ISSN 1883-9606

2019

Vol.139

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2018 ---- March 2019

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2018-March 2019

Introduction
This is volume 139(the edition of year 2019) 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, 2019

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

9

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

10

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

13

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

15

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

18

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

19

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

20

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

23

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

27

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

29

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

30

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

32

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

36

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

37

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

43

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

47

ii

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

48

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

51

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

54

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

55

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

59

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

60

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

69

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

70

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

74

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

76

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

79

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

80

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

83

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

89

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

90

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

92

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

93

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

98

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

119

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

120

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

123

iii

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

126

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

127

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

132

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

154

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.470] )Department of Transfusion Medicine ·········································································

168

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

171

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

172

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

174

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

177

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

179

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

181

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

182

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

189

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

192

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

193

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

197

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

198

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

202

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

206

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

210

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

214

iv

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

219

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

225

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

228

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

230

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

231

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

235

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

238

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

242

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

251

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

255

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

260

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

263

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

264

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

267

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

270

Department of Health Sociology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.349] )Department of Mental Health ··················································································

271

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

277

Department of Social Gerontology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.349] )Department of Biomedical Ethics & Department of Health Promotion Sciences ·······················

280

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

284

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

285

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

288

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

291

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

295

Department of Gerontological Home Care and Long-term Care Nursing/Palliative Care Nursing ···296

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

300

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

303

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

307

v

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

315

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

316

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

320

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

323

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

324

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

327

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

330

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

334

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

336

Department of Biostatistics(See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.277] )Department of Social and Preventive Epidemiology ························································

337

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

340

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

345

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

348

Department of Mental Health (See Department of Mental Health [P.271] )Department of Health Sociology and Health Education(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.349] )Departments of Health and Social Behavior & Health Education and Health Sociology ···············

349

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

354

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.123] )Department of Clinical Information Engineering ····························································

355

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.120] )Department of Global Environmental Health ································································

357

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

359

Department of Health Care Safety Management (Tokio Marine & Nichido) ································

360

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

362

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

366

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

368

vi

Science for joint reconstruction (See Department of Orthopaedic Surgery [P.242] )Department of Medical Genomics ·············································································

372

Department of Bone & Cartilage Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.522] )Department of Osteoimmunology ··············································································

376

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

379

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

381

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

383

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

385

Laboratory for New Generation Drug Discovery (See Laboratory of Molecular Biomedicine
for Pathogenesis [P.559] )Department of Biostatistics and Bioinformatics ·······························································

389

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

392

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

394

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

396

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

398

Department of Integrated Molecular Science on Metabolic Diseases ······································

402

Department of Cartilage & Bone Regeneration (Fujisoft)(See Central Clinical Facilities Division of Tissue Engineering [P.522] )Department of Molecular Structure and Dynamics ·························································

404

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

406

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

411

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

413

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

416

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

420

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

422

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

424

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

427

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

431

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

433

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

434

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

436

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

439

Voice Analysis of Pathophysiology ···········································································

448·
Department of Ubiquitous Health Informatics ·······························································

450

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

453

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

455

vii

Bariatric and Metabolic Care
(See Department of Gastrointestinal Surgery [P.206]
Department of Innovative Dementia Prevention ······························································

458

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

461

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

465

University Hospital
Clinical Divisions ····································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.127] )Respiratory Medicine (See Department of Respiratory Medicine [P.132] )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.154] )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.98] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.193] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.165] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.206] )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.210] )Vascular Surgery (See Department of Vascular Surgery [P.225] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.228] )Artificial Organ and Transplantation Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.210] )Cardiovascular Surgery (See Department of Cardiac Surgery [P.202] )Thoracic Surgery (See Department of Thoracic Surgery [P.198] )

468

viii

Neurosurgery (See Department of Neurosurgery [P.104] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.264] )Urology and Andrology (See Department of Urology [P.214] )Gynecologic Surgery (See Obstetrics and Gynecology [P.171] )Sensory and Motor System Medicine
Dermatology (See Department of Dermatology [P.231] )Ophthalmology (See Department of Ophthalmology [P.251] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.242] )Otorhinolaryngology and Head and Neck Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.255] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.260] )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.238] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.182] )Pediatrics Surgery (See Department of Pediatric Surgery [P.189] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.172,174,177] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.93] )Radiology
Radiology (See Department of Radiology [P.60] )Central Clinical Facilities ···························································································

469

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

470

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

474

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

477

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

479

Department of Emergency Services(See Department of Acute Medicine [P.267] )Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.168] )Rehabilitation Center ····························································································

483

ix

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

486

Department of Intensive Care Unit
(See Department of Acute Medicine [P.267] )Division of Diagnostic Pathology ··············································································

488

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

492

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

494

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

496

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

501

Department of Medical Community Network and Discharge Planning····································

504

Clinical Research Support Center ··············································································

506

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.51] )Department of Planning, Information, and Management(See Department of Biomedical Informatics [P.123] )University Hospital Medical Information Network (UMIN) Center ······································

514

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

517

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

518

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

522

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

527

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

529

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

533

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

536

Medical Genome Research Support Center
Department of Genome Informatics ········································································

538

Department of Genome Research Support Center ························································

540

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

542

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

544

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

550

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

552

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

553

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

558

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

559

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

562

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

565

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

568

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

573

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

577

x

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

580

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

583

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

586

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

587

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

588

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

590

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

594

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

597

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

600

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

602

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

604

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019xi

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. 139, October 2019

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. 139, October 2019

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.

xiv

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

Organization Chart
Cell Biology and Anatomy

Cell Biology
Structural Biology
Structural Cell Biology
Cellular Neurobiology

Molecular Cell Biology

Molecular Biology
Biochemistry and Molecular Biology

Cellular Signaling
Physiological Chemistry and Metabolism

Collaborative Department

Clinical Genome Informatics
Lipid Science
Advance Structural Studies
Integrative Physiology

