:30 Jan 2019)
7. 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)
8. Kita Y, Shiudou H, Shimizu T. Cytosolic
phospholipase A2 and lysophospholipid acyltransferases. Biochim Biophys Acta, 1864, 838-845(2019) (Available online 9 August 2018)
9. 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 state ofleukotriene B4 receptor BLT1. Nat Chem Biol, 14,262–269 (2018)
10. 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)
11. Tabe S, Hikiji H, Ariyoshi W, Hashidate-Yoshida T,
Shindou H, Shimizu T, Okinaga T, Seta Y, Tominaga
K, Nishihara T. Lysophosphatidylcholine acyltransferase 4 is involved in chondrogenic differentiation of ATDC5 cells. Sci Rep, 7, 16701(2017)
12. Kimura H, Suzuki M, Konno S, Shindou H, Shimizu
T, Nagase T, Miyazaki T, Nishimura M.
Orchestrating role of apoptosis inhibitor ofmacrophage in the resolution of acute lung injury. J
Immunol, 199, 3870-3882 (2017)
13. Iizuka-Hishikawa Y, Hishikawa D, Sasaki J, Takubo
K, Goto M, Nagata K, Nakanishi H, Shindou H,
Okamura T, Ito C, Toshimori K, Sasaki T, Shimizu T.
Lysophosphatidic acid acyltransferase 3 tunes themembrane status of germ cells by incorporating
docosahexaenoic acid during spermatogenesis. J
Biol Chem, 292, 12065-12076 (2017)14. Shindou H, Koso H, Sasaki J, Nakanishi H, Sagara
H, Nakagawa MK, Takahashi Y, Hishikawa D,
Iizuka-Hishikawa Y, Tokumasu F, Noguchi H,
Watanabe S, Sasaki T, Shimizu T. Docosahexaenoic

acid preserves visual function by maintaining
correct disc morphology in retinal photoreceptor
cells. J Biol Chem, 292, 12054-12064 (2017)
15. Takeda T, Komiya Y, Koga T, Ishida T, Ishii Y,
Kikuta Y, Nakaya M, Kurose H, Yokomizo T,
Shimizu T, Uchi H, Furue M, Yamada H. Dioxininduced increase in leukotriene B4 biosynthesis
through the aryl hydrocarbon receptor and its
relevance to hepatotoxicity owing to neutrophil
infiltration. J Biol Chem, 292. 10586-10599 (2017)16. Shindou H, Shiraishi S, Tokuoka MS, Takahashi Y,
Harayama T, Abe T, Bando K, Miyano K, Kita Y,
Uezono Y, Shimizu T. Relief from neuropathic painby blocking of platelet-activating factor-pain loop.
FASEB J, 31, 2973-2980 (2017)17. Shimura M, Shindou H, Szyrwiel L, Tokuoka SM,
Hamano F, Matsuyama S, Okamoto M, Matsunaga
A, Kita Y, Ishizaka Y., Yamauchi K, Kohmura Y,
Lobinski R, Shimizu I, Shimizu T. Imaging of intracellular fatty acids by scanning X-ray fluorescencemicroscopy. FASEB J. 30, 4149-4158 (2016) Epub.
18. Kita Y, Yoshida K, Tokuoka MS, Hamano F,
Yamazaki M, Sakimura K, Kano M, Shimizu T.
Fever is mediated by conversion of endocannabinoid 2-arachidonoylglycerol to prostaglandin E2.
PLoS ONE, 10, e0133663 (2015)19. Harayama T, Shindou H, Kita Y, Otsubo E, Ikeda
K, Chiba S, Weaver T, Shimizu T. Establishment
of LC-MS method for the analysis ofpalmitoylated surfactant proteins. J. Lipid Res., 56,
1370-1379 (2015)
20. Yamada M, Kita Y, Kohira T, Yoshida K, Hamano
F, Tokuoka SM, Shimizu T. A comprehensive
quantification method for eicosanoids and related
compounds by using liquid chromatography/mass
spectrometry with high speed continuous ionization polarity switching. J. Chrom. B, 995, 74-84(2015)
21. Hashidate-Yoshida T, Harayama T, Hishikawa D,
Morimoto R, Hamano F, Tokuoka SM, Eto M,
Tamura-Nakano M, Yanobu-Takanashi R,
Mukumoto Y, Kiyonari H, Okamura T, Kita Y,
Shindou H, Shimizu T. Fatty acyl-chain remodeling by LPCAT3 enriches arachidonate inphospholipid membranes and regulates triglyceride transport. eLife, 4, e06328 (2015)

461

22. Hayakawa EH, Tokumasu F, Usukura J, Matsuoka
H, Tsuboi T, Wellems TE. Imaging of thesubsurface structures of "unroofed" plasmodium
falciparum-infected erythrocytes. Exp. Parasitol.,
153, 174-179 (2015)23. Asahara M, Ito N, Yokomizo T, Nakamura M,
Shimizu T, Yamada Y. The absence of the leukotriene B4 receptor BLT1 attenuates peripheral
inflammation and spinal nociceptive processing
following intraplantar formalin injury. MolecularPain, 11.11 (2015)

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

464

Department of Clinical Laboratory
Professor
Yutaka Yatomi, M.D.

Lecturer
Makoto Kurano, M.D., Masao Daimon, M.D.,
Masato Yumoto, M.D., Kosuke Watanabe, M.D.

Associate
Tomoko Nakao, M.D., Masaya Sato, M.D.,
Masako Nishikawa, M.D

Chief Technologist
Tomoaki Sato, 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 2019, 234,558 outpatient blood
sampling were performed in this section. Furthermore,
266,792 urine samples were examined.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2019, 5,645,730 serum
enzyme tests (such as AST and ALT), and 578,422
immunological tests were performed.

The 3rd Section
This section deals with laboratory hematology and
DM-related tests, and gene analysis tests. In 2019,
1,196,165 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 2019, 43,907 ECG, 27,129
pulmonary function tests, and 11,207 EEG were
performed.
The 5th Section
This section deals with ultrasonography. In 2019,11,089 echocardiography tests, 14,325 abdominal
echography tests, and 7,320 other ultrasonography
tests were performed.

Teaching activities
Lectures are given to the fourth and sixth grade
medical students on clinical tests including
hematology, chemistry, endocrinology, immunology,
bacteriology, cardiology, and pulmonary function.

465

The reversed CPC program is presented to the sixth
grade students. Clinical clerkship is provided for thesixth year medical students, in small groups of 6-7
students for one-week duration. In this course,
students learn clinical and practical knowledge andtechniques on various laboratory tests. The second,
third, and fourth grade medical students can join
research activities in our department (Free Quartercourse). Students from professional schools also study
laboratory medicine under the guidance of members inClinical Laboratory Center.

2.

3.

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 areas included are: i) (Patho)
physiological roles of lysophospholipid mediators andits application into laboratory medicine, ii)
introduction of mass spectrometry into clinicallaboratory
practice,iii)
development
of
COVID-19-associated biomarkers, iv) platelet biology,v) AI and data mining in laboratory medicine, vi)
genetic testing, vii) oxidized albumin as a redox
marker, viii) analysis of cardiac functions using
ultrasound, ix) improvement and further clinicalapplication of pulmonary function tests, x) elucidationof abnormality in epigenetics in cancer and its clinicalapplication, and xi) analysis of brain function using
magnetoencephalography and near-infrared spectroscopy.

4.

5.

6.

References
Original article:
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Daimon, M., Desale, S., Fajardo, P.G., Kasliwal,
R.R., Kirkpatrick, J.N,, Monaghan, M.J., Mor-Avi,
V., Muraru, D., Ogunyankin K., Park, S.W.,
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A.C.T., Vivekanandan, A., Zhang, Y., Blitz, A., andLang, R.M. Similarities and Differences in Left
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Placental expression of lysophosphatidic acidreceptors in normal pregnancy and preeclampsia.
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and Chikuda, H. Lysophosphatidic acids and theirsubstrate lysophospholipids in cerebrospinal fluid asobjective biomarkers for evaluating the severity oflumbar spinal stenosis. Sci. Rep. 9: 9144, 2019.
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Daida, H., Yatomi, Y., Ozaki, Y., and Suzuki-Inoue,
K. Soluble CLEC-2 is generated independently of
ADAM10 and is increased in plasma in acutecoronary syndrome: comparison with soluble GPVI.
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Ishimaru, K., Yoshioka, K., Kano, K., Kurano, M.,
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T., Hiraki, K., Yamada, M., Matsusaka, S.,
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Di Carlo D,, Nakagawa, A., Hoshino, Y., Hosokawa,Y., Uemura, S., Sugimura, T., Ozek,i Y., Nitta, N.,
and Goda, K.A practical guide to intelligent
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Itoh, H., Kaneko, H., Kiriyama, H., Yoshida, Y.,466

Nakanishi, K., Mizuno, Y., Daimon, M., Morita, H.,
Yatomi, Y., and Komuro, I.Relation between theUpdated Blood Pressure Classification according to
the American College of Cardiology/American
Heart Association Guidelines and Carotid IntimaMedia Thickness. Am. J. Cardiol. 124: 396-401,
2019.
9. Itoh, H., Kaneko, H., Kiriyama, H., Nakanishi, K.,
Mizuno, Y., Daimon, M., Morita, H., Yamamichi,
N., and Komuro I. Effect of Body Weight Change
on Blood Pressure in a Japanese General Population
with a Body Mass Index ≥ 22 kg/m2. Int Heart J.
60: 1381-1386.
10. Kiriyama, H., Kaneko, H., Itoh, H., Uehara, M.,
Kodera, S., Kiyosue, A., Yamauchi, H., Daimon, M.,
Ando, J., Morita, H., Ono, M., and Komuro, I. Left
Main Coronary Artery Obstruction by Huge Noncoronary Cusp Calcification After Transcatheter
Aortic Valve Replacement. JACC Cardiovasc
Intervensions 12: 1285-1287, 2019.
11. Kiriyama, H., Kaneko, H., Itoh, H., Yoshida, Y.,
Nakanishi, K., Mizuno, Y., Daimon, M., Morita, H.,
Yatomi, Y., and Komuro I. Role of anemia andproteinuria in the development of subsequent renal
function deterioration in a general population withpreserved glomerular filtration rate: a communitybased cohort study. J. Nephrol. 32: 843-846, 2019.
12. Kiriyama, H., Kodera, S., Ando, J., Daimon, M.,
Morita, H., and Komuro, I. Worsening of mitral
regurgitation by balloon aortic valvuloplasty forsevere aortic stenosis: a case report. Int. Heart. J.
60: 768-771, 2019.
13. Kobayashi ,H., Lei, C., Wu Y, Huang, C.J.,
Yasumoto, A., Jona, M., Li, W., Wu, Y., Yalikun,
Y., Jiang, Y., Guo, B., Sun, C.W., Tanaka, Y.,
Yamada, M., Yatomi, Y., and Goda, K.Intelligent
whole-blood imaging flow cytometry for simple,
rapid, and cost-effective drug-susceptibility testingof leukemia. Lab Chip. 19: 2688-2698, 2019.
14. Kohsaka, S., Tatsuno, K., Ueno, T., Nagano, M.,
Shinozaki-Ushiku, A., Ushiku, T., Takai, D.,
Ikegami, M., Kobayashi, H., Kage, H., Ando, M.,
Hata, K., Ueda, H., Yamamoto, S., Kojima, S.,
Oseto, K., Akaike, K., Suehara, Y., Hayashi, T.,
Saito, T., Takahashi, F., Takahashi, K., Takamochi,
K., Suzuki, K., Nagayama, S., Oda, Y., Mimori ,K.,
Ishihara, S., Yatomi, Y., Nagase, T., Nakajima, J.,

Tanaka, S., Fukayama, M., Oda, K., Nangaku, M.,
Miyazono, K., Miyagawa, K., Aburatani, H., andMano, H. Comprehensive assay for the molecularprofiling of cancer by target enrichment fromformalin-fixedparaffin-embedded
specimens.
Cancer Sci. 110: 1464-1479, 2019.
15. Kurano, M., Kano, K., Hara, M., Tsukamoto, K.,
Aoki, J., and Yatomi, Y. Regulation of plasma
glycero-lysophospholipid levels by lipoprotein
metabolism. Biochem. J. 476: 3565-3581, 2019.
16. Kurano, M., Yasukawa, K., Ikeda, H., Aoki, J., andYatomi, Y. Redox state of albumin affects its lipid
mediator binding characteristics. Free Radic Res.
53: 892-900, 2019.
17. Kurano, M., Yatomi, Y. Use of gas chromatography
mass spectrometry to elucidate metabolites
predicting the phenotypes of IgA nephropathy in
hyper IgA mice. PLoS One. 14: e0219403, 2019.
18. Kurano, M., Tsuneyama, K., Morimoto, Y.,
Nishikawa, M., and Yatomi, Y. Apolipoprotein M
suppresses the phenotypes of IgA nephropathy in
hyper-IgA mice. FASEB J. 33: 5181-5195, 2019.
19. Liu, B., Yasukawa, K., Koid, S.S., Yeerbolati, A.,
Reheman, L., Wang, C., Yatomi, Y., andShimosawa, T. A rapid method for measuring serum
oxidized albumin in a rat model of proteinuria andhypertension. Sci Rep. 9:8620, 2019.
20. Matsuura, Y., Daimon, M., Notomi, Y., Miyasaka,N., Yamaguchi, Y., and Doi, S. Feasibility andReproducibility of Fetal Left Ventricular Twist
using Two-Dimensional Speckle-Tracking Analysis
in a Japanese Population. Int. Heart J. 60: 671-678,
2019.
21. Morita, Y., Kurano, M., Sakai, E., Nishikawa, M.,
Sawabe, M., Aoki, J., Yatomi, Y. Evaluation of
Lysophospholipid Measurement in Cerebrospinal
Fluid Samples using Liquid ChromatographyTandem Mass Spectrometry. Lipids. 54: 487-500,
2019.
22. Nakatsuka, T., Soroida, Y., Nakagawa, H., Shindo,
T., Sato, M., Soma, K., Nakagomi, R., Kobayashi,T., Endo, M., Hikita, H., Sato, M., Gotoh, H., Iwai,
T., Yasui, M., Shinozaki-Ushiku, A., Shiraga, K.,
Asakai, H., Hirata, Y., Fukayama, M., Ikeda, H.,
Yatomi, Y., Tateishi, R., Inuzuka, R., and Koike, K.
Identification of Liver Fibrosis Using the Hepatic
Vein Waveform in Patients with Fontan Circulation.

467

Hepatol Res. 49: 304-313, 2019.
23. Nakatsuka, T., Soroida, Y., Nakagawa, H., Okura,N., Sato, J., Akahane, M., Sato, M., Yatomi, Y., Abe,O., Tateishi, R., and Koike, K. Utility of hepaticvein waveform and transient elastography in patientswith Budd-Chiari syndrome who require angioplasty: Two case reports. Medicine 98:e17877,
2019.
24. Nishikawa, M., Kurano, M., Nitta, T., Kanoh, H.,
Inokuchi, J.I., and Yatomi, Y. Serum GM3(d18:116:0) and GM3(d18:1-24:1) levels may be
associated with lymphoma: An exploratory study
with haematological diseases. Sci Rep. 9: 6308,
2019.
25. Nojiri, T., Kurano, M., Araki, O., Nakawatari, K.,
Nishikawa, M., Shimamoto, S., Igarashi, K., Kano,
K., Aoki, J., Kihara, S., Murakami, M., and Yatomi,
Y. Serum autotaxin levels are associated with
Graves' disease. Endocr J. 66: 409-422, 2019.
26. Sato, M., Morimoto, K., Kajihara, S., Tateishi, R.,
Shiina, S., Koike, K., and Yatomi, Y.
Machine-learning Approach for the Development ofa Novel Predictive Model for the Diagnosis of
Hepatocellular Carcinoma. Sci. Rep. 9: 7704, 2019.
Press Release.
27. Sato, M., Ohkawa, R., Low, H., Nishimori, M.,
Okubo, S., Yoshimoto, A., Yano, K., Kameda, T.,
Yatomi, Y., and Tozuka, M. Serum amyloid A does
not affect high-density lipoprotein cholesterol
measurement by a homogeneous assay. Clin.
Biochem. 63: 97-101, 2019.
28. Sawada, T., Kurano, M., Shirai, H., Iwasaki, Y.,
Tahara, K., Hayashi, H., Igarashi, K., Fujio, K.,
Aoki, J., and Yatomi, Y. Serum phosphatidylserinespecific phospholipase A1 as a novel biomarker formonitoring systemic lupus erythematosus diseaseactivity. Int. J. Rheum Dis. 22: 2059-2066, 2019.
29. Sawada, N., Daimon, M., Kawata, T., Nakao, T.,
Kimura, K., Nakanishi, K., Kurano, M., Hirokawa,M., Xu, B., Yamanaka, Y., Kato, T.S., Watanabe,M., Yatomi, Y., and Komuro, I. The Significance of
the Effect of Visceral Adiposity on Left Ventricular
Diastolic Function in the General Population. Sci.
Rep. 9: 4435, 2019.
30. Sawada, N., Kawata, T., Daimon, M., Nakao, T.,
Hatano, M., Maki, H., Kimura, K., Hirokawa, M.,
Ishiwata, J., Xu, B., Yataomi, Y., and Komuro I.

Detection of Pulmonary Hypertension with Systolic
Pressure Estimated by Doppler Echocardiography:
Comparison with invasive mean pulmonary arterypressure. Int. Heart. J. 60: 836-844, 2019.
31. Sawada, N., Nakao, T., Daimon, M., Nawata, K.,
Tanaka, M., and Komuro, I. Multiple calcified
amorphous tumors in a patient with end-stage renal
disease. J. Echocardiogr. doi: 10.1007/s12574-01900416-1 , 2019.
32. Shimura, T., Kurano, M., Morita, Y., Yoshikawa, N.,
Nishikawa, M., Igarashi, K., Shimamoto, S., Aoki, J.,
and Yatomi Y. Autotaxin and soluble IL-2 receptor
concentrations in cerebrospinal fluids are useful forthe diagnosis of central nervous system invasion
caused by haematological malignancies. Ann. Clin.
Biochem. 56: 240-246, 2019.
33. Soroida, Y., Nakatsuka, T., Sato, M., Nakagawa, H.,
Tanaka, M., Yamauchi, N., Wake, T., Nakagomi, R.,
Kinoshita, M.N., Minami, T., Uchino, K., Enooku,
K., Asaoka, Y., Tanaka, Y., Endo, M., Nakamura,A., Kobayashi, T., Kurihara, M., Hikita, H., Sato, M.,
Gotoh, H., Iwai, T., Fukayama, M., Ikeda, H.,
Tateishi, R., Yatomi, Y., and Koike, K. A Novel
Non-invasive Method for Predicting Liver Fibrosis
by Quantifying the Hepatic Vein Waveform.
Ultrasound Med. Biol. 45: 2363-2371, 2019.
34. Suzuki, Y., Kobayashi, K., Wakisaka, Y., Deng, D.,
Tanaka, S., Huang, C.J., Lei, C., Sun, CW., Liu, H.,
Fujiwaki, Y., Lee, S., Isozaki, A., Kasai, Y.,
Hayakawa, T., Sakuma, S,, Arai, F., Koizumi, K.,
Tezuka, H., Inaba, M., Hiraki, K., Ito, T., Hase, M.,
Matsusaka, S., Shiba, K., Suga, K., Nishikawa, M.,
Jona, M., Yatomi, Y., Yalikun, Y., Tanaka, Y.,
Sugimura, T., Nitta, N., Goda, K., Ozeki, Y.
Label-free chemical imaging flow cytometry by
high-speed multicolor stimulated Raman scattering.
Proc. Natl. Acad .Sci. U.S. A. 116: 15842-15848,
2019.
35. Terao, R., Honjo, M., Ueta, T., Obinata, H., Izumi,
T., Kurano, M., Yatomi, Y., Koso, H., Watanabe, S.,
and Aihara, M. Light Stress-Induced Increase of
Sphingosine 1-Phosphate in Photoreceptors and Its
Relevance to Retinal Degeneration. Int. J. Mol. Sci.
20: 3670, 2019.
36. Matsuura, Y., Daimon, M., Notomi, Y., Miyasaka,N., Yamaguchi, Y., and Doi, S. Feasibility andReproducibility of Fetal Left Ventricular Twist468

using Two-Dimensional Speckle-Tracking Analysis
in a Japanese Population. Int. Heart. J. 3: 671-678,
2019.
37. Uranbileg, B., Ito, N., Kurano, M., Saigusa, D.,
Saito, R., Uruno, A., Kano, K., Ikeda, H., Yamada,Y., Sumitani, M., Sekiguchi, M., Aoki, J., andYatomi, Y. Alteration of the lysophosphatidic acidand its precursor lysophosphatidylcholine levels inspinal cord stenosis: A study using a rat cauda
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38. Yasukawa, K., Sato, M., Nojiri, T., Yoshikawa, N.,
Morita, K., Kai, M., Oike, Y., Yamazaki, T., Ikeda,
H., and Yatomi, Y. Establishment of a stablesampling method to assay mercaptoalbumin/nonmercaptoalbumin and reference ranges. Pract. Lab.
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39. Yoshida, Y., Nakanishi, K., Daimon, M., Ishiwata,J., Sawada, N., Hirokawa, M., Kaneko, H., Nakao,T., Mizuno, Y., Morita, M., Di. Tullio, M.R.,
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1789-1800, 2019.

469

Surgical Center
Professor (Director)
Kazuhiko Fukatsu M.D., Ph.D.

Lecturer
Mitsuaki Muroya, M.D., Ph.D
Satoshi Murakoshi, M.D., Ph.D.
Yuhei Saito, Ph.D.
Ryoji Fukushima, M.D., Ph.D.

Assistant Professor
Ryota Yamagami. M.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/syujutsu/index.html

Introduction and Organization
Uniform management of operating rooms (OR) firstbegan at the University of Tokyo Hospital in July
1955. The office, so called the surgical center, waslocated 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 surgicalcenter became to provide managerial services of the
OR to 18 surgical departments after moving into thenew office building. The total number of operations
remained to be below 6,300 a year between 1999 and2000 because of the limitation of number of ORs andnurses.
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 ofelective operations markedly increased and becameover 7,300. Two additional ORs began to be usedtentatively to accommodate an enormous increase in
the number of elective operations. The one OR was set
up on the ICU/CCU/HCU floor in the new Ward A
Building and the 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-stay and 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 theCentral Clinical Service Building 2 was renovated intoa hybrid OR which is equipped with advanced
interventional imaging system for the patients
undergoing interventional surgical treatment.
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 and 11,323 operations were performed in 2006,
2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014,2015, 2016, 2017, 2018 and 2019 fiscal year,
respectively. The number of operations in 2019 fiscal
year counts for approximately 1.8 times comparing tothat in 2001.
These days more and more patients undergo
endoscopic surgery such as laparoscopy/thoracoscopy

470

assisted operation. There is also an apparent increasein the number of patients who are at high risk withcritical morbidity or carrier of the particular types ofpathogens such as tuberculosis, MRSA, pseudomonas
aeruginosa, HBV, HCV and HIV.

Clinical Activities
All operations of in-patients are performed in 23
ORs at the surgical center. Computer system has beenutilized to handle the information on operation. In
May 1999, the on-line system was introduced to order
the elective and urgent/emergent operations throughthe computer terminal in the wards. The input of
postoperative patient information started from March
2000. This system also enabled the medical staff toknow the availability of the ORs of the next day. From
November in 2000, the medical staff can see theoperation 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. Thoseoperations include organ transplantation, microvascular surgery, cardiovascular surgery, minimallyinvasive surgery and navigation-guided orthopedic/
neurosurgical surgery and stent grafting for theabdominal or thoracic aortic aneurysms. Organtransplantation and intraoperative three-dimensional
echo-guided surgery are also frequently performed.
Minimally invasive surgery is another recent trend of
the operation. Those include endovascular treatment
for heart anomalies such as ASD and VSD. Morerecently, the robotic surgery has started at the surgicalcenter.
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 associatedwith emerging or re-emerging infectious diseases suchas HIV and tuberculosis has increased, all healthcare
staff are required to adhere to the principles ofstandard and/or transmission-based precautions also inthe surgical center.

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 understandhow to use them in a proper way.
Lectures for the nursing staff consist of a freshmancourse and an advanced course. The freshman course
is a basic training course for scrub nurses andcirculating nurses. It consists of lectures of aseptic
techniques, de-contamination/sterilization methods,
prevention of perioperative infections, and on-sitetraining of scrubbing and gown techniques as wall as
aseptic preparation of surgical instruments in the OR.
An advanced course is prepared to the experienced
nurses as well. The purpose of this course is toupgrade their perioperative nursing skills so that they
can demonstrate full nursing skills even in the471

complicated and long operations such as transplant
surgery, open-heart surgery neurosurgery and robotic
surgery.
There is also a training course to medical engineers
and students of biomedical engineers. This training
course consists of introduction on the medical devices
and electronic instruments, precautions of accidental
troubles in handling surgical instruments/medical
devices, development of new surgical instruments/
medical devices, cardiopulmonary bypass techniques
and illumination techniques in the operating fields.
The contents of this course are summarized in the
manual for the nursing staff and contribute to decrease
the frequency 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 theOR12) Maintenance and management of surgicalequipment13) Nutritional management of perioperative patients
14) Others

References（2019）
1. Fukatsu K. Role of nutrition in gastroenterological surgery. Ann Gastroenterol Surg. 25;3(2):160-168, 2019
2. Kobayashi K, Kaneko J, Yamaguchi T,
Kawaguchi Y, Arita J, Akamatsu N, Ishizawa T,
Sekine R, Ijichi H, Kubota N, Fukatsu K, Kokudo
N, Hasegawa K. Late-Evening Carbohydrate andBranched-Chain Amino Acid Snacks Improve the
Nutritional Status of Patients Undergoing
Hepatectomy Based on Bioelectrical Impedance
Analysis of Body Composition. Gastrointest
Tumors. 6(3-4):81-91, 2019
3. Higashizono K, Fukatsu K, Watkins A, Watanabe
T, Noguchi M, Ri M, Murakoshi S, Yasuhara H,
Seto Y. Influences of Short-Term Fasting andCarbohydrate Supplementation on Gut Immunityand Mucosal Morphology in Mice. JPEN J
Parenter Enteral Nutr. 43(4):516-524, 2019
4. Fukatsu K, Shineha R, Kawauchi Y, Saeki M,
Nakayama M. Optimizing Vitamin and Trace
Element Profiles in Blood after Gastrointestinal
Tract Surgery by a New Parenteral Nutrition
Formula. Ann Nutr Metab. 74(3):189-199, 2019

472

Department of Clinical Radiology
Professor (department manager)
Abe Osamu, M.D., Ph.D.

Lecturer (vice manager)
Jiro Sato, M.D.

Assistant Professor
Masaki Katsura, M.D., Ph.D.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/houshasenbu/

Introduction and Organization
In the Department of Clinical Radiology, clinicalservices on Diagnostic Radiology (imaging andintervention), Radiation Oncology (radiotherapy),
Nuclear Medicine, and the Radiation Safety Control
System are provided in cooperation with radiology
technologists and nurses. Present constituent members
are as follows: three medical doctors, 75 radiological
technicians and 1 technical official of the radiation
control. The staff members of the Department ofRadiology (teachers, the graduate school students,
medical staffs, and the clinical trainees) join this. In
addition, the doctors of other departments and thenurses cooperate and are also engaged in the clinicalradiology activities.
Department of Clinical Radiology is actively
participating in the following projects. 1) PACS: We
have recently developed a radiology information
system (RIS) networking with hospital information
system (HIS) and PACS (picture archiving andcommunicating system). The PACS of the whole
hospital (the film-less imaging system) wasestablished in 2003. The new reporting system wasinstalled in 2012. 2) Radiation Safety Control:
stimulated by the need for evaluating the individualaccumulated exposure dose by medical radiation, we
have started a working group to solve this problem.
We aim to provide the accumulated exposure dose
data on RIS. 3) Image Computing & Analysis
Laboratory: The clinical section of this project islocated at the reading room in the Diagnostic
Radiology Section. The main services are processingof volume image data into clinical 3D-images andanalysis of imaging data. 4) Researches on new
radiology
techniques:
Ongoingcollaborative
researches are as follows: image-guided radiation
therapy, clinical PET, multi-detector row CT, 3-Tesla
MRI, and flat panel detector.

Clinical activities
1) Diagnostic Radiology:
The section of diagnostic radiology is responsible
for all the clinical examinations of CT, MRI, andangiography/vascular interventional procedures except
for cardiac and peripheral arterial studies. All of these
examinations are performed under the requests ofclinicians. Over two hundred CT examinations are
performed using six MDCT scanners each day.
Interventional procedure such as percutaneous biopsy
and abscess drainage are also done by CT guidance.
About seventy MR examinations are done using twoof 1.5-Tesla and five of 3-Tesla scanners every day.
Diagnostic and interventional procedures are
performed using six angiographic units, including a
hybrid operating room.
2) Nuclear medicine:
The section of nuclear medicine is responsible forall the radionuclide imaging examinations including
conventional scintigraphy such as bone, kidney,473

thyroid scans, SPECT, and PET scans. Scanning is
performed at the first basement floor in the Central
Clinic Building 1. Blood flow, metabolism, andreceptor functions are measured for the understandingof normal and pathophysiological states, using avariety of positron-emitter radiotracer with F-18.
Whole body FDG-PET for staging of malignancy
plays an important role in the clinical management of
the patients. These nuclear imaging procedures are
performed and reported by radiologists andcardiologists.
3) Radiation Oncology:
The radiation therapy is performed with three linear
accelerators, an intracavitary irradiation device(RALS), a brachytherapy, and a gamma knife forradiosurgery. The network system connecting theseradiotherapy equipments, CT/MR devices, andtreatment planning systems was already constructed.
Each year, over 700 new patients receive radiation
therapy in the Radiation Oncology section. Highly
accurate 3D radiation therapy is the most outstanding
feature. We have developed a new linear accelerator
with C-arm and multi-leaf collimator systems, which
is utilized mainly for non-coplanar radiation therapy
in many patients, especially with brain tumor or headand neck tumor. The linear accelerator system withcone-beam CT technology has been introduced to our
hospital, which enables image-guided radiation
therapy.
4) Radiation safety control:
The educational training and registration of theradiation engaging persons are controlled according to
the University of Tokyo Hospital Ionizing Radiation
Injury Prevention Rules.
In conclusion, the department of clinical radiology
is a service section to all clinical departments. Main
supporter as the doctor is a radiologist. However, thecooperation with the radiation diagnosis and treatment
engaging persons of other clinical departments,
technicians and nurses must be reinforced. We want tomake still more effort to achieve the cooperation andimprove clinical activities in the department of clinicalradiology.

References
See the corresponding part of the Department ofRadiology.

Number of examinations in 2019
Inpatient

Outpatient

97,68580,080177,765

5,226

918

6,144

3,343

5

3,348

16,03337,61853,651

4,957

15,493

20,450

1,614

2,697

4,311

Radiotherapy

5,525

8,445

13,970Bone mineraldensitometry

380

3,379

3,759

Radiography(plain)Radiography(enhanced)
Angiography
Computed
tomography
Magnetic
resonance
imaging
Nuclearmedicine

Total

474

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Lecturer
Tappei Takada, Ph.D.,

Masashi Honma, Ph.D.

Research Associate
Takahiro Amemiya, Ph.D.,

Yuki Ikebuchi, Ph.D.,

Yoshiaki Kariya, Ph.D.,

Keita Tokuda, Ph.D.,

Hiroshi Miyata, Ph.D.,

Yoshihide Yamanashi, Ph.D.

Homepage

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

Introduction and Organization
We have 9 faculty members, 79 pharmacy staffs,
and 10 graduate students and 9 undergraduate students
from the faculty of pharmaceutical sciences (as ofJanuary 1st, 2020).

Clinical activities
Department of Pharmacy consists of the following
six sections:1) Drug information and research section
This section offers drug information for questions
from medical persons, executes and supports the
medicine management to inpatients. In addition,
the section prepares materials for pharmaceuticalaffair committee, where each medicine isdiscussed whether it should be adopted or deleted.
Preparation of several periodicals regarding drug
information for clinicians is also included.
2) The dispensing section
After inspecting all prescriptions for contraindications or improper use, medications are
dispensed. Drug information is given to outpatientsfrom this section, using a private room ifnecessary. The computerized order system islinked with automatic packaging machines fororal medicines, automatic dispensing system andbarcode label printer for injection drugs.

3) Pharmaceutical section
This section sterilizes formulations of a pharmaceutical such as injection medicines, instillation
medicines and decontaminating chemicals. They
prepare capsule medicines, ointment medicines,
suppositories, central vein nutrition (IVH) for
inpatients and in-home care patients. After strict
inspection of prescriptions, they also dispenseanti-malignant tumor medicine (database isconstructed based on the submitted protocols andpatients’ information). In order to support
advanced medical care, they develop and check
formulations (characterization of the uniformity,
stability and so on) of the medicine which is quite
necessary for certain patients, but is not marketed.
4) Drug matters and drug management section
Drug matter section manages the adoption of
medical supplies (in-hospital and out-hospital),
periodically reconsiders the adopted medicines,
and also manages the accountings of all the
medicines and other materials used in our
department. This section also takes statistics ofevery information of drug affairs. Drug management section takes care of supplying and safekeeping of all the in-hospital medicines (2,614
items), out-patient medicines, anesthetics, muscle
relaxation drugs, psychotropic drugs, poison
medicines.

4755) 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 2019)
Number of items on in-hospital formulary: 2,614
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
368,920 ps.
(outside :324,995 ps.)(inside :43,925 ps.)out-patient chemotherapy:
12,940 ps.

in-patients :253,720 ps.
injection drugs:
187,220 ps.
IVH:
2,633 pp.
chemotherapy:
10,485 pp.
TDM consultations (annual) :19,654 pp.
Numbers of hospital pharmaceutical cares (annual):
18,484 pp.

Education
The department of pharmacy takes various
responsibilities of education with regard to clinicalpharmacy, pharmacology, and pharmacokinetics forstudents and graduate students in the faculty of
medicine, in the faculty of pharmacy, and in theschool of integrated health sciences. We also have ourown half a year post-graduate training course
optimized for new pharmacists.
For students in the faculty of medicine, we are in
charge of "Pathogenetic and Pathology" as an optionalcourse lecture. We are providing a 3-days practicecourse as a part of compulsory clinical practice for theM3 or M4 students and teach clinical pharmaceutics
and practical knowledge of prescription and risk
management to them. For the students in the healthsciences and nursing, we are in charge of clinicalpharmacokinetics lectures as a part of a compulsory
subject, "Pharmacology and Toxicology".
For students in the faculty of pharmacy, we are in
charge of lectures for the undergraduate students:"Clinical Pharmacy" (compulsory subject). They are
educated for the clinical pharmacology andpharmacokinetics. For the graduate students, we are in
charge of “Special Lecture Basic Pharmaceutical
Science IV”, “Special Lecture Clinical Science”,“Advanced Course of Medical Pharmacy" as acooperator of the Clinical Pharmacokinetics. Recent
trends of the medical pharmacy as well as the practicaldevelopments and future visions of the department ofpharmacy are presented in this lecture. In addition tothem, we accept undergraduate and graduate students
from the faculty of pharmaceutical sciences andfaculty of medicine. They are doing various research
activities.
Six year course education system has been launchedin the field of pharmaceutical sciences since 2006. In
this system, the clinical training by pharmacists at the476

hospital is one of the most important curriculums. In
2017, we accepted clinical training students from The
University of Tokyo, Tokyo University of Pharmacy
and Life Sciences, Showa Pharmaceutical University,
Hoshi University, and Musashino University, Tokyo
University of Science, Keio University and educatedthem for 2.5 months. In addition, we have had an
original one-year post-graduate training course forpharmacists since long time before starting the 6-year
course education system. They learned various
practical knowledge and techniques necessary for
hospital pharmacists. Such education style is still
continuing by shortening the period to half a year. In
2019, 13 pharmacists finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

ment of new therapy for bone metabolic disease
based on those integrated understanding.
3. Establishment of the way to quantitative understanding and prediction of pharmacological-effectand adverse-effect of drugs directed against
particular molecular target. Finally, these outputs
would be feedbacked to early drug development
stages.
4. Elucidation of the molecular mechanism related tothe adverse effect of drugs using large-scale“-omics” analysis. Finally, the quantitative information would be applied to develop strategies toprevent / treat the adverse effect.
5. Absolute quantification of factors determining thepharmacokinetic profiles of drugs and its application to clinical pharmacokinetics and pharmacology field.

Research

Publications

It is evident that the molecular function ofparticular element cannot always be assigned to only
one function at whole body level, because one to one
simple correspondence is not common in our body. It
is also true that the understanding of the relationshipbetween drug and its ultimate target is not sufficient topredict the pharmacological/toxicological effects. We
need to understand not only the detailed molecularmachinery of drug target, but also its environment
surrounding the target (ex. other associated proteins,
signaling molecules, etc.), where and when it works,
and finally how it behaves as functional unit in our
body. This is a basic idea trying to understand “livingbody” as “system”. By further promoting this idea to“system pharmacology”, we will be able to identify amolecular target which is related to the pharmacological/toxicological output in clinical situation or evenat early drug development stage. Based on suchconcept, following projects are now ongoing:(1) Hamada S, Ohno Y, Kojima T, Ishii S, Okochi J,
Akishita M. Prevalence of cytochrome P450mediated potential drug-drug interactions inresidents of intermediate care facilities for older
adults in Japan. Geriatr Gerontol Int. 2019;19:513-17.
(2) Ishida T, Tokuda K, Hisaka A, Honma M, Kijima S,
Takatoku H, Iwatsubo T, Moritoyo T, Suzuki H,
Alzheimer's Disease Neuroimaging I. A novel
method to estimate long-term chronological changes
from fragmented observations in disease progression.
Clin Pharmacol Ther. 2019;105:436-47.
(3) Ito SM, Yamanashi Y, Takada T, Suzuki H. Clinicalimportance of drug-drug interaction between
warfarin and prednisolone and its potential
mechanism in relation to the Niemann-Pick C1-Like
1-mediated pathway. Circ J. 2019;83:471-80.
(4) Kawamura Y, Nakaoka H, Nakayama A, Okada Y,
Yamamoto K, Higashino T, Sakiyama M, Shimizu T,
Ooyama H, Ooyama K, Nagase M, Hidaka Y,
Shirahama Y, Hosomichi K, Nishida Y,
Shimoshikiryo I, Hishida A, Katsuura-Kamano S,
Shimizu S, Kawaguchi M, Uemura H, Ibusuki R,
Hara M, Naito M, Takao M, Nakajima M, Iwasawa
S, Nakashima H, Ohnaka K, Nakamura T,
Stiburkova B, Merriman TR, Nakatochi M, Ichihara
S, Yokota M, Takada T, Saitoh T, Kamatani Y,

1. Elucidation of the molecular mechanism which
controls in vivo disposition of lipids / bile acids /uric acid, and establishment of new therapy forlife-style related diseases based on those
integrated understanding.
2. Elucidation of the dynamic regulatory mechanismof bone resorption / bone formation, and establish-

477

Takahashi A, Arisawa K, Takezaki T, Tanaka K,
Wakai K, Kubo M, Hosoya T, Ichida K, Inoue I,
Shinomiya N, Matsuo H. Genome-wide association
study revealed novel loci which aggravate
asymptomatic hyperuricaemia into gout. Ann
Rheum Dis. 2019;78:1430-37.
(5) Malhotra P, Soni V, Yamanashi Y, Takada T, Suzuki
H, Gill RK, Saksena S, Dudeja PK, Alrefai WA.
Mechanisms of Niemann-Pick type C1 Like 1
protein degradation in intestinal epithelial cells. Am
J Physiol Cell Physiol. 2019;316:C559-C66.
(6) Manabe Y, Ichihara M, Fukuda K, Tomonaga N, Li
ZS, Yamanashi Y, Suzuki H, Takada T, Matsuo M,
Sugawara T. Niemann-Pick C1-like 1 promotes
intestinal absorption of siphonaxanthin. Lipids.
2019;54:707-14.
(7) Sone E, Noshiro D, Ikebuchi Y, Nakagawa M, Khan
M, Tamura Y, Ikeda M, Oki M, Murali R, Fujimori T,
Yoda T, Honma M, Suzuki H, Ando T, Aoki K. The
induction of RANKL molecule clustering could
stimulate early osteoblast differentiation. Biochem
Biophys Res Commun. 2019;509:435-40.
(8) Toyoda Y, Mancikova A, Krylov V, Morimoto K,
Pavelcova K, Bohata J, Pavelka K, Pavlikova M,
Suzuki H, Matsuo H, Takada T, Stiburkova B.
Functional characterization of clinically-relevantrare variants in ABCG2 identified in a gout andhyperuricemia cohort. Cells. 2019;8:363.
(9) Toyoda Y, Pavelcova K, Klein M, Suzuki H, Takada
T, Stiburkova B. Familial early-onset hyperuricemia
and gout associated with a newly identified
dysfunctional variant in urate transporter ABCG2.
Arthritis Res Ther. 2019;21:219.
(10) Toyoda Y, Takada T, Suzuki H. Inhibitors of human
ABCG2: From technical background to recent
updates with clinical implications. Front Pharmacol.
2019;10:208.
(11) Toyoda Y, Takada T, Umezawa M, Tomura F,
Yamanashi Y, Takeda K, Suzuki H. Identification ofhepatic NPC1L1 as an NAFLD risk factor
evidenced by ezetimibe-mediated steatosis prevention and recovery. FASEB Bioadv. 2019;1:283-95.
(12) Toyoda Y, Takada T, Yamanashi Y, Suzuki H.
Pathophysiological importance of bile cholesterol
reabsorption: Hepatic NAFLD-exacerbated steatosis
and decreasing VLDL-TG secretion in mice fed ahigh-fat diet. Lipids Health Dis. 2019;18:234.