Physiology

Cellular and Molecular Physiology
Neurophysiology

Functional Biology
Pharmacology

Cellular and Molecular Pharmacology
Systems Pharmacology
Human Pathology and Diagnostic Pathology

Pathology

Molecular Pathology

Microbiology

Microbiology

Surgical Pathology
Pathology, Immunology
and Microbiology

Infection Control and Prevention
Immunology

Immunology
Clinical Immunology
Infection Pathology

Collaborative Department

Tumor Pathology
Molecular Oncology
Diagnoatic Radiology

Radiology

Radiotherapy
Nuclear Medicine

Radiology and Biomedical
Engineering

System Physiology
Biomedical Engineering

Chemical Biology and Molecular Imaging
Biosystem Construction and Control
Neuropathology

Basic Neuroscience

Neurochemistry
Neurobiology

Graduate School of
Medicine

Developmental Neuroscience
Neuroscience

Integrativ Medical Neurosciences

Cognitive Neuroscience
Systems Medical Neuroscience
Child Neuropsychiatry
Neuropsychiatry

Clinical Neuroscience

Neurology
Neurosurgery
Molecular Preventive Medicine

Social Medicine

Occupational, Environmental andPreventive Medicine

Public HealthForensic Medicine, and Medical
Informatics and Economics

Forensic Medicine

Collaborative Department

Cancer Health Services ResearchRadiological Health

Medical Informatics

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

xv

Cardiovascular Medicine
Vascular Biology
Medicine I

Respiratory Medicine
Gastroenterology
Nephrology
Endocrinology

Internal Medicine

Diabetes and Metabolic Diseases
Medicine II

Hematology and Oncology
Allergy and Rheumatology
Infectious Diseases

Clinical Laboratory Medicine
and Pathology

Stress Sciences and Psychosomatic
Medicine
Clinical Laboratory Medicine
Transfusion Medicine

Collaborative Department

Molecular Diabetology
Reproductive Endocrinology

Obstetrics and Gynecology

Gynecological Oncology
Perinatal Medicine
Molecular Reproductive Endocrinology
Pediatrics

Reproductive,
Developmental andAging Sciences

Pediatric Sciences

Developmental Pediatrics
Pediatric Surgery
Pediatric Oncology

Aging Sciences

Geriatrics
Aging Research

Collaborative Department

Health Policy for Children and Families
Thoracic Surgery
Cardiovascular Surgery
Gastrointestinal Surgery
Hepato Biliary Pancreatic Surgery

Surgery

Urology
Artificial Organ and Transplantation
Division
Surgical Oncology

Surgical Sciences

Vascular Surgery
Breast and Endocrine Surgery
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
Acute Medicine

xvi

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019
Health Sociology
Mental Health
Epidemiology and Preventive Health
Sciences
Health Sciences

Social Gerontology
Health Promotion Sciences
Biostatistics
Biomedical Ethics

Health Sciences andNursing

Advanced Clinical Nursing
Preventive and Administrative
NursingNursing Administration
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

Public Mental Health Policy

International Social Medicine

Global Health Policy
Community and Global HealthInternational HealthInternational Biomedical
Sciences

Human Genetics
Developmental Medical Sciences
Human Ecology
Biomedical Chemistry

Medical Science (Master’s Program)

Biostatistics

Epidemiology and Health Sciences

Social and Preventive Epidemiology
Department of Clinical Epidemiology and
Health Economics
Health Communication
Mental Health

School of Public HealthBehavioral Health Sciences

Health Sociology and Health Education
Health and Social Behavior
Health Promotion Science
Biomedical Ethics
Health Policy

Health Services Sciences

Healthcare Informatics
Clinical Information Engineering
Forensic Medicine and Medical Law

Global Environmental HealthPublic Health Science
Laboratory of Molecular Biomedicine for Pathogenesis
Collaborative Department

Laboratory of Structural Physiology
Laboratory of Biomedical Equipment and Biomaterial
Center for Disease Biology
and Integrative medicine

Laboratory of Clinical Biotechnology
Laboratory of Environmental Health Sciences
Laboratory of Animal Resources

International ResearchCenter for Medical Education

Laboratory of Molecular Radiology

Section of Animal Research

Division of Research Resources and Support

Section of Radiation Biology

Department of Medical Education Studies

Section of Bioinformatics

Department of International Cooperation for
Medical Education

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

Global Nursing ResearchCenterxvii

Division of Care Innovation
Division of Nursing System
Office of International Academic Affairs
Medical Library
Medical Scientist Training Program

Institution

Museum of Health and Medicine
Office for Human Research Studies
Office for Life Science Research Equipment Supprt
Life Sciences Core Facility
Office for Clinical Practice and Medical Education
Advisory Office for Conflicts of interest
Bone & Cartilage Regenerative Medicine
Department of Cell & Tissue Engineering(Fujisoft)
Immunotherapeutics
Advanced Clinical Science and Therapeutics
Computational Diagnostic Radiology and Preventive Medicine
Department of Molecular Neurology
Clinical Trial Data Management
Ubiquitous Preventive Medicine
Science for Joint Reconstruction
Therapeutic Strategy for Heart Failure
Molecular Structure and Dynamics
Medical Genomics
Continence Medicine

Endowed Department

Department of Life Support Technology (Molten)
Department of Home Care Medicine
Department of Advanced Translational Research and Medicine in Management of Pulmonary Hypertension
Department of Immunotherapy Management
Department of Advanced Cardiology
Department of medical research and management for musculoskeletal pain
Department of Molecular Science on Diabetes
Department of Integrated Molecular Sciences on Metabolic Diseases
Department of Osteoimmunology
Department of medical and pharmaceutical community 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 Ubiquitous Health Informatics
Department of Lipidomics
Advanced Nursing Technology

Social Cooperation Program

Verbal analysis of pathophysiology
Department of Health Services Research

Department of Prevention of Diabetes
and Life-style Related Disease
Department of Next-Generation
Pathology Information Networking
Chronic kidney disease pathophysiology