(13) Uchida S, Asai Y, Kariya Y, Tsumoto K, Hibino H,
Honma M, Abe T, Nin F, Kurata Y, Furutani K,
Suzuki H, Kitano H, Inoue R, Kurachi Y. Integrative
and theoretical research on the architecture of abiological system and its disorder. J Physiol Sci.
2019;69:433-51.
(14) Yamamoto H, Yamanashi Y, Takada T, Mu S,
Tanaka Y, Komine T, Suzuki H. Hepatic expressionof Niemann-Pick C1-Like 1, a cholesterol
reabsorber from bile, exacerbates western
diet-induced atherosclerosis in LDL receptor mutant
mice. Mol Pharmacol. 2019;96:47-55.

478

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Associate Professor

Yusuke Shinoda, M.D.

Lecturer

Sayaka Fujiwara, M.D.

Research Associate
Yasuaki Karasawa, M.D., Kentaro Morita, M.D.,
Haruhi Inokuchi, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The physical therapy service started in 1963 at the
University of Tokyo Hospital, and then expanded toinclude occupational therapy and social work section.
In 1966 this service was converted to the central
rehabilitation service department as a part of theCentral Diagnostic and Therapeutic Service Department. The Central Rehabilitation Service became an
independent unit in 1970. After the reorganization of
the University of Tokyo Hospital according to majororganic classification in 1998, outpatient clinic asrehabilitation medicine was installed. The formal titleof our unit was changed from the Physical Therapy
Department to the Rehabilitation Department by thebudget measures in the fiscal year 2001, and we
integrated the related personnel categories, which
belonged to the orthopedic surgery department and thephysical medicine department.
At present our department consists of four sections.
Rehabilitation physicians’ section includes fivefull-time doctors and two other part-time doctors.
They work chiefly for clinical practice in medical
rehabilitation service, but also have to engage inteaching activities for medical students. Nineteen
physical therapists are working in the physical therapy
section. In the occupational therapy section, six

occupational therapists work for the generalrehabilitation service and the other four therapists
work for the psychiatric rehabilitation. Four acupuncture therapists perform acupuncture and moxbustion.
In the Day-care Unit, clinical psychologists and nurses
also work. In 2006, speech therapists who had
belonged to other departments in the University ofTokyo Hospital were included in our department.
From 2009, a speech therapist added to ourdepartment, and now three therapists perform therapy
for patients with aphasia, dysarthria, and dysphagia.

Clinical activities
The professor serves as a director of Rehabilitation
Center, the University of Tokyo Hospital. The Rehabilitation Center and the Department of Rehabilitation
Medicine are united and engage in clinical practice.
We have at present no charged ward, and treat about
4,700 new referrals annually from almost all the
departments of the university hospital. We always takecharge of 250-300 patients corresponding about
25-30% of the whole number of inpatients. We also
see 30 people per day at the outpatient rehabilitation
setting. The numerical ratio of outpatient is being
reduced in order to give priority to the clinical service

479

corresponding to needs expansion of service toinpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year
medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such ascerebrovascular disturbances, respiratory disorders,
neuromuscular diseases, bone and joint diseases, andpediatric disorders as well as on outline of rehabilitation, and amputation/prostheses. We have provided aclinical practice in small group, so-called clinicalclerkship for 5th and 6th year students from
Wednesday to Friday every week. They experience a
few patients and learn how to take a patients’ history,
physical findings, functional evaluation, and how toplan rehabilitation programs. We have introduced a
few of elective students for elective clinical clerkshipto our collaborating hospitals with specialized
rehabilitation ward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with other departments in our hospital, other faculties in our university,and institutions outside the University of Tokyo. The
ongoing and scheduled projects are as follows.
1) 3D Motion analysis of patients with musculoskeletal disorders
2) Study on the relationship between sensory deficit
and motor control
3) Rehabilitation and long-term outcome in patientswith skeletal dysplasias

4) Pathology and treatment for patients withcongenital limb deficiencies
5) Analysis of rehabilitation outcome using DPC
data

References
1. Goto M, Haga N, Takedani H: Physical activity andits related factors in Japanese people withhaemophilia. Haemophilia 25: e267-e273, 2019
2. Mano H, Fujiwara S, Haga N: Body knowledge inchildren with congenital lower limb deficiency.
Pediatr Int 61(2): 158-165, 2019
3. Matsushita M, Kitoh H, Mishima K, Yamashita S,
Haga N, Fujiwara S, Ozono K, Kubota T, Kitaoka
T, Ishiguro N: Physical, mental and social
problems of adolescent and adult patients withachondroplasia. Calc Tissue Int 104(4): 364-372,
2019
4. Nakahara Y, Kitoh H, Nakashima Y, Toguchida J,
Haga N: The longitudinal study of activities ofdaily living and quality of life in Japanese patientswith fibrodysplasia ossificans progressiva. Disabil
Rehabil 41(6): 699-704, 2019
5. Taya M, Amiya E*, Hatano M, Maki H, Hosoya Y,
Ishida J, Bujo C, Tsuji M, Konishi Y, Yokota K,
Haga N, Komuro I: Inspiratory muscle training foradvanced heart failure with lamin-related muscular
dystrophy. J Cardiol Cases 2019, jccase 20(6):232-234, 2019.9
6. Yamoto K, Saitsu H, Nishimura G, Kosaki R,
Takayama S, Haga N, Tonoki H, Okumura A, Horii
E, Okamoto N, Suzumura H, Ikegawa S, Kato F,
Fujisawa Y, Nagata E, Takada S, Fukami M, Ogata
T: Comprehensive clinical and molecular studies in
split hand/foot malformation: identification of twoplausible candidate genes (LRP6 and UBA2). Eur J
Hum Genet 27: 1845-1857, 2019
7. Yoshida M, Matsunaga A, Igawa Y, Fujimura T,
Shinoda Y, Aizawa N, Sato Y, Kamei J, Kume H,
Homma Y, Haga N, Sanada H*: May preoperative
ultrasound-guided pelvic floor muscle training
promote early recovery of urinary continence after
robot-assisted radical prostatectomy? Neurourol
Urodyn 38(1): 158-164, 2019
8. Ogura K, Uehara K, Akiyama T, Shinoda Y, Iwata
S, Tsukushi S, Kobayashi E, Hirose T, Yonemoto T,

480

Endo M, Tanzawa Y, Nakatani F, Kawano H,
Tanaka S, Kawai A: Development of apatient-oriented disease specific outcome measureof health-related quality of life (HRQOL) formusculoskeletal oncology patients. J Orthop Sci
24(3): 539-547, 2019
9. Fujimura T, Igawa Y, Aizawa N, Niimi A, Yamada
Y, Sugihara T, Kamei J, Sato Y, Matsunaga A,
Yoshida M, Shinoda Y, Fukuhara H, Nakagawa T,
Homma Y, Kume H: Longitudinal change ofcomprehensive lower urinary tract symptoms andvarious types of urinary incontinence during
robot-assisted radical prostatectomy. Neurourol
Urodyn 38(4): 1067-1075, 201910. Shinoda Y, Sawada R, Yoshikawa F, Oki T, Hirai T,
Kobayashi H, Matsudaira K, Oka H, Tanaka S,
Kawano H, Haga N: Factors related to the qualityof life in patients with bone metastases. Clin Exp
Metastasis 36(5): 441-448, 201911. Shinoda Y, Kobayashi H, Kaneko M, Ohashi S,
Bessho M, Hayashi N, Oka H, Imanishi J, Sawada
R, Ogura K, Tanaka S, Haga N, Kawano H:
Prediction of the pathological fracture risk during
stance and fall-loading configurations formetastases in the proximal femur, using acomputed tomography-based finite element method.
J Orthop Sci 24(6): 1074-1080, 201912. Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Kudo N, Azechi H, Okada N,
Koshiyama D, Shiino T, Fukunaga M, Watanabe Y,
Ikeda M, Kasai K, Hashimoto R: Eye‐movement
characteristics of schizophrenia and theirassociation with cortical thickness. Psychiatry Clin.
Neurosci. 73: 508–9, 201913. Morita K, Miura K, Kasai K, Hashimoto R: Eyemovement characteristics in schizophrenia: A
recent update with clinical implications.
Neuropsychopharmacol Rep. Epub ahead of print,
2019
14. Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Kudo N, Azechi H, Okada N,
Koshiyama D, Ikeda M, Kasai K, Hashimoto R:
Eye movement abnormalities and their association
with cognitive impairments in schizophrenia.
Schizophr. Res. 209: 255–62, 2019

481

Central Supply Service
Professor
Kazuhiko Fukatsu, M.D., Ph.D.

Assistant Professor
Satoshi Murakoshi, M.D, Ph.D.

Homepage

http://www.cc.h.u-tokyo.ac.jp/mulins/zairyobu/

Introduction
Central supply service is an integrated place inthe hospital for cleaning and sterilization ofpreviously used devices. All re-usable devices aretransported to our division via automated guided
vehicle system from surgical center, ward andoutpatient clinics. The used instruments are cleaned
using standard precautionary procedures, disinfected,
reassembled, packaged, and sterilized. The sterilized
instruments are then placed at designated sites for use.
One professor and one assistant professor, one
nurse, 8 staff members, and 26 members from external
staff sources are the main members of this division.

Facilities

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.
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.

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

Activities

1. Fukatsu K. Role of nutrition in gastroenterological surgery. Ann Gastroenterol Surg. 25;3(2):160-168, 2019
2. Kobayashi K, Kaneko J, Yamaguchi T,
Kawaguchi Y, Arita J, Akamatsu N, Ishizawa T,
Sekine R, Ijichi H, Kubota N, Fukatsu K, Kokudo

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,

To establish more efficient procedures forcleaning, intensive trials have been performed and thedata have been presented at academic conferences.
Moreover, basic research on host response to surgicalinsult is another theme of our division. The research isimportant for improving outcome of surgical patientsand our data have been published as original articles

References

482

N, Hasegawa K. Late-Evening Carbohydrate andBranched-Chain Amino Acid Snacks Improve the
Nutritional Status of Patients Undergoing
Hepatectomy Based on Bioelectrical Impedance
Analysis of Body Composition. Gastrointest
Tumors. 6(3-4):81-91, 2019
3. Higashizono K, Fukatsu K, Watkins A, Watanabe
T, Noguchi M, Ri M, Murakoshi S, Yasuhara H,
Seto Y. Influences of Short-Term Fasting andCarbohydrate Supplementation on Gut Immunityand Mucosal Morphology in Mice. JPEN J
Parenter Enteral Nutr. 43(4):516-524, 2019
4. Fukatsu K, Shineha R, Kawauchi Y, Saeki M,
Nakayama M. Optimizing Vitamin and Trace
Element Profiles in Blood after Gastrointestinal
Tract Surgery by a New Parenteral Nutrition
Formula. Ann Nutr Metab. 74(3):189-199, 2019

483

Division of Diagnostic Pathology
Director (Professor)
Tetsuo Ushiku, M.D., Ph.D.

Deputy Director (Lecturer)
Masako Ikemura, M.D., Ph.D. (Office for “Promotion of CPC Education and General
Integrative Medicine”)
Aya Shinozaki-Ushiku, M.D., Ph.D.,

Project Professor
Takeshi Sasaki, M.D., Ph.D. (Next-Generation Pathology Information Networking, Chief,
Telepathology & Remote Diagnosis Promotion Center)

Lecturer
Hiroyuki Abe, M.D., Ph.D.

Research Associate
Yukako Shintani-Domoto, M.D., Ph.D. (Hospital Lecturer),
Mariko Tanaka, M.D., Ph.D. (Hospital Lecturer),
Hirofumi Rokutan, M.D., Ph.D.,

Munetoshi Hinata, M.D., Ph.D.,

Sho Yamazawa, M.D., Ph.D.,

Naoko Yamauchi, M.D., Ph.D.,

Naohiro Makise, M.D., Ph.D.,

Yu Miyama, M.D., Ph.D.,

Project Research Associate
Ruri Saito, M.D., Ph.D. ("Tsunagu"- Fukushima-Kanto Pathology- Forensic Pathology
Cooperation Program)Intern Doctor
Akiko Iwasaki, M.D., Ph.D.,

Mana Ideyama, M.D.

Homepage http://pathol.umin.ac.jp/
Introduction and Organization
Department of Pathology and Diagnostic Pathology
and Division of Diagnostic Pathology of the
University of Tokyo Hospital have been organized tofunction as a unit to perform pathology practice(autopsy and surgical pathology) at the University ofTokyo Hospital as well as education and research on
human pathology. On May 1st, 2019, Dr. Tetsuo

Ushiku was appointed to a professorship at the
Department of Pathology and Diagnostic Pathology of
the University of Tokyo and continued to serve as adirector of the Diagnostic Pathology Division of thehospital.
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

484

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.
We registered substantial cases of whole slide
images (WSI) in the research project of JapaneseSociety of Pathology “Database of Pathology-WSI for
Development of Artificial Intelligence (AI) Techniqueand AI-based Support System for Pathology
Diagnosis” which was started in 2016.

Clinical activities(diagnostic pathology and autopsy)
The annual statistics of the pathology practice in 2019fiscal year consisted of 17,370 surgical cases, 16,216
cytology, 1,115 intraoperative histologic diagnosis,
401 intraoperative cytology, 38 autopsy cases (autopsy
rate, 13.7%).
The following surgical pathology conferences are
regularly held; thoracic organs (Drs. ShinozakiUshiku and Hinata in charge), liver and pancreatobiliary tract (Drs. Yamauchi and Tanaka), liver
metastasis (Dr. Abe), and female genital tracts (Drs.
Ikemura and Shintani-Domoto), breast (Dr. Ikemura,and bone and soft tissues (Drs. Ushiku and Makise).
Biopsy conferences are also held in the cases ofkidney (Drs. Shintani-Domoto and Hinata), and skin(Dr. Tanaka) and hematology (Dr. Shinozaki-Ushiku).
We provide FFPE specimens suitable formultiplex genomic testing with Todai OncoPanel.
We also join clinicopathologic and genomic
conference which is held twice a month to present
histology of the cases and join the discussion.
Our mission is to provide the correct diagnosis assoon as possible. We also perform double check byreviewing the reports and slides of all cases to assure
the quality of pathologic diagnosis. Virtual slide

scanners have been installed, which enabled us todeposit the biopsy specimens as digital information.
We hold autopsy case conferences every Monday.
Hospital clinico-pathologic conferences (CPC) arealso held every month, in which two cases are
discussed. The contents are provided as CPC Digest
through the hospital internet.

Teaching activities
The lectures and exercise course of systemic
pathology are for the 2nd grade medical students.
Clinical Clerkship (CC) courses of autopsy andsurgical pathology are for the 4th grade medical
students. We accepted several medical students inElective Clerkship course as well as Free Quarter
program.
We instructed all clinical residents (junior course)
to submit a report of CPC case as an obligatory
requirement of their medical training. We have madeout the digest version of CPC slides open in thehospital and started e-learning program for interns tosolve the problems in CPC by themselves, thereby
facilitating their understanding.
The Division of Diagnostic Pathology accepted
seven junior residents (total 16 months) in 2019 fortheir second-year program.

Research activities
Dr. Sasaki conducts the research to evaluate feasibilityof telepathology for daily practice of diagnostic
pathology. We also conduct research of developing
artificial
intelligence(AI)-system,
suchas“Development of a support tool of pathology
diagnosis such as rare cancers, intraoperative reportand double check using artificial intelligence (Dr.
Sasaki)”, and cooperate the project by “Efficiency
improvement and diagnostic support of pathologic
diagnosis by automatic classification of renal biopsy
pathology images using Deep Learning Technology(Prof. Kazuhiko Ohe)”
The development of automatic grossing andsectioning system using AI-equipped robot is inprogress as collaborative research with engineering
faculty-of the University of Tokyo (Prof. Mamoru
Mitsuishi) and National Institute of Advanced
Industrial Science and Technology (Dr. Kiyoyuki

485

Chinzei, director).
We continue the study to investigate the usefulness of post-mortem CT images for hospital autopsy(Drs. Shintani-Domoto and Abe). We obtain postmortem images with a CT apparatus in the autopsyassisting CT room, and compare the results with thoseof autopsy to better understand the patients’ pathophysiology.
We continue the pathologic research of neoplastic
diseases based on observation obtained from
pathologic diagnosis as well as discussion withclinicians at surgical pathology conferences.

References(See the corresponding section of
Department Pathology and Diagnostic
Pathology)
1. Ando M, Kobayashi H, Shinozaki-Ushiku A,
Chikuda H, Matsubayashi Y, Yoshida M, Saito Y,
Kohsaka S, Oda K, Miyagawa K, Aburatani H,
Mano H, Yamasoba T. Spinal solitary fibroustumor of the neck: Next-generation sequencingbased analysis of genomic aberrations. Auris
Nasus Larynx. 2019-12. [Epub ahead of print]
2. Ebisawa K, Masamoto Y, Koya J, Shimura A,
Shinozaki-Ushiku A, Toyama K, Nakazaki K,
Kurokawa M. Long-term Remission by
Brentuximab Vedotin for Non-mediastinal Gray
Zone Lymphoma Refractory to Autologous Stem
Cell Transplantation. Clin Lymphoma Myeloma
Leuk. 2019-11;19(11):e602-e604.
3. Fujii T, Kawasoe K, Nishizawa Y, Kashima J,
Tonooka A, Ohta A, Nitta K. A suspected case ofdrug-induced tubulointerstitial nephritis bypilocarpine hydrochloride. CEN Case Rep 201911;8(4):246-251.
4. Fujita A, Ushiku T, Miyai T. Huge Corneal
Fibroma. Ophthalmology 2019-11;126(11):1526.
5. Hayashi Y, Masui Y, Miyagawa T, Yamada D,
Miyagaki T, Ikegami M, Kobayashi H, ShinozakiUshiku A, Takekoshi T, Sato S. Osteogenic
melanoma of the right fifth toe. J Dermatol
2019-7;46(7):e265-e266.
6. Kashima J, Motoi T, Nishimaki M, Hayashi Y,
Ogawa M, Kato I, Yamada R, Tonooka A,
Horiguchi SI, Funata N, Hishima T, Yoshino K. A

case report of cutaneous melanocytoma with
CRTC1-TRIM11 fusion: Is CMCT distinct fromclear cell sarcoma of soft tissue? Pathol Int
2019-7;69:496-501.
7. Kobayashi H, Hirai T, Makise N, Ushiku T, Ito N,
Koga M, Ikegami M, Shinoda Y, Akiyama T,
Tanaka S. Reconstruction Using Frozen Autograftfor Disseminated Phosphaturic Mesenchymal
Tumor of the Humerus after a Pathological
Fracture. Case Rep Orthop 2019-9; Arctice ID
3015675.
8. Makise N, Sekimizu M, Kobayashi E, Yoshida H,
Fukayama M, Kato T, Kawai A, Ichikawa H,
Yoshida A. Low-grade endometrial stromal
sarcoma with a novel MEAF6-SUZ12 fusion.
Virchows Arch. 2019-10;475(4):527-531.
9. Nishikawa K, Okuma Y, Hashimoto K, Kashima J.
Development of Hepatocellular Carcinoma
During Nivolumab Treatment for Recurrent
Non-Small Cell Lung Cancer: A Case Report.
Tohoku J Exp Med 2019-4;247(4):247-250.
10. Noda A, Abe M, Shinozaki-Ushiku A, Ohata Y,
Zong L, Abe T, Hoshi K. A Bilocular Radicular
Cyst in the Mandible with Tooth Structure
Components Inside. Case Rep Dent. 2019-9;
Arctice ID 6245808.
11. Sasahara A, Tanabe M, Hayashi K, Konishi T,
Oya M, Sakiyama K, Morizono A, Harada M,
Otsuji K, Ishibashi Y, Sato A, Kikuchi Y, Niwa T,
Hinata M, Nishioka K, Seto Y. A case of primarybreast angiosarcoma with multiple discontinuous
small lesions. Surg Case Rep. 2019-10;5(1):157.
12. Sato M, Taguchi A, Fukui Y, Kawata A, Taguchi
S, Kashiyama T, Eguchi S, Inoue T, Tomio K,
Tanikawa M, Sone K, Mori M, Nagasaka K,
Adachi K, Ikemura M, Domoto Y, Arimoto T,
Oda K, Fukayama M, Osuga Y, Fujii T.
Enormous Aneurysm in Coronary Artery FistulaWith Immunoglobulin G4-Related Disease. Can J
Cardiol. 2019-2;35(2):230.e1-230.e3.
13. Sawai Y, Katsuya Y, Shinozaki-Ushiku A,
Iwasaki A, Fukayama M, Watanabe K, Nagase T.
Rapid temporal improvement of pembrolizumabinduced pneumonitis using the anti-TNF-α
antibody infliximab. Drug Discov Ther 2019-7;
13(3):164-167.
14. Takeuchi M, Sato J, Manaka K, Tanaka M,

486

Matsui H, Sato Y, Kume H, Fukayama M, Iiri T,
Nangaku M, Makita N. Molecular Analysis andLiterature-Based Hypothesis of an Immunonegative Prostate Small Cell Carcinoma Causing
Ectopic ACTH Syndrome. Endocr J 2019-6;66:
547-554.
15. Yonenaga A, Hasumi E, Fujiu K, Ushiku A,
Hatano M, Ando J, Morita H, Watanabe M,
Komuro I. Prognostic Improvement of Acute
Necrotizing Eosinophilic Myocarditis (ANEM)
Through a Rapid Pathological Diagnosis andAppropriate Therapy. Int Heart J 2019-5;59(3):641-646.
16. Yoshihara R, Komai T, Nagafuchi Y, Tsuchida Y,
Shoda H, Tanaka M, Ushiku T, Fujio K.
Eosinophilic cholangitis with eosinophilic
granulomatosis with polyangiitis: A case reportand review of the literature. Allergol Int 2020-1;
69(1):154-156.

487

Department of Corneal
Transplantation
Professor
Makoto Aihara, M.D., Ph.D.

Lecturer
Takashi Miyai, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kakumaku.html

Introduction and Organization
The department of corneal transplantation wasestablished in 1976 as one of clinical sections in the
University of Tokyo Hospital. The purpose of theestablishment of this section is to carry out andpromote corneal transplantation and to perform
clinical and basic research in the corneal diseases andcorneal transplantation. The section is composed oftwo members (Professor Makoto Aihara, Lecturer
Takashi Miyai).

Clinical activities
The clinical activities of this section include corneal
transplantation and outpatient clinics for various
corneal diseases as a consulting corneal service. The
members are responsible not only for corneal transplantation but also for general ophthalmologicalpractice as a senior staff member of Department ofOphthalmology, University of Tokyo. The corneal
service for special cases is held every Monday (PM),Wednesday (AM), Thursday (AM), and Friday (AM).
Contact lens clinic for keratoconus and postkeratoplasty eyes and keratoconus clinic for providing
corneal crosslinking surgery, which is a brand-new
treatment to halt keratoconus progression, were heldin the afternoon of Thursday. At the corneal service,
we determine indication for corneal transplantationand follow up patients after the surgery. Total 54
corneal surgeries including keratoplasty were

performed in 2019. In addition to the full-thickness
corneal transplantation (penetrating keratoplasty), we
have successfully performed corneal endothelial transplantation for patients with bullous keratopathy, themost common disease of corneal transplantation.
Generally, corneal transplantation is performed as
emergency operation, because we need to transplant
corneas as soon as possible.
The other important activities of the section include
mediation of donor eyes to other university hospitals
and medical institutes that need donor eyes for corneal
transplantation with cooperation of Eyebank. We arealso performing corneal transplantation using corneas
from American Eyebank as needed.
Followings are our main clinical themes to be
pursued to improve the safety and prognosis ofcorneal transplantation.
1) Positive proof that donors were free of such
infectious diseases as viral hepatitis, syphilis,
AIDS and acute T-cell leukemia to prevent
transmission to recipient patients through grafting.
2) Postoperative clinical outcomes are evaluated inregenerative medicine for ocular surface
reconstruction, such as cultured corneal limbal,
oral mucosal and conjunctival epithelial sheettransplantation on the amniotic membrane, fullthickness corneal transplantation, lamellar keratopasty, and endothelial keratoplasty.
3) Critical factors to affect clinical outcomes are
statistically investigated in various kinds of488

corneal operation technique.

Teaching activities
We give lectures on corneal diseases and corneal
transplantation to medical students and practitioners.
In addition, we are engaged in practical training foryoung ophthalmologists on ophthalmological examinations at the outpatient clinic.

Research activities
We are conducting clinical research of postoperative results of DSAEK, clinical results of corneal
crosslinking, and clinical research of corneal biometryby using anterior segment OCT.
In addition, we are investigating the delivery of
nucleic acid based drug in corneal neovascularizationor corneal dystrophy, genetic analysis and genome
editing for corneal dystrophy.

References
1: Fujita A, Yoshida J, Toyono T, Usui T, MiyaiT.
Severity Assessment of Acute Hydrops Due to
Recurrent
Keratoconus
after
Penetrating
Keratoplasty Using Anterior Segment Optical
Coherence Tomography. Curr Eye Res. 2019
Nov;44(11):1189-1194
2: Fujita A, Ushiku T, Miyai T. Huge Corneal
Fibroma. Ophthalmology. 2019 Nov; 126(11):1526.
3: Inamochi A, Tomioka A, Kitamoto K, MiiyaiT,
Usui T, Aihara M, Yamagami S. Simple oral
mucosal epithelial transplantation in a rabbit
model. Sci Rep. 2019 Dec 2; 9(1):18088. doi:
10.1038 /s41598 -019 -54571 -7.
4: Kitamoto K, Taketani Y, Fujii W, Inamochi A,
Toyono T, Miyai T, Yamagami S, Kuroda M,
Usui T, Ouchi Y. Sci Rep. 2020 Feb 6;10(1):2000.
doi: 10.1038 /s41598 -020 -58876 -w.

489

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Mitsuteru Hiwatari, M.D., Ph.D. (Pediatrics/Hematology-Oncology)
Yuki Kagoya, M.D., Ph.D. (Hematology-Oncology)

Assistant Professor
Hideaki Mizuno, M.D., Ph.D. (Hematology-Oncology)

Homepage

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

Introduction and Organization
The Department of Cell Therapy and Transplantation Medicine was institutionally established in
1995, and was formally organized in 1996. At present,
the staff consists of the above-mentioned medical
doctors. Clinical facilities include 8 single-patient
rooms with high- efficiency particulate air filtrationand other high standards. Patients who are eligible forthe treatment with high-grade infectious prophylaxis
are admitted to the facilities.

Clinical activities
Approximately 100 patients have undergone
hematopoietic stem cell transplantation (HSCT) in our
department since 1995. Allogeneic bone marrowtransplantation from donors Japan Marrow Donor
Program (JMDP) as well as international bone marrowdonor programs, HSCT from HLA-mismatcheddonors, and donor lymphocyte infusion are available.
In 2017, 17 patients (including 2 children) received
autologous HSCT and 26 patients (including 8
children) allogeneic HSCT. We cooperate with themembers of Department of Hematology and Oncology,
Hematology/Oncology group in the Department ofPediatrics, and Department of Transfusion Medicine.

Allogeneic hematopoietic stem cell transplantation:
Bone marrow cells are operatively harvested andinfused without preservation. For peripheral blood
stem cell transplantation, leukapheresis is performed
with the use of an automated continuous flow blood
cell separator, and harvested cells are preserved at-196°C in cooperation with Department of Transfusion Medicine. Recently, transplantation after preconditioning of reduced intensity (RIST for reducedintensity HSCT or NST for non-myeloablative HSCT)
is commonly performed for the elderly and patientswith organ dysfunction. The development of thisstrategy is expanding the eligibility of transplant
recipients.
Some patients cannot get transplantation treatment
because they don’t have eligible donors with at least a
90% match of HLA. Recently, with the developmentof new methods of transplantation management, suchas immunosuppression, it has become possible tosafely carry out transplants from donors with a 50%
HLA match(HLA haploidentical transplantation; haplotransplants), and the procedure is expected to spread
more widely in the future. The department proactively
performs haplo transplants for patients in need toovercome diseases.
Allogeneic HSCT for the elderly and HLA
haploidentical transplantation are performed under the490

admission of Patient Relations and Clinical Ethics
Center.
High-dose chemotherapy with or without autologous stem cell support: High-dose chemotherapy isadministered according to the malignant disease. For
the autologous stem cell support, peripheral blood
stem cell is usually selected as a source of stem cells.
Similar procedures used in the allogeneic stem cell
harvest are performed for leukapheresis and preservation of autologous stem cell.
Clinical conference for hematopoietic stem celltransplantation: The conference is held monthly. The
members of Department of Hematology and Oncology,
Hematology/Oncology group in Department ofPediatrics, and Department of Transfusion Medicine
join the conference and discuss on HSCT recipients.

Teaching activities
Together with the members of Department of
Hematology and Oncology and Hematology/Oncology
group in the Department of Pediatrics, lecture courses
on etiology, pathogenesis, clinical and laboratory
features, differential diagnosis, therapy and prognosis
for all hematological diseases are provided to thesecond grade medical students. Clinical clerkshipcourses are given to the third grade medical students,
who join the patient care teams consisting of juniorand senior medical doctors and learn medical practices
and patient management, through playing a role as a
junior member of the team, as well as throughdiscussions and presentations.

Research activities
The major research projects are focused on clinicalstudies such as development of improved/new
methods for hematopoietic stem cell transplantation,
immunotherapy for hematopoietic malignancies, andbasic studies on hematopoietic stem cells, leukemogenesis and regenerative medicine using hematopoietic cells. In the area of pediatric oncology, we
continue the studies on molecular mechanisms ofpediatric malignancies such as neuroblastoma,
rhabdomyosarcoma, and infant leukemia.

References
1. Takenaka S, Kuroda Y, Ohta S, Mizuno Y,
Hiwatari M, Miyatake S, Matsumoto N, Oka A. A
Japanese patient with RAD51-associated Fanconi
anemia. Am J Med Genet A 179(6): 900-902,
2019.
2. Mitani Y, Hiwatari M, Seki M, Hangai M, Takita
J. Successful treatment of acute myeloid leukemia
co-expressing NUP98/NSD1 and FLT3/ITD withpreemptive donor lymphocyte infusions. Int J
Hematol 110(4): 512-516, 2019.
3. Bruun MT, Yazer MH, Spinella PC, Titlestad K,
Lozano M, Delaney M, Lejdarová H, Pavlova DE,
Trakhtman P, Starostin N, Zhiburt E, van Kraaij
MGJ, Huisman E, Kutner JM, Sakashita AM,
Yokoyama APH, Zubicaray J, Sevilla J, Okazaki
H, Hiwatari M, Nagura Y, Manzini PM, Facco G,
Avdis C, Singh L, Hans R, Sharma RR, Kumar P,
Wikman A, Deschmann E, Kaur H, Mei JLC,
Ying SHK, Pei Lin K, New HV, Moss R,
Kinmonth A, Comande M, Savoia H, Crighton G,
Yacobovich J, Yahalom V, Lau W.
Vox
Sanguinis International Forum on paediatricindications for blood component transfusion:
Summary. Vox Sang 114(5): 523-530, 2019.
4. Miyamura T, Kudo K, Tabuchi K, Ishida H,
Tomizawa D, Adachi S, Goto H, Yoshida N,
Inoue M, Koh K, Sasahara Y, Fujita N, Kakuda H,
Noguchi M, Hiwatari M, Hashii Y, Kato K,
Atsuta Y, Okamoto Y. Hematopoietic stem celltransplantation for pediatric acute myeloid
leukemia patients with KMT2A rearrangement; A
nationwide retrospective analysis in Japan. LeukRes. 87: 106263, 2019.
5. Mori T, Onishi Y, Ozawa Y, Kato C, Kai T,
Kanda Y, Kurokawa M, Tanaka M, Ashida T,
Sawayama Y, Fukuda T, Ichinohe T, Atsuta Y,
and Yamazaki H.
Outcome of allogeneic
hematopoietic stem cell transplantation in adultpatients with hepatitis‑associated aplastic anemia.
International Journal of Hematology 109(6): 711717, 2019.
6. Kubota Y, Arakawa Y, Sekiguchi M, Watanabe K,
Hiwatari M, Kishimoto H, Nakazawa A, Yoshida
A, Ogawa S, Hanada R, Oka A, Takita J, Koh K.
A case of malignant rhabdoid tumor mimicking

491

yolk sac tumor. Pediatr Blood Cancer 66(8):e27784, 2019.
7. 三谷友一、関 正史、鬼澤真実、日高もえ、
藤村純也、樋渡光輝、滝田順子. IST 不応の
小児最重症再生不良性貧血に対する臍帯血移植 例 . The Japanese Journal of PediatricHematology/Oncology 56(3): 338-342, 2019.
8. Amano K, Takasugi N, Mitani Y, Kubota Y,
Skiguchi M, Watanabe K, Fujimura J, Oka A,
Takaita J, Hiwatari M.
CBFA2T3-GLIS2positive acute megakaryoblastic leukemia in apatient with Down syndrome. Pediatr Blood
Cancer 67(2): e28055, 2020.
9. Yokoyama Y, MaieK, Fukuda T, Uchida N,
Mukae J, Sawa M, Kubo K, Kurokawa M,
Nakamae H, Ichinohe T, Yoshiko Atsuta Y, andChiba S. A high CD34+cell dose is associatedwith better disease-freesurvival in patients with
low-risk diseases undergoing peripheralblood
stem cell transplantation from HLA-matched
related donors. Bone Marrow Transplantation
55(9): 1726-1735, 2020. Epub Feb 10, 2020.
10. Matsukawa T, Yamamoto T, Honda A, Toya T,
Ishiura H, Mitsui J, Tanaka M, Hao A, Shinohara
A, Ogura M, Kataoka K, Seo S, Kumano K, Hosoi
M, Narukawa K, Yasunaga M, Maki H, Ichikawa
M, Nannya Y, Imai Y, Takahashi T, Takahashi
Y, Nagasako Y, Yasaka K, Koshi Mano K,
Kawabe Matsukawa M, Miyagawa T, Hamada M,
Sakuishi K, Hayashi T, Iwata A, Terao Y,
Shimizu J, Goto J, Mori H, Kunimatsu A, Aoki S,
Hayashi S, Nakamura F, Arai S, Momma K,
Ogata K, Yoshida T, Abe O, Inazawa J, Toda T,
Kurokawa M, Tsuji S. Clinical efficacy of
haematopoietic stem cell transplantation for adultadrenoleukodystrophy. Brain Communications
2(1): fcz048, 2020.

492

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Yousuke Nakai, M.D., Ph.D.

Associate
Shuntaro Yoshida, M.D., Ph.D.

Homepagehttps://www.h.u-tokyo.ac.jp/patient/depts/kougaku/

Introduction and Organization
Department of Endoscopy and Endoscopic Surgery
were established in April 1997. Although the present
regular staffs of our department include only two
doctors, about 80 doctors from other departments
including the department of gastroenterology,
gastrointestinal surgery, surgical oncology, respiratory
medicine, thoracic surgery, gynecologic oncology andotorhinolaryngology, perform endoscopic procedures.

Clinical activities
Endoscopic procedures, including upper gastrointestinal endoscopy, colonoscopy, bronchoscopy,
otorhinolaryngological endoscopy and gynecologicalendoscopy, are performed from Monday to Friday.
Emergency endoscopy is performed in the nighttime
or holidays. The numbers of endoscopic procedures ineach field are increasing gradually year by year andthe total number during 2016 reached to 20,000. In thegastrointestinal tract, image enhanced endoscopy fordetailed inspection and therapeutic endoscopy,
including endoscopic submucosal dissection foresophageal, gastric and colorectal tumors, are majoradvanced fields. In addition, endoscopic diagnosis andmanagement of pancreatobiliary diseases is also
performed. Our recent clinical activities are
summarized in Table 1.
Another important activity of our department is thedisinfection and maintenance of endoscopic
apparatuses used in other units including theoutpatient clinic, radiotherapy department, surgery
department or intensive care units. All endoscopes in
our hospital are collected in our department after use
and disinfected.

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.

493

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
2009

2010

2011

2012

2013

2014

2015

2016

2017

EGD*

10682

10556

10963

11376

11840

11740

11874

11944

11490

Colonoscopy

4996

5152

5208

5688

6000

6043

6394

6814

5921

Bronchoscopy

226

255

197

196

169

218

228

362

350

316

ERCP

959

943

1072

956

912

1035

946

1206

1137

1057

518

551

630

698

763

766

882

1084

1023

923

Enteroscopy

181

181

282

282

375

396

310

86

304

138

Laryngoscopy

75

70

108

83

128

102

105

125

114

92

Colposcopy

307

361

378

365

404

327

295

417

430

414

Total

17944

18069

18838

19644

20591

20627

21034

22038

20769

20169

EUS

**

†

2018
11699
(2177‡)

5530(109‡)*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. Nakai Y, Kogure H, Isayama H, Koike K.
Endoscopic ultrasound-guided pancreatic ductdrainage. Saudi J Gastroenterol. 2019;25(4):210217.
2. Nakai Y, Kogure H, Isayama H, Koike K.
Endoscopic Ultrasound-Guided Biliary Drainage
for Benign Biliary Diseases. Clin Endosc. 2019;52(3):212-219.
3. Nakai Y, Kogure H, Isayama H, Koike K.
Endoscopic Ultrasound-Guided Biliary Drainage
for Unresectable Hilar Malignant Biliary
Obstruction. Clin Endosc. 2019;52(3):220-225.
4. Nakai Y, Isayama H, Kawakami H, Ishiwatari H,
Kitano M, Ito Y, Yasuda I, Kato H, Matsubara S,
Irisawa A, Itoi T. Prospective multicenter study ofprimary EUS-guided choledochoduodenostomy
using a covered metal stent. Endosc Ultrasound.
2019;8(2):111-117.

5. Hakuta R, Hamada T, Nakai Y, Isayama H,
Kogure H, Takahara N, Mizuno S, Yagioka H,
Togawa O, Matsubara S, Ito Y, Yamamoto N,
Tada M, Koike K. Early pancreatic stentplacement in wire-guided biliary cannulation: amulticenter retrospective study. J Gastroenterol
Hepatol. 2019; 34(6):1116-1122.
6. Saito T, Nakai Y, Mizuno S, Isayama H, SasahiraN, Watanabe T, Matsubara S, Arizumi T, Togawa
O, Hirano K, Tsujino T, Ishigaki K, Hakuta R,
Saito K, Takahara N, Hamada T, Kogure H, Tada
M, Koike K. A randomized-controlled trial ofearly endotherapy versus wait-and-see policy for
mild symptomatic pancreatic stones in chronicpancreatitis. Eur J Gastroenterol Hepatol 2019;31(8):979-984.
7. Lee TY, Nakai Y. Is the July effect real in patients
undergoing endoscopic retrograde cholangiopancreatography? Clin Endosc. 2019; 52(5):399-400.
8. Nakai Y, Takahara N, Mizuno S, Kogure H,
Koike K. Current Status of Endoscopic
Ultrasound Techniques for Pancreatic Neoplasms.
Clin Endosc. 2019;52(6): 527-532.
9. Isayama H, Nakai Y, Itoi T, Yasuda I, Kawakami
H, Ryozawa S, Kitano M, Irisawa A, Katanuma A,
Hara K, Iwashita T, Fujita N, Yamao K, Yoshida
M, Inui K. Clinical practice guidelines for safe
performanceofendoscopic
ultrasound/494

ultrasonography- guided biliary drainage: 2018. J
Hepatobiliary Pancreat Sci. 2019;26(7): 249-269.
10. Seo DW, Sherman S, Dua KS, Slivka A, Roy A,
Costamagna G, Deviere J, Peetermans J,
Rousseau M, Nakai Y, Isayama H, Kozarek R;
Biliary SEMS During Neoadjuvant Therapy Study
Group. Covered and uncovered biliary metal
stents provide similar relief of biliary obstruction
during neoadjuvant therapy in pancreatic cancer: arandomized trial. Gastrointest Endosc. 2019;
90(4):602-612.
11. Ishibashi R, Yoshida S, Odawara N, Kishikawa T,
Kondo R, Nakada A, Hakuta R, Takahara N,
Tanaka E, Sekiba K, Seimiya T, Ohnaga T, Otsuka
M, Koike K. Detection of circulating colorectal
cancer cells by a custom microfluid system before
and after endoscopic metallic stent placement.
Oncol Lett. 2019; 18(6): 6397-6404.
12. Nakai Y. Treatment of long-limb biliary- entericanastomotic strictures: ERCP, PTBD, or EUS?
Dig Dis Sci. 2019:64(9): 2379-2380.
13. Kawaji Y, Isayama H, Nakai Y, Saito K, Sato T,
Hakuta R, Saito T, Takahara N, Mizuno S, Kogure
H, Matsubara S, Tada M, Kitano M, Koike K.
Multiple recurrences after endoscopic removal ofcommon bile duct stones: A retrospective analysisof 976 cases. J Gastroenterol Hepatol. 2019;34(8):1460- 1466.
14. Hamada T, Isayama H, Nakai Y, Iwashita T, Ito Y,
Mukai T, Yagioka H, Saito T, Togawa O, Ryozawa
S, Hirano K, Mizuno S, Yamamoto N, Kogure H,
Yasuda I, Koike K. Antireflux covered metal stentfor nonresectable distal malignant biliary
obstructtion: a multicenter randomized controlled
trial. Dig Endosc. 2019;31(5): 566-574.
15. Sato T, Kogure H, Nakai Y, Hamada T, Takahara
N, Mizuno S, Kawaguchi Y, Akamatsu N, Kaneko
J, Hasegawa K, Tada M, Tsujino T, Isayama H,
Koike K. Long-term outcomes of endoscopic
treatment for duct-to-duct anastomotic strictures
after living donor liver transplantation. Liver Int.
2019;39(10): 1954-1963.
16. Ogura T, Nakai Y, Iwashita T, Higuchi K, Itoi T.
Novel fine gauge electrocautery dilator for
EUS-guided biliary drainage: experimental andclinical evaluation study (with video). Endosc Int
Open 2019;7(12): E1652-E1657.

17. Hakuta R, Hamada T, Nakai Y, Oyama H, Kanai S,
Suzuki T, Sato T, Ishigaki K, Saito K, Saito T,
Takahara N, Mizuno S, Kogure H, Watadani T,
Tsujino T, Tada M, Abe O, Isayama H, Koike K.
Natural history of asymptomatic bile duct stones
and association of endoscopic treatment withclinical outcomes. J Gastroenterol. 2020; 55(1):78-85.

495

Department of Hemodialysis andApheresis
Professor
Masaomi Nangaku, M.D.,Ph.D.

Lecturer
Daisuke Yamada, M.D., Ph.D.
Yoshifumi Hamasaki, M.D., Ph.D.

Introduction and Organization
Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for
Hemodialysis in 2000 at the University Hospital. The
Center for Hemodialysis was further renovated andstarted operations in Fall of 2006. This new Center for
Hemodialysis is equipped with one pressure control
unit in addition to 12 hemodialysis machines under astate-of-the-art hemodialysis control system. Ourconcept of a hemodialysis controlling system is a hub
to transfer all digital and analog data from patients andto monitor machines, including blood purification
machines, to the host computer in our hospital,
centralizing all data and administering medical coding
and billing robustly. Blood purification machines in
the ICU are also connectable to this system, which
was developed collaboratively with Nihon Kohden
Corp. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.

Clinical activities
1.
2.

Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
Regular hemodialysis therapy for hospitalized

3.
4.

5.
6.
7.
8.

ESRD patients. Please note that our center does
not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasmapheresis for neurodegenerative diseases,
myasthenia gravis, dermatological disorders,waldenstrom
macroglobulinemia,
collagendiseases, TMA(TTP), and pre/post solid organtransplant patients.
LDL apheresis for familial hypercholesterolemia,
nephrotic syndrome, and PAD patients.
White blood cell elimination therapy for inflamematory bowel diseases such as ulcerative colitis.
Cell-free and concentrated ascites reinfusion
therapy (CART) for refractory ascites.
Induction and maintenance of peritoneal dialysis
for ESRD.

Teaching activities
1.

2.
3.
4.
5.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acutekidney injury and acute renal failure.
Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course to
second year residents on request.
Our state-of-the-art blood purification protocols

496

6.

are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. English and Chinese version of“Apheresis Pocket Manual” is available for
global experts of Apheresis therapy.
Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.

Research activities
1.
2.

3.

4.

5.
6.
7.
8.

Prognostic analysis for post-liver transplantpatients received plasma exchange therapy.
Identification of prognostic factors in AKI/CRRT
patients. AKI biomarkers and those clinicalsignificance in ICU/CCU.
Associations between factors at the initiation ofrenal replacement therapy and prognosis in
ESRD patients.
Identification of prognostic factors at initiation of
peritoneal dialysis (PD), and at the onset of
infectious complications in PD patients.
Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
Renal biomarker to determine clinicalactionability in CKD and type-2 DN.
The potentiality of urine biomarker tests fordeveloping country [JICA-JST: Science andTechnology Research Partnership for Sustainable
Development].

References
1. Miyamoto Y, Iwagami M, Aso S, Yasunaga H,
Matsui H, Fushimi K, Hamasaki Y, Nangaku M,
Doi K. Association between intravenous contrast
media exposure and non-recovery from dialysisrequiring septic acute kidney injury: a nationwide
observational study. Intensive Care Med. 45, 15701579 (2019).
2. Hayase N, Doi K, Hiruma T, Matsuura R,
Hamasaki Y, Noiri E, Nangaku M, Morimura N.
Recombinant Thrombomodulin on Neutrophil
Extracellular Traps in Murine Intestinal IschemiaReperfusion. Anesthesiology. 131, 866-882 (2019).

3. Miyamoto Y, Iwagami M, Aso S, Yasunaga H,
Matsui H, Fushimi K, Hamasaki Y, Nangaku M,
Doi K. Temporal change in characteristics andoutcomes of acute kidney injury on renal
replacement therapy in intensive care units:
analysis of a nationwide administrative database inJapan, 2007-2016. Crit Care. 23, 172 (2019).
4. Matsuura R, Doi K, Komaru Y, Miyamoto Y,
Yoshida T, Isegawa T, Yoshimoto K, Yamashita T,
Noiri E, Nangaku M. Endogenous Erythropoietin
and Hepatic Dysfunction in Acute Kidney Injury
Requiring Renal Replacement Therapy. Nephron.
142, 10-16(2019).
5. Yoshida T, Matsuura R, Komaru Y, Miyamoto Y,
Yoshimoto K, Hamasaki Y, Noiri E, Morimura N,
Nangaku M, Doi K. Kinetic estimated glomerular
filtration rate as a predictor of successful
continuous renal replacement therapy discontinuation. Nephrology (Carlton). 24, 287-293 (2019).
6. Miyamoto Y, Hamasaki Y, Matsumoto A, Doi K,
Noiri E, Nangaku M. Prediction of immuneglobulin M reduction via therapeutic dose of
simple plasma exchange and double filtration
plasmapheresis using membrane separation inpatients with hyperviscosity syndrome caused by
Waldenstrom macroglobulinemia. J Clin Apher. 33,
611-615 (2018).
7. Nakamura Y, Kurata Y, Hamasaki Y, Nangaku M.
Extraperitoneal Placement of a Peritoneal Dialysis
Catheter. Intern Med. 58, 147-148 (2019).
8. Isshiki R, Asada T, Sumida M, Hamasaki Y,
Nangaku M, Noiri E, Doi K. Modest Impact ofSerial Measurements of Acute Kidney Injury
Biomarkers in an Adult Intensive Care Unit.
Nephron. 139, 243-253 (2018).
9. Matsuura R, Srisawat N, Claure-Del Granado R,
Doi K, Yoshida T, Nangaku M, Noiri E. Use of the
Renal Angina Index in Determining Acute Kidney
Injury. Kidney Int Rep. 3, 677-683 (2018)
10. Matsuura R, Komaru Y, Miyamoto Y, Yoshida T,
Yoshimoto K, Isshiki R, Mayumi K, Yamashita T,
Hamasaki Y, Nangaku M, Noiri E, Morimura N,
Doi K. Response to different furosemide doses
predicts AKI progression in ICU patients withelevated plasma NGAL levels. Ann Intensive Care.
8, 8 (2018)
11. Komaru Y, Inokuchi R, Ueda Y, Nangaku M, Doi

497

K. Use of the anion gap and intermittent hemodialysis following continuous hemodiafiltration in
extremely high dose acute-on-chronic lithium
poisoning: A case report. Hemodial Int. 22, E15E18 (2018)
12. Iwagami M, Yasunaga H, Matsui H, Horiguchi H,
Fushimi K, Noiri E, Nangaku M, Doi K. Impact ofend-stage renal disease on hospital outcomesamong patients admitted to intensive care units: A
retrospective
matched-paircohortstudy.
Nephrology (Carlton). 22, 617-623 (2017)
13. Iwagami M, Yasunaga H, Noiri E, Horiguchi H,
Fushimi K, Matsubara T, Yahagi N, Nangaku M,
Doi K. Potential Survival Benefit of Polymyxin B
Hemoperfusion in Septic Shock Patients on
Continuous Renal Replacement Therapy: A
Propensity-Matched Analysis. Blood Purif. 42,
9-17 (2016)
14. Isshiki R, Asada T, Sato D, Sumida M, Hamasaki Y,
Inokuchi R, Matsubara T, Ishii T, Yahagi N,
Nangaku M, Noiri E, Doi K. Association of
Urinary
Neutrophil
Gelatinase-AssociatedLipocalin With Long-Term Renal Outcomes in
ICU Survivors: A Retrospective Observational
Cohort Study. Shock. 46, 44-51 (2016)15. Mayumi K, Yamashita T, Hamasaki Y, Noiri E,
Nangaku M, Yahagi N, Doi K. IMPACT OF
CONTINUOUS
RENALREPLACEMENTTHERAPY INTENSITY ON SEPTIC ACUTEKIDNEY INJURY. Shock. 45, 133-138 (2016)16. Hasegawa S, Kato H, Hamasaki Y, Koiwa T,
Nangaku M. Positron emission tomography in the
diagnosis of cyst infections. Kidney Int. 91, 759(2017)
17. Katagiri D, Hamasaki Y, Doi K, Negishi K, Sugaya
T, Nangaku M, Noiri E. Interstitial renal fibrosis
due to multiple cisplatin treatments is ameliorated
by semicarbazide-sensitive amine oxidase inhibition. Kidney Int. 89, 374-385 (2016)18. Yamashita T, Noiri E, Hamasaki Y, Matsubara T,
Ishii T, Yahagi N, Nangaku M, Doi K.
Erythropoietin concentration in acute kidney injury
is associated with insulin-like growth factorbinding protein-1. Nephrology (Carlton). 21, 693699 (2016)
19. Iwagami M, Yasunaga H, Noiri E, Horiguchi H,
Fushimi K, Matsubara T, Yahagi N, Nangaku M,

Doi K. Current state of continuous renal replacement therapy for acute kidney injury in Japaneseintensive care units in 2011: analysis of a national
administrative database. Nephrol Dial Transplant.
30, 988-995 (2015)
20. Okamoto K, Honda K, Doi K, Ishizu T, Katagiri D,
Wada T, Tomita K, Ohtake T, Kaneko T, Kobayashi
S, Nangaku M, Tokunaga K, Noiri E. Glypican-5
Increases Susceptibility to Nephrotic Damage in
Diabetic Kidney. Am J Pathol. 185, 1889-1898(2015)
21. Sumida M, Doi K, Ogasawara E, Yamashita T,
Hamasaki Y, Kariya T, Takimoto E, Yahagi N,
Nangaku M, Noiri E. Regulation of Mitochondrial
Dynamics by Dynamin-Related Protein-1 in Acute
Cardiorenal Syndrome. J Am Soc Nephrol. 26,
2378-2387 (2015)22. Shimizu K, Doi K, Imamura T, Noiri E, Yahagi N,
Nangaku M, Kinugawa K. Ratio of urine and bloodurea nitrogen concentration predicts the responseof tolvaptan in congestive heart failure.
Nephrology(Carlton). 20, 405-412 (2015)
23. Iwagami M, Yasunaga H, Noiri E, Horiguchi H,
Fushimi K, Matsubara T, Yahagi N, Nangaku M,
Doi K. Choice of renal replacement therapy
modality in intensive care units: data from aJapanese Nationwide Administrative Claim Database. J Crit Care. 30, 381-385 (2015)24. Hanafusa N, Torato T, Katagiri D, Usui T,
Matsumoto A, Noiri E, Nangauku M. Deep veinpuncture under ultrasonographic guidance-an alternative approach for vascular access of apheresis
therapies. J Clin Apher. 30, 380-381 (2015)
25. Ito T, Hanafusa N, Iwase S, Noiri E, Nangaku M,
Nakagawa K, Miyagawa K. Effects of cell-free andconcentrated ascites reinfusion therapy (CART) on
symptom relief of malignancy-related ascites. Int J
Clin Oncol. 20, 623-628 (2015)

498

Medical Community Network andDischarge Planning Center
Associate Professor
Masahiko Sumitani, M.D., Ph.D. (concurrently)

Assistant Profeesor
Jun Hozumi, M.D, Ph.D.

Homepage https://www.h.u-tokyo.ac.jp/english/centers-services/central-clinicalfacilities/medical-community-network-and-discharge-planning/index.html
Introduction and Organization
In April 1997, plans for the Department of Medical
Social Service and Welfare were initiated by the
University of Tokyo Hospital with the aim ofsupporting inpatients upon discharge. The Department
was officially authorized in April 2000, the firstamong national universities. In April 2005, theDepartment began providing assistance to outpatientsreferred from other hospitals and was renamed theDepartment of Medical Community Network andDischarge Planning. Further, in 2019, the departmentchanged the name to Medical Community Network
and Discharge Planning Center. The Center provides
assistance to outpatients referred from local medical
institutions, to inpatients being discharged to theirhomes, and to inpatients being transferred to local
medical institutions.

Clinical activities
Assistance to patients receiving 9 medica I treatment:
The Department provides assistance to outpatientsreferred from local medical institutions. Our staff
helps patients make appointments and follow procedures to receive medical treatment. The Department
assists new outpatients in arranging general consultations, helps outpatients schedule spedalized treatment,
and provides assistance to patients who have beenreferred to a specific physician.
Assistance to inpatients upon discharge: The

Department provides assistance to patients for whomtransfer to a local medical institution or discharge tohome if need arises.
Many of such patients are highly dependent on
medical care due to the severity of their condition. For
those receiving medical care at home, our department
staff arranges home visits by primary care doctors andnurses. For patients being transferred to local
institutions, our staff provides assistance both togeneral hospitals and hospice care units.
Home Care Support (Home Care Support clinic): Our
Home Care Support Clinic, which offers home care
support to our outpatients, has been running since
Janualy 2003. The clinic supports the implementationand coordination of home care services, and refers
outpatients requesting hospital admission to otherhospitals or facilities.
Consultation by Social Worker (Consultation on
Recuperation): Our consultation service provided bysocial workers has been running since 2012. Oursocial workers mainly consult enquiries regarding
patient recuperation.
Transferring out patients to local institutes: Aiming todefining the distinction of the medical role between
the University Hospital and local institutes andfacilitate transferring our outpatients to them, theproportion of such transferring patients to first-visit
patients keeps more than 80%.

499

Teaching activities
We educate undergraduate students of the Medical
Social Working and Welfare of other university.

Research activities
Our research field covers investigating appropriate
patient numbers for assistance to inpatients upondischarge in the University hospital; and investigating
how to assist working and job in patients with severe
illness.

500

University Hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Tsuyoshi Okuhara, Ph.D., M.P.H.

Instructor
Hiroko Okada, R.N., Ph.D., M.P.H.
Eiko Goto, R.D., M.P.H.

Homepage

http://www.umin.ac.jp/

Introduction and Organization
The University hospital Medical Information Network(UMIN) (the original name was the University Medical
Information Network), was established in 1989.
While
general-use
computersystems
wereimplemented at all national university hospitals aroundthe end of the Showa era (late 1980s), Dr. Shigekoto
Kaihara, chair and professor at the Hospital Computer
Center, University of Tokyo Hospital, led a project toconnect these computer systems in a network in orderto share information for better communication.
Finally, the Ministry of Education, Culture, Sports,
Science and Technology approved a budget to initiate
the UMIN Center. The UMIN Center was foundedwithin the Hospital Computer Center, University ofTokyo Hospital, and was officially opened in March
1989. Dr. Tsunetaro Sakurai became an associate
professor as the first full-time UMIN staff. The
following are the objectives of the UMIN Center, as
initially outlined in 1989 (No.6 was added later):

1. Provide up-to-date information for healthcare
professionals
2. Promote digitalized communication among
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

501

Dr. Sakurai was promoted to professor at Hokkaido
University. Dr, Kiuchi updated the system to be webbased. With the rapid spread of the Internet in Japan,
UMIN users dramatically increased.
The UMIN Center subsequently started to provide threemajor information services: (1) the ELBIS (Electronic
Library for Biomedical Sciences) as of 1997, (2) the
INDICE (Internet Data and Information Center ofClinical Research) as of 2000, and (3) the EPOC
(Evaluation System of Postgraduate Clinical Training)
as of 2004.
In April 2002, the UMIN Center became an
independent entity, with the adjusted name of
University Hospital Medical Information Network
Center, as per an internal arrangement at the Universityof Tokyo Hospital. In 2003, a budget for a new
professor position was officially approved by the
Ministry of Education, Culture, Sports, Science andTechnology. Then, Dr. Kiuchi was promoted to become
the first professor of the UMIN Center on April 1, 2004.
The UMIN Center became part of the Faculty of
Medicine, as the Department of Health Communication,
School of Public Health, which was established in April
2007.

Clinical Activities
Although the UMIN Center is one of the central
medical examination and treatment institutions of the
University of Tokyo Hospital, the center does notprovide direct patient care services, but provides
services for medical researchers and practitioners
throughout Japan. We currently have about 470,000
registrants, and approximately 120,000,000 monthly
website accesses, which is currently in the scale of theworld’s highest access rates. The service extends tostudy / education / medical examination and treatment/ hospital duties and encompasses many divergences as
indicated below:
 Research: http://www.umin.ac.jp/research
AC:
Information for Academic Conferences
ELBIS:
Electronic Library for Biomedical
Sciences
FIND:
Fund Information Database
INDICE: Internet Data and Information Center ofClinical Research

ROCOLS: Recruiting System for Our Colleagues’
and Students’
CTR:
Clinical Trial Registry
ICDR:
Individual Case Data Repository Education: http://www.umin.ac.jp/education
SUPERCOURSE:
Online Lectures Compiled by Pittsburgh
Univ., U.S.A
EPOC:
Evaluation System of Postgraduate
Clinical Training
Debut:
Dental Training Evaluation andTabulation System
Web-QME: Medical Education Evaluation System
ARIA:
Online Recruiting System for General
Use Medical Examination and Treatment
http://www.umin.ac.jp/uhosp/
 Intoxication database Medical supplies and materials database Classification for Nursing
 Ministry of Education, Culture, Sports,
Science and Technology document public
information system National university hospital-related medical
dispute report Lists for people and committees
 Various government official appointments,
administrative websites and ML
 General Services(1) General information and search Medical / biology related websites
 Medical terminology A medical research organization / medical
institution database(2) Services for information providersWeb service for publicWeb service for members
Website preservation service(3) Communication support
 E-mail Listserv
 Discussion board
 File exchange

502

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.

References
Please refer to Department of Health Communication.

503

Organ Transplantation Service
Director
Kiyoshi Hasegawa

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/1512ishokugeka/index.html

The University of Tokyo Hospital has aggressively
performed organ transplantation, and is one of the
major organ transplant centers in Japan. In 1966, thefirst kidney transplantation in Japan was performed. In
1996, the first living donor liver transplantation was
performed. Organ Transplant Service started tofunction since 2003. As for liver transplantation, till
the end of 2018, 609cases of living donor livertransplantation and 28 deceased donor livertransplantations have been performed, and the 5-year
survival rate is around 85% which is much superior to
the national average (~70%). The University of Tokyo
Hospital has been one of the authorized institutions
for heart transplantation, and lung transplantation. At
the end of 2018, 111 heart transplantations and 20
lung transplantations (18 deceases donors and 2 live
donors) have been performed. In addition, 77 kidneytransplantations (17 deceased donors and 60 live
donors) have been undergone.
In Japan, the organ transplantation is still not accepted
as a common clinical practice, and the number of
deceased organ donors is extremely low whencompared to other developed countries. The Organ
Transplant Service at the University of Tokyo Hospitalintegrates the heart, lung, liver, and kidneytransplantation, and promotes the awareness campaign
regarding the organ donation and the transplantation
not only in the institution but also widely among
Kanto area.

References (2018)
1. Akamatsu N, Hasegawa K, Kokudo N. Response
to: Factors Associated With the Early Outcome in
Living Donor Liver Transplantation in Reply to

2.

3.
4.

5.

6.

Sonbare. Ann Surg. 2018Epub ahead of print]
Kaido T, Shinoda M, Inomata Y, Yagi T,
Akamatsu N, Takada Y, Ohdan H, Shimamura T,
Ogura Y, Eguchi S, Eguchi H, Ogata S, Yoshizumi
T, Ikegami T, Yamamoto M, Morita S, Uemoto S.
Effect of herbal medicine daikenchuto on oral andenteral caloric intake after liver transplantation: A
multicenter, randomized controlled trial. Nutrition.
2018;54:68-75.
赤松延久、長谷川潔 成人生体肝移植の現状と展望 外科 80 巻 2 号 138-143，2018
日本移植学会臓器移植抗体陽性診療ガイドラ
イン策定委員会 臓器移植抗体陽性診療ガイ
ドライン 2018 年版
Miyazaki T, Sato S, Kondo T, Kusaka M, Gotoh
M, Saiki Y, Ono M, Kokudo N, Enosawa S, SatohS, Soeda E, Furukawa H, Kobayashi E, Nagayasu
T. National survey of de novo malignancy after
solid organ transplantation in Japan. Surg Today
2018; 48: 618-624.
Hasumi E, Fujiu K, Kojima T, Kinoshita O,
Nawata K, Yamauchi H, Ono M, Komuro I.:
Novel extraction technique of retained pacemakerand defibrillator lead during heart transplantation.
PLoS One. 2018;13:e0203172

504

Department of Clinical Research
GovernanceDirector & Project Professor
Hideaki Ui, Ph.D.

Research Associate
Kazuyoshi Ichihashi, Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/english/centers-services/organization/l4/
researchgovernance.html

History and Overview of theOrganization
The Department of Clinical Research Governance
was established independently from the ClinicalResearch Support Center on January 1st, 2015, for the
management of clinical research. The aim of thedepartment is an appropriate and rapid response tovarious issues surrounding clinical research in recent
years, to prevent problems related to research ethics
and research misconduct, and to promote highly
reliable clinical research. The intention of the
Department of Clinical Research Governance is toestablish a system that would enable the University ofTokyo Hospital to take the initiative in managing andpromoting clinical research so as to ensure thereliability of clinical research and compliance with the
ethics of clinical research promoted by university
hospitals providing advanced medical care.
The Department of Clinical Research Governance is
now composed of three offices: 1) Office of Strategic
Planning and Promotion , 2) Office of ResearchIntegrity and Promotion, and 3) Office of Clinical
Quality & Compliance. These offices mutually
cooperate to promote and strengthen governancefunctions within the hospital.
The following activities are carried out by the
Office of Strategic Planning and Promotion : (1)formulating comprehensive strategies for research anddevelopment at the University of Tokyo Hospital; (2)adopting the role of administrative headquarters whenpublicly applying for large-scale research projects; (3)serving as a liaison for consultations regarding theacquisition of research funds and intellectual
properties; (4) examination financial self-reliancestrategies of the clinical research base; (5) discoveringneeds and seeds in clinical practice; (6) investigating
research activities at the University of Tokyo Hospitaland creating a database; (7) collecting clinicalresearch information from external organizations; (8)activities related to conflicts of interest at the
University of Tokyo Hospital; (9) clerical work related
to the Advanced Medicine Development Support
Management Committee; and (10) clerical work
related to the Special Clinical Research Steering
Committee.
The activities of the Office of Research Integrity
and Promotion are as follows: (1) responding to
problems related to research ethics and research
misconduct, (2) educational activities for clinicalresearchers; and (3) the dissemination of workshop
summaries.
The activities of the Office of Clinical Quality &Compliance are as follows: (1) auditing of clinicalresearches and clinical trials, (2) giving guidance andadvice on the reliability of clinical trials, (3)performing trend-analysis of audit findings andcompliance issues, report and make recommendations
to the hospital director to become a high reliability
organization,(4) providing support for the
preparation of GCP inspections by regulatory505

authorities, and integrated management of findings,(5) integrated management of outsourced auditing,(6) integrated management of audit results of the
University of Tokyo Hospital, (7) collecting
information for corrective action and preventive
action after audits and investigations, (8) collecting
and analyzing regulatory information on reliability ofclinicalresearch/trials,
andproviding
education/training, and (9) the secretariat of the
Auditing Working Group of Core Centers’ Network
for Translational and Clinical Research, Project ofTranslational and Clinical Research Core Centers,
TR-SPRINT (AMED).
The Department of Clinical Research Governanceconsists of a director (full-time post from August,2015), a Research Associate/URA in the Office ofStrategic Planning and Promotion, and 7 staffs (4auditors
and3
temporarystaffs(auditor/audit-assistant/support staff)) in the Office ofClinical Quality & Compliance as of March 2019. The
Office of Research Integrity and Promotion. has no
additional member, and the director serves as it.

Activities
The Office of Strategic Planning and Promotion has
undertaken the following activities in fiscal year 2018.
1) Coordination of organization for clinical
trials/researches: assisting the holding of Specified
Clinical Research Steering Committee and theSpecified Clinical Research Auditing Committee, andassisting the preparation of reports on clinical research
activities as the Clinical Research Core Hospitals
under the Medical Care Act (Act No. 205 of July 30,1948) for surveys conducted by the Ministry of Health,Labour and Welfare.
2) Others: investigations of research paper publication
activities, co-operating the “Forum for Developmentof Seeds for Advanced Medicine”, etc.
The Office of Clinical Quality Assurance &Compliance has undertaken the following activities infiscal year 2018.
1) Audit activities: (1) As regards to trials/researches
conducted by the University of Tokyo Hospital, theoffice conducted 4 audits for investigator-initiatedclinical trials, 3 audits for Specified ClinicalResearches, and 2 audits for other trials. (2) One audit
for investigator-initiated clinical trial conducted atother university hospital which lead by the UniversityofTokyo
Hospital.
(3)
One
audit
for
investigator-initiated clinical trial conducted at otheruniversity hospital. (4) provided assistance in the
preparation of audit SOPs and audit plan, etc. for othersome clinical trials and researches.
2) Support for surveys/investigations: Regarding TR
Core Centers surveys by AMED, and ClinicalResearch Core Hospital investigations, the Officeattended to explain the system and structure of quality
assurance, etc.
3) Consolidating information: The office collected all
the information on audit results including directly
outsourced by principal investigators, and has been
centrally managing the GCP inspections findings
conducted at the University of Tokyo Hospital.
4) Advisory: provided advice on compliance andreliability related matters to the Central Coordinating
Unit, Site Coordinating unit, and prepares advisory
records.
5) TR program: In June/2017, the University of Tokyo
Hospital was appointed as the secretariat of new
initiative, Audit Working Group of AMED describedabove. The Working Group consists of one to threeauditors from each Center. The secretariat conducted
three meetings with all members (May 5th, November
6th, and March 12th), one Training for auditors (March5th), and 24 times meetings in total on three themes (1)Auditors education and training, (2) Collect issues inauditing and solve them, and (3) Optimal conduct ofaudit & quality assurance, at each sub-working group.
6) Networking: (1) As a part of UCHT Allianceactivity, monitoring took place among the eight
member universities in the Kanto Koshinetsu region toevaluate the implementation system. (2) Participatedin the study to evaluate the reliability as a part of the
National University Hospital Clinical Research
Promotion Initiative (NUH-CRPI). (3) Participated in
the Japan Society of Quality Assurance (JSQA).

506

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

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

Homepage

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

http://kokoro.umin.jp/

Introduction and Organization
The Department of Child Psychiatry was establishedin April 2005 as the clinical counterpart to the Clinical
Education Center of Mental Development, both ofwhich are funded by the special grant for faculty
development. The major aim of the Clinical Education
Center is to train mental health specialists in various
fields with a fundamental grounding in childpsychiatry and neurosciences. Much of the services
provided are based on the 37 years of experience inintervention and treatment for developmentallydisabled children established in the former childpsychiatry division of Department of Neuropsychiatry.
Our department uses a multidisciplinary approach byworking in collaboration not only with the Departmentof Neuropsychiatry, Department of Pediatrics andGraduate School of Education in the University ofTokyo but also several other educational and/or
clinical facilities on mental development or developmental disorders. The Department of Child Psychiatry
complemented the Clinical Education Center by
providing fieldwork for clinical training and offeredclinical services to patients with various development
problems also.
The Clinical Education Center of Mental Development was closed in March 2010 because of time limitof the fund, and Department of Child Neuropsychiatry,
Graduate School of Medicine was established in April
2010. The Department of Child Psychiatry, as theclinical counterpart to the department in graduate
school, focuses on clinical activity related to research
as well as quality practice of child psychiatry andeducation of leading child psychiatrists and allied

professionals. In addition to professors of the graduate
school, 2 psychiatrists and 3 psychologists (2 full-timeones for a definite term and 1 part-time one) areofficially assigned to the Department of Child
Psychiatry. One psychiatric social worker works
mainly for the Department of Child Psychiatry since2013 also.

Clinical activities
In the year 2019, 8 psychiatrists and 6 psychologists(full-time and part-time) are in charge of treatment at
the Department of Child Psychiatry. Although patientswith various disorders are seen, the focus of thedepartment is mainly on patients with developmental
disorders. We offer services to patients with a broad
range of developmental disorders including Autism
Spectrum
Disorder(ASD),
Attention-Deficit/
Hyperactivity Disorder (ADHD), Learning Disabilities(LD), Intellectual Disability (ID), tic disorders, andchild & adolescent Obsessive-Compulsive Disorders(OCD).
Number of new patients in 2019 was 274, and about
two thirds of the new patients consisted of patientswith ASD, ADHD or tic disorders. Out of 274 patients,
children of elementary school age were 125, andchildren of junior high school age were 41. In otherwords, children of elementary or junior high school
age were more than half of the patients. Number ofpreschool children was 70, suggesting our response toincreasing 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 and507

decision about treatment course are provided forchildren and adolescents with any kinds of mental
problems. After fine adjustment of treatment course
within a given period, the patients are referred tocommunity hospitals/clinics or intervention/education
facilities with a detailed report. The special clinic
meets a need for high level services and works withresearch for special diseases.
Services for the general child psychiatry outpatientsare provided by psychiatrists in the areas of pharmacotherapy, psychotherapy, psychoeducation and also
work closely with the schools and community.
Psychologists have charge of psychological consultation as well as psychological examination. Patients
involved in those are mainly individuals with
developmental disabilities, and individualized treatment focusing on developmental viewpoint is plannedfor each. Psychological consultation includes services
in the following areas: (1) evaluation of cognitive andbehavioral development, (2) individualized treatmentof the disabled individual (3) counseling of parents
and providing information to the disabled individual’s
support network (relatives, schools) and environmental coordination. In addition to psychologists,
psychiatric social worker participates in actual
environmental coordination. Cognitive behavior
therapy for obsessive-compulsive symptoms oranxiety is sometimes provided also.
As for intervention for preschool children with ASD,
intensive individualized therapy consisting of weekly
10 sessions was provided for children aged 3 years or
younger.
Parent-training for parents with ADHD children,which started in 2011, was provided. This program
aimed that the parents learn deeper understanding ofdifficult children and appropriate strategy of copingwith them.
In addition to these outpatient services, “inpatient
assessment on developmental disorders” program
started in 2010. This program is provided in theinpatient ward of neuropsychiatry for adolescents oradults who have mental problems such as depression
and wish a detailed examination about possibility ofhidden developmental disorders including ASD and
ADHD.
We also focus on psychiatric liaison activity withother departments in the University hospital,

especially pediatrics.

Education
Undergraduates of the University of Tokyo haveopportunities to participate in an assessment anddiagnosis session at the general first visit outpatient
clinic and intervention for preschool children.
Graduate students in clinical psychology course fromthe University of Tokyo participate in intervention forpreschoolers also.
One month training course is offered to juniorresidents especially in pediatric specialty course. This
course includes intake interview of first visit patients,
observation of assessment and treatment for follow-up
patients and intervention for preschoolers, and visit tocommunity hospital and intervention/guidance
facilities for child and adolescent mental health. For
general psychiatrists including senior residents of the
Department of Neuropsychiatry, round for developmental disorders and an inpatient program of assessment about developmental disorders are provided asopportunity to get knowledge and experience ofdevelopmental disorders.
In response to the increasing interest to adults with
developmental disorders, a seminar of developmental
disorders was held in July 2019, and about 200
medicaldoctors,
psychologists,
andalliedprofessionals attended.

Research
We participate in investigation of etiology anddevelopment of effective treatment on ASD and
ADHD, which are organized in collaboration with the
Department of Neuropsychiatry and other research,educational and clinical facilities. In addition, research
related specifically to the clinical activities in the
Department of Child Psychiatry is currently being
investigated.
Clinical evaluation and treatment
Effectiveness study of early intervention for autisticpreschoolers is being undertaken. We focused oninvestigating early intervention including treatment
for children and parent support.
Effectiveness of a program of group cognitive
behavior therapy for adults with high-functioning508

ASD is investigated in a randomized control trial.
In order to develop predictor of parent training for
ADHD, we are collecting and analyzing data.
The possible relations among clinical characteristics
such as tics and obsessive-compulsive symptoms in
Tourette syndrome (chronic tic disorder with multiple
motor tics and one or more vocal tics) and child &adolescent OCD are being evaluated.
Multi-institutional collaborative study about
treatment-refractory Tourette syndrome in which
severe tics persist even after adulthood are conductedwith multidisciplinary professionals including
neurosurgeons who perform deep brain stimulation.
Comprehensive Behavioral Intervention for Tics
(CBIT) is provided for children and adolescents with
Tourette syndrome, and preliminary study of its
effectiveness is undertaken.
We continued survey of tics and related symptoms
in community preschoolers and development ofobjective assessment for tics also.
Neuropsychological research
Neuropsychological data on ASD, ADHD andTourette syndrome are being collected. Analysis of therelations among neuropsychological findings and theclinical evaluation as well as comparisons between
patients and their healthy siblings are being
conducted.
Genetic research
As we are interested in gene-environment interaction, we are examining influence of age of parents
on emergence of ASD.
Neuroimaging
Studies include structural MRI, Near-Infrared Spectroscopy (NIRS) and functional MRI with exploring
the pathogenesis of developmental disorders such as
ASD.

References
1. Kimura Y, Ikegaya N, Iijima K, Takayama Y,
Kaneko Y, Omori M, Kaido T, Kano Y, Iwasaki
M : Withdrawal of deep brain stimulation inpatients with gilles de la tourette syndrome.
MovDisord.2019;34(12):1925-1926.
2. Goto R, Fujio M, Matsuda N, Fujiwara M,
Nobuyoshi M, Nonaka M , Kono T, Kojima M,
Skokauskas N & Kano Y : The effects ofcomorbid Tourette symptoms on distress causedby compulsive-like behavior in very young
children: a cross-sectional study, Child andAdolescent Psychiatry and Mental Health. 2019;13: 28.
3. Murakami J, Tachibana Y, Akiyama S, Kato T,
Taniguchi A, Nakajima Y, Shimoda M, Wake H,
Kano Y, Takada M, Nambu A, Yoshida A : Oral
splint ameliorates tic symptoms in patients withtourette syndrome. Mov Disord. 2019; 34(10):1577-1578.
4. Owada K, Okada T, Munesue T, Kuroda M,
Fujioka T, Uno Y, Matsumoto K, Kuwabara H,
Mori D, Okamoto Y, Yoshimura Y, Kawakubo Y,
Arioka Y, Kojima M, Yuhi T, Yassin W, Kushima I,
Benner S, Ogawa N, Kawano N, Eriguchi Y,
Uemura Y, Yamamoto M, Kano Y, Kasai K,
Higashida H, Ozaki N, Kosaka H, Yamasue H :Quantitative facial expression analysis revealed
the efficacy and time course of oxytocin in autism.
Brain.2019; 142(7):2127-2136.
5. Yassin W, Kojima M, Owada K, Kuwabara H,
Gonoi W, Aoki Y, Takao H, Natsubori T, Iwashiro
N, Kasai K, Kano Y, Abe O, Yamasue H. Paternal
age contribution to brain white matter aberrationsin autism spectrum disorder. Psychiatry Clin
Neurosci.2019;73(10): 649-659.
6. Ochi K, Ono N, Owada K, Kojima M, Kuroda M,
Sagayama S, Yamasue H. Quantification of
speech and synchrony in the conversation of
adults with autism spectrum disorder. PLoS One,
14(12): e0225377, 2019.