Skincare Science
Imaging Nursing Science

General Affairs Office

Department of Healthcare Quality Assessment

Personnel Office

Bariatric & Metabolic Care

Research Support Office

Department of Innovative Dementia Prevention

Educational Affairs
Graduate Student Affairs

xviiiThe Tokyo Journal of Medical Sciences. Vol. 139, October 2019

Finance Office

Administrative officeContract Office
External Fund Management Office
Faculty of Medicine
Graduate School of
Medicine

Finance Office
Facilities Office

Administrative Division

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

Administrative Office

Cell Biology and Anatomy
Biochemistry and Molecular Biology
Physiology
Pharmacology
Pathology
Microbiology
Immunology
Radiology
Biomedical Engineering
Basic Neuroscience
Speech and Cognitive Sciences
School of Medicine

Clinical Neuroscience
Occupational, Environmental and Preventive Medicine
Medical Principles and Medical Ethics
Forensic Medicine, and Medical Informatics and Economics
Medicine I
Medicine II
Clinical Laboratory Medicine and Pathology
Obstetrics and Gynecology
Pediatric Science
Aging Science
Surgery
Sensory and Motor System Medicine
Vital Care Medicine

Faculty of
Medicine

Family Nursing
Comunity Health Nursing
Fundamental Nursing
Gerontological Nursing
School of Integrated
Health Sciences

Midwifery and Women’s Health
Adult Health and Nursing
Mental Health and Nursing
Health Sociology
Health Administration
Epidemiology and Biostatistics
Human Ecology
Biochemistry and Nutrition
Maternal and Child Health

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

General Medicine
Cardiovascular Medicine
Respiratory Medicine
Gastroenterology
Nephrology and Endocrinology
Internal Medicine

Diabetes and Metabolic Medicine
Hematology and Oncology
Allergy and Rheumatology
Infectious Diseases

ClinicalDivisions

Neurology
Geriatric Medicine
Psychosomatic Medicine
General Surgery
Stomach and Esophageal Surgery

University
Hospital

Colon and Rectal Surgery
Hepatobiliary Pancreatic Surgery
Vascular Surgery
Breast and Endocrine Surgery
Surgery

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

Sensory and Motor System
Medicine

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

Pediatrics, Perinatal and
Women's Medicine

Pediatrics
Pediatric Surgery
Obstetrics and Gynecology

Neuropsychiatry

NeuropsychiatryRadiology

Radiology
Pharmaceutical Department
Nursing Department

Office of General Administration

Administration Office

Office of Procurement andFacility Management

Clinical Laboratory
Operation Center
Imaging Center
Central Clinical Facilities

Emergency Services
Blood Transfusion
Perinatal Center
Rehabilitation Service
Medial Engineering
Central Supply Service

Office of Management Planning
Office of Research Support
Office of Medical Accounting

xix

xx

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019
Intensive Care Unit
Pathology
Corneal Transplantation
Department of Cell a Therapy and Transplantation Medicine
Department of Endoscopy and Endoscopic Surgery
Department of Hemodialysis and Apheresis
Medical Community Network and Discharge Planning
Infection Control and Prevention Service
Department of Planning, Information, and Management
University Hospital Medical Information Network Center
Organ Transplantation Service
Labor Safety and Health Management Office
Department of Child Psychiatry
Tissue Bank
Epidemiology and Preventive Medicine
Cancer Resource Center
Center for Liaison and Public Relations
Database Center of the National University Hospitals
Department of Chemotherapy
Department of Health Record Management
Critical Care Center
Department of Palliative Medicine
Children's Medical Center
Department of Disaster Medical Management
International Medical Center
Department of Clinical Nutrition Therapy
Department of Pediatric and Neonatal Intensive Care
Department of Clinical Genomics
Clinical Research Support Center
22nd Century Medical and Research Center
Tissue Engineering
Clinical Research Division

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

Organization of ClinicalManagement Support

Department of Performance
Monitoring and Risk
Management

Department of Education andStaff Development

Medical Specialists
Training Center
Office of Performance Monitoring
Medical Safety management
CenterInfection Control Center
Patient Help and Clinical
Ethics Center
General Education Center
Hospitality Center

Department of Hospital Planning and Management
Department of Research Support
Inpatient Services
Administration
Organization of ClinicalManagement

Outpatient Services
Administration
Central Clinical Services
Administration

Department of Clinical Research
Governance
Cancer Board
Inpatient Center

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019xxi

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

Kohei Miyazono(Dean, Faculty of Medicine)
Chairman, School of Health Sciences and Nursing

Yutaka Matsuyama

Director, Medical Library

Hideo Yasunaga

Director General, University Hospital

Nobuhito Saito

Director, Center for Disease Biology and Integrative Medicine

Shigeo Okabe

Director, International Research Center for Medical Education

Tatsuya Yamasoba

Director, Global Nursing Research Center

Hiromi Sanada

Graduate School of Medicine
Molecular Cell Biology
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

Masashi Fukayama

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 Cell Biology and Anatomy
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

xxii

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

Neuroscience
Department of Basic Neuroscience

Professor

Takeshi Iwatsubo

Professor

Haruhiko Bito

Professor

Kenzo Hirose

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 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

Professor

Kazuto Hoshi

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

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

xxiii

Professor

Sakae Tanaka

Professor

Makoto Aihara

Professor

Tatsuya Yamasoba

Professor

Nobuhiko Haga

Professor

Yoshitsugu Yamada

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

Norito Kawakami

Professor

Hiromi Sanada

Professor

Kenji Shibuya

Professor

Masamine Jinba

Professor

Katsushi Tokunaga

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

xxiv

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

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 Biomedical Equipment and Biomaterial

Professor

Takashi Azuma

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

Tatsuya Yamasoba

Global Nursing Research Center

Professor

Hiromi Sanada

Medical LibraryProfessor

Hideo Yasunaga

International Academic Affairs

Professor

Yasuyuki Seto

Medical Scientist Training Program

Professor

Haruhiko Bito

Museum of Health and Medicine

Professor

Kazuhiko Ohe

Office for Human Research Studies

Professor

Yutaka Yatomi

Life Sciences Core Facility

Associate Professor

Yoshihiro Kita

Office for Clinical Practice and Medical Education

Professor

Tatsuya Yamasoba

Artificial Intelligence in Healthcare

Project Associate professor

Yoshimasa Kawazoe

Department of Bone & Cartilage Regenerative Medicine

Project Associate professor

Takumi Matsumoto

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 Medical Genomics

Project Associate professor

Noriko Hosoya

Continence medicine

Project Professor

Yasuhiko Igawa

Department of Life Support Technology (Molten)

Project professor

Taketoshi Mori

Department of Advanced Translational Research andProject Associate professor

Haruhiro Toko

Division of Research Resources and Support

Endowed Departments

Therapeutics
Computational Diagnostic Radiology and Preventive
Medicine
Healthcare Safety Management (Tokio Marine &Nichido)Clinical Trial Data Management

Medicine in Management of Pulmonary Hypertension

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

Department of Immunotherapy Management

xxv

Project Associate professor

Hiroko Kanda

Project Professor

Koh Matsudaira

Department of Osteoimmunology

Project Associate professor

Kazuo Okamoto

Department of medical and pharmaceutical community

Project Professor

Hirohisa Imai

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 Ubiquitous Health Informatics

Project Associate professor

Kayo Waki

Department of Lipidomics

Project Professor

Takao Shimizu

Project Associate professor

Fuyuki Tokumasu

Advanced Nursing Technology

Project Associate professor

Ryoko Murayama

Verbal analysis of pathophysiology

Project Associate professor

Shinichi Tokuno

Department of Health Services Research

Project Associate professor

Taisuke Jo

Skincare Science

Project Associate professor

Takeo Minematsu

Imaging Nursing Science

Project Associate professor

Koichi Yabunaka

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

Next-Generation Pathology Information Networking

Project Professor

Takeshi Sasaki

Department of Prevention of Diabetes andProject Professor

Takashi Kadowaki

Division of Chronic Kidney Disease Pathophysiology

Project Professor

Reiko Inagi

Department of Functional Genomics andProject Associate professor

Tomohisa Okamura

Chronic kidney disease pathophysiology
Department of medical research and management formusculoskeletal pain
Department of Molecular Science on Diabetes

healthcare

Organ Disordersof Metabolic Diseases

Social Cooperation Program

Lifestyle-Related Diseases

Immunological Diseases

xxvi

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

University Hospital
Clinical Divisions
General Medicine

Head

Masaomi Nangaku

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

Infectious Diseases

Head

Kyoji Moriya

Neurology

Head

Tatsushi Toda

Geriatric Medicine

Head

Masahiro Akishita

Psychosomatic Medicine

Head

Kazuhiro Yoshiuchi

General Surgery

Head

Yasuyuki Seto

Stomach and Esophagus Surgery

Head

Yasuyuki Seto

Colon and Rectal Surgery

Head

Hiroaki Nozawa

Hepatobiliary Pancreatic Surgery

HeadKiyoshi Hasegawa

Vascular Surgery

Head

Katsuyuki Hoshina

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

Yoshitsugu Yamada

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

The Tokyo Journal of Medical Sciences. Vol. 139, October 2019

Acute Medicine

xxvii

Head

Naoto Morimura

Pharmaceutical Department

Head

Hiroshi Suzuki

Department of Clinical Laboratory

Head

Yutaka Yatomi

Surgical Center

Head

Hiroshi YasuharaRadiology 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 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

Medical Community Network and Discharge Planning

Head

Kiyoto Kasai

Infection Control and Prevention Service

Head

Kyoji Moriya

Department of Healthcare Information Management

Head

Kazuhiko Ohe

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Organ Transplantation Service

Head

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

Cancer Resource Center

Head

Sachiyo Nomura

Center for Liaison and Public Relations

Head

Masahiro Akishita

Department of Chemotherapy

Head

Mineo Kurokawa

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

Masaomi Nangaku

Clinical Research Support Center

Head

Takashi Moritoyo

Central Clinical Facilites

xxviii

The Tokyo Journal of Medical Sciences. Vol. 139, October 201922nd Century Medical and Research Center

Head

Masaomi Nangaku

Department of Tissue Engineering

Head

Kazuto Hoshi

Cooperative Unit of Medicine and Engineering Research

Head

Minoru Ono

Translational Research Center

Head

Mineo Kurokawa

Genomic Research Support Center

Head

Masaomi Nangaku

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.
Our laboratory studies molecular architecture,3

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. Homma, N. R., Zhou, M. I. Naseer, A. G.
Chaudhary, M. H. Al-Qahtani, and N. Hirokawa.
KIF2A regulates the development of dentate
granule cells and postnatal hippocampal wiring.
eLife 7: e30935. DOI: https://doi.org/10.7554/
eLife. 30935, 2018
2. Morikawa, Mo., Y. Tanaka, H. –S. Cho, M.
Yoshihara, and N. Hirokawa. The molecularmotor KIF21B mediates synaptic plasticity andfear extinction by terminating Rac1 activation.
Cell Rep. 23: 3864-3877, 2018.
3. Xu, F., H. Takahashi, Y. Tanaka, S. Ichinose, S.
Niwa, M. P. Wicklund, and N. Hirokawa. KIF1B
beta mutations detected in hereditary neuropathy
impair IGF1R transport and axon growth. J. Cell
Biol. 217:3480-3496, 2018.
4. Wang, L., Y. Tanaka, D. Wang, R. Zhou, N. Homma,
Y. Miyamoto and N. Hirokawa. The atypicalkinesin KIF26A facilitates termination of noticeptive
responses by sequestering focal adhesion kinase.
Cell Rep. 24:2894-2907, 2018
5. Shima, T., M. Morikawa, J. Kaneshiro, T. Kambara,
S. Kamimura, T. Yagi, H. Iwamoto, S. Uemura, H.
Shigematsu, M. Shiromizu, T. Ichimura, T.
Watanabe, R. Nitta, Y. Okada, N. Hirokawa.
Kinesin-binding triggered conformation switchingof microtubules contributes to polarized transport.
J. Cell Biol. 217:4164-4183, 2018

4

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

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

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

Research activities

Our laboratory is one of the laboratories in
Department of Cell Biology and Anatomy. Since thereorganization of School of Medicine in 1997, the lab
was named as “Structural Biology”. The current lab
was established in 2009 when Masahide Kikkawa was
appointed as a professor.