509

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
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 since 2018. Dissemination and educational
activities for the advancement of tissue transplantationand transplantation medicine is our important mission.

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.

Target Diseases
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.

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
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.

510

Center for Epidemiology andPreventive Medicine
Director & Associate Professor
Nobutake Yamamichi, M.D., Ph.D.

Associate & Deputy Director
Lumine Matsumoto, M.D., Ph.D.

Associates
Atsuko Ozeki, M.D., Ph.D., Keiko Niimi, M.D., Ph.D., Yukari Masuda, M.D., Ph.D.
Hirotaka Matsuzaki, M.D., Ph.D., Toshihiro Yamaguchi, M.D., Ph.D.,
Hajime Takisawa, M.D., Kenta Gondo, M.D., Ph.D.,
Yoshiko Mizuno, M.D., Ph.D. (Department of Biostatistics and Bioinformatics)

Homepage:

http://www.h.u-tokyo.ac.jp/patient/depts/kenshin/index.html
https://www.todai-yobouigaku.com/

Introduction and Organization
Following the inauguration of a new Central
Clinical Service Building in November 2006 in the
University of Tokyo Hospital, the Center for
Epidemiology and Preventive Medicine wasestablished on January 1st, 2007, within the Central
Clinical Facilities and the relevant regulations wererevised. On January 9th, the Working Group for the
Establishment of the Center for Epidemiology andPreventive Medicine was organized; on April 1st,Steering Committee for the Establishment of theCenter 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,
our center has increased the number of examinees
from ten subjects per day to twelve per day (March2018). Following the reorganization in April 2018, theCenter was transferred to the 15th floor of theinpatient building B in September 2018. As the areafor examination was expanded, we have been able toincrease the number of examinees to 16 in October
2018, and to 20 in April 2019. Most of theexaminations except for MRI and CT scan can be
performed within our floor, which increased theconvenience and comfort for the examinees.
In the administrative organization of the Center for
Epidemiology and Preventive Medicine, the Director
directly under the head of the hospital is responsible
for the entire organization. Examinations in the511

Department are administered in collaboration withthree Central Clinical Facilities (Clinical Laboratory
Center, Radiological Center, and Department ofEndoscopy and Endoscopic Surgery) and six Clinical
Divisions (Gastroenterology, Breast and Endocrine
Surgery, Gynecologic Surgery, Ophthalmology and
Vision Collection, Neurology, and GeriatricMedicine).
The staff of the Center for Epidemiology andPreventive Medicine is composed of ten physicians(eight regular physicians and one physician from therelated departments). Three of the regular physiciansalso perform upper gastrointestinal endoscopy andcolonoscopy. Our department also has nine nurses,
five assistant clerks, and one medical clerk.

Clinical activities
In addition to basic examinations, we provide nine
optional examinations: 1) comprehensive cardiovascular examinations, 2) comprehensive cerebrovascularexaminations, 3) check up for dementia, 4) colorectal
cancer screening, 5) uterine cancer screening,6) breast cancer screening, 7) lung cancer screening,8) tumor marker diagnosis, and 9) estimation ofgastric cancer risk. While meeting the needs of
examinees, we have increased the number of theoptional examinations.
The physicians of our department are responsible
for analyzing the results of examinations andperforming overall evaluations. We take plenty of timeto perform comprehensive medical examinations andinstantly write a referral letter to each department in
the University of Tokyo Hospital when we find any
abnormality through the examinations. Formally, theexaminee is notified in writing within approximately
three weeks after the examination. We also offer eachexaminee a free consultation so that we can help
him/her understand the results or decide whether tohave further detailed examination.

Teaching activities
We started clinical teaching for medical students
in April 2017. Following the lecture of preventive
medicine, students observe explanations by physiciansto the examinees. They learn not only how to apply
preventive medicine to practice, but also the mannerof physicians to examinees.

Research activities
The University of Tokyo Hospital is expected not
only to provide its service of comprehensive medical
examinations but also to promote evidence-based
practice and scientific examinations, which is themission of our department. Academically, we aim toestablish a database from clinical data and to promoteepidemiological research. This will enable us toprevent disease based on scientific data. We haveconducted cross-sectional/longitudinal analysis. We
also work in collaboration with other departments in
our hospital and other facilities.

Past activities
In the fiscal year (FY) 2019 (from April 1, 2019 toMarch 31, 2020), the total number of examinees (whohad basic examinations and optional examinations)
was 8725 including 3161 in basic examinations, 608
in complete cardiovascular examinations, 759 incomplete cerebrovascular examinations, 90 in checkup for dementia, 327 in colorectal cancer screening,
651 in uterine cancer screening, 819 in breast cancer
screening, 723 in lung cancer screening, 1293 intumor marker diagnosis, 294 in estimation of gastriccancer risk, and 11 in upper gastrointestinal endoscopy(later). Check up for dementia was discontinued in
December 2018.
One of the most important role of our center is toprovide the appropriate medicine to the examinees
when any abnormal finding was detected. We provide
referral letters to the department within/outside of our
hospital for detailed examination or treatment,
according to the request by the examinees. Prompt
reference to the medical department in the Universityof Tokyo Hospital is one of the most contributablefactor for the satisfaction of the examinees. In the FY
2019, we issued 1330 letters of referral to otherdepartments in our hospital and 56 to other hospitals.
We have expanded our public relations efforts and15,000 brochures were delivered during the FY 2019.
We also prepared posters which were placed within
our hospital and on the campus of the University ofTokyo as well. We have established our original

512

website (https://www.todai-yobouigaku.com/) andoffering up-to-date information to the examinees.

References
Academic Papers in English
1. Sakaguchi Y, Yamamichi N, Tomida S, Takeuchi
C, Kageyama-Yahara N, Takahashi Y, Shiogama
K, Inada KI, Ichinose M, Fujishiro M, Koike K.
Identification of marker genes and pathways
specific to precancerousduodenal adenomas andearly stage adenocarcinomas.J Gastroenterol.
2019 Feb;54(2):131-140.
2. Satoh M, Nomura S, Harada M, Yamaguchi T, Ko
T, Sumida T, Toko H, Naito AT, Takeda N,
Tobita T, Fujita T, Ito M, Fujita K, Ishizuka M,
Kariya T, Akazawa H, Kobayashi Y, Morita H,
Takimoto E, Aburatani H, Komuro I. High-t
hroughput single-molecule RNA imaging analysis
reveals heterogeneous responses of cardiomyocytes to hemodynamic overload. J Mol Cell
Cardiol. 2019 Mar;128:77-89.
3. Kageyama-Yahara N, Yamamichi N, Takahashi Y,
Takeuchi C, Matsumoto Y, Sakaguchi Y, Koike K.
Tandem repeats of the 5' flanking region of human
MUC5AC have a role as a novel enhancer in
MUC5AC gene expression. Biochem Biophys
Rep. 2019 Apr 4;18:100632.
4. Nishizawa T, Sakitani K, Suzuki H, Yamakawa T,
Takahashi Y, Yamamichi N, Watanabe H, Seto Y,
Koike K, Toyoshima O. A combination of serumanti-Helicobacter pylori antibody titer and Kyoto
classification score could provide a more accurate
diagnosis of H pylori. United European
Gastroenterol J. 2019 Apr;7(3):343-348.
5. Togo R, Yamamichi N, Mabe K, Takahashi Y,
Takeuchi C, Kato M, Sakamoto N, Ishihara K,
Ogawa T, Haseyama M. Detection of gastritis by a
deep convolutional neural network from doublecontrast upper gastrointestinal barium X-ray
radiography. J Gastroenterol. 2019 Apr;54(4):321329.
6. Iino H, Okano T, Daimon M, Sasaki K, Chigira M,
Nakao T, Mizuno Y, Yamazaki T, Kurano M,
Yatomi Y, Sumi Y, Sasano T, Miyata T. Usefulness of carotid arterial strain values for evaluating

the arteriosclerosis. J Atheroscler Thromb. 2019
May 1;26: 476-487.
7. Kataoka Y, Tsuji Y, Hirasawa K, Takimoto K,
Wada T, Mochizuki S, Ohata K, Sakaguchi Y,
Niimi K, Ono S, Kodashima S, Yamamichi N,
Fujishiro M, Koike K. Endoscopic tissue
shielding to prevent bleeding after endoscopic
submucosal dissection: a prospective multicenter
randomized controlled trial. 2019 Jul;51(7):619627.
8. Shibamoto M, Higo T, Naito AT, Nakagawa A,
Sumida T, Okada K, Sakai T, Kuramoto Y,
Yamaguchi T, Ito M, Masumura Y, Higo S, Lee
JK, Hikoso S, Komuro I, Sakata Y. Activation of
DNA Damage Response and Cellular Senescencein Cardiac Fibroblasts Limit Cardiac Fibrosis
After Myocardial Infarction. Int Heart J. 2019 Jul
27;60(4):944-957.
9. Itoh H, Kaneko H, Kiriyama H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Komuro I. Relation between theUpdated Blood Pressure Classification according
to the American College of Cardiology/American
Heart Association Guidelines and Carotid
Intima-Media Thickness. Am J Cardiol. 2019 Aug
1;124(3):396-401.
10. Kiriyama H, Kaneko H, Itoh H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Komuro I. Role of anemia andproteinuria in the development of subsequent
renal function deterioration in a general
population with preserved glomerular filtration
rate: a community-based cohort study. J Nephrol.
2019 Oct;32(5):775-781.
11. Yoshida Y, Nakanishi K, Daimon M, Ishiwata J,
Sawada N, Hirokawa M, Kaneko H, Nakao T,
Mizuno Y, Morita H, Di Tullio MR, Homma S,
Komuro I. Alteration of cardiac performance andserum B-type natriuretic peptide level in healthy
aging. J Am Coll Cardiol. 2019 Oct 8;74(14):1789-1800.
12. Kiriyama H, Kaneko H, Itoh H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Komuro I. Correction to: Role ofanemia and proteinuria in the development ofsubsequent renal function deterioration in a
general population with preserved glomerular

513

filtration rate: a community-based cohort study. J
Nephrol. 2019 Oct;32(5):843-846.
13. Itoh H, Kaneko H, Kiriyama H, Nakanishi K,
Mizuno Y, Daimon M, Morita H, Yamamichi N,
Komuro I. Effect of Body Weight Change on
Blood Pressure in Japanese General Population
with Body Mass Index ≥ 22kg/m2. Int Heart J.
2019 Nov 30;60(6):1381-1386.
International conferences
1. Yoshida Y, Nakanishi K, Daimon M, Ishiwata J,
Sawada N, Hirokawa M, Kaneko H, Nakao T,
Mizuno Y, Morita H, Di Tullio MR, Yatomi Y,
Homma S, Komuro I. Association of arterial
stiffness with left atrial structure and phasic
function: A community-based cohort study
European Society of Cardiology 2019, Paris
2. Ito H, Kaneko H, Kiriyama H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Yamamichi N, Komuro I. Effect ofMetabolically Healthy Obesity on Carotid
Intima-Media Thickness in General Population: A
community-based cohort study. European Societyof Cardiology 2019, Paris
3. Kiriyama H, Kaneko H, Ito H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y, Yamamichi N, Komuro I. Effect ofcigarette smoking on carotid atherosclerosis: A
community-based cohort study. European Societyof Cardiology 2019, Paris
4. Nakanishi K, Daimon M, Yoshida Y, Ishiwata J,
Sawada N, Hirokawa M, Kaneko H, Nakao T,
Mizuno Y, Morita H, Marco Di Tullio, Homma S,
Komuro I. Association Between Increased Body
Mass Index and Adverse Right Ventricular
Mechanics: A Community-based Cohort Study.
American Heart Association 2019 (Philadelphia,
Nov. 2019)
5. Mizuno Y, Daimon M, Uemura K, Ito H,
Kiriyama H, Yoshida Y, Nakanishi K, Kaneko H,
Koide D, Yamamichi N, Komuro I. Lipoprotein(a)is associated with elevated mitral E/e’ ratio inJapanese non-Heart Failure population. American
College of Cardiology 2019 (New Orleans, Mar.
2019)

514

Department of Pain and Palliative
Medicine
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 tocollaborate 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.

5151) 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.
･ Multidisciplinary conference: Psychiatrists, pain
clinicians/Anesthesiologists, orthopaedicians, pharmacists, medical social workers and others
participate in the daily or weekly conference
besides the regular member of the pain andpalliative care team. Residents can discuss actively
the multidisciplinary palliative care plans which ourteam should carry out. Participants from each
occupation also guide the care plans from their
viewpoints of experts.

Research
The clinical information accumulated from thepalliative care consultation is input to the concise
database simultaneously and utilized for various kinds

516

of 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. Osumi M, Sumitani M, Otake Y, Morioka S. A
hypothetical explanatory sensorimotor model ofbilateral limb interference. Medical Hypotheses
2019; 122: 89-91
2. Saito Y, Yokota T, Tada Y, Sumitani M.
Naldemedine in Japanese patients with opioidinduced constipation and chronic noncancer pain:
open-label, phase 3 studies. J Pain Res 2019; 12:127-38
3. Hozumi J, Sumitani M, Nishizawa D, Nagashima
M, Ikeda K, Abe H, Kato R, Kusakabe Y, Yamada
Y. Resistin is a novel marker for postoperative
pain intensity. Anesthesia & Analgesia 2019;
128: 563-8
4. Hoshino H, Sakuramoto H, Matsuishi Y, Shimojo
N, Enomoto Y, Ohto T, Kido T, Ouchi A, Sumitani
M, Kawano S, Inoue Y. Development of theJapanese version of the State Behavioral Scale for
critically ill children. Acute Med & Surg 2019; 6:
101-8

5. Osumi M, Inomata K, Inoue Y, Otake Y, Morioka
S, Sumitani M. Characteristics of phantom limb
pain alleviated with virtual reality rehabilitation.
Pain Med 2019; 20: 1038-46
6. Osumi M, Sumitani M, Otake Y, Nishigami T,
Mibu A, Nishi Y, Imai R, Sato G, Nagakura Y,
Morioka S. Kinesiophobia modulates lumbar
movements in people with chronic low back pain:
A kinematic analysis of lumbar bending andreturning movement. Eur Spine J 2019; 28:
1572-8
7. Hayakawa K, Kurano M, Ohya J, Oichi T, Kano K,
Nishikawa M, Uranbileg B, Kuwajima K,
Sumitani M, Tanaka S, Aoki J, Yatomi Y, Chikuda
H. Lysophosphatidic acids and their substratelysophospholipids in cerebrospinal fluid as an
objective biomarkers for evaluating the severity oflumbar spinal stenosis. Scientific Reports 2019;
9: 9144
8. Ushio M, Sumitani M, Abe H, Mietani K, Hozumi
J, Inoue R, Tsuchida R, Ushida T, Yamada Y.
Characteristics of locomotive syndrome inJapanese patients with chronic pain and results ofa path analysis confirming the relevance of avicious cycle involving locomotive syndrome,musculoskeletal pain and its psychological factors.
JMA Journal 2019; 2: 184-9
9. Mietani K, Sumitani M, Ogata T, Shimojo N,
Inoue R, Abe H, Kawamura G, Yamada Y.
Dysfunction of the blood-brain barrier inpostoperative delirium patients, referring to theaxonal damage biomarker phosphorylated
neurofilament heavy subunit. PLoS ONE 2019;14: e0222721
10. Baasanjav U, Ito N, Kurano M, Saigusa D, Saito
R, Uruno A, Kano K, Ikeda H, Yamada Y,
Sumitani M, Sekiguchi M, Aoki J, Yatomi Y.
Alteration of the lysophosphatidic acid and its
precursor lysophosphatidylcholine levels in spinal
cord stenosis: A study using a rat cauda equina
compression model. Scientific Reports 2019; 9:
16578(And, 18 Japanese articles)

517

Department of Cancer Resource
CenterChief
Sachiyo Nomura, M.D.,Ph.D.

Associate chief
Takako Wakeda, M.D.,Ph.D.

Counseling staff
Megumi Yasuda, RN., Keiko Fukuda, RN., Kunie Wakao, RN.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/gansoudan/

Introduction and Organization
As part of national efforts to address cancer, thegovernment has been establishing a network of“cancer care hub hospitals.” In response to its being
designated as a regional cancer care hub hospital in2008, the University of Tokyo Hospital established theCancer Patient Support Center to provide consultations to cancer patients and their families as well as
residents in neighboring communities with the aim ofleading them to appropriate departments and facilities.

Medical Services
Provision of information if patient contracts cancer
If a person gets cancer, the first thing they need to
do is collect information on cancer. The Cancer
Counseling and Support Center provides information
and booklets on different types of cancer.
Furthermore, the person needs to accurately
understand the doctors’ explanations to select the besttreatment for oneself from the various options
presented by doctors. At the Cancer Counseling andSupport Center, we explain difficult medical terms in
simple language, and we help patients understand theirdoctors’ advice.

Various kinds of advice related to the medical careof cancer
If a person contracts cancer, besides the medical
problem of what kind of treatment to undergo andwhere, there are also issues related to medical carewhen receiving treatment, such as medical expenses,
how to get along after being discharged from hospital,
job, and nursing services. The Cancer Counseling andSupport Center provides patients with advice andsupport so that they can resolve such social worries.
Provision of information on second opinions
The Center provides information on how to get asecond opinion and on facilities that provide second
opinions.
Various kinds of advice related to the appearancechanges caused by cancer treatment
Cancer treatment often causes appearance changes
such as hair loss and skin pigmentation. The center
provides patients with practical advice and support
about wig and cover make-up.
Provision of general information and advice on
cancer
The Center sends out and provides information topeople who do not have cancer but who want to findout about cancer, for instance the treatment and518

screening for it.

Open hours
If you have any queries, please contact us on
03-5800-9061 between 9am-12noon, 1pm-4pm
weekdays.

Research activities
Our research field covers the relation between
appearance changes caused by cancer therapy andPatients’ quality of life.

References and Presentation
1. Makeup as care for changes in appearance due tocancer treatment. FRAGRANCE JOURNAL 22
Research and Development for Cosmetics,
Toiletries & Allied industries Special issue p126
2. Inadequacy of Appearance Care for cancer
patients in Japan. MASCC/ISOO Annual Meetingon Supportive Care in Cancer 2019, HYATTREGENCY SAN FRANCISCO

519

Department of Disaster Medical
Management
Professor
Naoto Morimura, M.D.,Ph.D.

Lecturer
Chiaki Toida M.D.,Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/dmm/index.html

Introduction and Organization
Responding to the Great East Japan Earthquake in2011, the University of Tokyo Hospital has decided to
set out to establish “disaster medical management
studies” in terms of need not only to provide medical
treatment at the time of disaster but also to develop a
new academic field that provides bird’s-eye view on
overall disaster medicine. In March 2012, we made anannouncement to establish “Department of Disaster
Medical Management” in the Public Comment.
In July 2012, Associate Professor Dr. Hiroyuki
Nakao was assigned the post as the first General
Manager of the Department of Disaster Medical
Management. Afterwards, in January 2015, Professor Dr. Tadashi Iwanaka, the Hospital Vice Director,
was assigned the post as the second General Manager.
In April 2015, Professor Dr. Masaomi Nangaku, theHospital Vice Director in charge of crisis managementand disaster prevention, was assigned the post as thethird General Manager. In April 2017, Professor Dr.
Naoto Morimura was assigned the post as the fourth
General Manager of the Department of Disaster
Medical Management and was appointed as the chairman of the in-hospital Disaster Prevention Committee.
This department belongs to the Central ClinicalFacilities Division and is involved in activities within
this hospital and inside/outside of the University.
In order to establish disaster medical management
studies, we are aiming at 1) fostering leaders who candevelop plans for disaster medicine and educate

personnel engaged in disaster medicine, 2) relationship building with relevant institutions for establishinga system for the University of Tokyo Hospital to leaddisaster medicine and 3) developing a system as abase of formation of organizations at the time ofdisaster.

Clinical activities
Since 2012, the Disaster Prevention Committee
carries out planning and conduct the University ofTokyo Hospital Comprehensive Disaster Drill
regularly. Drills of launching a new earthquake early
warning system, building hospital headquarter fordisaster control, reporting in-hospital damage situation,
establishing triage and casualty clearing station, triage
and rescue of mass casualties, were performed yearlywith cooperation of the University of Tokyo, theMetropolitan Tokyo Fire Department, and the Ministryof Health Labor and Welfare.

Teaching activities
As educational activities inside and outside of the
University, we are holding and teaching MIMMS,
Major Incident Medical Management and Support,
courses accredited by English ALSG, Advanced Life
Support Group, regularly for the purpose of developing leadership of health care professionals who canprovide ideal medical care in times of disaster. Also,
we are cooperating holding and teaching MCLS, Mass
Casualty Life Support, courses of Japan Association

520

for Disaster Medicine, and JATEC, Japan Advanced
Trauma Evaluation and Care, courses of Japanese
Association for Acute Medicine, and so on.

Research activities
We are seeking ways of cooperation between
institutions through workshops with relevant
institutions from the perspective that day-to-day
cooperation with relevant institutions can be alsoutilized at the time of disaster. We consider that it canbe also utilized for cross-business formation oforganizations at the time of disaster.
Other than that, we are holding outside researchgroups and cooperating for building up a functional
emergency medical system at the time of disaster.

References
1.

2.

3.

4.

5.

Yogo N, Toida C, Muguruma T, Gakumazawa M,
Shinohara M, Takeuchi I. Successful Managementof Airway and Esophageal Foreign Body
Obstruction in a Child. Case Rep Emerg Med.
2019 Dec 24;2019:6858171.
Muguruma T, Toida C, Furugori S, Abe T,
Takeuchi I. Validation of the PediatricPhysiological and Anatomical Triage Score in
Injured Pediatric Patients. Prehosp Disaster Med.
2019 Aug;34(4):363-369.
Muguruma T, Toida C, Gakumazawa M, Yogo N,
Shinohara M, Takeuchi I. Effects of establishing a
trauma center on the mortality rate among injured
pediatric patients in Japan. PLoS One. 2019 May
23;14(5)Toida C, Takeuchi I, Abe T, Hattori J, Hattori K,
Takahashi K, Uchiyama M, Honda H, Nakagawa
Y, Matsuda K, Asari Y, Morimura N. The
Imbalance in Medical Demand and Supply for
Pediatric Victims in an Earthquake. Disaster Med
Public Health Prep. 2019 Aug;13(4):672-676.
Naoto Morimura: n-hospital Medical Response to
Mass Casualty Incident：Lessons Learned from
Guidelines and Experiences Overseas. The
Journal of Japan Society for Clinical Anesthesia.
2019 May 39(3):313-320.

521International 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
One of the University of Tokyo’s significant
challenges is globalization. The International Medical
Center was established within the Central ClinicalFacilities Division to enhance The University ofTokyo Hospital’s development as an international
medical hub. 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.

522

Department of Clinical Nutrition
Therapy
Head of the Department
Naoto Kubota (Associate Professor)

Assistant Head of the Department
Hideaki Ijichi (Lecturer)
Rie Sekine

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/eiyoukanri/index.html

Introduction and Organization
In 1922, a stall in the outpatient department of thehospital and hospital ward shop sold milk, baked goods,
cider and ice cream. In 1925, a service contract between
the hospital and the Kojinkai Foundation resulted in thestart of a patient food service. In 1936, a “special
therapeutic diet” approach for newborn infants,
diabetes, nephropathy in which a physician prescribed
the food composition individually for each patient was
instituted for the first time in Japan. In 1950, a nationalhospital complete food service system was announced,
and the nutrient content provided was standardized.
The nutrient content provision for patient meals at thetime was 2400 kcal/day. In 1952, the inpatient meal
service was officially outsourced to a foundation.
In 1957, the first nationwide meeting of nationaluniversity-hospital head dietitians was held at the
University of Tokyo with the aim of improving patients’
diets.
In 1958, the complete food service was abolished.
Implementation of a standard food service and staffing
with a dietitian became required conditions, and thefood service section was staffed by a part-time section
chief and a dietitian. In 1962, a request from thenationwide meeting of national-university-hospitalhead dietitians, which primarily conducted its activities
at the University of Tokyo, was realized, and the
managerial dietitian system was established by a partial
revision of the Nutritionists Act. In 1972, nutritional

guidance was actively provided to inpatients andoutpatients with the aim of obtaining approval tocharge fees, and in 1978 a medical diet charge andnutrition guidance charge were established. In 1988, atimely tray service achieved by using hot and cold
food-tray carts was instituted in order to dispel the “tooearly, cold, unappetizing” reputation of hospital meals.
In 1991, the name of the food service section waschanged to the “Department of Nutrition Management”,
a change that had a long been sought by nationwide
national-university-hospital managerial dietitian staff
members. At the same time, the nutrition sections of themain hospital and branch hospital were consolidated,
and the head of the Department of Nutrition
Management, who was a managerial dietitian, assumed
the section manager post to form a system composed of
5 managerial dietitians at the main hospital and 3
managerial dietitians at the branch hospital.
In 1994, as a result of a partial revision of the
National Health Insurance Act, a diet therapy
notification system on admission was set up. An onadmission nutrition guidance fee was also established.
In 1998, the first Diet Therapy Exhibit organized by
the Department of Nutrition Management was
conducted as part of the diabetes week events by the
Tokyo Diabetes Association. Since then, Diet Therapy
Exibit has been conducted every year for over 20 years.
In 2001, integration of the branch hospital with themain hospital resulted in an 8-managerial- dietitian

523

system. In 2004, the Department of Nutrition
Management was separated from the medical service
division. In 2005, the introduction of the self-pay
system for inpatient meals meant that inpatients began
to be charged for their meals. During the same year one
managerial dietitian (limited-term employment) was
added to the staff.
In 2006, charges for the performance of nutrition
management were newly established, and that meant
providing nutrition management for all patients. The
increase in work was accompanied by the addition of
one managerial dietitian (limited-term employment) to
the staff. Team care was introduced the same year, andin-hospital activity in the form of an all-department
nutrition support team (NST) was inaugurated. Eachhospital ward was staffed with a physician, managerial
dietitian, and nurse in charge of an NST, and whenevernecessary members from other fields (pharmacists,
medical technologists, physical therapists) joined, andthey held a hospital ward meeting once a week. In 2010,
an NST committee was created as a result of theestablishment of charges for NSTs. The NST director
up until that time became a member of the committee
and played an active role as the center of in-hospital
NST activities. The addition of one managerial dietitian(full time) was approved as a full-time employee toengage in the activities of charges for the NST. In 2011,
the inauguration of a nutritional guidance service forrecipients of health checkups in the Department of
Epidemiology and Preventive Medicine wasaccompanied by the addition of one managerial
dietitian (limited-term employment) to the staff. In
2012, charges for conducting nutrition management
were abolished. They were incorporated into the basic
hospital-admission fee, and the nutrition management
system by physicians, managerial dietitians, and nurses
was improved.
In 2013, the Department of Nutrition Management
was reorganized as the Department of ClinicalNutrition Therapy. A physician (Professor, the head of
the Central Clinical Services Administration) assumed
the concurrent post of head of the Department, and thehead of the Department of Nutrition Management
assumed the post of Assistant Head of the Department;
they undertook responsibility for managing the foodservice, maintaining activities of the NST, andstrengthening its functions. In 2014, two physicians,

full-time department head (associate professor) and
lecturer, were assigned and improvements were madeto NST activities and to the nutrition therapy, education,and research system. As a result of a managerial
strategic personnel distribution, 5 new managerial
dietitians (full-time) have also been assigned this fiscal
year. Along with the increase in work of managerial
dietitians for strengthening the nutrition management
system and expanding the number of clinical trials in
P1 unit, another managerial dietitian (limited-term
employment) was added to the staff in May 2015.
Long-coveted introduction of the New Cook Chill
System was eventually admitted by the University ofTokyo and the process was started in October 2016.
Renovation of the main kitchen was started in June
2017. During the renovation, the makeshift kitchen wasplaced on the 1st floor (the main kitchen) and the 3rdbasement floor (the washing room and the formularoom) of the Inpatients Ward A and the menu wasrestricted for the makeshift kitchen use. In February
2018, the New Cook Chill System in the University ofTokyo Hospital began. The menu was considerably
modified for the new cooking system. In April 2018, a
new formula room was launched on the first floor of
the Inpatients Ward A for the expansion of PediatricMedical Center. Monthly issue of diet news for thepatients 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.

Clinical Activities
The Department is proactively conducting
nutritional guidance in regard to metabolic diseases,
including diabetes, chronic kidney disease, dyslipidemia, and obesity, perioperative guidance,
including in regard to postgastrectomy diets, hepatobiliary and pancreatic disease diets, and cardiac disease
diets, etc., mothers’ classes, etc.
In 2019, individual nutritional guidance was more
focused on compared to group guidance and the records
show that there were 2481 instances of inpatient524

nutritional guidance and 5152 instances of outpatient
nutritional guidance. Especially, nutritional guidance
for malignant tumor patients increased up to 501
instances. Perioperative guidance was 337 instances.
In July 2012, a physician, managerial dietitian, andnurse formed a dialysis prevention team, and started
calculating fees for diabetes and dialysis prevention
guidance and management in the outpatient clinic.
There were 140 guidance sessions in 2019.
In April 2014, the department started calculating
charges for NST and counted 1261 instances in the firstfiscal year. In 2018, according to the conditions forcalculating NST charges, efforts of full-time
managerial dietitians were changed and NST round
twice a week. In 2019, 1044 instances were calculated,mostly adding cooperation with dentists.
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 are now screened through the common
criteria in our hospital and monitored by the medical
team. The high-risk patients picked up through thistwo-step screening are weekly referred to the NST ofeach floor. In April 2015, alternative initial screening
criteria specific for pediatric and pregnant patientswere added to the procedure manual of nutritional
management, respectively. Mobile terminals specificfor managerial dietitian were provided on every floorof Inpatients ward A&B, which enhanced the practiceefficiency. By 2019, almost all the floor started the NST,
which indicated raised awareness of nutritional care asa team medicine in our hospital.
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 accepts managerial dietitian clinicaltrainees. 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 3 to 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.
In 2017, the department was involved in the
curriculum of Clinical Clerkship, the medical education program of the Faculty of Medicine, the Universityof Tokyo. 102 medical students at M4 grade
participated in the two-day practice course in 2019.
To disseminate NST activities fully in the hospital,
the department organizes two NST-related seminars
throughout the year: Basic Series for Nutrition Therapy
and Clinical Nutrition Seminar. The department alsoorganizes NST Conference and Joint Conference ofTeam Medicine for case discussions to facilitate
cooperation with each floor NST and other medical
teams. In 2015, the department started “Nutritional
Management e-learning” for all employee to learn basic
knowledge of nutritional management procedure. In
December 2016, the exchange training program wasstarted between the Department of Nutrition
Management of The Institute of Medical Science andour department.
In October 2015, “The Manual of The Department ofClinical Nutrition Therapy 2015-2016” was published.
After that, “The Pocket Manual of The Department ofClinical Nutrition Therapy 2016-2017” was publishedin 2016, “The Manual of The Department of ClinicalNutrition Therapy 2017-2018” and “Records of the
Kitchen Renewal” were published in 2018, “ThePocket Manual of The Department of Clinical Nutrition
Therapy 2018-2021”, “New Cook Chill Manual 20182020” and “Illustrated Tools of Nutritional Guidance”
were published in March 2020.

525

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”
・Joint research with the Department of Hepatobiliaryand Pancreatic Surgery
Research topic: “Assessment of perioperative
improvement in nutrition status by an open trial ofbranched amino acids fourmula in patients ofhepatocellular carcinoma derived from livercirrhosis with abnormal ICGR15 and patients who
have undergone liver transplantation”
Research topic: “Feasibility study assessing
improvement of postoperative complication rate byintroducing home enteral feeding for patients who
have undergone pancreaticoduodenectomy”
・Joint research with multiple institutes directed by
Chiba University
Research topic: “Interventional study to discover theappropriate target body weight for effective
treatment strategy and improvement of healthdisorder of obesity patients”
・Joint research with the Department of Stomach andEsophageal Surgery
Research topics: “A randomized control trial
evaluating exercise and nutritional intervention for
gastric cancer patients in the perioperative period forsarcopenia prevention”

3.

4.

5.

6.

7.

References<Publications (English)>
1. Igarashi M, Watanabe K, Tsuduki T, Kimura I,
Kubota N. NAPE-PLD controls OEA synthesis andfat absorption by regulating lipoprotein synthesisin an in vitro model of intestinal epithelial cells.
FASEB Journal 33:3167-3179, 2019.
2. Wakabayashi T, Yamaguchi K, Matsui K, Sano T,
Kubota T, Hashimoto T, Mano A, Yamada K,
Matsuo Y, Kubota N, Kadowaki T, Iwatsubo T.
Differential effects of diet-and genetically-induced
brain insulin resistance on amyloid pathology in amouse model of Alzheimer's disease. Mol

8.

9.

Neurodegener. 14:15, 2019.
Ito D, Arita J, Yamamoto M, Akamatsu N, Kaneko
J, Ijichi H, Kubota N, Sakamoto Y, Kokudo N,
Hasegawa K. Effect of home enteral nutrition afterpancreaticoduodenectomy. Nutrition. 60:206-211,
2019.
Saito K, Isayama H, Nakai Y, Takahara N, Ishigaki
K, Takeda T, Hakuta R, Saito T, Uchino R,
Kishikawa T, Hamada T, Mizuno S, Sasaki T,
Kogure H, Matsubara S, Yamamoto N, Ijichi H,
Tateishi K, Tada M, Koike K. A phase II trial of
gemcitabine, S-1 and LV combination (GSL)
therapy in patients with advanced pancreaticcancer. Invest New Drugs. 37:338-344, 2019.
Mizuno S, Isayama H, Nakai Y, Ishigaki K, Saito
K, Sato T, Takeda T, Hakuta R, Saito T, Takahara
N, Kogure H, Ijichi H, Tateishi K, Tada M, Shikata
N, Tagami T, Kikuchi S, Yamamoto H, Yamakado
M, Koike K. Diagnostic yield of the plasma freeamino acid index for pancreatic cancer in patientswith diabetes mellitus. Pancreatology. 19:695-698,
2019.
Sasaki T, Moro K, Kubota T, Kubota N, Kato T,
Ohno H, Nakae S, Saito H, Koyasu S. Innate
Lymphoid Cells in the Induction of Obesity. Cell
Rep. 28:202-217, 2019.
Kobayashi K, Kaneko J, Yamaguchi T, Kawaguchi
Y, Arita J, Akamatsu N, Ishizawa T, Sekine R,
Ijichi H, Kubota N, Fukatsu K, Kokudo N,
Hasegawa K. Late-Evening Carbohydrate andBranched-Chain Amino Acid Snacks Improve the
Nutritional Status of Patients Undergoing
Hepatectomy Based on Bioelectrical Impedance
Analysis of Body Composition. Gastrointest
Tumors. 6:81-91, 2019.
Fujiwara H, Tateishi K, Misumi K, Hayashi A,
Igarashi K, Kato H, Nakatsuka T, Suzuki N,
Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H,
Tanaka Y, Ijichi H, Kogure H, Nakai Y, Isayama H,
Hasegawa K, Fukayama M, Soga T, Koike K.
Mutant IDH1 confers resistance to energy stress innormal biliary cells through PFKP-induced aerobic
glycolysis and AMPK activation. Sci Rep. 9:18859,
2019.
Ichimaru Y, Sano M, Kajiwara I, Tobe T, Yoshioka
H, Hayashi K, Ijichi H, Miyairi S. Indirubin 3'Oxime Inhibits Migration, Invasion, and526

Metastasis In Vivo in Mice Bearing Spontaneously
Occurring Pancreatic Cancer via Blocking theRAF/ERK, AKT, and SAPK/JNK Pathways.
Transl Oncol. 12:1574-1582, 2019.
10. Oyama H, Tada M, Takagi K, Tateishi K, Hamada
T, Nakai Y, Hakuta R, Ijichi H, Ishigaki K, Kanai
S, Kogure H, Mizuno S, Saito K, Saito T, Sato T,
Suzuki T, Takahara N, Morishita Y, Arita J,
Hasegawa K, Tanaka M, Fukayama M, Koike K.
Long-term Risk of Malignancy in Branch-Duct
Intraductal Papillary Mucinous Neoplasms.
Gastroenterology. 158:226-237, 2020.

527

Department of Clinical Genomics
Director & Professor
Katsutoshi Oda, 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 forphysicians preparing for board-certified clinicalgeneticists. Many medical staffs with diverse
specialties including pediatricians, obstetricians,
neurologists, cardiologists diabetologists andsurgeons participate in the activities 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 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 andFoundationOne® CDx Cancer Genomic Profililng)
were approved by PMDA in June, 2019. As well, we

provide an original multiplex genome sequencing,named "Todai OncoPanel”, which is composed of
DNA panel and RNA panel. The room (Room 204) is
specifically allocated in the outpatient clinic forgenomic medicine in cancer (twice weekly).

Publications
Inoue S, Hirota Y, Ueno T, Fukui Y, Yoshida E,
Hayashi T, Kojima S, Takeyama R, Hashimoto T,
Kiyono T, Ikemura M, Taguchi A, Tanaka T,
Tanaka Y, Sakata S, Takeuchi K, Muraoka A,
Osuka S, Saito T, Oda K, Osuga Y, Terao Y,
Kawazu M, Mano H. Uterine adenomyosis is anoligoclonal disorder associated with KRAS
mutations. Nat Commun 2019;10(1):5785.
2. Kohsaka S, Tatsuno K, Ueno T, Nagano M,
Shinozaki-Ushiku A, Ushiku T, Takai D, Ikegami
M, Kobayashi H, Kage H, Ando M, Hata K, Ueda
H, Yamamoto S, Kojima S, Oseto K, Akaike K,
Suehara Y, Hayashi T, Saito T, Takahashi F,
Takahashi K, Takamochi K, Suzuki K, Nagayama
S, Oda Y, Mimori K, Ishihara S, Yatomi Y,
Nagase T, Nakajima J, Tanaka S, Fukayama M,
Oda K, Nangaku M, Miyazono K, Miyagawa K,
Aburatani H, Mano H. Comprehensive assay forthe molecular profiling of cancer by target
enrichment from formalin-fixed paraffinembedded specimens. Cancer Sci 2019;110(4):1464-79.
3. Kojima M, Sone K, Oda K, Hamamoto R, Kaneko
S, Oki S, Kukita A, Machino H, Honjoh H,
Kawata Y, Kashiyama T, Asada K, Tanikawa M,
Mori-Uchino M, Tsuruga T, Nagasaka K,
Matsumoto Y, Wada-Hiraike O, Osuga Y, Fujii T.
The histone methyltransferase WHSC1 isregulated by EZH2 and is important for ovarian
1.

528

clear cell carcinoma cell proliferation. BMC
Cancer 2019;19(1):455.
4. Makii C, Ikeda Y, Oda K, Uehara Y, Nishijima A,
Koso T, Kawata Y, Kashiyama T, Miyasaka A,
Sone K, Tanikawa M, Tsuruga T, Mori-Uchino M,
Nagasaka K, Matsumoto Y, Wada-Hiraike O,
Kawana K, Hasegawa K, Fujiwara K, Aburatani
H, Osuga Y, Fujii T. Anti-tumor activity of dual
inhibition of phosphatidylinositol 3-kinase andMDM2 against clear cell ovarian carcinoma.
Gynecol Oncol 2019;155(2):331-9.
5. Takeuchi M, Tanikawa M, Nagasaka K, Oda K,
Kawata Y, Oki S, Agapiti C, Sone K, Miyagawa
Y, Hiraike H, Wada-Hiraike O, Kuramoto H,
Ayabe T, Osuga Y, Fujii T. Anti-Tumor Effect of
Inhibition of DNA Damage Response Proteins,
ATM and ATR, in Endometrial Cancer Cells.
Cancers 2019;11(12).

529

Clinical Research Promotion
CenterProfessor, Director
Takashi Moritoyo M.D., Ph.D.

Associate Professor, Vice Director
Chie Sakanaka, M.D., Ph.D. (until July), Tatsuya Maruyama, M.D., Ph.D. (from August)

Project Lecturer
Kosuke Kashiwabara, Ph.D.

Assistant Professor
Yukari Uemura, Ph.D. (until May), Gaku Oguri, M.D., Ph.D.,
Takuya Kawahara, Ph.D., Mihoko Shibuya, M.D., Ph.D. (from June)

Project Assistant Professor
Keiko Ueda, M.D., Ph.D., Mariko Inoue, M.D., Ph.D.

Homepage https://www.h.u-tokyo.ac.jp/english/centers-services/central-clinicalfacilities/clinical-research-support-center/index.html
History and Organization
The Clinical Research Support Center was
established in 2010. It originated from Clinical Trial
Managing Center, which was established in 1998, andsubsequently the former Clinical Research Center,
which was established in 2001. It belongs to thecentral clinical division of the hospital and provides
supports not only for clinical trials but also forinvestigator-initiated (independent) clinical studies.
However, given the increasing diversity and volume
of clinical research conducted in the University ofTokyo Hospital, demand mounted for the structural
framework to provide support for multi-centercollaborative studies, research on new technology inevidence-based medicine and translational researchetc. In response to such diversified demands, theformer Clinical Research Center was reorganized in
April 2010 into the Clinical Research Support Center,enabling strengthened support and expeditious

promotion of clinical 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, new divisions such as Operation Division,
Biostatistics Division, Data Management Division,
Monitoring Division and Safety Information Division
and Operation Division have been added to theCentral Coordinating Unit.

530

The Center was selected in 2011 as an MHLWfunded Center of Excellence for early stage andexploratory clinical trials of drugs for psychiatric andneurological diseases, enabling the Center to reinforce
the staff and to be equipped with Phase 1 Unit that canconduct Phase I first-in-human clinical trial. Thus, thethird 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 thecomplete clinical development 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 ofclinical research functions aimed at strengthening
governance functions of the University of Tokyo
Hospital.
In January 2015, we established Clinical Research
Governance Division and later Office of Clinical
Quality Assurance & Compliance was createdindependently of the Clinical Research Center
responsible for conducting quality assurance audits.
Also, with the aim to improve quality of clinicalresearch in clinical departments, we appointed 1-2 tostaff from each clinical department to serve asconcurrent clinical instructors, thereby strengthening
supervision and monitoring system in the departments.
In April 2016, we transferred ethical review processof specific clinical trials (involving invasion andintervention) to the Faculty of Medicine IRB to ensuretransparency of clinical research. IRB for evaluating
industry-sponsored and investigator-initiated clinical
trials was newly established in the hospital. With
respect to the secretarial and administrative duties,
center will continue to take responsibilities.
Moreover, a specific clinical research steeringcommittee was established under the hospital director
and external audit committee to seek external
evaluation. In addition, we integrated clinical research
management system by strengthening management ofconflicts of interest, created educational environment
for clinical research personnel, formed collaboration
with the Clinical Evaluation and Safety Division tostrengthen safety management system. As a result, theUniversity of Tokyo Hospital received accreditation asa core clinical research hospital under Medical Care
Act. Since then our hospital has been functioning as acore clinical research hospital in Japan.
Based on the enforcement of the Act on the Safety ofRegenerative 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
duties.
In addition, in order to strengthen the functions
involved widely by the Clinical Research Support
Center, in 2015, we established 3 new divisions
outside the unit, Education and Training Division,
Clinical Trial Implementation Division and University
Hospital Network Promotion Division. In fiscal year
2017, we further integrated safety information
functions of the Site Coordinating Unit and theCentral Coordinating Unit and set it as 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 wasmove outside the unit. Regulatory Strategy Division
was also established in the Central Coordinating Unit
in 2017.
In order to strengthen governance and functionality
within the center, Central Clinical Research Manager
and Advanced Medical Care Program Manager wereplaced to ensure that the clinical research are
implementation appropriately by collaborating with
the Department of Clinical Research Governance. We
established Clinical Research Site Secretariat, enacted
general and individual rules to respond to the Clinical
Trials Act enforced in April 2018.
In December 2019, the center was renamed as
Clinical Research Promotion Center to clarify that it isan organization that will further advance clinicalresearch. The Clinical Research Promotion Center was
reorganized by 8 departments.
<Investigator-Initiated Clinical Trials Promotion
Department>
The department is responsible for: (1) secretariat
duties for investigator-initiated clinical trials,
advanced medical treatment, patient-initiated medical
treatment and regenerative medicine; (2) Support forphysicians and others in formulating development
strategies for clinical trials, advice on study design,and support for pharmaceutical affairs, funding,531

intellectual
property,andindustry-academia
collaborations; (3) Support for the promotion of
investigator-initiated clinical trials conducted byphysicians and others; (4) Monitoring, data
management and data analysis required to ensure thequality of investigator-initiated clinical studies; (5)Collecting and reporting on safety information related
to investigator-initiated clinical trials and providing
advice to physicians and others on the safe conduct ofclinical trials.
<Sponsor-Initiated Clinical Trials Promotion
Department>
The department is responsible for: (1) Supporting thesafe and smooth implementation of sponsor-initiatedclinical trials; (2) CRC operations, study drug
management, and clinical psychological examinations.
<IRB Office>The office is responsible for: (1) Managing theInstitutional Review Board (IRB) and coordinatingwith related departments; (2) Providing support forphysicians and others who wish to be reviewed by the
IRB.
<Dedicated Clinical Trial Ward Department (P1unit)>The department is responsible for: (1) The safe andsmooth conduct of clinical trials related topharmaceuticals and medical devices; (2) the
recruitment of human subjects.
<Medical Safety and Personal Information
Management Department>
The department is responsible for: (1) Managementof safety reports and collection and reporting of safety
information; (2) Management of personal information.
<Planning,
Strategy
andManagement
Department>
The department is responsible for: (1) Planning for
responding to authorities, acquisition of funds for
projects and expansion of the Center's functions; (2)Management of the Center's budget, personnel anddocuments; (3) General management of the Center's
information system, including information security;(4) Education and training for and provision of
information to physicians and others who wish to
conduct clinical research; (5) Management of the
progress of clinical research conducted by physiciansand others and supported by the Center.
<Network Promotion Department>

The department is responsible for: (1) Secretariat
duties for the National University Hospitals ClinicalResearch Promotion Initiative joined by 45 hospitalsof 42 national universities; (2) Secretariat duties for
the University Hospital Clinical Trial Alliance joinedby 8 universities and 9 hospitals in the KantoKoshinetsu region, a network of university hospitals
engaged in clinical research.
<Clinical Trials Patient Counseling Department>
The department is responsible for providing
consultation and public relations services for patients
who would like to use advanced medical care.

Clinical Research Support
Activities
The duties of the Center range from serving as thesecretariat for the IRB to supporting the implementation and reporting of clinical trials.

<Site Coordinating Unit>
In 2004, the Site Coordinating Unit began providing
assistance for investigator-initiated clinical trials
evaluating therapeutic drugs and studies involving
unapproved drugs in addition to conventional clinical
trials (use of unapproved drugs in clinical research
was shifted to Research Ethics Committee of Graduate
School of Medicine and School of Medicine in 2015.
In 2018, it was moved to Evaluation Committee on
Unapproved News Drugs). To further improve thequality of these research we decided to adopt
ICH-GCP guidance and complied with the following
guidelines, procedure manuals, styles and guidanceetc.
1) Guidelines for investigator-initiated study and useof unapproved drugs in clinical research.
(Guidelines for implementing specified clinical
trial, as of April 2016)2) Procedures for conducting investigator-initiatedclinical study and use of unapproved drugs inclinical research.
(Procedure manual for implementing specificclinical trial, as of April 2016)
3) Guidance for writing research protocol forvoluntary clinical research.
(Guidance for writing research protocol for
specific clinical trial, as of April 2016)

5324) Guidance for writing informed consent forvoluntary clinical research.
(Guidance for writing informed consent for
specific clinical research, as of April 2016)5) Handling guidelines for financial burden on
patients participating in investigator-initiatedtrials and clinical research.
From 2009, we have been providing support for allinvasive and interventional clinical research.
For secure process of the applications of industrysponsored clinical trials to IRB, we hold preliminary
hearing system (named as “protocol presentation”)
before IRB. As a result, we could avoid
re-examination of research.
Clinical research coordinators (CRC) of the Center
have been supporting all clinical trials for approvaland post marketing research since 2002. We started
supporting in part investigator-initiated research in2004. In 2005 we started providing CRC support toinvestigator-initiated research on a beneficiary-paysbasis, and clinical pharmacology studies in healthy
volunteers in 2012. CRCs exclusively involved ininvestigator-initiated research, have been employed asneeded. CRC support for Advanced Medical Care
Program B which Tokyo University Hospital
participated as a head investigational site was initiatedin 2017.
As part of patient awareness campaign, we continued
updating the Center website, prepared leaflets anddistributed them at outpatient receptions. The leaflets
contain information about research currently recruiting participants. CRCs 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.

<Central Coordinating Unit>
Central Coordinating Unit, established in 2010, hasbeen implementing the system successively partly
supported by the MHLW-funded Early-Stage andExploratory Clinical Trial Project.
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
and exploratory studies and started accepting all
assistance requests for validation studies at the central
coordinating unit, starting from May 2015. Moreover,since clinical departments were placed in charge ofmonitoring and data management of all exploratory
studies, and the center undertook responsibility forsupervision of the quality control (QC). One of the
major achievements is the investigator-initiatedclinical trial of the pediatric ventricular assist device;
the trial was initiated in February 2012, applied forregulatory approval in November 2014, and approved
marketing in June 18, 2015.

< Safety Information Management Division >This division manages SAE (severe adverse event)reporting and supports various safety reporting inorder to ensure that clinical studies are conductedsafely.
<P1 Unit>
Since its establishment in May 2012, the Phase 1
Unit has undertaken various preparations to respond toearly phase clinical research, such as development of
SOP program, procedure manuals, establishment of
in-house collaboration system, on-the job training forstaff and the system for recruiting health volunteers.
P1 unit conducted its very first clinical study in
October 2012. In September 2018 we move to newward with augmented 30 beds (one room for 15 beds,
three rooms for 5beds) exclusively aimed for clinical
trial on the 12th floor of the inpatients’ ward B 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.

533

From April 2014 on, as a second phase of the project,
we developed a system to strengthen cooperation inclinical research education and training and development of seeds. As part of the Alliance activities the
University of Tokyo developed a clinical researchsupport system UHCT ACReSS jointly with Fujitsu in
2011, to support clinical researchers in the quality andproject management. UHCT ACReSS can easily becustomized by researchers. Currently, we are
expanding the use to researchers other than Alliancemembers.
We have also developed curriculum called CREDITS(Continuous Systematic Education & Training
Curriculum for Clinical Researchers and Specialists)
jointly with the Education and Training Division in
2015. Currently, we are expanding the use outside thealliance members. Activities between the UHCT
Alliance and the University of Tokyo Translational
Research (TR) based regional network started in 2015,
as seeds development project of Alliance members.

<National University Hospital Clinical Research
Initiative>
In October 2012, we launched National University
Hospital Clinical Research Initiative (NUH-CRI). The
administrative affairs of the Initiative have been takenover by the Alliance Office (located within the
University of Tokyo) from the preparatory meeting inJuly 2012. The initiative considered to share education
curriculum as one of the common educational
programs of national university hospitals nationwide.
The curriculum was provided to each university
hospital by the National University Hospital Councilof Japan.
Feasibility assessment system was developed forinvestigator-initiated clinical study in order to support
and promote clinical trials conducted at the National
University Hospitals.

Education/Training
The Center has been accepting M3/M4 students fortraining course in ‘Clinical Clerkship’ since it become
mandatory in 2013. In addition, resident physicians
underwent one-month training at the Center, as a partof the M.D. residency-training program. Starting in
2017, we have been offering systematic lectures on“Clinical Research” for M2 medical students.
Education and Training Division was established in2015 and since then it has been providing educationand training for students and researchers. In particular,
we have developed curriculum called CREDITS(Continuous Systematic Education & Training
Curriculum for Clinical Researchers and Specialists)
jointly with the University Hospital Clinical Trial
Alliance or (UHCT Alliance).
In 2015, we introduced clinical instructor system inwhich physicians from clinical departments
concurrently serve as a clinical instructor, centrally
manage information on clinical research conducted intheir own departments and hold regular training
sessions to disseminate information on education andtraining 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. In addition, we held a joint workshop
series with 8 alliance universities in the Kanto
Koushinetsu area. Since 2017, Japan Agency for
Medical Research and Development (AMED)
sponsored training workshop for clinical researchpersonnel has been held at the University of Tokyo.
Furthermore, in response to the shortage ofbiostatisticians, biostatistics and bioinformatics course
was established by AMED, at the university hospital.
Master’s course starting in FY2018 was alsoestablished within the Graduate School of Interdisciplinary Information Studies and the ClinicalResearch Support Center has established a system toconduct practical training for course participants.

Research Activities
In April 2007, with the cooperation of the
Biostatistics Department, the Center launched theClinical Trial Data Management course (endowed
course).
As of fiscal 2019, the Center was involved inscientific meetings, which include The Japan Societyof Clinical Pharmacology and Therapeutics,
Conference on CRC and Clinical Research, etc. 19
publications and academic papers etc. (English papers
17, Japanese papers 2) were produced.

534

Publications
1) Ishida T, Tokuda K, Hisaka A, Honma M, Kijima
S, Takatoku H, Iwatsubo T, Moritoyo T, Suzuki
H; Alzheimer's Disease Neuroimaging Initiative.
A Novel Method to Estimate Long-Term
Chronological Changes From Fragmented
Observations in Disease Progression. Clin
Pharmacol Ther. 105(2):436-447, 20192) Jensen B, Moritoyo T, Kaufer-Horwitz M, Peine S,
Norman K, Maisch MJ, Matsumoto A, Masui Y,
Velázquez-González A, Domínguez-García J,
Fonz-Enríquez E, Salgado-Moctezuma SG, BosyWestphal A. Ethnic differences in fat and muscle
mass and their implication for interpretation ofbioelectrical impedance vector analysis. Appl
Physiol Nutr Metab. 44(6):619-626, 20193) Kozuma K, Shinozaki T, Kozuma K, Kashiwabara
K, Oba K, Aoki J, Awata M, Nanasato M, Shiode
N, Tanabe K, Yamaguchi J, Kimura T, Matsuyama
Y. Impact of Residual Stenosis on the
Angiographic Edge Restenosis of SecondGeneration Drug-Eluting Stent —Integrated
analysis of Quantitative Coronary Angiography
from four Post-Marketing Surveillances of
Cobalt-Chromium Everolimus-Eluting Stent inJapan—. International Heart Journal. 60(5): 10501060, 20194) Hino H, Karasaki T, Yoshida Y, Fukami T, Sano A,
Tanaka M, Furuhata Y, Kashiwabara K, Ichinose J,
Kawashima M, Nakajima J. Competing risk
analysis in lung cancer patients over 80 years oldundergoing surgery. World Journal of Surgery.
43(7): 1857-1866, 20195) Terada Y, Takahashi T, Morita S, Kashiwabara K,
Nagayama K, Nitadori J, Anraku M, Sato M,
Shinozaki-Ushiku A, Nakajima J. Spread throughair spaces is an independent predictor ofrecurrence in stage III (N2) lung adenocarcinoma.
Interactive Cardiovascular and Thoracic Surgery.
29(3): 442-448, 20196) Terada R, Ikeda T, Mori Y, Yamazaki S,
Kashiwabara K, Yamauchi H, Ono M, Yamada Y,
Okazaki H. Comparison of two point of carewhole blood coagulation analysis devices andconventional coagulation tests as a predicting toolof perioperative bleeding in adult cardiac

surgery—a pilot prospective observational study
in Japan—. Transfusion. 59(11): 3525-3535, 2019
7) Fukami Y, Kaneoka Y, Maeda A, Kumada T,
Tanaka J, Akita T, Kubo S, Izumi N, Kadoya M,
Sakamoto M, Nakashima O, Matsuyama Y,
Kokudo T, Hasegawa K, Yamashita T,
Kashiwabara K, Takayama T, Kokudo N, Kudo M,
Liver Cancer Study Group of Japan. Liver
resection for multiple hepatocellular carcinomas:
a japanese nationwide survey. Annals of Surgery.
272(1): 145-154, 20198) Hiraoka A, Michitaka K, Kumada T, Izumi N,
Kadoya M, Kokudo N, Kubo S, Matsuyama Y,
Nakashima O, Sakamoto M, Takayama T, Kokudo
T, Kashiwabara K, Eguchi S, Yamashita T, Kudo
M, The Liver Cancer Study Group of Japan.
Prediction of prognosis of intermediate-stage
HCC patients: validation of the tumor marker
score in a nationwide database in Japan. Liver
Cancer. 8(5): 403-411, 2019
9) Mayanagi S, Kashiwabara K, Honda M, Oba K,
Aoyama T, Kanda M, Maeda H, Hamada C,
Sadahiro S, Sakamoto J, Maehara Y, Yoshikawa T.
Risk factors for paraaortic lymph-node recurrencein colorectal cancer. Annals of Cancer Research
and Therapy. 27(2): 52-56, 201910) Tsuchiya A, Yasunaga H, Tsutsumi Y, Kawahara T,
Matsui H, Fushimi K. Nationwide observational
study of mortality from complicated intraabdominal infections and the role of bacterial
cultures. British Journal of Surgery. 106:606-615,
2019.
11) Fujimoto C, Kinoshita M, Kamogashira T, Egami
N, Kawahara T, Uemura Y, Yamamoto Y,
Yamasoba T, Iwasaki S. Noisy vestibular
stimulation has a greater ameliorating effect on
posture in unstable subjects: a feasibility study.
Scientific Reports. 9(1):17189, 201912) Yanagiya M, Matsumoto J, Kawahara T,
Yamaguchi H, Nagayama K, Anraku M, Sato M,
Nakajima J. Influence of smoking and histologic
subtype on developing extrathymic malignancy inthymoma patients. The Annals of Thoracic
Surgery. 107(5):1532-1539, 201913) Uemura Y, Taguri M, Kawahara T, Chiba Y.
Simple methods for the estimation and sensitivity
analysis of principal strata effects using marginal535

structural models: application to a bone fracture
prevention trial. Biometrical Journal. 61(6):14481461, 201914) Niikura R, Hirata Y, Hayakawa Y, Kawahara T,
Yamada A, Koike K. Effect of aspirin use on
gastric cancer incidence and survival: a systematic
review and meta-analysis. JGH open. 4(2):117125, 201915) Bae SK, Akamatsu N, Togashi J, Ichida A,
Kawahara T, Maki H, Nishioka Y, Kokudo T,
Mihara Y, Kawaguchi Y, Ishizawa T, Arita J,
Kaneko J, Tamura S, Hasegawa K. Hepatitis B
virus recurrence after living donor liver transplantation of anti-HBc-positive grafts: A 22-year
experience at a single center. BioScience Trends.
13(5):448-455, 201916) Yoshikawa F, Fujiwara S, Nakahira Y, Mikami T,
Ogino A, Miyagawa T, Shibuya M, Fujio K, Haga
N. Repeated Expansion of Cerebral Infarction
Accompanied by Takayasu's Arteritis and
Subclavian Steal Syndrome Causes Difficulty inRehabilitation: A Case Report. The Japanese
Journal of Rehabilitation Medicine. 56(7): 579584, 201917) Inoue M, Okamura T, Komai T, Yamamoto K,
Fujio K. CD4+CD25−LAG3+ regulatory T cells
in humoral immunity. Clinical and Experimental
Neuroimmunology. 10 (Suppl. 1), 4-11, 2019

536

Division of Tissue Engineering
Director & Professor
Kazuto Hoshi, M.D., Ph.D.

Vice Director
Atsuhiko Hikita, M.D., Ph.D.

Project Associate Professors
Atsuhiko Hikita, M.D., Ph.D.,

Fumiko Yano, D.D.S., Ph.D.

Project Lecturer
Ysunori Omata, M.D. Ph.D.

Research Associates
Yukiyo Asawa, D.V.M., Ph.D.,

Makoto Komura, M.D., Ph.D.,

Ryota Chijimatsu, Ph.D.

Homepage

http:// square.umin.ac.jp/t-e/

Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo
Hospital, in October 2001 and has a fully equipped
800 m2 laboratory on the 8th floor of the In-patient
Ward B. In May 2016, it moved to Molecular and Life
Innovation building. Division of Tissue Engineering
consists of Department of Bone & Cartilage
Regenerative Medicine, Department of Cell & Tissue
Engineering,andLaboratory
for
Pediatric
Regenerative Medicine. One project associate
professor and one project research associates who areassigned to each department are conducting researchwith many graduate students. The researchers
continue their studies to make the center function as atranslational research center.
Tie-up with companies, technical transfer, patenting developed technologies, producing materials
for treatment at a GMP level, safety evaluation studies
and organization for clinical trials are necessary inorder to realize regenerative medicine, which is now
recognized as a national project. As foundation andoperation of venture companies as well as industry-

university-government cooperation is essential to thesuccess, 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 Universityof Tokyo Hospital.
June, 2002 Department of Corneal Tissue Engineering founded by a donation from HOYA health careCO., 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
Regeneration founded by a donation from MOCHIDA
Pharmaceutical Co., Ltd.

537

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 ofFuji 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 Nephrology and Regenerative Medicine founded by a donationfrom Zenjinkai.
April, 2016 The Cell Processing & Banking
Center set 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.

Research activities
As for bone and cartilage regeneration, we areresearching and developing the treatment of
osteoarthritis using human adipose stem cells (ASCs)
from the renewal of the department in 2018. To clarify
the protective effects of human ASCs for cartilage
more precisely, we are planning to establish the assay
system for the knee pain of mouse. We are also
developing the culture medium by which highlyfunctional human mesenchymal cells can be amplified
stably and effectively. We are also working on basic
research for (1) elucidation of molecular mechanisms
underlying osteoarthritis（2）clarification of the rolesof tissue stem cells in the homeostasis of joints andpathogenesis of osteoarthritis. In addition, for therealization of bone regeneration, we are trying toapply a nanosheet which can induce osteogenesis.
Now we are testing its effectiveness in large animals.
In the Department of Cell & Tissue Engineering, we
aim to produce regenerated cartilage and bone withhigh safety and usefulness, to realize production
system and establish practical quality control and topromote the application of regenerated cartilage andbone. To achieve these goals, we are conducting
research on adult stem cell biology in mesenchymal
tissues, application of molecular biology on cartilage
repair for regenerative medicine, development ofnovel scaffolds in cartilage and bone regeneration,
development of 3-D reconstruction system forregenerated tissues, evaluation on biochemical andbiophysical properties of regenerated tissues in vivo
and clinical trials and application of regenerated
cartilage and bones. Based on the findings andknowledge gained through our clinical study“Development of implant-type tissue-engineered
cartilage for patients with nasal deformity in cleft lip
and palate” conducted previously, we carried out an
investigator-initiated clinical trial “A clinical trial forthe validation of safety and efficacy of the implanttype tissue-engineered cartilage using autologous
cells”. Another investigator-initiated clinical trial
applying implant-type tissue-engineered cartilage forthe treatment of tracheal stenosis has also been started.
In addition, we are preparing for a clinical study oftreatment for temporomandibular joint disorder taking

538

advantage of anti-inflammatory and tissue repairing
abilities of adipose stem cells.
In the laboratory for pediatric regenerative medicine,
we are doing research to fabricate an engineered
airway by tissue engineering technique to fabricate
generic technology for clinical study. In addition,
fundamental researches to perform a clinical study ofthe cytokine therapy for the trachea malacia arecarried out.

2.

3.

Clinical Studies
Of particular note is clinical studies started as aresult of basic research. In Department of Bone &Cartilage Regenerative Medicine, a clinical study onbone implants into non-loading parts (IRB approval
number #1310) was conducted on 10 patients
successfully and a large-scale clinical trial was started
across the nation. In project for cartilage regeneration,
an investigator- initiated clinical trial “A clinical trial
for the validation of safety and efficacy of theimplant-type tissue-engineered cartilage using autologous cells” was carried out. As stated above, we areproceeding translational research aiming at clinicalapplication of tissue engineering and regenerative
medicine. Contribution to the Hospital

4.

5.

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
this facility.

References
1. Okada K, Mori D, Makii Y, Nakamoto H,
Murahashi Y, Yano F, Chang SH, Taniguchi Y,
Kobayashi H, Semba H, Takeda N, Piao W,
Hanaoka K, Nagano T, Tanaka S, Saito T.
Hypoxia-inducible factor-1 alpha maintains
mouse articular cartilage through suppression of
NF-κB signaling. Sci Rep. 2020 Mar 25;10(1):

6.

7.

8.

5425. doi: 10.1038/s41598-020-62463-4.
Hamamoto S, Chijimatsu R, Shimomura K,
Kobayashi M, Jacob G, Yano F, Saito T, Chung UI,Tanaka S, Nakamura N.
Enhancement ofchondrogenic differentiation supplemented by anovel small compound for chondrocyte-based
tissue engineering. J Exp Orthop. 2020 Mar 7;
7(1):10. doi: 10.1186/s40634-020-00228-8.
Sugimoto H, Murahashi Y, Chijimatsu R, Miwa S,
Yano F, Tanaka S, Saito T. Primary culture ofmouse adipose and fibrous synovial fibroblasts
under normoxic and hypoxic conditions. Biomed
Res. 2020; 41(1):43-51. doi: 10.2220/biomedres.
41.43.
Murahashi Y, Yano F, Chijimatsu R, Nakamoto H,
Maenohara Y, Amakawa M, Miyake Y, Yamanaka
H, Iba K, Yamashita T, Tanaka S, Saito T. Oraladministration of EP4-selective agonist KAG-308
suppresses mouse knee osteoarthritis development
through reduction of chondrocyte hypertrophy andTNF secretion. Sci Rep. 2019 Dec 30;9(1):20329.
doi: 10.1038/s41598-019-56861-6.
Xuan F, Yano F, Mori D, Chijimatsu R,
Maenohara Y, Nakamoto H, Mori Y, Makii Y,
Oichi T, Taketo MM, Hojo H, Ohba S, Chung UI,Tanaka S, Saito T. Wnt/β-catenin signaling
contributes to articular cartilage homeostasis
through lubricin induction in the superficial zone.
Arthritis Res Ther. 2019 Nov 27;21(1):247. doi:
10.1186/s13075-019-2041-5.
Kawata M, Mori D, Kanke K, Hojo H, Ohba S,
Chung UI, Yano F, Masaki H, Otsu M, Nakauchi
H, Tanaka S, Saito T. Simple and Robust
Differentiation of Human Pluripotent Stem Cells
toward Chondrocytes by Two Small-Molecule
Compounds. Stem Cell Reports. 2019 Sep 10;
13(3):530-544. doi: 10.1016/j.stemcr.2019.07.
012.
Oichi T, Taniguchi Y, Soma K, Oshima Y, Yano F,
Mori Y, Chijimatsu R, Kim-Kaneyama JR, Tanaka
S, Saito T. Adamts17 is involved in skeletogenesis
through modulation of BMP-Smad1/5/8 pathway.
Cell Mol Life Sci. 2019 Jun 14. doi: 10.1007/
s00018-019-03188-0.
Yano F, Ohba S, Murahashi Y, Tanaka S, Saito T,
Chung UI. Runx1 contributes to articular cartilage
maintenance by enhancement of cartilage matrix

539

production and suppression of hypertrophic
differentiation. Sci Rep. 2019 May 21;9(1):7666.
doi: 10.1038/s41598-019-43948-3.
9. Okada H, Kajiya H, Omata Y, Matsumoto T, Sato
Y, Kobayashi T, Nakamura S, Kaneko Y,
Nakamura S, Koyama T, Sudo S, Shin M,
Okamoto F, Watanabe H, Tachibana N, Hirose J,
Saito T, Takai T, Matsumoto M, Nakamura M,
Okabe K, Miyamoto T, Tanaka S. CTLA4-Ig
Directly Inhibits Osteoclastogenesis by InterferingWith Intracellular Calcium Oscillations in Bone
Marrow Macrophages. J Bone Miner Res. 2019
Sep;34(9):1744-1752. doi: 10.1002/jbmr.3754.
Epub 2019 Jul 16.
10. Izawa N, Kurotaki D, Nomura S, Fujita T, Omata
Y, Yasui T, Hirose J, Matsumoto T, Saito T,
Kadono Y, Okada H, Miyamoto T, Tamura T,
Aburatani H, Tanaka S. Cooperation of PU.1 With
IRF8 and NFATc1 Defines Chromatin Landscapes
During RANKL-Induced Osteoclastogenesis.
Bone Miner Res. 2019 Jun;34(6):1143-1154. doi:
10.1002/jbmr.3689.
11. Okubo R, Asawa Y, Watanabe M, Nagata S, Nio
M, Takato T, Hikita A, Hoshi K. Proliferation
medium in three-dimensional culture of auricularchondrocytes promotes effective cartilage
regeneration in vivo. Regen Ther. 2019 Oct 15;11:306-315.
12. Fujihara Y, Abe T, Asawa Y, Nishizawa S, Saijo H,
Hikita A, Hoshi K. Influence of DamageAssociated Molecular Patterns from Chondrocytes
in Tissue-Engineered Cartilage.Tissue Eng Part A.
2019 Nov 14. doi: 10.1089/ten.TEA.2019.0185.
[Epub ahead of print]
13. Tsai CH, Ting CC, Wu SY, Chiu JY, Chen H,
Igawa K, Lan TH, Chen CM, Takato T, Hoshi K,
Ko EC. Clinical significance of buccal branchesof the facial nerve and their relationship with the
emergence of Stensen's duct: An anatomical study
on adult Taiwanese cadavers. J Craniomaxillofac
Surg. 2019 Nov;47(11):1809-1818.
14. Komura M, Komura H, Satake R, Suzuki K,
Yonekawa H, Ikebukuro K, Komuro H, Hoshi K,
Takato T, Moriwaki T, Nakayama Y. Fabricationof an anatomy-mimicking BIO-AIR-TUBE withengineered cartilage Regen Ther 2019 Aug 8;
11:176-181. doi: 10.1016/j.reth.2019.07.004.

【総説】
1. Chijimatsu R, Saito T. Mechanisms of synovial
joint and articular cartilage development. Cell
Mol Life Sci. 2019 Oct;76(20):3939-3952. doi:
10.1007/s00018-019-03191-5.
2. Oichi T, Taniguchi Y, Oshima Y, Tanaka S, Saito T.
Pathomechanism of intervertebral disc degeneration. JOR Spine. 2020 Feb 13;3(1):e1076. doi:
10.1002/jsp2.1076.
【著書】

540

Cooperative Unit of Medicine andEngineering Research
Organization

The University of Tokyo Hospital
Cardiovascular Medicine, Nutrition and Metabolism, Surgical Oncology, Vascular Surgery,
Artificial Organ and Transplantation, Cardiac Surgery, Thoracic Surgery, Neurosurgery,
Urology, Orthopaedic Surgery, Oral and maxillofacial Surgery, Radiology, Tissue
Engineering Unit, Department of Clinical Epidemiology & Systems, Bone & Cartilage
Regenerative Medicine, Cartilage of Bone Regeneration, Department of
Immunotherapeutics (Medinet), Division of Science for Joint Reconstruction

Engineering and Pharmaceutical Research

Chemical System Engineering, Mechanical Engineering, Precision Engineering, Quantum
Engineering and System Science, Nuclear Engineering and Management, Chemistry andBiotechnology, Material Engineering, Information Science and Technology, Frontier
Sciences, Pharmaceutical Sciences Laboratory of Chemistry and Biology, Center for Disease
Biology and Integrative Medicine, Center for Disease Biology and Integrative Medicine
Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine
Clinical Biotechnology, Research Center for Advanced Science and Technology, Institute ofIndustrial Science

Introduction and Organization
The application of an advanced bioscience to a newtechnical development of clinical medicine has
become an important subject for research in the 21st
century. We’ve established Cooperative Unit ofMedicine and Engineering Research at The Universityof Tokyo Hospital to create a new research andeducation center, which cross-sectionally unites
medicine with engineering research for the development of a next generation medical technology.
2002 June. The establishment of Cooperative Unitof Medicine and Engineering Research was approvedby a hospital administration committee as a special
practice unit that belongs to The University of Tokyo
Hospital.
2002 September. A steering committee of Cooperative Unit of Medicine and Engineering Research
was organized by representative members of relevant

clinical departments. The committee made a decisionof the following basic principles; recruitment for theparticipation to this unit should be, as a general rule,
an open call for a joint project of clinical department
and engineering or pharmaceutical research group in
The University of Tokyo, an equipment/administration
expense of a laboratory should be a responsibility of
the user, and a basic participation period to this unit
should be three years and for the continued
participation in the unit, a review and approve of thesteering committee is indispensable.
2002 October. An open call for participants to thisunit started. There were 18 applications and thesteering committee approved all projects after review.
A liaison conference of Cooperative Unit of Medicine
and Engineering Research was organized by arepresentative member of each project. 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 the541

conference.
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

Research activities
Development of Advanced Stereotactic Radiation
Cancer Therapy System
Department of Radiology
Nuclear Professional School, Department of Nuclear
Engineering and Management
Department of Chemical System Engineering
High Precision Stereotactic X-ray Cancer Therapy
System. Development of Advanced Compact Electron
Linear Accelerator for Cancer Inspection and Therapy
The aim of this research is to apply the in-vivo
visualization technique developed by our group in
high-precision radiation therapy and to develop the
motion prediction system for a real-time
tumor-tracking radiation therapy. For the visualizationof the treatment area during treatment, afour-dimensional cone-beam computed tomography(4D CBCT) reconstruction algorithm is developed bytaking the anatomy or tumor motion analysis into
account. In-treatment 4D CBCT requires the
projection images acquired during treatment. The
projection images are analyzed online, and comparedwith the reprojection images from the treatment
planning CT or registration CT. The time lag due tothe analysis can be compensated by the prediction
using a multi-channel singular spectrum analysis. Thissystem will remove a delay problem during thereal-time tumor-tracking radiation therapy, and will
provide a safer radiation therapy than the current ones
because this will be able to detect an irregularbreathing motion of the tumor.
Research and development of micro-neurosurgicalrobotic systems
Department of Neurosurgery, The University of Tokyo
Hospital
Mitsuishi Laboratory, Department of MechanicalEngineering, School of Engineering
Development of micro-neurosurgical robotic systems
and advanced microscopic image processing forautonomous surgical task recognition.

542

Laboratory of Cavitation & Lithotripsy
Department of Urology, Faculty of Medicine
Department of Mechanical Engineering, School ofEngineering
Development of a new method of lithotripsy using
high intensity focused ultrasound induced cavitation.
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.
Division of Neutron Capture Therapy & Immunotherapy for Cancer
Department of Cardiothoracic Surgery, Graduate /School of Medicine
Department of Radiology, University of Tokyo
Hospital
Department of Nuclear Engineering and Management,
School of Engineering
Endowment Department, Department of Immunotherapeutics (Medinet)
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 withimmunotherapeutic approaches. We develop thetumour specific drug delivery systems entrappedboron or gadolinium compounds as neutron capture
agents.
Development of new method of detecting andimaging chemical probes for biomolecules
Laboratory of Chemistry and Biology,
Graduate School of Pharmaceutical Sciences
Department of Cardiovascular Medicine

To develop chemical probes for imaging of
biomolecules. To visualize arteriosclerotic andischemic lesions by using fluorescent probes and MRI
contrast media.
Development of adhesion barrier materials using a
new animal model of liver-peritoneal adhesion
Artificial Organ and Transplantation Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Hepato-Biliary-Pancreatic
Surgery
Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Organs and Biosystems Engineering Laboratory,
Institute of Industrial Science, The University of Tokyo
Division of Biomedical Equipment and Biomaterials,
Center for Disease Biology and Integrative Medicine,
Graduate School of Medicine, The University of Tokyo
Department of Chemical System Engineering,
Graduate School of Engineering, The University ofTokyo
Department of Bioengineering, Graduate School ofEngineering, The University of Tokyo
Adhesions between liver and other organs are an
important issue in the cases of second surgeries suchas hepatic resection. Adhesions extend operative
duration; in addition, they increase the risk ofsurgeries. Thus, it is important to avoid adhesions at afirst surgery. However, no one report both the animalmodel and adhesion barrier materials of liver adhesion.
We try to develop a new adhesion model by hepatic
resection, instead of a usual peritoneal abrasion model.
Also, we develop new materials for preventing theadhesions.
Development of new therapy of life style-relateddeseases by Applied Metabolic Biotechnology
Department of Cardiovascular Medicine, Graduate
School of Medicine
Department of Diabetes and Metabolic Diseases,
Graduate School of Medicine
Department of Chemistry and Biotechnology, Schoolof Engineering
To establish the system and methods for engineering
the novel model mice of life style-related diseases
using RNAi technology and biotechnology. To
elucidate the mechanisms by which adipose tissue

543

derived factors, adipokines, contribute to thedevelopment of the metabolic syndrome. To explore
the molecular mechanisms of sarcopenia.
Development of bone and cartilage regeneration byscaffold and mechanical stress
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Division of Science for Joint Reconstruction,
Graduate School of Medicine, The University of Tokyo
Ishihara & Takai Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Laboratory of Regenerative Medical Engineering,
Center for Disease Biology and Integrative Medicine,
Faculty of Medicine, The University of Tokyo
Department of Oral and Maxillofacial Surgery,
Faculty of Medicine, The University of Tokyo
Inhibition of aseptic loosening of artificial joints bynano-grafting of a novel biocompatible polymer MPC.
Creation of biocompatible biomaterials optimized forbone, cartilage and vascular regeneration. Regeneration of bone and cartilage tissue in vitro promoted byphysical stimulation
Development of a non-viral gene delivery system bysupramolecular nanotechnology.
Department of Materials Science, Graduate School ofEngineering, The University of Tokyo
Department of Bone & Cartilage Regenerative
Medicine, Graduate School of Medicine, The
University of Tokyo
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Department of Oral and Maxillofacial Surgery,
Faculty of Medicine, The University of Tokyo
Division of Clinical Biotechnology, Center for Disease
Biology and Integrative
Medicine, Graduate School of Medicine, The
University of Tokyo
Division of Tissue Engineering, The University ofTokyo Hospital
Development of a non-viral siRNA delivery system bysupramolecular nanotechnology. Production ofregenerated cartilage and bone with high safety andusefulness. Establishment of practical production

and quality control systems. Promotion of the clinicalapplication of regenerated cartilage and bone.
Development of easy, precise, non-invasive systems todetect osteoblastic and chondrogenic differentiation.
Determination of a finite set of signaling factors
sufficient for induction of osteoblasts andchondrocytes. Development of a method to induce
osteogenesis and angiogenesis simultaneously.
Development of a cell-sheet culture system for bone
and cartilage. Screening for compounds that inducebone and cartilage regeneration
Development of gene therapy of cardiovasculartherapy by polymeric micelles.
Department of Vascular Surgery, Division of Tissue
Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering,
The University of Tokyo
To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we aredeveloping non-viral gene vectors based on nanoscaled polymer assemblies (polymeric micelles).
Polymeric micelles, which are spontaneously formed
from block copolymers, have a core containing
packaged genes surrounded by biocompatiblepoly(ethylene glycol) (PEG) palisades, and a varietyof pilot molecules can be installed on the surface ofpolymeric micelles. This "virusmimicking" nanoparticles might achieve efficient gene transfer to thetargeted tissues or cells because of protection of theloaded DNA from nuclease attack, their lowered
non-specific interaction with proteins and cells andfacilitated internalization by the targeted cells throughspecific interaction of the pilot molecules. Currently,
our research has been focused on in vivo gene transfer
to artery walls and muscles using polymeric micelles
incorporated genes.
Development and application of biomolecule
visualization probes
Department of Cardiovascular Medicine
Laboratory of Chemistry and Biology, Graduate
School of Pharmaceutical Sciences
We have developed biomolecule visualization probes
and investigated model animals for application. As abiomolecule visualization probe, we are improving

544

and more applying fluorescent probes for cancer
lesion detection. Moreover, we are going to develop
labeled probes which can elucidate disease treatment
mechanism of microRNA and adipose stem cells. Now
as fundamental study, we are researching diseasemodels for applying these treatments. In particular, we
are investigating diabetic nephropathy, liver fibrosis
and atherosclerosis models as non-coding RNA andadipose stem cells treatment targets.