Our lab 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.

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).

To study the functions of flagella/cilia, we employ
various imaging techniques, including cryo-electron
microscopy and 3D-tracking microscope incombination with genetic manipulations.

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.

Cryo-electron microscopy and cryo-electron
tomography
One of our strength is in the high-resolution
cryo-electron microscopy (cryo-EM). This techniqueenables preserving biological samples by quickly
freezing them and observing the frozen samples
without staining. Using electron microscopy, we areable
toobtainnano-meter
resolutionofmacromolecular complexes such as axonemes. We
have been developing new techniques, such asasymmetric helical reconstruction and Ruby-Helix
software.
A new project for cryo-electron microscopy started in
October 2017 with a grant from AMED (Japan
Agency for Medical Research and Development). This
project is intended to make cryo-EM techniques

5available to many biological/medical researchers. New
state-of-the-art cryo-electron microscopes will be
installed and available to Japanese researchers.
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. Kuroki K., K. Mio, A. Takahashi, H. Matsubara, Y.
Kasai, S. Manaka, M. Kikkawa, D. Hamada, C.
Sato, K. Maenaka
Class II-like Structural Features and Strong
Receptor Binding of the Nonclassical HLA-G2
Isoform Homodimer.
J Immunology 198:3399, 2017

6

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

Lecturer
Hirohide Iwasaki, Ph.D

Research Associate
Shinji Tanaka, Ph.D., Hiroaki Oshiro, Ph.D., Yutaro Kashiwagi, Ph.D.

Homepage

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

Introduction and Organization

Research

The Department of Cellular Neurobiolgy was
initially established as Neuroanatomy department offormer Brain Institute of Medical School of Imperial
University of Tokyo in 1936. Since the structural
reconstruction of School of Medicine in 1997 thisdepartment became one of the departments of Cell
Biology and Anatomy of Graduate School of Medicine.
This department is currently organized by Professor
Shigeo Okabe since September in 2007. The
department is constituted of other 28 members.

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 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 a long term to realize
fidelity of various animal behaviors, but also shouldbe altered rapidly when animals adapt to a newenvironment. Molecular basis of this dichotomy,
which is unique to synapses, is the main interest of ourlaboratory.
Synapse formation during development
Synapse is one of the major elements to transduce
information from neuron to neuron. Most of thesynapses are formed during the early development andthereafter they become stable after the intensive
pruning. We are interested in how synapse is formed
and maintained.
The postsynaptic densities (PSDs) are protein dense
structures which are located closely to postsynaptic
membranes. PSDs include a variety of receptors,

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 ofexperiment.
4. Joint seminar with other departments

7

scaffolding proteins and signaling molecules. We
focus on some PSD proteins and examine their roles
in synapse formation and maintenance.
Two-photon excitation microscopy allows imagingof living brain. We examine synapse remodeling invivo by observing the postsynaptic structures andsome PSD proteins tagged by fluorescent proteins. We
are also investigating abnormality of synapse
remodeling in developmental disorders by using somemouse models. Our laboratory is investing theproperties and molecular basis of synapses in vitro
and in vivo by various imaging techniques.

Publications
1. Nakayama, H., Abe, M., Morimoto, C., Iida, T.,
Okabe, S., Sakimura, K., and K. Hashimoto.
Microglia permit climbing fiber elimination bypromoting GABAergic inhibition in thedeveloping cerebellum. Nature Communications
2018, 9, 2830. doi: 10.1038/s41467-018-05100-z
2. Tzeng, T-C, Hasegawa, Y., Iguchi, R., Caffrey, D.
R., Thatcher, E. J., Mao, W.J., Germain, G.,
Tamburro, N. D., Okabe, S., Heneka, M., Latz, E.,
Futai, K., and D. T. Golenbock The
inflammasome-derived cytokine IL18 suppresses
amyloid-induced seizures in Alzheimer’s prone
mice. Proc. Natl. Acad. Sci. USA 2018 115, 90029007. doi: 10.1073/pnas.1801802115.
3. Ito, H., Kawamata, Y., Kamiya, M., Tsuda, K.,
Tanaka, S., Ueno, T., Komatsu, T., Hanaoka, K.,
Okabe, S., Miura, M. and Y. Urano Red-shifted
fluorogenic substrate for detecting lacZ-positive
cells in living tissue with single-cell resolution.
Angewandte Chemie Int Ed Engl. 2018 57,
15702-15706. doi: 10.1002/anie.201808670.
4. Sato, Y., and S. Okabe Nano-scale analysis ofsynapse morphology in an autism mouse modelwith 15q11-13 copy number variation using
focused ion beam milling and scanning electron
microscopy. Microscopy (Oxf). 2019 68, 122-132.
doi: 10.1093/jmicro/dfy128
5. Iida, T., Tanaka, S., and S. Okabe Spatial impactof microglial distribution on dynamics ofdendritic spines European Journal of Neuroscience 2018 doi: 10.1111/ejn.14325. [Epubahead of print]

6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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 2019
doi: 10.1111/ejn.14421. [Epub ahead of print]
14. Iguchi, R., Tanaka, S., and S. Okabe Neonatal

8social isolation increases the proportion of theimmature spines in the layer 2/3 pyramidal
neurons of the somatosensory cortex. Neuroscience Research 2019 pii: S0168-0102(19)30046-X. doi: 10.1016/j.neures.2019.05.004.
[Epub ahead of print]

Molecular Cell Biology
2. Biochemistry and Molecular Biology

10Department of Molecular Biology
Professor
Noboru Mizushima, M.D., Ph.D.

Lecturer
Hayashi Yamamoto, Ph.D.

Research Associate
Hideaki Morishita, M.D., Ph.D., 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.,

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, who established this
Biochemistry or Medical Chemistry Department for
the first time in Japan, graduated from The Universityof Tokyo Faculty of Medicine in 1882. In 1884 hewent to Germany to study in Department of 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 waspromoted to Professor of this Department. In 1908, hediscovered a lack of glycogenecity in lipids, which has
been firmly established besides some exceptions, andsucceeded in purification of vitamin B1, which had
been discovered by Dr. C. Eijkman in 1906. His lab
produced many famous researchers including Dr.
Masahiro Sakaguchi, who developed a world-famouscolorimetric method for arginine and Dr. Takaoki
Sasaki, who first succeeded in generating liver cancer
with chemicals.
Professor Samuro Kakiuchi graduated from theImperial University of Tokyo, Faculty of Medicine in1906 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 the Imperial
University of Tokyo in 1918. After studying at
Cambridge University, he became Professor of
Biochemistry at Kyushu Imperial University. In 1943,

11

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 andhexose metabolism.
Professor Tamio Yamakawa graduated from theImperial 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 graduated from the
University of Tokyo Faculty of Medicine in 1955. He
began studies at the Department of Internal Medicine,and then went to Baylor College of Medicine to study
under Dr. H. Busch. After coming back to Japan, hetook 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 and cloned interferon andp450 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, at Osaka University
Institute for Infectious Diseases. In 1993 he succeeded
Professor Muramatsu. At Stanford and the NIH, hestudied gene cloning and developed a full-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 graduated from Tokyo
Medical and Dental University, Faculty of Medicine in
1991. After receiving Ph.D., he studied at National
Institute for Basic Biology in Okazaki and started
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.
Macroautophagy requires many ATG(autophagy-related) genes, most of which wereidentified by genetic screens in model organisms
such as yeasts and worms. We performed agenome-wide CRISPR/Cas9 screen using the
autophagic flux reporter GFP-LC3-RFP and
identified TMEM41B as a novel autophagy-related
gene (Morita et al. J Cell Biol 2018). TMEM41B
is a multi-spanning membrane protein localized in
the endoplasmic reticulum (ER). It has aconserved domain also found in VMP1, anotherER multi-spanning membrane protein essential for
autophagy. Deletion of TMEM41B blocks theformation of autophagosomes at an early step. The
phenotypeof
TMEM41B-knockout
cells
resembles those of VMP1-knockout cells. Indeed,
TMEM41B and VMP1 form a complex. These12

results suggest that TMEM41B and VMP1
function together and provide new insights intomolecular mechanisms of autophagosome
formation.
Macroautophagy is achieved by fusion
between autophagosomes and lysosomes. We
previously identified syntaxin 17 (STX17) as an
autophagosomal SNARE protein (Itakura et al.
Cell 2012), which is conserved in metazoans suchas mammals, Drosophila melanogaster, andCaenorhabditis
elegans.
However,
autophagosome-lysosome fusion is partiallyretained in STX17 knockout cells. By screening
approximately 40 human SNARE proteins, we
identified YKT6 as a second autophagosomal
SNARE (Matsui et al. J Cell Biol 2018).
Depletion of both STX17 and YKT6 has anadditive inhibitory effect on autophagosomelysosome fusion. We suggested that autophagosomes have two SNARE proteins—STX17
and YKT6—that function independently.
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
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.
Damaged mitochondria can also be eliminated by
autophagy (called "mitophagy") and this function
is linked to pathogenesis of Parkinson disease.
We are analyzing physiological roles of
autophagy using novel mouse models zebrafish.
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 course students, themolecular biology course consisting of lectures andexperiments is provided.

Publication
1. Morita, K., Hama, Y., Izume, T., Tamura, N.,
Ueno, T., Yamashita, Y., Sakamaki, Y., Mimura,K., Morishita, H., Shihoya, W., Nureki, O., Mano,
H., *Mizushima, N. Genome-wide CRISPR
screen identifies TMEM41B as a gene required
for autophagosome formation. J Cell Biol.
217:3817-3828 (2018)
2. Matsui, T., Jiang, P., Nakano, S., Sakamaki, Y.,
Yamamoto, H., *Mizushima, N. Autophagosomal
YKT6 is required for fusion with lysosomes
independently of syntaxin 17. J Cell Biol. 217:
2633-2645 (2018)
3. Takahashi, S., Kagami, Y., Hanaoka, K., Terai, T.,
Komatsu, T., Ueno, T., Uchiyama, M., KoyamaHonda, I., Mizushima, N., Taguchi, T., Arai, H.,
Nagano, T., Urano, Y. Development of a series ofpractical fluorescent chemical tools to measure
pH values in living samples. J Am Chem Soc.
140:5925-5933 (2018)
4. Wallot-Hieke, N., Verma, N., Schlütermann, D.,
Berleth, N., Deitersen, J., Böhler, P., Stuhldreier,F., Wu, W., Seggewiß, S., Peter, C., Gohlke, H.,
Mizushima, N., *Stork, B. Systematic analysis of
ATG13 domain requirements for autophagy
induction. Autophagy. 14:743-763 (2018)
5. Deretic, V. et al. Autophagy, Inflammation, andMetabolism (AIM) Center of Biomedical
Research Excellence: supporting the next
generation of autophagy researchers and fosteringinternational collaborations. Autophagy. 14:925929 (2018).
6. *Mizushima, N. A brief history of autophagy fromcell biology to physiology and disease. Nat. Cell
Biol. 20:521-527 (2018).
7. *Mizushima, N. A dual binding receptor for
ER-phagy. Dev. Cell 44:133-135 (2018).

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.
We performed following researches in 2018.