References (in 2019)
1. Sasako T, Kadowaki T, Ueki K. ADDITIONEurope: the first decade and beyond. Lancet
Diabetes Endocrinol 2019;7(12): 891-893.
2. Enooku K, Tsutsumi T, Kondo M, Fujiwara N,
Sasako T, Shibahara J, Kado A, Okushin K,
Fujinaga H, Nakagomi R, Minami T, Sato M,
Uchino K, Nakagawa H, Kondo Y, Asaoka Y,
Tateishi R, Ueki K, Ikeda H, Yoshida H, Moriya K,
Yotsuyanagi H, Kadowaki T, Koike K. Hepatic
FATP5 expression is associated with histologicalprogression and loss of hepatic fat in NAFLD
patients. J Gastroenterol. 2020; 55(2): 227-243.
Epub 2019 Oct 10.
3. Sugiyama T, Imai K, Ihana-Sugiyama N, Tanaka
H, Sugita-Yanagisawa A, Sasako T, Higashi T,
Okamura T, Yamauchi T, Ueki K, Ohsugi M,
Kadowaki T. Variation in process quality
measures of diabetes care by region andinstitution in Japan during 2015-2016: anobservational study of nationwide claims data.
Diabetes Res Clin Pract 2019;155: 107750.
4. Sasako T, Ohsugi M, Kubota N, Itoh S, Okazaki Y,
Terai A, Kubota T, Yamashita S, Nakatsukasa K,
Kamura T, Iwayama K, Tokuyama K, Kiyonari H,
Furuta Y, Shibahara J, Fukayama M, Enooku K,
Okushin K, Tsutsumi T, Tateishi R, Tobe K,
Asahara H, Koike K, Kadowaki T, Ueki K:
Hepatic Sdf2l1 controls feeding-induced ER stressand regulates metabolism. Nat Commun 2019;10(1): 947.
5. Murahashi Y, Yano F, Nakamoto H, Maenohara Y,
Iba K, Yamashita T, Tanaka S, Ishihara K,
Okamura Y, Moro T, Saito T. Multi-layered
PLLA-nanosheets loaded with FGF-2 induce
robust bone regeneration with controlled releasein critical-sized mouse femoral defects. Acta
Biomater. 2019; 85: 172-179.
6. Moro T, Ishihara K, Takatori Y, Tanaka S,
Kyomoto M, Hashimoto M, Ishikura H, Hidaka R,
Tanaka T, Kawaguchi H, Nakamura K. Effects ofa roughened femoral head and the locus ofgrafting on the wear resistance of thephospholipid polymer-grafted acetabular liner.
Acta Biomater. 2019; 86: 338-349.
7. Kyomoto M, Moro T, Yamane S, Watanabe K,
Hashimoto M, Tanaka S, Ishihara K. A hydrated
phospholipid polymer gel-like layer for increased
durability of orthopedic bearing surfaces.
Langmuir. 2019; 35(5): 1954-1963.
8. S. Kida, S. Kaji, K. Nawa, T. Imae, T. Nakamoto,S. Ozaki, T. Ohta, Y. Nozawa and K. Nakagawa,“Visual enhancement of Cone-beam CT by use of
CycleGAN”, Medical Physics 2020;47 (3).
9. S. Aoki, H. Yamashita, W. Takahashi, K. Nawa, T.
Ota, T. Imae, S. Ozaki, Y. Nozawa, J. nakajima, M.
Sato, M. Anraku, J. Nitadori, T. Karasaki, O. Abe
and K. Nakagawa, “Salvage stereotactic bodyradiotherapy for post-operative oligo-recurrenceof non-small cell lung cancer: A single-institution
analysis of 59 patients”, Oncology Letters 19,
2695-2704 (2020). T. Nakamoto, W. Takahashi, A.
Haga, S. Takahashi, S. Kiryu, K. Nawa, T. Ohta, S.
Ozaki, Y. Nozawa, S. Tanaka, A. Mukasa and K.
Nakagawa, “Prediction of malignant glioma
grades using contrast-enhanced T1-weighted andT2-weighted magnetic resonance images based ona radiomic analysis”, Scientific Reports 2019;9,
19411.
10. W. Takahashi, K. Nawa, A. Haga, H. Yamashita, T.
Imae, M. Ogita, K. Okuma, O. Abe, and K.
Nakagawa, “Acceptable fetal dose using ﬂattening
ﬁlter-free volumetric arc therapy (FFF VMAT) in
postoperative chemoradiotherapy of tongue
cancer during pregnancy”, Clinical andTranslational Radiation Oncology 2020;20, 9-12.
11. T. Mizutani, T. Magome, H. Igaki, A. Haga, K.
Nawa, N. Sekiya, and K. Nakagawa,“Optimization of treatment strategy by using amachine learning model to predict survival timeof patients with malignant glioma afterradiotherapy”, Journal of Radiation Research
2019;60(6), 818-824.

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12. R. Takenaka, A. Haga, K. Nawa, Y. Hideomi, and
K. Nakagawa, “Improvement of the robustness to
set up error by a virtual bolus in total scalp
irradiation with Helical TomoTherapy”, Radiological Physics and Technology 2019;12(4), 433437.
13. Qi P, Zheng Y.G, Ohta S, Kokudo N, Hasegawa K,
and Ito T. In situ fabrication of double-layeredhydrogels via spray processes to prevent postoperative peritoneal adhesion. ACS Biomaterials
Science and Engineering, 2019; 5(9): 4790-4798.
14. Ohta S, Toda T, Inagaki F, Omichi K, Shimizu A,
Kokudo N, Hasegawa K, and Ito T. The
Prevention of Hepatectomy-induced Adhesions by
Bilayer Sponge Composed of Ultrapure Alginate.
Journal of Surgical Research. 2019; 242: 286-295.
15. Qin C., Hou X., Khan T., Nitta N., Yanagawa M.,
Sakurai Y., Suzuki M., Masunaga S., Tanaka H.,
Sakurai Y., Takahashi H., Aoki I., Yanagie H.,
Cabral H., Enhanced MRI-Guided Gadolinium(III) Neutron Capture Therapy by Polymeric
Nanocarriers Promoting Tumor Accumulation andIntra-cellular Delivery, ChemNanoMat, 2019,
EMID:3d5802a01fa4be1b,
16. Furuya Y., Wakahara T., Furuya A., Yanagie H.,
Yasuhara H.: Rare bowel emphysema withsuperior mesenteric artery syndrome after surgery.
Ann R Coll Surg Engl. 2020 Feb;102(2):e26-e28.
17. Murahashi Y, Yano F, Chijimatsu R, Nakamoto H,
Maenohara Y, Amakawa M, Miyake Y, Yamanaka
H, Iba K, Yamashita T, Tanaka S, and Saito T*.
Oral administration of prostaglandin E2 receptor
4-selective agonist KAG-308 suppresses mouseknee osteoarthritis development through reductionof chondrocyte hypertrophy and TNF secretionfrom synovium. Sci Rep 2019;9:20329.
18. Oichi T, Taniguchi Y, Oshima Y, Tanaka S, andSaito T. Pathomechanism of intervertebral discdegeneration. JOR Spine. 2020;3:e1076.
19. Sugimoto H, Murahashi Y, Chijimatsu R, Miwa S,
Yano F, Tanaka S, and Saito T*. Primary cultureof mouse adipose and fibrous synovial fibroblasts
under normoxic and hypoxic conditions. Biomed
Res. 2020;41:43-51.
20. Inagawa Y, Komeno Y, Saito S, Maenohara Y,
Yamagishi T, Kawashima H, Saito T, Abe K,
Iihara K, Hatada Y and Ryu T. Prolonged

myelosuppression due to progressive bonemarrow fibrosis in a patient with acutepromyelocytic leukemia. Case Rep Hematol 2019:1616237.
21. Xuan F, Yano F, Mori D, Chijimatsu R,
Maenohara Y, Nakamoto H, Mori Y, Makii Y,
Oichi T, Taketo MM, Hojo H, Ohba S, Chung UI,Tanaka S, and Saito T*. Wnt/β-Catenin Signaling
Contributes to Articular Cartilage Homeostasis
through Lubricin Induction in the Superficial
Zone. Arthritis Res Ther 2019;21:247.
22. Miyauchi A, Kim-Kaneyma JR, Lei XF, Chang
SH, Saito T, Haraguchi S, Miyazaki T, andMiyazaki A. Alleviation of murine osteoarthritis
by deletion of the focal adhesion mechanosensitive adapter, Hic-5. Sci Rep 2019;9:15770.
23. Kawata M, Mori D, Kanke K, Hojo H, Ohba S,
Chung UI, Yano F, Masaki H, Otsu M, Nakauchi
H, Tanaka S, and Saito T*. Simple and robust
differentiation of human pluripotent stem cells
toward chondrocytes by two small-moleculecompounds. Stem Cell Reports 2019;13:530-544.
24. Chijimatsu R, Saito T*. Mechanisms of synovial
joint and articular cartilage development. Cell
Mol Life Sci 2019;76:3939-3952.
25. Oichi T, Taniguchi Y, Soma K, Oshima Y, Yano F,
Mori Y, Chijimatsu R, Kim-Kaneyma JR, Tanaka
S, and Saito T*. Adamts17 is involved in
Skeletogenesis through Modulation of BMPSmad1/5/8 Pathway. Cell Mol Life Sci 2019;76:4795-4809.
26. Okada H, Kajiya H, Omata Y, Matsumoto T, Sato
Y, Kobayashi T, Nakamura S, Kaneko Y,
Nakamura S, Koyama T, Sudo S, Shin M,
Okamoto F, Watanabe H, Tachibana N, Hirose J,
Saito T, Takai T, Matsumoto M, Nakamura M,
Okabe K, Miyamoto T, Tanaka S. CTLA4-Ig
directly inhibits osteoclastogenesis by interferingwith intracellular calcium oscillations in bonemarrow macrophages. J Bone Miner Res. 2019;34:1744-1752.
27. Yano F*, Ohba S, Murahashi Y, Tanaka S, Saito T,
Chung UI. Runx1 contributes to articular cartilage
maintenance by enhancement of cartilage matrix
production and suppression of hypertrophic
differentiation. Sci Rep 2019;9:7666.
28. Chang SH, Mori D, Kobayashi H, Mori Y,

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Nakamoto H, Okada K, Taniguchi Y, Sugita S,
Yano F, Chung UI, Kim-Kaneyma JR, Yanagita M,
Economides A, Canalis E, Chen D, Tanaka S, andSaito T*. Excessive mechanical loading promotes
osteoarthritis through the gremlin-1–NF-κB
pathway. Nat Commun 2019;10:1442,2019.
29. Izawa N, Kurotaki D, Nomura S, Fujita T, Omata
Y, Yasui T, Hirose J, Matsumoto T, Saito T,
Kadono Y, Okada H, Miyamoto T, Tamura T,
Aburatani H, Tanaka S*. Cooperation of PU.1
with IRF8 and NFATc1 defines chromatin
landscapes during RANKL-induced osteoclastogenesis. J Bone Miner Res 2019;34:1143-1154.
30. Chijimatsu R, Yano F, Saito T, Kobayashi M,
Hamamoto S, Kaito T, Kushioka J, Hart DA,
Chung UI, Tanaka S, Yoshikawa H, Nakamura N*.
Effect of the small compound TD-198946 on
glycosaminoglycan synthesis and chondrogenesisof 10.1002/term.2795human synovial derived
stem cell in vitro. J Tissue Eng Regen Med 2019;13:446-458.
31. Murahashi Y, Yano F, Nakamoto H, Maenohara Y,
Iba K, Yamashita T, Tanaka S, Ishihara K,
Okamura Y*, Moro T*, and Saito T*. Multilayered PLLA-nanosheets loaded with FGF-2
induce robust bone regeneration with controlled
release in critical-sized mouse femoral defects.
Acta Biomaterialia 2019;85:172-179.
32. Iino H, Okano T, Daimon M, Sasaki K, Chigira M,
Nakao T, Mizuno Y, Yamazaki T, Kurano M,
Yatomi Y, Sumi Y, Sasano T and Miyata T.
Usefulness of Carotid Arterial Strain Values for
Evaluating the Arteriosclerosis. J Atheroscler
Thromb. 2019;26:476-487.
33. Itoh H, Kaneko H, Kiriyama H, Nakanishi K,
Mizuno Y, Daimon M, Morita H, Yamamichi N
and Komuro I. Effect of Body Weight Change on
Blood Pressure in a Japanese General Population
with a Body Mass Index ≥ 22 kg/m. Int Heart J.
2019;60:1381-1386.
34. Itoh H, Kaneko H, Kiriyama H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y and Komuro I. Relation between theUpdated Blood Pressure Classification according
to the American College of Cardiology/American
Heart Association Guidelines and Carotid IntimaMedia Thickness. Am J Cardiol. 2019;124:396-

401.
35. Kiriyama H, Kaneko H, Itoh H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y and Komuro I. Correction to: Role ofanemia and proteinuria in the development ofsubsequent renal function deterioration in a
general population with preserved glomerular
filtration rate: a community-based cohort study. J
Nephrol. 2019;32:843-846.
36. Kiriyama H, Kaneko H, Itoh H, Yoshida Y,
Nakanishi K, Mizuno Y, Daimon M, Morita H,
Yatomi Y and Komuro I. Role of anemia andproteinuria in the development of subsequent
renal function deterioration in a general
population with preserved glomerular filtration
rate: a community-based cohort study. J Nephrol.
2019;32:775-781.
37. Yoshida Y, Nakanishi K, Daimon M, Ishiwata J,
Sawada N, Hirokawa M, Kaneko H, Nakao T,
Mizuno Y, Morita H, Di Tullio MR, Homma S and
Komuro I. Alteration of Cardiac Performance andSerum B-Type Natriuretic Peptide Level in
Healthy Aging. J Am Coll Cardiol. 2019;74:17891800.

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Genomic Research Support Center(GresCent)
Director & Professor
Yutaka Osuga, M.D., Ph.D.

1. Organization
Genomic Research Support Center was establishedin 2017 to support appropriate and harmonious
achievements of advanced genomic researches at the
University of Tokyo Hospital. Genomic Research
Support Center deals with cancer, life-style disease,
hereditary disorders, and so on. This center is directedby Professor Yutaka Osuga. Experts of these fields,
including Project Associate Professor Nobuhiro
Shojima, participate in the activities as follows; (1)large scale analysis of genomes utilizing next
generation sequencers and establishment of pipelinesof genome informatic analysis, (2) elucidation ofhereditary factors and pathogenesis of various
diseases, (3) integrated research and education of
genomic and clinical information, (4) analysis ofpolymorphism and mutation of genes involved insusceptibility and response to treatment in various
diseases such as life-style disease, and (5)establishment of database and integrated data miningof associated clinical information.

2. Activities
In collaboration with RIKEN, we have identified
genetic variations conferring susceptibility to type 2
diabetes, myocardial infarction, renal dysfunction,
and atherosclerosis obliterance (ASO) in the Japanese
population. We are now performing a genome-wide
association study to identify variations conferring
susceptibility to type 2 diabetes in the Japanese
population. About 500,000 variants directly
genotyped were imputed using the 1000 Genomes
Project Phase 3 reference panel in 36,000 cases andmore than 155,000 controls. We identified novel type2 diabetes associated loci, which had distinct minor
allele frequency spectra between Japanese andEuropeans, such as the missense variants in genes
related to insulin secretion. Trans-ethnic comparisonsof the molecular pathways from the genome-wide
association study (GWAS) results highlighted bothethnically shared and distinct impacts of a series ofpathways on type 2 diabetes. These findings
illustrated the etiology of type 2 diabetes in Japaneseand Europeans. We identified 88 type 2 diabetes –associated loci, of which 28 loci were novel. Twentyeight missense variants were in linkage disequilibriumwith the lead variants, including missense variants ingenes related to insulin secretion (GLP1R) （Suzuki
K, et al. Nat Genetics 51, 379-386, 2019）. Mahajan
et al. reported type 2 diabetes genome-wide
association
study
meta-analysis
dataonapproximately 900,000 individuals of European
ancestry, increasing the association signals in over
240 loci associated with type 2 diabetes (Mahajan A,
et al. Nature Genetics 50, 1505-1513, 2018). Type 2
diabetes GWAS meta-analysis performed in a
Japanese population identified no less than 20 novel
type 2 diabetes loci that were not associated with type2 diabetes in Europeans. This article is referenced in
the position statement from science council of Japan.
To examine type 2 diabetes risk in East Asian
individuals, our team carried out a meta-analysis of
GWAS data from 77,418 individuals with type 2
diabetes and 356,122 healthy control individuals. We
identified 61 loci that are newly implicated in
predisposition to type 2 diabetes. (Spracklen CN, et al.
Identification of type 2 diabetes loci in 433,540 East

548

Asian individuals, Nature 582, 240-245, 2020).
We conducted whole genome sequence andanalyzed the sequence data of 1,987 subjects with type2 diabetes in collaboration with the Osaka University,
RIKEN and BioBank Japan. We conducted
metabolome analysis and analyzed the data of 300
subjects with diabetic complications. We aredeveloping the methods to predict diabetic
complications and deterioration of diabetes bybioinformatics algorithms including the Penalized
regression method, often used in machine learningand public OmiX database.
In collaboration with Department of Clinical
Genomics, we supported the meetings and expertpanel regarding cancer and rare diseases. We hadclinical and genomic WEB conference with hospitals
related to cancer treatment.
We shared genomic data with researchers abouttype 2 diabetes association study, Set3 (121,950
controls, 18,688 cases) and Set4 (7,065 controls,
2,483 cases) through national bioscience databasecenter, NBDC (https://humandbs.biosciencedbc.jp/
hum0014-v18#diabet3).
We made paper to inform for the participants of theresearch on ‘Realization of personalized medicine for
Metabolic syndrome related disease.’ in collaboration
with research ethics support center.
We are interviewed and contributed to the report by
the project of Japan Agency for Medical Research andDevelopment (AMED) concerning ethical, legal andsocial issue of secondary findings in genomic research(Aizawa Y, et al. A proposal on the first Japanesepractical guidance for the return of individual
genomic results in research settings. J Hum Genet. 65,
251-261, 2020).
We used panel analysis applying next-generation
sequencer and revealed the genetic diagnosis on
extreme phenotypes of diseases related to life-styles
including, maturity onset diabetes of the young andlipodystrophy and predicted the prognosis andselected effective therapies.

3．References
1. Suzuki K, Akiyama M, Ishigaki K, Kanai M,
Hosoe J, Shojima N, et al. Identification of 28

new susceptibility loci for type 2 diabetes in theJapanese population. Nat Genet. 2019 Mar; 51(3):379-386. doi:10.1038/s41588-018-0332-4. Epub
2019 Feb 4.
2. Inoue S, Hirota Y, Ueno T, Fukui Y, Yoshida E,
Hayashi T, Kojima S, Takeyama R, Hashimoto T,
Kiyono T, Ikemura M, Taguchi A, Tanaka T,
Tanaka Y, Sakata S, Takeuchi K, Muraoka A,
Osuka S, Saito T, Oda K, Osuga Y, Terao Y,
Kawazu M, Mano H. Uterine adenomyosis is anoligoclonal disorder associated with KRAS
mutations. Nat Commun. 2019 Dec 19; 10(1):5785. doi: 10.1038/s41467-019-13708-y.
3. Yamada T, Lee CL, Liu WJ, Shojima N. Slow
Weight Loss During Comprehensive Treatment
and Worse Metabolic Control with Higher Weight
Regain: A Trajectory Analysis. Obesity (Silver
Spring). 2019 Dec; 27(12): 1925-1926. doi:10.
1002/oby.22655. Epub 2019 Nov 3.

Center for Disease Biology andIntegrative Medicine

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Laboratory of Molecular
Biomedicine for Pathogenesis
Professor
Toru Miyazaki, M.D., Ph.D.

Associate Professor
Satoko Arai, Ph.D.

Assistant Professor
Natsumi Maehara, Ph.D.

Project Associate Professor
Hideaki Ando, Ph.D. (Laboratory for New Generation Drug Discovery)

Project Associate Professor
Risa Suzuki, Ph.D. (Laboratory for New Generation Drug Discovery)
Kaori Taniguchi, Ph.D. (Laboratory for New Generation Drug Discovery)

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

551

studies showed that AIM plays an important role inregulating the pathological condition of the modern
diseases.
AIM is produced by macrophage and largely
presents in bloodstream as a soluble molecule. Once
AIM is incorporated into adipose tissue, it
decomposes fatty droplets resulting in controlling the
progression of obesity. However, when this process
undergoes effectively and excessively under the obese
condition, oppositely to control the progression ofobesity, chronic inflammation of adipose tissue andinsulin resistance are triggered and Type II diabetes
and atherosclerosis are worsen.
Moreover, because AIM binds to IgM in bloodstream, it leads to production of various autoantibodies, especially under the obese condition.
This suggests that the obesity is the cause of
autoimmune disease. Other studies showed that liverdisease, cancer, and kidney disease worsen under low
concentration of AIM. It is suggested that theconcentration of AIM in bloodstream differentiates theoutcome and the risk of getting various diseases.
The project was accepted for Advanced Researchand Development Programs for Medical Innovation,
Leading Advanced Projects for medical innovation(LEAP) 2019, on Japan Agency for Medical Researchand Development (AMED).
Finding the mechanism on the regulation of AIM
activity will shed light on developing a diagnostics
and potential treatments to modern diseases. We will
focus on the details of involvement of AIM to thevarious diseases by generating a mouse model. Also,
cohort study is carried out using and analyzing thehuman specimen, aiming to develop a novel drug
treatment.

system and the structural analysis of AIM. This
laboratory is coming to completion this 3rd year.
Joint Meeting
In July 2019, several medical laboratories from
Shimane University and our laboratory jointly held the
4th summer seminar in Tsuwano, Shimane. The
members from the both universities including theteaching staffs, graduate students and researchers,
fully enjoyed this work shop, and having intense
research sessions with lively discussions, which canlead to future collaborations. We could also strike up afriendship through the dinners and recreations during
the three days.
Similar meetings are organized by our laboratory
every year, e.g. Taiwan-Japan Joint Meeting in 2013
(hosted by National Taiwan University, National Yang
Ming University, and the University of Tokyo), theCREST joint meetings in 2014 and 2015 (hosted by
Kumamoto University and the University of Tokyo)
and, Scientific Meeting in 2016 and 2018 (hosted by
Shimane University and the University of Tokyo) and,Taiwan-Japan Joint Meeting in 2017 (hosted by
National Taiwan University and the University ofTokyo). We will keep planning such Joint Meetings in
the future.
Seminar hosted by our lab
Title: Study of the involvement of MIC in thepathological regulation of autoimmune diseases
by AIM. / Prof. Seiamak Bahram (University ofStrasbourg, France)
In January 2020, we organized an invited lecture by
Prof. Seiamak Bahram. He introduced his research
regarding MHC class I-related sequence (MIC) gene.

Lab Activities

Publications

Laboratory for New Generation Drug Discovery
This endowed laboratory was established in 2017
for the purpose of the drug development aiming at theclinical application of AIM protein and relatedmaterials. In this laboratory, we investigate theprocess development for the AIM protein manufacturing under the GMP condition. In addition, we aretrying to find small molecules that can activate AIM
through developing the high throughput screening

1. Takano T, Bareke E, Takeda N, Aoudjit L,
Baldwin C, Pisano P, Matsuda J, El Andalousi J,
Muhtadie L, Bernard C, Majewski J, Miyazaki T,
Yamamura KI, Gupta IR. Recessive mutation in
CD2AP causes focal segmental glomerulusclerosis in humans and mice. Kidney Int. 2019
Jan;95(1):57-61.
2. Komatsu G, Nonomura T, Sasaki M, Ishida Y,
Arai S, Miyazaki T. AIM-deficient mouse fed a552

high-trans fat, high-cholesterol diet: a new animalmodel for nonalcoholic fatty liver disease. Exp
Anim. 2019 May 8;68(2):147-158.

553

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Lecturer
Sho Yagishita, M.D. Ph.D.

Research Associates
Makiko Negishi, Ph.D.

Homepage

http://www.bm2.m.u-tokyo.ac.jp/

Introduction and Organization
The Center for Disease Biology and Integrative
Medicine (CDBIM) has been established in 2003, andelected Dr. Kasai as the professor of the Division of
Basic Medical Sciences (2) of CDBIM in July of 2004.
Dr. Kasai was in the National Institute forPhysiological Sciences, and officially took office inthe University of Tokyo in November, 2005. The
Kasai laboratory has moved to the first building ofFaculty of Medicine in January, 2006. It belongs to theSection of Functional Biology in the Graduate Schoolof Medicine. Its name has been changed from
Division of Biophysics to Laboratory of Structural
Physiology in the April, 2008. Dr. Kasai has also
appointed as a principal researcher in the International
Research Center of Neurointelligence (IRCN), theInstitute of Advanced Studies of the University ofTokyo since it has established in 2018.10, and thelaboratory is cooperating the activity of IRCN.
The 20 members of our laboratories in the March of2019 are Haruo Kasai, Sho Yagishita (Lecturer),
Makiko Negishi (Research Associate), Kazuhiko Ishii(Research Associate), Kenji Yamagushi (Project
Researcher), Hasan Ucar (Project Researcher), Yusuke
Iino (Doctor course student D4), Mio Tajiri (Doctor
course student D3), Takeshi Sawada (D3), Yuichi
Morimoto (D3), Toshiaki Kume (D2), Hongyu Amy
Chang (Master course student, M1), Hitoshi Okazaki(Medical Intern), Monami Nishio (Medical school

student, M1), and as technical staffs, Haruka Ohno,
Arisa Kurabayashi, Yuki Sakata, Masayoshi Asaumi,
Rie Yonemoto and Yumiko Saikachi.

Teaching activities
We gave three lectures of physiology forundergraduate students, was responsible for one
student experiment, four lectures of physiology andneuroscience for master course students, organized ten
lectures of the functional biology for graduate students.
One undergraduate student joined the activity of ourlaboratory for free quarter (FQ).

Research activities
Functional imaging is a central theme in modern
biology and medicine. All biological functions involvea multitude of interactions at the molecular, cellular,
and system levels, and it is ultimately desirable toperform molecular and cellular imaging in intact
preparations in which the original in vivo functions
are preserved. We have been exploring two-photon
excitation microscopy with a new type of laser, an
infrared femtosecond-pulse laser, as a means toachieve this goal. The two-photon microscope has theability to penetrate deep into tissues and is the only
imaging instrument that allows investigations of intact
tissues at the cellular and molecular levels. Twophoton microscopy can also be readily combined with554

molecular biological and other physiological methods,
and it promises to provide important insight into
various biological processes in the coming years. Our
research interests have two main focuses: (1) the
dynamics of synapses in the cerebral cortex and (2)exocytosis in both neurons and secretory cells. We
welcome multidisciplinary collaborations to promote
our research goals and to help to adapt the new
microscopic techniques and lasers to a wide range of
biomedical applications.
(1) Dendritic spines are postsynaptic to most
excitatory synapses in the brain, and their structuralchanges are a major cellular basis for learning andmemory (Kasai, et al. 2010. Spine generation andelimination are robust processes, even in the adultbrain, and spine enlargement and shrinkage play key
roles in the plasticity of dendritic spines. We
previously used two-photon glutamate uncaging tostimulate individual spines and demonstrated that
dendritic spine enlargement underlay long-term
potentiation (LTP) at the level of single spines(Matsuzaki,, Kasai, Nature 2004). We also reported
that spine shrinkage and elimination can be induced
when glutamate uncaging was paired with action
potentials in the presence of GABAergic inhibition(Hayama,,Kasai, 2013). Spine structures are
dynamically maintained by the regulation of actin
fibers (F-actins). Cofilin is a highly abundant
actin-regulatory protein, which binds to and alters thephysical properties of F-actin. Dephosphorylated
cofilin at its serine-3 residue (dp-cofilin) cleaves
F-actin to generate new barbed ends that are sites for
actin polymerization and depolymerizes F-actin at its
pointed end to reduce fiber length. These bidirectional
enzymatic activities of cofilin are inhibited by its
phosphorylation at the serine-3 residue, as
phosphorylated cofilin (p-cofilin) dissociates from
F-actin. Thus, the entire lifecycle of F-actin isregulated by cofilin. Dendritic spine enlargement andshrinkage are likely also regulated by thephosphorylation and dephosphorylation of cofilin1(Noguchi,, Kasai 2016). We previously showed thatbidirectional structural plasticity is controllable inindividual
spinesbymodulating
cofilinphosphorylation (Hayama,, Kasai, Nat, Neurosci.
2013). We have also made a optic probe which labels

enlarged spines, and optically erase them after
learning, and first demonstrated the causal relationshipbetween spine enlargement and memory (Hayashi,2015).
Dendritic spines can change their forms alsowith day-by-day fluctuations of the sizes of
postsynaptic densities (Yasumatsu,, Ksai J. Neurosci2008). Such spontaneous fluctuations are slow, buthappening continuously, and play a determinant rolein determining the spine size (distribution), and spine
elimination and generation. These dynamics areimportant for the brain function in health anddisorders. In fact, calcineurin is required for long-term
depression and activity-dependent spine shrinkage,and calcineurin mutations have been identified inpatients with schizophrenia. Moreover, mice withconditional knockout of calcineurin B (CNB-KO)
exhibit behavioral abnormalities suggestive of
schizophrenia. Changes in the dendritic spines ofthese mice, however, have not been investigated. We
therefore examined the dendritic spines of CNB-KO
mice, and observed a significant reduction in small
spines and an increase in large spines in the prefrontal
and visual cortices of CNB-KO mice. The effect of
CNB-KO on the spine sizes was relatively moderate,possibly due to the presence of spontaneous
fluctuations of dendritic spines. Thus, CNB-KO mice
showed the spine phenotype similar to those recently
reported in patients with schizophrenia (Okazaki,,Kasai, Neurosci. Lett, 2018, Ref. 1).
In this year, we revealed that the fluctuations
have a stabilized role in recurrently connected neuralnetwork with Hebbian learning rule, which tends toshow runaway activities. This was diminished by thefluctuations, and the spine volume distributions were
unimodal as we found in vivo. Despite the fluctuations,the circuits can store memory due to the plasticity
induced by the spontaneous activity using simulation
with large scale neural network (Humble, 2019, Ref.
3). Using AS probe, we have demonstrated that thelong-term ketamine effects on depressive symptoms
were due to spine generation in the prefrontal cortex(Mod-Sada, 2019, Ref. 1). Two-photon glutamate
uncaing is the most method to investigate spine
enlargement, but never been introduced in vivo
neocortex. We have developed a method to apply
two-photon uncaing in vivo, and found that spine

555

enlargement can be induced also in neocortex but only
20% population of spines. In contrast, we weresuccessful in inducing spine shrinkage in most spines
as in hippocampus, indicating that the selective
induction of spine enlargement is not due to technicalissue, while spines in neocortex are selected forenlargement (Noguchi, 2019, Ref.4). This property of
neocortical spine may act to reduce overwriting, andthe mechanisms of selection should be investigated in
the future.
(2) The presynaptic functions:
We have established a new imaging approach tomonitor presynaptic function using the presynaptic
proteins called SNARs which mediate exocytosis by
their assembly and a fluorescent life-time imaging tomonitor FRET between the two SNAREs spaning thetwo membranes (VAMP2 and Syntaxin1, Takahashi,,Kasai, Nat. Commun. 2015). We are now applying
this technique to investigate the interaction of pre- andpostsynaptic parts of synapses in a single identified
spine synapses. We have obtained the preliminary data
showing the effects of spine enlargement on its
presynaptic terminals.

References
1. Moda-Sava, R.N., Murdock, M.H., Parekh, P.K.,
Fetcho, R.N., Huang, B.S., Huynh, T.H., Witztum,J., Shaver, D.C., Rosenthal, D.L., Always, E.J.,
Lopez, K., Meng, Y., Nellissen, L., Grosenick, L.,
Deisseroth, K., Bito, H., Kasai, H. & Liston, C.
(2019). Sustained rescue of prefrontal circuit
dysfunction by antidepressant-induced postsynaptic spine formation. Science, 364: eaat8078.
DOI: 10.1126/science.aat8078.
2. Park, I., Kim,H-J., Kim, Y., Kasai, H., Kim, J-H.
& Park, J-W. (2019). Nanoscale imaging reveals
miRNA-mediated control of functional states ofdendritic spines. Proc. Natl. Acad. Sci. U.S.A.,
116:9616-9621. DOI 10.1073/pnas.1819374116
3. Humble, J., Hiratsuka, K., Kasai, H. & Toyoizumi, T.
(2019). Intrinsic spine dynamics are critical forrecurrent network learning in models with andwithout autism spectrum disorder. Frontiers in
Computational Neuroscience 13,A38 DOI: 10.3389/
fncom.2019.00038

4.

Noguchi, J., Nagaoka, A. , Hayama, T. , Ucar, H.,
Yagishita, S., Takahashi, N. & Kasai, H. (2019).
Bidirectional in vivo structural dendritic spine
plasticity revealed by two-photon glutamate
uncaging in the mouse neocortex. Scientific
Reports, 9: 13922. DOI: 10.1038/s41598-01950445-0

556Laboratory of Biomedical
Equipment and Biomaterials
Associate Professor
Taichi Ito, Ph.D.

Assistant Professor
Naoki Tomii, Ph.D., Seiichi Ohta, Ph.D.

Homepage

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

Introduction and Organization
The Division tightly collaborates with Faculty ofEngineering. Prof. Ito charged at Department ofChemical System Engineering and Bioengineering.
The current laboratory members include AssistantProfessor Ohta, one posdoc, three associates, and 16
graduate students School of Engineering andMedicine.

Teaching activities
Associate Prof. Ito is sharing duties for undergraduate
and graduate students of both Graduate School of
Medicine and Graduate School of Engineering. They
give lectures on biomedical engineering at Graduate
School of Medicine. Prof. Ito gives a lecture
concerning biosystemengineering, separation
technology I, biotechnology II, Basic Biology, andOverview of Chemical Bioengineering at theChemical System Engineering course and Bioengineering course at Graduate School of Engineering
School.

Research activities
Biomaterials are one of important keys in medicine
and medical engineering. In the field of tissue
engineering, scaffold materials are extremely
important. In the drug delivery field, drugs areencapsulated in various materials which achieve ideal
release kinetics. The functions of these biomaterials

and phenomena inside and outside biomaterials invivo are complicated both in terms of chemistry andbiology. Ito Laboratory is trying to design and develop
novel biomaterials for tissue engineering and drugdelivery by the combination of medicine and chemicalsystem engineering. Especially we focus on hydrogels
which can be utilized for islet regeneration and drugdelivery in peritoneum.
1) Development of Hydrogels for medical uses
- Development of novel in situ crosslinked hydrogels
for a medical use using hyaluronan, chitosan,
dextran, alginate, gelatin, carboxymethyl cellulose
and synthetic dendritic polymers.
2) Development of particles for medical uses
- Nano-sized semi-conductor and metal particles forimaging- Micro-sized particles composed of PLGA, PEG,
Albumin.
3) Challenge to establish novel treatments using new
medical hydrogels and particles.
- Peritoneal adhesion prevention- Hemostats- Drug delivery for peritoneal dissemination,
Mesothelioma, Liver cirrhosis- Hydrogel scaffolds for regeneration of islets andbones- Artificial Oxygen Carriers
In addition, Assistant Professor Tomii and his
students are developing an advanced imaging system

557

using ultrasound with large interaction and low
invasiveness with the living body, minimally invasive
treatment using ultrasound, and a combination device
with drugs.
1. Ultrasonic imaging
An ultrasonic CT (Computed Tomography)
We are developing clinical testing equipment for
ultrasonic CT screening and diagnosis system aiming
at the early detection of breast cancer. Ultrasound CT
uses ultrasound which is minimally invasive and has
many interactions with the living body (large amountof information that can be acquired) as the imaging
method. The amount of obtained information is large
in proportion to the computation cost. We aredeveloping high precision image reconstruction
algorithm utilizing parallel computing and application
technology extracting new biological information.
2. Ultrasound therapy1) Development of minimally invasive treatment
equipment and systems
We are developing an intracranial ultrasonicirradiation system and conduct research aiming to
induce action potential and stimulated motion byadding mechanical stimulus to nerve cells. In addition,
we are also developing therapy monitoring method
aiming at high accuracy of minimally invasive
treatment.
2) Ultrasonic drug delivery system
We are also developing ultrasonic drug delivery as atherapeutic application of ultrasound. In particular, we
aim to realize the enhancement of drug permeabilityof the cerebrovascular barrier by combining
ultrasound and microbubbles.