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 in
WAT. Thus, our present findings underscore the contribution of the M2 macrophage-driven PLA2G2DPUFA axis to metabolic health (submitted in revision).
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 oflysophosphatidylcholine to glycerophosphocholine

14(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
with adipocyte browning. Accordingly, mutant mice
were lean, displayed growth retardation, and diedprematurely. Thus, the methyl group flux from choline
endogenously generated through PC breakdown by the
PNPLA7 axis is essential for liver functions andsystemic energy homeostasis.
2) Skin diseases
Lipids play crucial roles in skin homeostasis anddiseases. We have currently reported that PLA2G2F(sPLA2-IIF) mobilizes lysoplasmalogen, a uniquelysophospholipid that promotes epidermal hyperplasic
diseases such as psoriasis and skin cancer (Yamamoto
et al, J Exp Med 2015), and that PNPLA1, a memberof the intracellular iPLA2 family whose mutations
cause autosomal recessive congenital ichthyosis, acts
as a transacylase to produce ω-O-acylceramide, anessential lipid component for skin barrier function(Hirabayashi et al, Nat Commun 2017). In this year,by phenotypic screening (with perturbation of skinbarrier function as a readout) using a series of PLA2
knockout strains, as well as by gene expression
profiling of PLA2-related genes in mouse and humanskins, we have identified several PLA2s (e.g.
sPLA2-III, cPLA2 and cPLA2) that appear to belinked to skin diseases. Currently, we are analyzing
the phenotypes in knockout strains for these PLA2s toclarify their roles and underlying lipid metabolism inskin homeostasis and diseases.
3) Allergic diseases
We have currently shown that PLA2G3 (sPLA2III) 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 PAFAH2, 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.

As another collaborating research with a Koreangroup, we have found that the SIRT1-LKB1-AMPK
pathway negatively regulates FcRI signaling in mast
cells (Li et al, Sci Rep 2017; Li et al, Biochem
Pharmacol 2018; Jin et al, Allergy 2019).

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,
with a focus on the diversity, structures and functionsof lipids, have been provided to medical students(M0).

Publications
1. Li X, Park SJ, Jin F, Deng Y, Yang JH, Chang JH,
Kim DY, Kim JA, Lee YJ, Murakami M, Son KH,
Chang HW. Tanshinone IIA suppresses FcεRImediated mast cell signaling and anaphylaxis byactivation of the Sirt1/LKB1/AMPK pathway.
Biochem. Pharmacol. 152, 362-372, (2018)
2. Tsukayama I, Toda K, Takeda Y, Mega T, Tanaka
M, Kawakami Y, Takahashi Y, Kimoto M,
Yamamoto K, Miki Y, Murakami M, SuzukiYamamoto T. Preventive effect of Dioscorea
japonica on squamous cell carcinoma of mouseskin involving down-regulation of prostaglandin
E2 synthetic pathway. J. Clin. Biochem. Nutr. 62,
139-147 (2018)
3. Murakami M, Yamamoto K, Taketomi Y.
Phospholipase A2 in skin biology: new insightsfrom gene-manipulated mice and lipidomics.
Inflamm Regen. 38, 31. (2018) (Review)

15

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

Lecturer
Yukiko Kurihara, M.D.

Research Associate
Kazuo Tonami, M.D.

Associate
Yasunobu Uchijima, Ph.D.

URL http://bio.m.u-tokyo.ac.jp/home-j.html
Introduction and Organization
The Department of Physiological Chemistry andNutrition, the predecessor of the present department,
was founded in 1952. Upon the restructuring of theuniversity system in 1997, the department was
renamed ‘Department of Physiological Chemistry andMetabolism’ as one unit of the Specialty of Molecular
Cell Biology. The present members include the above
stuffs, 1 postdoctoral fellow, 6 graduate students(doctor course 4, master course 2) and 1 secretary.
Professor Tomoichiro Asano (Hiroshima University) is
invited as a part-time lecturer to instruct graduate
students and give lectures to undergraduate students.

Teaching Activities
We give a series of lectures and laboratory courses
on biochemistry and molecular biology forundergraduate students from Faculty of Medicine andFaculty of Science. We also accept undergraduate
students taking “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. We also provide a monthly
training course of theoretical biology for young
researchers and students in cooperation with themembers of Institute for Biology and Mathematics ofDynamical Cell Processes (iBMath), The Universityof Tokyo (lead by Professor Yasuo Ihara) and Core
Research for Evolutional Science and Technology(CREST), Japan Science and Technology Agency.

Research Activities
1. Developmental Biology and Medicine
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

16

receptor ETAR signaling acts as a molecular switchthat determines the lower jaw identity by using mouse
genetics. Recently, human ETAR gene mutations
causing craniofacial abnormalities and alopecia wereidentified, and the causal relationship was confirmed
by our experiments recapitulating the same mutations
in mice. 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
signaling results in loss of the tympanic membrane inmouse, but causes duplication of the tympanic
membrane in chicken.
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. Isono W, Wada-Hiraike O, Kawamura Y, Fujii T,
Osuga Y, Kurihara H. Administration of oral
contraceptives could alleviate age-related fertility
decline possibly by preventing ovarian damage ina mouse model. Reprod. Sci. 25(9):1413-1423,
2018.
2. Hayashi T, Tokihiro T, Kurihara H, Nomura F,
Yasuda K. Integrate and fire model with refractory
period for synchronization of two cardiomyocytes.
J. Theor. Biol. 437:141-148, 2018.
3. Shimizu M, Narboux-Nême N, Gitton Y, deLombares C, Fontaine A, Alfama G, Kitazawa T,
Kawamura Y, Heude E, Marshall L, Higashiyama
H, Wada Y, Kurihara Y, Kurihara H, Levi G.
Probing the origin of matching functional jaws:
roles of Dlx5/6 in cranial neural crest cells. Sci.
Rep. 8(1):14975, 2018.
4. Maruyama K, Miyagawa-Tomita S, Mizukami K,
Matsuzaki F, Kurihara H. Isl1-expressing
non-venous cell lineage contributes to cardiac

17

lymphatic vessel development. Dev. Biol.
452(2):134-143, 2019.
5. 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.