References(1) K. Mitsuhashi, P. Qi, A. Takahashi, S. Ohta, and T.
Ito, “Prevention of postoperative peritoneal
adhesions in rats with sidewall defect-bowel
abrasions using metal ion-crosslinked N-succinyl
chitosan hydrogels”, Reactive and Functional
Polymers 2019 (145) 104374(2) P. Qi, Y. G. Zheng, S. Ohta, N. Kokudo, K.
Hasegawa, T. Ito, “In situ fabrication of
double-layered hydrogels via spray processes toprevent postoperative peritoneal adhesion”, ACS
Biomaterials Science and Engineering, 2019, (5),4790-4798.
(3) Y. Amano, S. Ohta, K. L. Sakura, T. Ito,
"Pemetrexed-conjugated hyaluronan for thetreatment of malignant pleural mesothelioma",
European Journal of Pharmaceutical Sciences,
2019, 138, 105008(4) Y. Oki, K. Kirita, S. Ohta S. Ohba, I. Horiguchi, Y.
Sakai, T. Ito,” Switching of cell proliferation/differentiation in thiol- maleimide clickablemicrocapsules triggered by in situ conjugation of
biomimetic peptides", Biomacromolecules, 2019,(20), 2350-2359(5) S. Ohta, M. Matsuura, Y. Kawashima, X. Cai, M.
Taniguchi, H. Okochi, Y. Asano, S. Sato, T. Ito,”
Facile fabrication of PEG-coated PLGA microspheres via SPG membrane emulsification for thetreatment of scleroderma by ECM degrading
enzymes", Colloids and Surfaces B: Biointerfaces,
2019, (179), 453-461(5) Y. Amano, Y. Nakagawa, S. Ohta, T. Ito,
“Ion-responsive fluorescence resonance energy
transfer between grafted polyacrylic acid arms ofstar block copolymers” Polymer, 2018, 137(14),169-172.
(6) T. Hozumi, T. Kageyama, S. Ohta, J. Fukuda, T. Ito,
“An Injectable Hydrogel with Slow Degradability
Composed of Gelatin and Hyaluronic Acid
Crosslinked by Schiff’s Base Formation”
Biomacromol., 2018, 19(2), 288–297.
(7) P. Qi, S. Ohba, Y. Hara, M. Fuke, T. Ogawa, S. Ohta,
T. Ito “Fabrication of calcium phosphate-loaded
carboxymethyl cellulose non-woven sheets for boneregeneration” Carbohydr. Polym., 2018, 189, 322330.
(8) S. Ohta, K. Hashimoto, X. Fu, M. Kamihira, Y.
Sakai, T. Ito, "Development of Human-derived
Hemoglobin/Albumin Microspheres as Oxygen
Carriers Using Shirasu Porous Glass Membrane
Emulsification" J. Biosci. Bioeng, 2018, 126(4),533-539.
(9) M. Sakoda, M. Kaneko, S. Ohta, P. Qi, S. Ichimura,Y. Yatomi, T. Ito, "An Injectable Hemostat
Composed of a Polyphosphate- ConjugatedHyaluronan Hydrogel" Biomacromol., 2018, 19(8),3280–3290.

558(10) Y. Amano, P. Qi, Y. Nakagawa, K. Kirita, S. Ohta, T.
Ito, “Prevention of peritoneal adhesions by ferricion-crosslinked hydrogels of hyaluronic acidmodified with iminodiacetic acid” ACS Biomater.
Sci. Eng., 2018, 4(9), 3405-3412.
(11) A. Sakamoto, P. Qi, S. Ohba, S. Ohta, Y. Hara, T.
Ogawa, M. Tomokiyo, A. Sasaki, H. Takizawa, M.
Mochizuki, T. Ito, M. Honnami,"Bone regeneration by calcium phosphate-loaded
carboxymethyl cellulose nonwoven sheets in canine
femoral condyle defects" J. Biomed. Mater. ResPart B – Appl. Biomater., 2018, 107 (5), 1516-1521.

559

Laboratory of Clinical
Biotechnology
Professor
Yuichi Tei/ Ung-il Chung, M.D.,Ph.D.

Associate Professor
Shinsuke Ohba, D.D.S., Ph.D. (by April 2019), Hironori Hojo, Ph.D. (from October 2019)

Homepage http://www.tetrapod.t.u-tokyo.ac.jp/index_en.html
http://www.cdbim.m.u-tokyo.ac.jp/english/index.php
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 inwhich medical biology and engineering are integrated
and play important roles. Since the medicine-560

engineering 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;
Regen Ther 6, 100-107, 2017; Int J Mol Sci. 20(24).
pii: E6324, 2019). 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

561

the

cells (Arthritis & Rheumatology 50:3561, 2004;
FASEB Journal 21:1777, 2007).

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). We are attempting toapply the protocols to the generation of PSC-derived
bone-like tissues, in which distinct cell populations
regulating bone formation 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 toreproduce human bone development and metabolism
in a physiologically relevant manner. These systems
will also allow us to visualize bone metabolism invitro with imaging techniques, contributing to drug
discoveries for the treatment of various bone diseases
such as osteoporosis, and to our understanding of thediseases' pathophysiology and of the molecularmechanisms underlying skeletal formation andmaintenance.
We have also worked on the development of
direct reprogramming methods in which osteoblasts
and chondrocytes are directly generated from somatic
cells including fibroblasts, without the use of stem

3. The identification of bioactive factors that inducebone/cartilage formation and their application tobone/cartilage repair
Skeletal formation is regulated by various signaling
pathways and transcription factors. The manipulationof key pathways and/or factors would enable us to not
only induce skeletal formation and regeneration, butalso suppress the progression of skeletal degeneration.
Thus, we are carrying out molecular-biological andmouse genetic studies to elucidate the roles ofosteogenic and chondrogenic signaling pathways aswell as the modes of their actions. Based on thesebasic findings, we are also working on theidentification and application of bioactive moleculesthat induce osteogenesis and chondrogenesis.
We have been focusing on: (1) hedgehog (Hh)signaling-mediated cell fate specification duringosteoblast development (Development 131:1309,
2004； Journal of Biological Chemistry 282:17860,
2012; Journal of Biological Chemistry 288:9924,
2013), and (2) transcriptional regulation mediating
osteoblast differentiation and maturation (Developmental Cell 14:689, 2008; PLOS ONE, 2014). Thesestudies further extend to the development of the small
molecule-based treatment of bone fractures, using the
Hh signaling-activator molecule SAG (Biochemical
and Biophysical Research Communications 479:772,
2016) and bone regenerative therapy with SAG-loaded
calcium phosphate artificial bones (Biomaterials
34:5530, 2013). By combining biological findings
with engineering techniques, we are working on boneregeneration by plasmid delivery using polymericnanomicelles as nucleic acid carriers (Molecular
Therapy 15:1655, 2007) and the suppressive treatmentof cartilage degeneration by mRNA delivery(Scientific Reports 6:18743, 2016).
We have also identified novel small moleculesthat induce bone and cartilage formation (Biochemical
and Biophysical Research Communications 357:854,
2007; Annals of Rheumatic Diseases 72:748, 2013),
through the screening of compound libraries withcell-based sensors enabling the high-throughput
detection of osteoblast and chondrocyte differentiation(Biochemical and Biophysical Research Communica-

repair and regeneration are induced
manipulation of the specification processes.

by

562

tions 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 Associate Professor
Takamasa Sakai at the Department of Bioengineering,
UTokyo, we are developing a high-performancehydrogel unit that fulfills the necessary characteristics,
based on knowledge and techniques that we haveaccumulated regarding the design and fabrication ofnovel hydrogels (Macromolecules 41:5379, 2008;
Science 343:873, 2014; Advanced Materials 27:7407,
2015; Nature Biomedical Engineering 1:44, 2017).
The high-performance hydrogel unit would integratesignaling factors with shape-controlled scaffold
materials, leading to the development of implant
devices that work as scaffolds for tissue repair andalso as carriers of bioactive factors. Through a seriesof 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. Hojo H, Ohba S. Insights into Gene Regulatory
Networks in Chondrocytes. International journalof molecular sciences. 2019;20(24).
2. Kawata M, Mori D, Kanke K, Hojo H, Ohba S,
Chung UI, et al. Simple and Robust
Differentiation of Human Pluripotent Stem Cells
toward Chondrocytes by Two Small-Molecule
Compounds. Stem cell reports. 2019;13(3):53044.
3. Xuan F, Yano F, Mori D, Chijimatsu R,

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Maenohara Y, Nakamoto H, et al. Wnt/β-cateninsignaling contributes to articular cartilage
homeostasis through lubricin induction in the
superficial zone. Arthritis Res Ther. 2019;21(1):247.
4. Fujinaga I, Yasuda T, Asai M, Chung UI,Katashima T, T. Sakai. Cluster growth in percolation process from diluted system. Polymer Journal
2019;52:289–297
5. Katashima T, Chung UI, and Sakai T. Mechanical
Properties of Doubly Crosslinked Gels. Polymer
Journal, 2019;51:851-859
6. Katashima T, Sakurai H, Chung UI, and Sakai T.
Dilution effect on the cluster growth near thegelation threshold. Nihon Reoroji Gakkaishi,
2019;47(2):61-66

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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.

Research Assistant
Hiroyasu Sato, Ph.D.

Project Assistant
Rina Takamiya, Ph.D.

Home Page

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

Introduction

Research activities

Laboratory of Environmental Health Sciences of theCenter for Disease Biology and Integrative Medicine
moved the laboratory from the 3rd floor of the Medical
Faculty of Medicine Building 1 to the 8th floor of theClinical Research Center A on October 2016 andmodified the laboratory name to Laboratory ofMicroenvironmental and Metabolic Health Sciences on
April 2017, aiming at examining biochemistry andmicroenvironmental biology of lipids as well as
environmental toxicology. One professor, one associate
professor, one research assistant, one project assistant,
one project researcher, one visiting researcher, six
graduate students (three for the doctoral course andthree for the master course), three external researchers,
and one research assistant conducted the researches
together during the year of 2019.
This laboratory belongs to the Department of Social
Medicine, cooperates to the Departments International
Health Sciences and Social Public Health, and isengaged in education and research on relationships.
The laboratory is also associated with the Department
of Cellular Signaling, the Molecular Cell Biology.

Laboratory of Microenvironmental and Metabolic
Health Sciences was constituted by two major research
projects; “lipid biology” by a group of Murakami(professor) and “environmental toxicology” by a groupof Ohsako (associate professor).
1. Lipid biology (Murakami’s group)
The main theme of this research project is to clarify
the role of lipids in health and diseases. Lipids supply
the largest source of energy in living organisms, aremain components of cell membranes, act as signal
molecules, and constitute a barrier covering the bodysurface (four major functions of lipids). Lipids areenvironmental nutritional factors ingested from foods,
as well as tissue microenvironmental regulators thatspatiotemporally coordinate various biologicalresponses after being metabolized to specific bioactive
lipids. By performing comprehensive lipid analysis(lipidomics) on gene-manipulated mice for lipidmetabolizing enzymes, particularly those in thephospholipase A2 (PLA2) family, we aim to elucidate
the molecular pathophysiology of diseases (e.g.
metabolic and immune diseases) that are problematic

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in modern society. Based on this, we will promote theresearch of Quality of Lipids (QOL) for Quality of Life
(QOL) and aim at building a theoretical foundation for
diagnosis, prevention and treatment of diseases
involving alteration of lipid metabolism.
1) Metabolic diseases
Polyunsaturated fatty acids (PUFAs) confer healthbenefits by preventing inflammation and obesity and byincreasing thermogenesis in brown and beige
adipocytes. As well as being supplied exogenously as
nutrients, PUFAs are largely stored in membrane
glycerophospholipids and released by phospholipase
A2s (PLA2s). However, the molecular identity of the
PLA2 subtype(s) that supplies endogenous PUFAs formetabolic homeostasis remains unclear. PLA2G2D, asecreted phospholipase A2 (sPLA2) isoform, isconstitutively expressed in M2 macrophages in white
adipose tissue (WAT) and shows a reciprocal
correlation with obesity. Studies using global andmacrophage-specific Pla2g2d-/- mice have revealed
that PLA2G2D ameliorates diet-induced obesity andinsulin resistance and counteracts the proinflammatory
M1 macrophage bias in WAT. Moreover, PLA2G2D
increases energy expenditure and thermogenesis bypromoting WAT browning. Mechanistically, PLA2G2D
constitutively supplies a pool of PUFAs, 3 inparticular, in WAT. These results underscore thecontribution of the M2 macrophage-driven PLA2G2DPUFA axis to metabolic health (Sato et al, Cell Reports2020).
Choline supplies methyl groups for regeneration ofmethionine and the universal methyl donor Sadenosylmethionine (SAM) in the liver. Althoughphosphatidylcholine (PC) is the main cellular reservoir
for choline, the pathway for hepatic PC catabolism thatgenerates free endogenous choline remains unexplored.
We found that PNPLA7, a lysophospholipase thatcatalyzes the conversion of lysophosphatidylcholine 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, and reduced fat mass with adipocyte
browning. Accordingly, mutant mice are lean, display
growth retardation, and die prematurely. Thus, themethyl group flux from choline endogenously
generated through PC breakdown by the PNPLA7 axis
is essential for liver functions and systemic energy
homeostasis (manuscript in preparation).
2) Cardiovascular diseases
Aortic dissection is a life-threatening aortopathy
involving separation of the aortic wall, yet theunderlying mechanisms are still incompletely
understood. Epidemiological evidence suggests thebeneficial effects of unsaturated fatty acids on
cardiovascular health. Here we show that PLA2G5, asPLA2 isoform expressed in aortic endothelial cells,
plays a protective role against aortic dissection byendogenously mobilizing vasoprotective lipids. Global
and endothelial cell-specific Pla2g5-deficient micefrequently develop aortic dissection shortly after
infusion of angiotensin II (AT-II). In the AT-II-treatedaorta, endothelial PLA2G5 mobilizes oleic and linoleic
acids, which attenuate ER stress, increase theexpression of lysyl oxidase, and thereby stabilize theextracellular matrix in the aorta. The increased
susceptibility of Pla2g5-/- mice to aortic dissection was
rescued by dietary supplementation with oleic or
linoleic acid. These findings reveal an unexploredfunctional link between sPLA2-driven phospholipid
metabolism and aortic stability, possibly contributing
to the development of novel diagnostic and/or
therapeutic strategies for aortic dissection (Watanabe etal, J Biol Chem 2020; selected as an Editors’ Pick).
3) Skin diseases
Lipids play crucial roles in skin homeostasis anddiseases. We have currently reported that PLA2G2F,
an epidermal sPLA2, mobilizes lysoplasmalogen, aunique lysophospholipid that promotes epidermal
hyperplasic diseases such as psoriasis and skin cancer(Yamamoto et al, J Exp Med 2015), and that PNPLA1,
a member of the intracellular iPLA2 family whose
mutations cause autosomal recessive congenitalichthyosis, acts as a transacylase to produce ω-Oacylceramide, an essential lipid component for skinbarrier function (Hirabayashi et al, Nat Commun2017). Furthermore, by phenotypic screening (withperturbation of skin barrier function as a readout)using a series of PLA2 knockout strains, as well as bygene expression profiling of PLA2-related genes inmouse and human skins, we have identified several
PLA2s that appear to be linked to skin diseases. Of

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these, we found that PLA2G4E (cPLA2, which isexpressed in epidermal keratinocytes, exhibits aunique N-acyltransferase activity that transfers a fatty
acid from the sn-1 position of PC to the amino groupof phosphatidylethanolamine (PE) to give rise to Nacyl PE (NAPE), a precursor of the non-canonicallipid mediator N-acylethanolamine (NAE) that has ananti-inflammatory function. Pla2g4e deficiency leadto exacerbation of psoriasis with marked reduction ofvarious NAE species, suggesting that PLA2G4E plays
a role in putting a brake on psoriasis by generating theanti-inflammatory lipid mediator NAE. This is thefirst demonstration of the biological role of PLA2G4E
as an N-acyltransferase in vivo (manuscript in
preparation).
4) Allergic diseases
We have currently shown that PLA2G3, an sPLA2
isoform secreted from mast cells, promotes mast cellmaturation by driving the paracrine PGD2 circuit incooperation with microenvironmental fibroblasts(Taketomi et al, Nat Immunol 2013) and that PAF-AH2,
a unique PLA2 that hydrolyzes oxidized phospholipids,
ensures optimal mast cell activation and thereby
allergic responses through producing unique EPA/DHA
metabolites (ω3 epoxides) (Shimanaka et al, Nat Med2017). We are now analyzing other PLA2 knockout
strains that have alterations in allergic responses.
5) Neuronal diseases
Mutations in the PLA2G6 gene, which encodes
PLA2G6 or iPLA2, are responsible for PARK14linked Parkinson’s disease with -synucleinopathy.
However, it is unclear how PLA2G6 mutations leadto-synuclein (-Syn) aggregation and dopaminergic(DA) neurodegeneration. We found that PLA2G6deficient Drosophila exhibits the degeneration of DA
neurons, leading to defects in neurotransmission andmotor ability. Lipidomics analysis of the brain reveals
that the acyl-chain length of phospholipids is shortenedby PLA2G6 loss, which causes membrane lipid
disequilibrium-induced ER stress. Introduction of wildtype human PLA2G6 or C19orf12, an orphan protein
residing in the mitochondria-ER contact site, in
PLA2G6-deficient flies rescues the phenotypes
associated with altered lipid composition, ER stress andDA neurodegeneration, whereas that of a diseaseassociated missense mutant, PLA2G6 A80T, fails tosuppress these phenotypes. The acceleration of -Syn

aggregation by PLA2G6 loss or A80T expression issuppressed by the administration of linoleic acid, whichcorrects lipid composition in the brain. These results
suggest that membrane remodeling by PLA2G6 isrequired for the survival of DA neurons and -Synstability (Mori et al, PNAS 2019).
2. Environmental Toxicology (Ohsako’s group)
Ohsako’s group is studying various themes related
to the environmental issues from the point of view ofsocial medicine. This year one paper was published asshowed below, and one project is still going on. 1)
Analysis method of the effect of environmental toxic
substances by an in vitro test system using human ES
cells: Human ES cells have an in vitro test system thatmimics an experiment of exposure to environmental
chemicals to a fetus that can never be performed inhumans. We devised a new method by utilizing theprocess of differentiation into nerve cells, andsummarized the report of the experiment that was once
performed with the dioxin exposure model (Sarma etal., 2019). 2) Regarding the physiological function of
the aryl hydrocarbon receptor (Ahr): A new phenotype
was accidentally discovered in the course of a projectusing Ahr-deficient mice (Ahr-KO), which has long
been known for its environmental toxicity.
1) Effect of environmentally toxic substances by invitro test system using human ES cells
After maintaining and culturing human ES cells
and proliferating in large quantities, MEF used as
feeder cells was removed by about 80% with unit
gravity, and EB was seeded on a 96-well multi-platewith a low-adhesive round bottom at 9000 / well. It wasformed for 7 days. Then, the EBs were transferred to amatrix coat dish to cause outgrowth, and the cells were
cultured until a neural rosette was confirmed. After replating, when a large number of cells with MAP2positive neurites were differentiated, TH, MAP2, andHoechst were stained and image analysis was
performed. The results showed that TCDD used for
exposure unexpectedly increased the incidence of THpositive cells (Sarma et al., IJMS 2019).
2) Physiological function of Ahr
A new phenotype was unexpectedly found in thecourse of a project using AhrKO, which has long been
known for environmental toxicology study. Phenotypes
such as liver fibrosis, decreased fertility, and immune

567

system abnormalities have been reported in AhrKO
mice. On the other hand, endogenous ligands for Ahr
include the tryptophan metabolite FICZ and ITE
produced by the intestinal flora, and Ahr regulates
Th17/Treg differentiation in association with theseligands and is involved in autoimmune diseases. At 10
weeks of age, loose stools and melena were observed
only in AhrKO, followed by clear rectal prolapse.
Compared to the wild type, AhrKO mice showed
hypertrophy of the spleen and mesenteric lymph nodes,
thickening of the colon and marked inflammatory cell
infiltration of the lamina propria. CD4+IL17+IFNγTh17 cells were increased significantly in the spleen,mesenteric lymph nodes, and colonic lamina propria,
whereas there was no difference in CD4+Foxp3+Treg
cells. Previous reports have reported that Th17
differentiation is suppressed in spleen cells of Ahrdeficient mice, which is different from this finding. In
addition, liver fibrosis did not cause clear lesions.
Metagenomic analysis of the contents of the large
intestine revealed a facility-specific flora. The AhrKO
phenotype we discovered here indicates that Ahr
dysfunction in inflammatory bowel disease andchanges in the intestinal flora that produce Ahr
endogenous ligands are involved in pathogenesis.

Teaching activities
The Laboratory of Microenvironmental andMetaboilic Health Sciences/ the Department of Cellular
Signaling has important missions to train postdoctoral
fellows to become promising scientist leaders in thefield of medical sciences and environmental toxicology
and to provide biochemistry, molecular biology,
toxicology and environmental health courses forgraduate and undergraduate students. The following
lectures have been provided to students.
Graduate education
Lectures, Seminars, and laboratory practices, as wellas guidance for the dissertation for the Master’s andDoctor’s degrees, have been provided.
Undergraduate education
Lectures on biochemistry and molecular biology,
with a focus on the diversity, structures and functionsof lipids, for medical students (M0).

Publications
1. Mori A, Hatano T, Inoshita T, Shiba- Fukushima
K, Koinuma T, Meng H, Kubo SI, Spratt S, Cui
C, Yamashita C, Miki Y, Yamamoto K,
Hirabayashi T, Murakami M, Takahashi Y,
Shindou H, Nonaka T, Hasegawa M, Okuzumi A,
Imai Y, Hattori N.
Parkinsin’s diseaseassociated
iPLA2-VIA/PLA2G6
regulates
neuronal functions and α-synuclein stability
through membrane remodeling. Proc Natl Acad
Sci U S A. 116, 20689-20699, 2019.
2. Jin F, Li X, Deng Y, Timilshina M, Huang B, Kim
DY, Chang JH, Ichinose H, Baek SH, Murakami
M, Lee YJ, Chang HW. The orphan nuclear
receptor NR4A1 promotes FcεRI-stimulated mastcell activation and anaphylaxis by counteracting
the inhibitory LKB1/AMPK axis. Allergy 74,1145-1156, 2019.
3. Murakami M. Novel functions of phospholipase
A2s: Overview. Biochim. Biophys. Acta 1864, 763765, 2019. (Review, Guest Editor)
4. Murakami M, Miki Y, Sato H, Murase R, Taketomi
Y, Yamamoto K. Group IID, IIE, IIF and III
secreted phospholipase A2s. Biochim. Biophys.
Acta 1864, 803-818, 2019. (Review, Guest Editor)
5. Hirabayashi T, Murakami M, Kihara A. The roleof PNPLA1 in ω-O-acylceramide synthesis andskin barrier function. Biochim. Biophys. Acta 1864,
869-879, 2019. (Review, Guest Editor)
6. Sato H, Taketomi Y, Miki Y, Murase R, Yamamoto
K, Murakami M. Secreted phospholipase
PLA2G2D contributes to metabolic health bymobilizing w-3 polyunsaturated fatty acids inwhite adipose tissue. Cell Rep. 31, 107579, 2020.
7. Watanabe K, Taketomi Y, Miki Y, Kugiyama K,
Murakami M. Endothelial group V secreted
phospholipase A2 plays a protective role against
aortic dissection. J. Biol. Chem. 295, 1009210111, 2020. (selected as an Editors’ Pick)
8. Toda K, Tsukayama I, Nagasaki Y, Yuka K,
Tamenobu A, Ganeko N, Ito H, Kawakami Y,
Takahashi Y, Miki Y, Yamamoto K, Murakami M,
Yamamoto T. Red-kerneled rice proanthocyanidin
inhibits
arachidonate
5-lipoxygenase
anddecreases psoriasis-like skin inflammation. Arch.
Biochem. Biophys. 689, 108307, 2020.

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9. Sano Y, Toyoshima S, Miki Y, Taketomi Y, Ito M,
Lee H, Saito S, Murakami M, Okayama Y.
Activation of inflammation and resolution
pathways of lipid mediators in synovial fluid frompatients with severe rheumatoid arthritis comparedwith severe osteoarthritis. Asia Pac. Allergy. 10,
e21, 2020.
10. Aiba T, Saito T, Hayashi A, Sato S, Yunokawa H,
Fukami M, Hayashi Y, Mizuno K, Sato Y,
Kojima Y, Ohsako S. Exploring disease-specificmethylated CpGs in human male genitalabnormalities by using MSD-AFLP. J. Reprod. Dev.
65(6):491-497. 2019.
11. Zong C, Hasegawa R, Urushitani M, Zhang L,
Nagashima D, Sakurai T, Ichihara S, Ohsako S,
Ichihara G. Role of microglial activation andneuroinflammation in neurotoxicity of acrylamide,
an environmental soft electrophile. Arch. Toxicol.
93(7):2007-2019. 2019.
12. Sarma SN, Nagano R, Ohsako S. Tyroxinehydroxylase-positive neuronal cell population isincreased by temporal dioxin exposure at earlystage of differentiation from human embryonicstem cells. Int. J. Mol. Sci. 20(11): 2019.

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Laboratory of Animal Resources
Professor
Atsu Aiba, Ph.D.

Associate Professor
Hidetoshi Kassai, Ph.D.

Assistant Professor
Harumi Nakao, Ph.D., Hiromitsu Kono, Ph.D.

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 4
teaching staffs, 6 technical support staffs, anadministrative staff, a project academic support
specialist, 2 assistant laboratory animal technicians,
and 4 assistant clerks. In addition, about 15 contracted
employees are involved in animal breeding andmaintenance of the animal facility.
The laboratory animals in our facility include
macaque monkeys, dogs, swine, rabbits, rats, mice,and marmosets. The number of registered users of ourfacility was 885 at the end of academic year 2019.
We provide quality care for all animals in our facility
and assist animal experimentation carried out by the
researchers. The office of our section is in charge ofthe secretariat of the Institutional Animal Care and the
Use Committee (IACUC) of the Graduate School of
Medicine, the University of Tokyo. The committee(Chair, Prof. Atsu Aiba) reviews the plans of animal

experimentation and helps researchers carry out
animal experiments in accordance with law,regulations and University policies governing the useof animals.

Teaching activities
We are responsible for the education of laboratory
animal science to the 2nd-year students (M0) of theFaculty of Medicine. The lecture includes animal
welfare, refinement of animal experiments, animal
breeding, infectious diseases of laboratory animals
and zoonoses. We also give a lecture on mouse
molecular genetics and molecular embryology.
We are also involved in lectures by IACUC for the
researchers at the Graduate School of Medicine.

Research activities
Our laboratory focuses on understanding themolecular mechanisms which underlie the synaptic
plasticity, activity dependent formation of neuronal
circuitry, and neuropsychiatric disorders. We generateknockout mice and transgenic mice of signaltransduction molecules including the glutamate
receptors and mammalian target of rapamycin(mTOR). We also try to generate murine andmarmoset models for human genetic diseases.

570

1. Establishment of model marmosets for fragile
X syndrome
Common marmoset (Callithrix jacchus) is a nonhuman primate and recently used for human model,
especially focusing on brain function. We haveestablished a novel protocol in which embryos arecollected from already mated females by oviductflushing and immediately transferred into the oviductof the very same donors following injections withgenome-editing components. Using this autologoustransfer protocol, we introduced guide RNAs for
FMR1 (fragile X mental retardation 1) gene encoding
fragile X mental retardation protein (FMRP) and Cas9
proteins into marmoset embryos. We obtained 5
mutant marmosets which carried mutations in coding
region of FMR1 gene.

autism spectrum disorders and other psychiatricdisorders. Particularly, about 30% of patients with thissyndrome
developschizophrenia.
We havesuccessfully generated mice with 3 Mb deletion(Del(3Mb)/+) by genome editing techniques using
CRISPR/Cas9 system. Del(3Mb)/+ mice showed
reduction of auditory prepulse inhibition andhypoactivity in the open field test. Furthermore, wehave generated two model mice with 1.5 Mb deletion(Del(1.5Mb)/+) and 1.4 Mb deletion (Del(1.4Mb)/+)by genome editing. Del(1.4Mb)/+ mice displayed
decreased locomotor activity, which possibly
reproduces the negative symptoms of schizophrenia,
and Del(1.5Mb)/+ mice showed reduction of prepulse
inhibition and impairment of contextual- andcued-dependent fear memory.

2. Analysis of Group I mGluRs
Metabotropic glutamate receptor subtype 1 (mGluR1)
and subtype 5 (mGluR5) are coupled to trimeric G
protein Gq, shared ligand specificity and homologous
amino acid sequences, and constitute group I mGluRs.
They exhibit nearly complementary distributions,spatially and temporally, throughout central nervous
system. Significance of complementary expression of
the receptors and their functional redundancy are still
unknown.
Therefore,
we
have
generated“mGluR5-rescue” mice, in which mGluR5 is
specifically expressed in cerebellar Purkinje cells in
mGluR1-KO background. We found that themGluR5-rescue mice showed apparently normal
motor coordination, although mGluR1-KO mice show
severe ataxia. This result indicates a functional
redundancy between mGluR1 and mGluR5 in
cerebellar Purkinje cells.

References

3. Generation of 22q11.2 DS syndrome modelmouse
22q11.2 deletion syndrome (22q11.2DS) is a genetic
syndrome caused by a heterozygous deletion ofchromosomal region 22q11.2. Most patients have adeletion of 3 Mb in this region, whereas some patients
have smaller deletions of 1.5 Mb or 1.4 Mb. Genes ofhuman chromosome 22q11.2 have been highly
conserved in mouse chromosome 16qA13. This
syndrome has been shown to increase the risk ofdeveloping schizophrenia, intellectual disability,

1. Narushima M, Yagasaki Y, Takeuchi Y, Aiba A,
Miyata M.
The metabotropic glutamate receptor subtype 1
regulates development and maintenance oflemniscal
synaptic
connectivity
inthesomatosensory thalamus.
PLoS One, 14(12), e0226820, 2019.
2. Kumita W, Sato K, Suzuki Y, Kurotaki Y, Harada
T, Zhou Y, Kishi N, Sato K, Aiba A, Sakakibara Y,
Feng G, Okano H, Sasaki E.
Efficient generation of Knock-in/Knock-out
marmoset embryo via CRISPR/Cas9 gene editing.
Sci Rep, 9(1), 12719, 2019.
3. Ueyama T, Sakuma M, Nakatsuji M, Uebi T,
Hamada T, Aiba A, Saito N.
Rac-Dependent Signaling from Keratinocytes
Promotes Differentiation of Intradermal White
Adipocytes.
J Invest Dermatol, 140(1), 75-84, 2019.
4. Ogonuki N, Abe Y, Kurotaki YK, Nakao K, Aiba
A, Sasaki E, Ogura A.
Birth of a marmoset following injection ofelongated spermatid from a prepubertal male.
Mol Reprod Dev, 86(8), 928-930, 2019.
5. Nakao H, Kishimoto Y, Hashimoto K, Kitamura K,
Yamasaki M, Nakao K, Watanabe M, Kano M,
Kirino Y, Aiba A.
mGluR1 in cerebellar Purkinje cells is essential

571

for the formation but not expression of associativeeyeblink memory.
Sci Rep, 9(1), 7353, 2019.
6. Koebis M, Urata S, Shinoda Y, Okabe S,
Yamasoba T, Nakao K, Aiba A, Furuichi T.
LAMP5 in presynaptic inhibitory terminals in thehindbrain and spinal cord: a role in startle
response and auditory processing.
Mol Brain, 12(1), 20, 2019.
7. Sakai Y, Kassai H, Nakayama H, Fukaya M,
Maeda T, Nakao K, Hashimoto K, Sakagami H,
Kano M, Aiba A.
Hyperactivation of mTORC1 disrupts cellular
homeostasis in cerebellar Purkinje cells.
Sci Rep, 9(1), 2799, 2019.

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Laboratory of Molecular Radiology
Professor
Kiyoshi Miyagawa, M.D., Ph.D.

Associate Professor
Noriko Hosoya, M.D., Ph.D.

LecturerAtsushi Enomoto, Ph.D.

Research Associate
Claudia Juliane Krause, Ph.D.

Homepage

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

Introduction and Organization
When the Center for Disease Biology and Integrative
Medicine was established in 2003, the Department ofRadiation Oncology established in 1967 and theRadiation Research Institute established in 1992 werejoined to form the Section of Radiation Biology as apart of Divisions of Research Resources and Support.
In 2008, the Laboratory of Molecular Radiology was
also established to strengthen research activities inthis section. The scientists and staffs belong to boththe section and the laboratory.
The aim of this laboratory is to facilitatetranslational research from frontier life science toapplied radiology by introducing molecular biology
into conventional radiology.
To maintain the facility of radiation research,
responsible staffs at two facilities are elected from oursection. This year, the hospital radioisotope researchfacility was continued to be closed to prepare theopening of the new facility in the newly-constructed
Clinical Research Building.

Education
We are responsible for the education of basic radiation
medicine for the 3rd year medical students. The
students are expected to start with understanding of
the physics and the chemistry for radiation and thenunderstand the basic biology of radiation. Furthermore,they learn how to handle radioactive materials by the
2-day practical course.
In addition to these courses, the 4th year medical
students are expected to learn how to use clinicalradiation technology safely in hospitals. The
background for this addition is that clinical problems
arising from the lack of knowledge of radiation effects
have been increasing. Furthermore, the education ofradiation emergency medicine is included in thiscourse. Even though radiation casualty is rare, allclinicians should know how to treat patients exposed
to radiation. The importance of this education has
been widely recognized since the accident at the
Fukushima nuclear power plant.
We also take part in the education of radiation
health science for the 3rd year students specialized in
integrated health sciences. Radiation protection isemphasized in this course.
For graduate students, the education of molecularbiology of the DNA damage response to radiation and
DNA repair is more intensively integrated.
In addition, education courses for users of radioactive materials frequently take place.

Research
We focus on the mechanism underlying the cellular573

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

574

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. Enomoto A, Fukasawa T, Tsumoto H, Karube M,
Nakagawa K, Yoshizaki A, Sato S, Miura Y,
Miyagawa K: Prevention of calpain-dependentdegradation of STK38 by MEKK2-mediatedphosphorylation. Sci Rep 9:16010, 2019.
2. Kato R, Miyagawa K, Yasuhara T: The role ofR-loops in transcription-associated DNA doublestrand break repair. Mol Cell Oncol 6:1542244,
2019.
3. Kohsaka S, Tatsuno K, Ueno T, Nagano M,
Shinozaki-Ushiku A, Ushiku T, Takai D, Ikegami
M, Kobayashi H, Kage H, Ando M, Hata K, Ueda
H, Yamamoto S, Kojima S, Oseto K, Akaike K,
Suehara Y, Hayashi T, Saito T, Takahashi F,
Takahashi K, Takamochi K, Suzuki K, Nagayama
S, Oda Y, Mimori K, Ishihara S, Yatomi Y,
Nagase T, Nakajima J, Tanaka S, Fukayama M,
Oda K, Nangaku M, Miyazono K, Miyagawa K,
Aburatani H, Mano H: Comprehensive assay forthe molecular profiling of cancer by target
enrichment
fromformalin-fixedparaffinembedded specimens. Cancer Sci 110:1464-1479,
2019.
4. Watanabe K, Kage H, Shinozaki-Ushiku A,
Kohsaka S, Takai D, Nakajima J, Miyagawa K,
Aburatani H, Mano H, Nagase T: Spontaneoustransdifferentiation from small cell lungcarcinoma to squamous cell carcinoma. J Thorac
Oncol 14:e31-e34, 2019.

5.

Kage H, Kohsaka S, Shinozaki-Ushiku A,
Hiraishi Y, Sato J, Nagayama K, Ushiku T, Takai
D, Nakajima J, Miyagawa K, Aburatani H, Mano
H, Nagase T: Small lung tumor biopsy samples
are feasible for high quality targeted next
generation sequencing. Cancer Sci 110:2652-2657,
2019.
6. Gonoi W, Okuma H, Hayashi TY, Akahane M,
Nakai Y, Tateishi R, Mizuno S, Suzuki Y,
Mitsuda M, Matsuda K, Nakagawa K, Isayama H,
Miyagawa K, Koike K, Abe O. Development ofpancreatic cancer during observation forhepatocellular carcinoma: A retrospective cohort
study. Saudi J Gastroenterol 25:390-396, 2019.
7. Ando M, Kobayashi H, Shinozaki-Ushiku A,
Chikuda H, Matsubayashi Y, Yoshida M, Saito Y,
Kohsaka S, Oda K, Miyagawa K, Aburatani H,
Mano H, Yamasoba T: Spinal solitary fibroustumor of the neck: Next-generation sequencingbased analysis of genomic aberrations. Auris
Nasus Larynx S0385-8146(19)30932-0, 2019.

575

Laboratory of Biomedical
Informatics
Associate Professor
Takeshi Imai, Ph.D.

Homepage

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

Introduction and Organization
When the Center for Disease Biology andIntegrative Medicine was established in 2003, Sectionof 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 andcontributions 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 andapplying diagnosis support systems. Besides thestudies, our laboratory takes a roll of graduate
education for the doctor’s program in the Departmentof Biomedical Informatics at the Division of Social
Medicine, the master’s program in the Medical
Science Graduate Program, and the 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 2019, we took charge of lectures: “Description
and Processing of Medical Knowledge” in the 2-year
master course in the Medical Science Graduate
Program, “Computer Processing of Medical
knowledge and AI application” in School of Public
Health course, and “AI in Medicine” in the GCLSpecial Lecture III.
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. Two students in the doctor’s
program, two students in the master’s program areenrolled in our laboratory in FY2019. Additionally,
five undergraduate students took practice education in
our laboratory through M3 Elective Clerkshipprogram.

Research activities
Our primary research domains are: (1) methods toknowledge representation and processing knowledge
in healthcare, (2) analysis of electronic medical
records and gaining medical knowledge with natural
language processing and machine learning, (3)576

developing
diagnosis
supportsystem,(4)
standardization in the field 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 andconcepts marshaled in a structured manner, isrequired for the study besides the techniques ofmachine learning and knowledge deduction. We
have developed the clinical ontologies inparticular fields such as anatomy, diseases, andabnormal status, as a funded research by the
Ministry of Health, Labor and Welfare, Japan.
For example, the ontology for diseases has beendeveloped with approximately 6,000 diseases,that they are described as causal chains ofabnormal states. We have also participated in“Research and development of intellectual
information system infrastructure in medicine”
project, sponsored by AMED since 2015. As
further developing the ontology, we haveworked on the study that clinical information ofa targeted patient is automatically mapped on
chronic disease ontology in order to perceive
changes of disease states.
(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 expertsof regional communities are required to havecomprehensive diagnosis skills and technicalknowledge in the domain they specialize in.
However, given the difficulty of such asituation that physicians take all the
responsibilities, depending on only theirknowledge and experiences, the need of

diagnosis support system is pointed out. In thisstudy, we have developed support system, thatgives physicians in outlying regions access torefer to information matching experiences andknowledge matured general physicians have, tosolve the issues. This project has been launchedsponsored by AMED since January 2017. The
current developed system is made up of
approximately 20,000 case reports in internal
medicine. The reports are transformed into
knowledge database, described as chains ofclinical states, so that the system can suggest alist of candidate diseases corresponding to aquery, with certainty scores and reasons. We
also have worked on a study to automaticallyextract knowledge from raw texts in casereports using natural language processing forthe continuous updating of the system. In future,
we plan to achieve the social implementation of
the support 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 deeplearning, intended for standard 12-leads ECG
data. The current clinical annotations used fortraining our model is the ones given by theautomatic analyzers; however we plan to apply
diagnosis confirmed by echocardiogram as
annotation data in future, so that our proposedmodel can be specialized in more specificabnormal findings and achieve comparable
performance to diagnosis by experts.
In addition to the researches, we have worked onother studies such as automatic selection of theunderlying cause of death from death certificatesusing machine learning, and developing prescription
support system in medical care for hypertension

577

patients based on the clinical guidelines. Furthermore,
we also have promoted a project aimed at theapplication of ICD-11 released in June 2018 fordomestic use in Japan.

References
1. Hayakawa M, Imai T, Kawazoe Y, Kozaki K, Ohe
K. Auto-Generated Physiological Chain Data for
an Ontological Framework for Pharmacology andMechanism of Action to Determine Suspected
Drugs in Cases of Dysuria. Drug Saf. 2019
Sep;42(9):1055-1069.
2. Kagawa R, Shinohara E, Imai T, Kawazoe Y, Ohe
K. Bias of Inaccurate Disease Mentions inElectronic Health Record-based Phenotyping. Int
J Med Inform. 2019 Apr;124:90-96.
3. Ishihara S, Fujiu K, Imai T. An analysis of
one-shot screening methods of ECG with different
types of 2-D CNN. Journal of Neuroscience andBiomedical Engineering, 2019, 1(1): 1-9.

4. Shinohara E, Kawazoe Y, Imai T, Ohe K. String

similarity metric for clinical concept extraction.
Japan Journal of Medical Informatics. 2019;
39(suppl.): 382-384. (In Japanese)

5. Takizawa M, Ogawa T, Imai T, Imamura T. A

Study on Classification System of ICD-11.
Japan Journal of Medical Informatics. 2019;
39(suppl.): 272-275. (In Japanese).

6. Imai T. AI in medicine and its future direction byintroducing ICD11. Japan Journal of Geriatrics
Society. 2019:56(3):242-247. (In Japanese).

7. Imai T, Kozaki K, Hamamoto R, Takamura H,

Ichise R, So M, Masumoto H. AI applications inhealthcare. Japan Journal of Medical Informatics.
2019; 39(suppl.): 33-35. (In Japanese).

The International Research Center
for Medical Education (IRCME)579

Department of Medical Education
Studies
Professor
Masato Eto, M.D., Ph.D.

Lecturer
Daisuke Son, M.D., Ph.D.

History and organization
International Research Center for Medical
Education (IRCME), established in 2000, hadfunctioned as a center for the whole university andkept relations with Graduate School of Medicine invarious ways. IRCME became an affiliated center for
education and research under the control of Graduate
School of Medicine since April 2013. IRCME
previously consisted of two departments of International Cooperative Study in Medical Education, andPlanning & Cooperation for International Cooperative
Projects and Information on Medical Education.
Names of two new departments are Department ofMedical Education Studies and Department ofInternational Cooperation for Medical Education.
The mission of Department of Medical Education
Studies includes promotion of medical education not
only in Faculty of Medicine of the University ofTokyo but also of the whole country. Specific contents
are as follows:(1) Research in medical education and dissemination
within and outside of the University
Medical and health professions education needs tocontinue revisions to meet health care needs of thecountry or the region. However, since every country
or region has different culture or social system,
experiences to apply updated evidences 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 Its 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 member(s) as to the education ofFaculty of Medicine in such as academic affair
committee, medical education reform working group,and clinical clerkship. Moreover, the department
offers educational activities such as PBL (problembased learning) and clinical skill practical training.
The department operates OSCE (objective structured
clinical examination). The department also runs andmanages “Tsutsuji no kai” under the consortium with
Tokyo Medical Dental University to develop
simulated patients indispensable for education of
medical interview.

580

Department of International
Cooperation for Medical
Education
Lecturer
Hirotaka Onishi, M.D., M.H.P.E., Ph.D.

Homepage https://www.icme.m.u-tokyo.ac.jp/
Introduction and Organization

Education

International Research Center for Medical Education(IRCME), established in 2000, had functioned as acenter for the whole university and kept relations with
Graduate School of Medicine in various ways.
IRCME became an affiliated center for education andresearch under the umbrella of Graduate School of
Medicine since April 2013. IRCME currently consistsof Department of Medical Education Studies andDepartment of International Cooperation for Medical
Education (ICME).
Department of ICME is a handling comprehensive
practices and research, both in the field ofinternational cooperation in health-professionseducation-related area and in the field linking policies
and actual practices such as international health,community medicine, and general practice.
Specifically, it is as follows.

The Department of ICME offers classes as cooperative
department for School of International Health (SIH)and School of Public Health (SPH). In SIH special
lectures of international cooperation for medical
education are offered twice a year (spring and autumn).
In SPH the class in spring is human resource
development in health and medical practice and theclass in autumn is learner assessment.
Since 2019, multiple graduate students are
studying in ICME, and weekly seminars are provided
every Wednesday.

International Cooperation
Since March 2020, a faculty member has participatedas an expert in the "Information Gathering andConfirmation Survey on Higher Education and
Vocational Education in Indonesia" conducted by
JICA. However, the pandemic of COVID-19 greatly
affected the progress of the survey. The dispatch of thefaculty remains suspended.

Research(1) International Cooperation in the Field of HealthProfessions Education: We explore how education andpolicies in the health and medical fields should bebased through participation in international
cooperation projects in countries mainly in Asia. We
try to become the core center for the research in thisarea by conducting practical efforts as an expert on the
project under Japan International Cooperation Agency,
by accumulating experiences in the area such as
evaluation
method,policyrecommendation,
coordination of stakeholders, and by disseminating
the research results.
(2) Study on Learner Assessment: When certifying thecompletion of the program, it is very important toinvestigate how the learner's assessment is conductedand how the decision is made. Various changes are581

seen in the concept of assessment itself. As forresearch, development of work-based assessment
methods, verification of reliability and validity,
improvement of methods for setting pass / failjudgment criteria are examples.
(3) Practice and research in the field linking healthpolicy and clinical practice: We currently work for
how to train the professionals contributing tocommunity-based integrated care system.

References
1. Onishi H. Community-based Integrated Care.
의료정책포럼 17(1), 22-49, 2019
2. Hayashi M, Son D, Onishi H, Eto M. Contributionof short-term global clinical health experience tothe leadership competency of health professionals:
a qualitative study. BMJ open, 9(7), e027969, 2019

582

Global Nursing Research Center
Director, Professor
Hiromi Sanada, R.N., P.H.N., W.O.C.N., Ph.D.

Vice Director, Professor
Kiyoko Kamibeppu, R.N., P.H.N., Ph.D.
Noriko Yamamoto-Mitani, R.N, Ph.D.

Project Associate Professor
Makoto Oe, R.N., P.H.N., Ph.D.

Project Assistant Professor
Hiromi Tobe, R.N., P.H.N., Ph.D.

Project Researcher
Mayumi Morisaki, R.N., P.H.N., Ph.D., Sofoklis Koudounas, Ph.D.

Homepage

http://gnrc.m.u-tokyo.ac.jp/en/

Introduction and Organization
With a falling birthrate and a super-aging society,Japan is in need of a paradigm shift toward a medical
and nursing care that supports the aging, as well as
those dealing with chronic health conditions, to lead
lives with maximum independence and well-being. In
order to provide a healthy life expectancy for its
people, it will be necessary for Japan to face its
forthcoming challenges and bring about the realizationof a ‘care’ society that lightens the difficulty of theliving and brings a self-reliant way of life to theJapanese nation. Nursing, which plays a central role inproviding care, must develop into a new field as ascience for the realization of this ‘care’ society.
Currently, however, the dominant paradigm employedin various nursing fields embraces a structure that
supports the training of clinical nurses, not thedevelopment of a science aimed at producing a'medical and nursing care that supports.’ Thus, GNRC
seeks to promote research into an innovative,
transdisciplinary nursing science that systematizes thistype of care. In particular, our focus is to create atransdisciplinary research and educational environ-ment that fosters young leaders in nursing research
who will promote care innovation and develop nursing
systems for implementation.
In order to achieve this, we must work toward
integrating nursing with fields it has yet to fully
collaborate with, such as bio-engineering, molecularbiology, human engineering, philosophy, educational
psychology, information science, and policy science.
Moreover, as the field of nursing science continues todevelop, further attention must be paid to both thedevelopment of the necessary human resources thatwill be required to promote this transdisciplinary
research, as well as the networks necessary to create
collaborative relationships among industry, government, and academia. In short, our aim is to create along-term research system that allows young
researchers to conduct transdisciplinary work that
ranges from fundamental research to studies withcommercial application.
Thus, the Global Nursing Research Center has been
established as an affiliated research center, which isthe first of its kind in nursing science. The GNRC willcontinue to execute the following three goals:
1) Establish an innovative nursing research field based

583

on transdisciplinary integration;2) Carry out cutting-edge research and present it to theworld with young researchers pursuing the sciences;
3) Build up a foundation of these new fields throughrepeated research trials that will strengthen the newresearch and education systems.

Establishing an Innovative Nursing Research
Field
1. Division of Care Innovation
The Division of Care Innovation promotes various
research activities, such as robotics nursing, biologicalnursing, visualized nursing, clinical nursing technology and reverse translational research, with the aimof ‘developing and producing patient care productsthat lighten unfavorable conditions of daily life due tothe health impairment of each person.’
2. Division of Nursing Systems
The Division of Nursing Systems promotes suchresearch activities as health-quality outcome researchand care quality management, in order to provide‘nursing practice solutions that reflect important
cultural and social concerns, constructing Japan-origin
nursing theories that support high quality practices,and making policy proposals.’

research knowledge, skills, and global awareness forthe training of youth for leadership.
These five required seminars are, as follows: (1) How
to Write a Research Paper in English, (2) Leadershipin Nursing Research, (3) Qualitative Research
Methods, (4) Health Quality Outcome Research, and(5) Introductory Seminar to Nursing Science andEngineering.
Further, there are an additional five optional seminars:(1) Skin Assessment, (2) Ultrasonography, (3)Qualitative Sketch Techniques, (4) Biological Nursing,and (5) 3D Measurement and Modeling Hands-on
Seminar for Nursing Science and Engineering.
In 2019, two PD researchers participated in thisprogram, and completed the program.
3. Other Universities’ Young Researchers
In 2019, our PD seminars were opened to young
researchers from other universities, and by the end of
the year, a total of 288 researchers attended.
Furthermore, we conducted research consultations or
technical assistance and training for five of theseyoung researchers.
We held an international summer program, and 20
young researchers attended it from four countries.

Building Future Research
3. Achievements
In 2019, three international joint research projects andan industry-government-academia research projects
were undertaken. In addition, two patent applications
were submitted, and 32 original English articles were
published.

Executing Innovative Research
1. International Invited Faculty
In 2019, we invited two researchers: Prof. Joan E.
Haase: Holmquist Professor in Pediatric Oncology
Nursing, Indiana University, Prof. Carolina D. Weller:
Professor, Head of Wound Research Group, Monash
University.
2. Post-doctoral Program
Post-doctoral (PD) researchers engage in focusedresearch projects, the findings of which will be madeknown to the public. In addition, PD researchers musttake five essential seminars that cover comprehensive

1. Global Nursing Research Center FundThe Global Nursing Research Center Fund wascontinued for the purpose of fostering young
researchers.

Accomplishments
1. Haruna M, Matsuzaki M, Ota E, Shiraishi M,
Hanada N, Mori R. Guided imagery for treating
hypertension in pregnancy. Cochrane Database of
Systematic Reviews. 2019; 4(4): CD011337
2. Abe M, Murayama R, et al. Ultrasonographic
assessment of an induration caused byextravasation of a non-vesicant anti-cancer drug:
A case report. Medicine, Medicine. 2019;98(14):e15043.
3. Kita S, Hayashi M, Umeshita K, Tobe H, Uehara
N, Matsunaga M, Kamibeppu K. Intimate partner
violence and maternal child abuse: The mediating
effects of mothers’ postnatal depression, mother-

584

to-infant bonding failure, and hostile attributions
to children’s behaviors. Psychology of Violence,
2020; 10(3), 279–289.
4. Soejima T, Sato I, Takita J, Koh K, Kaneko T,
Inada H, Ozono S, Kamibeppu K. Do childhood
cancer and physical late effects increase worries
about future employment in adulthood? Cancer
Reports, 2019; 2(3): e1175.
5. Honda C, Naruse T, Tsuchiyia-ito R, Yamamoto N,
Nagata S. Home Safety Practices to Prevent Child
Injury and its Association with Family andChildren’s Daily Routines in Japan: A
Cross-sectional Study. Japan Journal of Nursing
Science, JJNS.2020; 17)1: e12274.
6. Dai M, Nakagami G, Sugama J, Kobayashi N,
Kimura E, Arai Y, Sato A, Mercier G, Moffatt C,
Murray S, Sanada H. The prevalence andfunctional impact of chronic edema andlymphedema in Japan: LIMPRINT Study.
Lymphat Res Biol. 2019;17(2):195-201.
7. Takahashi T, Murayama R, Yabunaka K, Tanabe H,
and Sanada H. Using Tablet-Type Ultrasonography to Assess Peripheral Veins for
Intravenous Catheterization: A Pilot Study.
Journal of the Association for Vascular Access.
2019 24(3) 1-6.
8. Kitamura A, Yoshimura M, Nakagami G,
Yabunaka K, Sanada H. Changes of tissue images
visualised by ultrasonography in the process ofpressure ulcer occurrence. Journal Wound Care.
2019;28(sup4):18-22.
9. Matsumoto M, Tsutaoka T, Yabunaka K, H, a M,
Yoshida M, Nakagami G, Sanada H. Development
and evaluation of automated ultrosonographic
detection of bladder diameter for estimation of
bladder urine volume. PLOS ONE. 2019;14(9).
10. Igarashi A, Matsumoto H, Takaoka M, Kugai H,
Suzuki M, Yamamoto-Mitani N. Educational
Program for Promoting Collaboration Between
Community CareProfessionals and Convenience
Stores.Journal of Applied Gerontology. 2019.
11. Noguchi-Watanabe M, Maruyama-Sakurai K,
Yamamoto-Mitani N, Matsumoto Y, Yoshie S,
Iijima K, Yamanaka T, Akishita M. A communitybased program promotes interprofessional
collaboration
among
home
healthcare
professsionals: A non-randomized controlled

study. Geriatrics & Gerontology International.
2019 ;19(7):660-666.
12. Kitamura A, Minematsu T, Nakagami G,
Miyagaki T, Sasaki S, Hayashi C, Sanada H.
Assessing subclinical inflammation by peroxidase
detection in patients with pressure ulcers. Journalof Wound Care. 2019;28(9):586-91.
13. Nakagami G, Gregory S, Kitamura A, Minematsu
T, Akamata K, Suga H, Kurita M, Hayashi C,
Sanada H. Rapid detection of biofilm by woundblotting following sharp debridement of chronicpressure ulcers predicts wound healing: A
preliminary study. International Wound Journal.
2019; 17(1): 191-196.
14. Matsumoto M, Yabunaka K, Yoshida M,
Nakagami G, Miura Y, Okawa Y, Sugama J,
Okada S, Ohta H, Sanada H. Improvement ofconstipation symptoms in an older adult patient bydefecation care based on using a hand-held
ultrasound device in home care settings: a casereport. Journal of Wound, Ostomy and Continence
Nursing. 2020; 47(1): 75-78.
15. Takahashi T, Minematsu T, Murayama R,
Nakagami G, Mori T, Sanada H. Catheter tips area possible resource for biological study oncatheter failure. Drug Discoveries & Therapeutics.
2019;13(5):280-287.
16. Oe M, Sasaki S, Shimura T, Takaki Y, Sanada H.
Effects of multi-layer silicone foam dressings forthe prevention of pressure ulcers in high-riskpatients: A randomized clinical trial. Advances in
Wound Care. 2019. In press
17. Matsumoto M, Yoshida M, Yabunaka K,
Nakagami G, Miura Y, Fujimaki S, Okawa Y,
Sugama J, Okada S, Ohta H, Sanada H. Safety andefficacy of a defecation care algorithm based on
ultrasonographic bowel observation in Japanesehome-care settings: a single-case, multiplebaseline study. Geriatrics & Gerontology International. 2020; 20(3): 187-194.
18. Yonezawa, K., Haruna, M. Short-term skinproblems in infants aged 0–3 months affect foodallergies or atopic dermatitis until 2 years of age,among infants of the general population. Allergy
Asthma Clin Immunol 2019;15, 74.
19. Yonezawa, K., Haruna, M. Validity of infant faceskin assessment by parents at home. Asian/Pacific585

Island Nursing Journal. 2020;4(4):128-134
20. Hikita N, Haruna M, Matsuzaki M, Sasagawa E,
Murata M, Ariunaa Y, Oidovsuren O. Is highmaternal body mass index associated withcaesarean section delivery in Mongolia? A
prospective observational study. Asian / PacificIsland Nursing Journal, 019; 4(3), 128-134.
21. Hikita N, Haruna M, Matsuzaki M, Sasagawa E,
Murata M, Ariunaa Y, Oidovsuren O. Factors
associated with hypertension among men in
darkhan-uul province, mongolia: a cross-sectional
study. Asian / Pacific Island Nursing Journal.
2020;4(4):151-158
22. Murayama R, Oya M, Abe-Doi M, Oe M,
Komiyama C, Sanada H. Characteristics ofsubcutaneous tissues at the site of insertion of
peripheral infusion in patients undergoing
paclitaxel and carboplatin chemotherapy. Drug
Discoveries & Therapeutics.2019;13(5):288-293.
23. Abe-Doi M, Murayama R, Komiyama C, Sanada
H. Incidence, risk factors, and assessment of
induration by ultrasonography after chemotherapy
administration through a peripheral intravenous
catheter. Japan Journal of Nursing Science. 2020;
e1232924. Tobe H, Sakka M, Kamibeppu K. The efficacy ofa resilience-enhancement program for mothers inJapan based on emotion regulation: study protocol
for a randomized controlled trial. BMC
Psychology, 2019;7(1):69.
25. Takemura Y, Kunie K, Ichikawa N. The effect ofwork environment on burnout among nurse
directors: a cross sectional study. Journal of
Nursing Management. 2020; 28: 157–166.
26. Takahashi T, Murayama R, Abe-Doi M,
Miyahara-Kaneko M, Kanno C, Nakamura M,
Mizuno M, Komiyama C, Sanada H. Preventing
peripheral intravenous catheter failure by
reducing mechanical irritation. Scientific Reports.
2020;10(1550).
27. Oe M, Tsuruoka K, Ohashi Y, Takehara K,
Noguchi H, Mori T, Yamauchi T, Sanada H.
Prevention of diabetic foot ulcers using aself-monitoring device smartphone and mobile
thermography: Case study. Journal of Wound Care.
2020. In press
28. Tamai N, Minematsu T, Maeda T, Yabunaka K,

Sanada H. The relationship between skinultrasound images and muscle damage using skinblotting in wheelchair basketball athletes. Spinal
Cord. 2020. In press
29. Nakagami G, Morita K, Matsui H, Yasunaga H,
Fushimi K, Sanada H. Association between
pressure injury status and hospital discharge tohome: A retrospective observational cohort study
using a national inpatient database. Annals ofClinical Epidemiology. 2020;2(2):38–50.
30. Matsumoto M, Tsutaoka T, Nakagami G, Tanaka S,
Yoshida M, Miura Y, Sugama J, Okada S, Ohta H,
Sanada H. Deep learning-based classification ofrectal fecal retention and property using
ultrasound images in older adult patients. Japan
Journal of Nursing Science. 2020. In press
31. Oe M, Rie YR, Defa A, i, Suriadi, Sakai Y, Imran,Takehara K, Nakagami G, Tamaki T, Sugama J,
Sanada H. Validity of DMIST for monitoringhealing of diabetic foot ulcers. Wound Repair andRegeneration. 2020. In press
32. Naruse T, Kitano Y, Matsumoto H, Nagata S. A
Logic Model for Evaluation and Planning in an
Adult Day Care for Disabled Japanese Old
People.Int. J. Environ. Res. Public Health 2020,17(6), 2061;

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Office ofInternational Academic Affairs
HeadYasuyuki Seto

Assistant Professors
Joseph Green
Keiko Nanishi
Yosuke MatsumiyaHomepage: http://koryu.m.u-tokyo.ac.jp
Status and functions
The Office of International Academic Affairs(OIAA) is under the direct authority of the Dean of
the Faculty of Medicine. Its three most importantroles, as defined by the Committee on International
Academic Affairs, are facilitating 1) international
academic exchange, 2) international academic andresearch agreements, and 3) education and research
activities.

Activities
This report details the activities of the OIAA during
the 2019 academic year (April 1, 2019 through March
31, 2020).
1. International Academic Exchange
1.1 Student guidance on education and research
The OIAA assists international students in applying
for various scholarships, and the OIAA on-campus
screening committee evaluates applicants forscholarships that require university recommendations.
To promote friendship among international students,
the OIAA organizes a get-together every spring at
Capo Pellicano, a restaurant in the Faculty of
Medicine
Experimental
Research
Building.
Unfortunately, this year’s event was cancelled
because of the COVID-19 pandemic.

The OIAA oversees undergraduate clinical training(elective clerkships) for international students at the
University of Tokyo Hospital, and ten students weretrained at the hospital in 2019-20: three from Ludwig
Maximilian University of Munich, one from Imperial
College London, two from Peking University, twofrom National Taiwan University, and two from
University of Cagliari, in Italy. However, thepandemic forced two students to cancel elective
clerkships scheduled in March 2020.
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.
The University of Tokyo Faculty of Medicine has
agreements for exchange programs—for one to twomonths of clinical training—with the University ofPennsylvania, Johns Hopkins University, Universityof Michigan, University of Hawaii, University of
Chicago, National Taiwan University, National
University of Singapore, and Ludwig Maximilian
University of Munich. The OIAA nominates qualified

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students for each university and assists in their
preparation for study abroad. During April throughJuly 2019, one student studied at the University ofPennsylvania, two at Johns Hopkins University, twoat the University of Michigan, three at National
Taiwan University, two at National University ofSingapore, and one at Ludwig Maximilian Universityof Munich. In addition, in collaboration with the
University of Tokyo International Research Center for
Neurointelligence, the OIAA sent four researchers to
Harvard University for one to two months of researchstudy during April through July 2019.
Among universities and organizations with which
the Faculty of Medicine does not have an exchange
agreement, the OIAA provided support for one
clinical internship at Harvard University, one clinicalinternship at Mahidol University, one clinicalinternship at Thammasat University, two internships
in international community health in Cambodia, andone clinical internship at the University of Toronto.
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 2019-20, the OIAA assisted
in preparing Medical Student Performance Evaluations for two applicants.
2. International Academic and Research
Agreements
During the 2019-20 academic year, the OIAA
renewed a Faculty of Medicine agreement with the
University of Pennsylvania, a Faculty of Medicine
memorandum of understanding with the University of
Hawaii, and a university-wide agreement with the
University of Gothenburg.
3. Education and Research Activities
Dr. Yosuke Matsumiya supervised and taught thecourses Medical English I/II and trained undergraduate students, graduate students, and faculty in
English oral presentation skills.
Dr. Keiko Nanishi taught the course, “Basic Tools
for Population/Public Health Research,” and offeredclasses in the School of International Health, where
she and Dr. Joseph Green supervised graduate

students and conducted research on international
health.

Publications
1. Okawa S, Gyapong M, Leslie H, Shibanuma A,
Kikuchi K, Yeji F, Tawiah C, Addei S, Nanishi K,
Oduro AR, Owusu-Agyei S, Ansah E, Asare GQ,
Yasuoka J, Hodgson A, Jimba M; Ghana
EMBRACE Implementation Research ProjectTeam. Effect of continuum-of-care intervention
package on improving contacts and quality ofmaternal and newborn healthcare in Ghana: acluster randomised controlled trial. BMJ Open.
2019 Sep 11;9(9):e025347.
2. Adjei KK, Kikuchi K, Owusu-Agyei S, Enuameh
Y, Shibanuma A, Ansah EK, Yasuoka J, PokuAsante K, Okawa S, Gyapong M, Tawiah C,
Oduro AR, Sakeah E, Sarpong D, Nanishi K,
Asare GQ, Hodgson A, Jimba M; Ghana
EMBRACE Implementation Research ProjectTeam. Women's overall satisfaction with healthfacility delivery services in Ghana: a mixedmethods study. Trop Med Health. 2019 Jul
5;47:41.
3. Okawa S, Win HH, Leslie HH, Nanishi K,
Shibanuma A, Aye PP, Jimba M. Quality gap inmaternal and newborn healthcare: a crosssectional study in Myanmar. BMJ Glob Health.
2019 Mar 19;4(2):e001078.
4. Okawa S, Win HH, Nanishi K, Shibanuma A, Aye
PP, Saw TN, Jimba M. Advice on healthy
pregnancy, delivery, motherhood and information
on non-communicable diseases in the maternalcare programme in Myanmar: a cross-sectional
study. BMJ Open. 2019 Mar 30;9(3):e025186.
5. Nanishi K, Kitamura T. Do perinatal Care andBreastfeeding Prevent Mother-to-Infant Bonding
Disorder? In: Kitamura T, Ohashi Y, editors.
Perinatal
Bonding
Disorders-CausesandConsequences. Newcastle upon Tyne (UK):
Cambridge Scholar Publishing; 2019. pp.270-295.

588

MD Scientist Training Program
Professor and Director
Haruhiko Bito, M.D., Ph.D.

Assistant Professor

Yuki Sugaya, M.D., Ph.D.
Kei Takahashi, Ph.D.

Homepage

http://www.ut-mdres.umin.jp/ (in Japanese)

Introduction and Organization
The MD Scientist Training Program (MDSTP) was
founded in 2008 to achieve the goal of systematicallyproviding an intensive basic medical research training
framework to the next generation of MD scientists
during their MD training at the School of Medicine,
The University of Tokyo. Capitalizing on the advances
made by launching a reliable and sustainable program
through the leadership of its first directors, Prof.
Shigeo Okabe (2008-2010) and Prof. Masahide
Kikkawa (2011-2014), the Program currently consistsof its director Prof. Haruhiko Bito and two assistantprofessors Yuki Sugaya and Kei Takahashi, and over
100 students who are seeking extracurricular basic
medical research training through the Program’sframework. With the help of two assistants for clericalwork, it provides a variety of support programs toassist the research activities of medical students. From2011 on, the MDSTP at the University of Tokyo has
cooperated with its sister programs at Kyoto
University, Osaka University and Nagoya University,and has received governmental funding support todramatically boost its activities.
The number of the enrolled students during the launchyear (2008) of the MDSTP was 6. Since then, theProgram has expanded and now enrolls more than 100
students (during Year 3 to 6 of the Medical School). A
sizable number of students write research honors
theses during their final year, which they defend to
become certificated as MDSTP graduates. The numberof research publications in scientific journal or awards

at international scientific meetings, which resulted
from these theses, is growing.

Achieving basic medical researchtraining in parallel with medical
education
The Program offers a platform of activities aimed atproviding an early exposure to basic medical researchand to basic skills required for achieving leadership inacademic medicine.
During the first 2 years after the entrance to the
University of Tokyo, we initially organize a lecture
series entitled ‘Introduction to Medical Biology’. In
this lecture series, top researchers of various fields at
the University of Tokyo provide exciting but
intelligible talks to students with little medical
knowledge. This helps students to get introduced
various research subjects in various fields of medical
research and strongly motivate them to find bythemselves a laboratory suitable to their aspirations.
Furthermore, we offer an opportunity to read the
textbook ‘Molecular Biology of the Cell’ in English,
in a small group setting, to get an exposure toscientific English, and to be formally introduced tobasic molecular and cellular biology, the foundation ofcurrent medical research.
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

589

research and courses of medical researchcommunications are held every 2 weeks. In the journalclub, students are trained to critically read recent
scientific papers published in top journals, often in thepresence of the first authors, if they are available. In
medical research communications courses, thestudents discuss scientific topics and research issues
with a native English speaker with a strong researchbackground.
Students who have shown their research abilities arehighly recommended to write their honors researchtheses by the end of the summer of Year 6. After
successfully defending their theses, they are certified
as qualified MDSTP trainee and, as such, they become
eligible for an exemption of a part of an entrance
examination for the Graduate School of Medicine. The
Dean’s Prize is awarded to the best thesis.

Enhancing awareness andproviding opportunities forexcellence in basic medical
research
1) Providing assistance for research and clinicalexperience in foreign laboratories and hospitals
We encourage students to plan and seek for basic
medical research experience in other countries during
their MD training. Based on research proposals
submitted to the Program, travel supports are provided
on a competitive basis. In FY2019, a total of 8
students received the Program’s support for carryingout basic medical research abroad and to present theirresearch achievements at international scientificmeetings. Unfortunately, 5 other students had tocancel the research abroad in March because of the
COVID-19 pandemic. We also support exposure toclinical training in foreign hospitals with the Osamu
Otsubo Tetsumon Fellowship, however, a total of 14
fellows canceled the clinical training in foreign
hospitals and studied cutting-edge medical care indomestic hospitals instead.
2) Organizing an MD scientist training program
retreat
A MDSTP retreat was held on February, 15-16, 2020to present ongoing research progress in a closed

meeting among peers. More than 50 participants,
mostly medical school students, but also some medical
interns, graduate students and Program-affiliatedprofessors attended it. Lively discussions among peers
were exciting throughout the meeting and thefeedback from all participants was outstanding andunequivocal in emphasizing the critical importance fora research progress retreat to promote their future
research projects. One important aspect of the retreat
was to provide students, interns and professors to
discuss opportunities in various career paths available
in the basic medical research field.
3) Cooperating with other medical universities acrossJapan
With the availability of governmental support from2011 on, the MDSTP at the University of Tokyo has
been in close touch with sister organizations at Kyoto
University, Osaka University and Nagoya University.
With a view to enhancing collaborative efforts inimproving the basic medical research training at the 4
medical schools, Joint Retreats were held to promote
communication and networking among the medical
students with research minds. In 2019, the joint retreat
was held in Nagoya, at the occasion of the Japan
Medical Congress. More than 90 people including
medical school students and teachers from all overJapan participated in this retreat and enthusiastically
discussed about their research and future career as
researchers. Four celebrated MD scientists presented
their research achievements and carrier path in a joint
forum of this meeting.
The MSDTP also currently cooperates with 10 otheruniversities in eastern Japan to organize annual
research students’ retreats. In 2019, this was held on
August, 17-18 at the Tetsumon memorial hole in the
University of Tokyo. More than 70 people participatedin the retreat and presented their ongoing research
progress and future plans.

Activities (2019)
The number of registered students: 116 (3rd and 4th
grade: 73, 5th and 6th: 43)
Lectures for students in Years 1 and 2

590

Introduction to Medical Biology: 13 lectures
Group reading of Molecular Biology of the Cell: 12
lectures
Seminar for students (in Year 3 or above)
Journal Club for basic medical research: 2 lectures
Medical Research Communications: 66 lectures
Presentation of research progress: 3 times (including
the retreat of MD scientist training program in the
University of Tokyo)
The number of students receiving travel supports forresearch : 8
The number of students receiving Osamu Otsubo
Tetsumon Fellowship : 14
The number of Year 6 students who passed theirhonors thesis defense: 2 (the Dean’s Prize and theSatoshi Arima memorial fellowship were awarded to
one student each)

591

Museum of Health and Medicine
Director
Kazuhiko Ohe

Associate
Atsushi Kitade

Homepage

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

History and overview
The origins of the School of Medicine and the
University of Tokyo Hospital can be traced back to theestablishment of the Kanda Otamaga-Ike Vaccination
Center in 1858. In 2008, it celebrated its 150th
anniversary. The Museum of Health and Medicine wasplanned as part of commemorative projects tocelebrate the 150th anniversary of the founding of the
School and the Hospital, and was opened on January
20, 2011. One of the themes for the commemorative
projects marking the 150th anniversary was the“development of communication between healthscience and care and society,” and the Museum of
Health and Medicine forms one of the pillars of this.
In establishing the Museum of Health andMedicine, we renovated the School of Medicine’s
Central Building (Medical Library), which hadoriginally been instituted as part of thecommemorative projects celebrating the 100th
anniversary of the founding of the School and the
Hospital. The Museum has about 400m2 areas,
including about 70m2 of a permanent gallery and230m2 of special exhibition rooms.
The aims of the Museum are to: (1) provide healthand medical information to the public, (2) educate
students studying medicine, health care services andrelated areas, (3) research the history of medicine andhealth care through archives, instruments andtechnology, and (4) preserve and investigate valuable
medical archives and instruments, etc.
In addition to the permanent gallery exhibiting
accomplishments related to the School and the
Hospital and its contributions made to modern andcontemporary development in Japan, a feature of theexhibitions is that a large space has also been set aside
for special exhibitions to promote understanding
among the public regarding the latest advances inmedical science and health care. Planning andsupervision of the permanent exhibition and special
exhibition is done with the cooperation of the various
research units within the School and the Hospital,
other departments within the University, industry, andmuseums. Special exhibitions will be changed several
times a year.
The first permanent exhibition since the openingof the Museum was a display of medical texts andinstruments from the early Meiji era, an Ishihara’s
Color Blind Test Chart and a gastroscope developed at
the University. The first special exhibition was related
to the beginnings of the School and the Hospital,
Entitled “the Challenge to Infectious Diseases”. It
introduced the history of vaccinations against
smallpox, research into infectious diseases conductedin the University and by its graduates since the Meiji
era (1868-1912), and the latest knowledge about
infectious diseases. The second was “the Secret of
Vessel System”, which introduced the circulatory
system. The third “diagnosis of cancer”, the fourth“Our brain”, the fifth “Locomotive syndrome”, thesixth “Diabetes Mellitus”, the seventh "Pediatrics",
the eighth "Forensic Medicine”, the ninth “the Colon”
followed, the tenth “Virus”, the eleventh “Kidney”
and the special exhibition “Mental Diseases”.
In April 2019, we reopened our museum in theSouth Clinical Research Building of The University ofTokyo Hospital.

592

Since the opening of the Museum, more than143,701 people had visited by the end of FY2019.

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.

593

Office for Human Research Studies(OHRS)
Director of OHRS ( Professor / Vice Dean)
Masaomi Nangaku, M.D., Ph.D.

Vice Director of OHRS ( Professor )Akira Akabayashi, M.D., Ph.D.

Vice Director of OHRS ( Associate Professor )Yuzaburo Uetake, M.D., Ph.D.

Homepage: http://www.m.u-tokyo.ac.jp/ethics/ethcom/gakugai2/index.html
http://www.u-tokyo-ohrs.jp/
Top page of online application system: https://u-tokyo.bvits.com/esct/
Introduction and Organization
The Office for Human Research Studies (OHRS) wasestablished in October 2009 for the advancement ofresearch ethics standards. OHRS aims to protect therights, health, and dignity of research participants.
Based on this principle, OHRS is providing research
ethics support services to researchers at Graduate
School of Medicine and Faculty of Medicine, theUniversity of Tokyo and the University of Tokyo
Hospital to enable them to better perform their studies
in an ethical manner. Our primary task is the management of the Ethics Committee secretariat. Additionally,
OHRS plans and manages research ethics seminars,
provides ethics education to researchers throughconsultation and develops human resources for future
research ethics specialists.

Activities
・Management of Ethics Committee
・Prior review of research activity documents (except
for clinical trial, GCP), at Graduate School of
Medicine and Faculty of Medicine, the Universityof Tokyo and the University of Tokyo Hospital.
Correspond in response to various research ethics
inquiries.

・Coordination of various matters with Ethics
Committee members, and other similar bodies anduniversities.
・New clinical documentary examinations inconnection with,-Medical treatments to implemented for the firsttime at the University of Tokyo Hospital,-Examination of the clinical use of the unapproved
medicines and medical devices,・Preperation and maintenance of the organ transplantation manuals for the liver, kidney and hearttransplants.
◇ Specific items reviewed and examined by each
Ethics Committee in fiscal year 2019・Research Ethics Committee (except for clinical
trial, GCP):
361 new applications, 908 minor alterations ofapproved studies
・Clinical Research Review Board:153
・New clinical documentary examinations: 106

594

Research activities

2000
1800

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.

1600
1400
1200
1000
800
600
400
200
0

New clinical documentary examinations
Clinical Research Review Board
Specified Clinical Research
Human Genome, Gene Analysis Research Ethics Committee
Research Ethics Committee

Though OHRS adopts various inclusive applications,the number of studies applied to and reviewed by
ethics committees over the last several years is on theincrease.
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 2019 with 2289 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.

595

The Office for Clinical Practice andMedical Education
Professor
Masato Eto, M.D., Ph.D.

Research Associate
Shoko Horita, M.D., Ph.D.

Homepagehttps://igaku-kyoiku.m.u-tokyo.ac.jp/training.html

Introduction and Organization
The Office for Clinical Practice and Medical Education
was established in April 2015, to support and promote
medical education, especially clinical practice at grade
5 and 6. The office used to be the Clinical ClerkshipSupport Center, which was established to meet thechange from bedside learning to clinical clerkship in
February 2013. Our aim is to run the clinical clerkship(CC) smoothly, as well as to improve the curriculumand evaluation methods in cooperation with teachersand students. In addition, we try to support each student
in cooperation with tutors, the instruction department
and the office for student assistance in the faculty of
medicine. The Information and Communication
Technology (ICT) system has launched in January 2018,
which greatly improved the efficiency of clerical works.
The office now consists of a general manager(professor), a research associate, and three staffs.

Activities
Before the CC begins in January for 4th grade medical
students, we have a meeting to explain the details to thestudents, and then make a schedule of the CC based on
the questionnaire. Just before the CC starts, we hold aceremony to name students that passed OSCE and CBTexaminations as “student doctors”, which the dean andthe chair of the academic affairs committee of the
medical faculty of The University of Tokyo, and the
director and the chief nursing officer of The Universityof Tokyo Hospital attend.

After the CC starts, we support students,
teachers and the external cooperative institutions to run
the clerkship smoothly, by making necessary contacts
with them. In addition, we handle with problems andconsiderations occurred during the practice if needed.
Particularly, we manage and support students who needhelps, with the instruction department, tutors, and theoffice for student assistance in the faculty of medicine.
The new ICT system permits the evaluations of thestudents in the CC to be revealed real-time, hence thestudents are able to look their scores, at the earliest on
the final day of each practice.
Twice a year, we hold a meeting with teachers
who are in charge of the CC. In this meeting, we
provide teachers the feedbacks about the practice fromstudents, and exchange the information and opinions
among the teachers, thus improving the CC. On theother hand, we have opportunities with students(working group on medical education), to discuss theCC and try to respond to comments from them.

Educations
Together with the IRCME department of medical
education studies, we take charge of “medical practice:the introduction” for 4th grade students and “tutorial
PBL” for 2th grade students, teaching medical
interview, physical examination and medical
professionalism. We also take charge of tutorials andindividual consultations related to the CC.

596

Research activities
Presently the “Research of the coherence between thestudents’ daily life and the outcome at the graduation”
is being conducted. The results-in-progress werereleased in the domestic and international conferencesof medical education in 2018 and 2019, being followedin 2020. This research is also developing into multiple
institutional investigation.