18

Department of Advanced
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 andis a member of the Department of Cell Biology andAnatomy.
The current 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 class.
3) Ph.D. student guidance.
4) School of Medicine Introductory Lecture.

Research activities
Our research is aimed at elucidating thestructure-function relationships of proteins andcellular components. We hope to contribute to thegeneral knowledge about the molecular mechanisms
behind chronic diseases and 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 family

in the human genome and are implicated in numerous
diseases. As such, they also represent the biggest
group of drug targets with approximately 30% of
approved drugs targeting GPCRs. We employ thepresently flourishing method of cryo-EM single
particle analysis to study the structure of theircomplexes with both native and synthetic agonists.
Our recent results comprise several full-length
unmodified GPRC structures at resolutions better than
3 Å. They showcase both the capabilities of cryo-EM
as a technique and the successful launch of the new
cryo-EM facility at the Graduate School of Medicine.
In parallel to our structural studies, we are also
working on the development of new methods forcryo-EM. The field is growing rapidly and there aremany areas where further advances are possible and/or
are highly desirable. We are working mainly on
improving the experimental aspects of the technique
but in future projects plan to expand our developments
towards deep learning and data processing.

References
1. 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

20

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

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

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

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system.
(1) Finding the relationship between individual
cognitive functions and cell-type-specific neuronal
circuits is a central topic in neuroscience. In cats, thelateral geniculate nucleus (LGN) contains several cell
types carrying spatially and temporally precise visual
information. Whereas LGN cell types lack selectivity
for motion direction, neurons in the primary visualcortex (area 17) exhibit sharp direction selectivity.
Whether and how such de novo formation of direction
selectivity depends on LGN cell types remains

21

unknown. Here, we addressed this question using invivo two-photon calcium imaging in cat area 17,
which consists of two compartments receiving
different combinations of inputs from the LGN cell
types. The direction map in area 17 showed uniquefragmented organization and was present only in small
and distributed cortical domains. Moreover,direction-selective domains preferentially localized in
specific compartments receiving Y and W inputs
carrying low spatial frequency visual information,
indicating that cell-type-specific thalamocorticalprojections constrain the formation of direction
selectivity (Nishiyama, Matsui et al., 2019).
(2) A comprehensive understanding of thestimulus-response properties of individual neurons isnecessary to crack the neural code of sensory cortices.
However, a barrier to achieving this goal is thedifficulty of analysing the nonlinearity of neuronal
responses. Here, by incorporating convolutional
neural network (CNN) for encoding models ofneurons in the visual cortex, we developed a new
method of nonlinear response characterisation,
especially nonlinear estimation of receptive fields(RFs), without assumptions regarding the type of
nonlinearity. Briefly, after training CNN to predict thevisual responses to natural images, we synthesised the
RF image such that the image would predictively
evoke a maximum response. We first demonstrated theproof-of-principle using a dataset of simulated cellswith various types of nonlinearity. We could visualise
RFs with various types of nonlinearity, such as
shift-invariant RFs or rotation-invariant RFs,suggesting that the method may be applicable toneurons with complex nonlinearities in higher visualareas. Next, we applied the method to a dataset ofneurons in mouse V1. We could visualise
simple-cell-like or complex-cell-like (shift-invariant)
RFs and quantify the degree of shift-invariance. These
results suggest that CNN encoding model is useful innonlinear response analyses of visual neurons andpotentially of any sensory neurons. (Ukita et al.,2019).
(3) Astrocytes are known to contact with a great
number of synapses and may integrate sensory inputs.
In the ferret primary visual cortex, astrocytes respondto a visual stimulus with a delay of several seconds
with respect to the surrounding neurons. However, inthe mouse visual cortex, it remains unclear whether
astrocytes respond to visual stimulations. In this study,
using dual-color simultaneous in vivo two-photon
calcium imaging of neurons and astrocytes in theawake mouse visual cortex, we examined the visual
response of astrocytes and their precise response
timing relative to the surrounding neurons. Neurons
reliably responded to visual stimulations, whereas
astrocytes often showed neuromodulator-mediatedglobal activities, which largely masked small visual
responses.
Administrationoftheselective
α1-adrenergic
receptor
antagonist
prazosin
substantially reduced such global astrocytic activities
without affecting the neuronal visual responses. In thepresence of prazosin, astrocytes showed weak but
consistent visual responses mostly at their somata.
Cross-correlation analysis estimated that the astrocytic
visual responses were delayed by approximately
5 seconds relative to the surrounding neuronal
responses. In conclusion, our research demonstrated
that astrocytes in the primary visual cortex of awake
mice responded to visual stimuli with a delay ofseveral seconds relative to the surrounding neurons,
which may indicate the existence of a common
mechanism of neuron-astrocyte communication acrossspecies (Sonoda et al., 2108).
(4) Although the processing of whisker deflections in
the barrel area of the rodent primary somatosensory
cortex (S1) has been studied extensively, howcutaneous vibro-tactile stimuli are processed in therodent S1 outside the barrel area has not been fully
examined. Particularly, the cell-type specificrepresentation of multiple vibration frequencies ingenetically identified inhibitory cells in the S1 has notbeen examined. Using two-photon calcium imaging,
we examined the responses to vibration stimuli of
excitatory and inhibitory neurons in the S1 hind limb
area of male and female mice. The excitatory cells
showed relatively sharp selectivity to vibration stimuli,
whereas the inhibitory cells exhibited less selectivity.
The excitatory and inhibitory cells with different
preferred stimuli were intermingled in a "salt andpepper" manner. Furthermore, the noise correlation
tended to be especially strong in excitatory-inhibitory

22

and inhibitory-inhibitory cell pairs that have similar
stimulus selectivity. These results suggest that
excitatory cells tend to represent specific stimulus
information and work together with similarly tuned
inhibitory cells as a functionally connected network(Hayashi et al., 2018).

References(1) Ukita J, Yoshida T, Ohki K.
Characterisation of nonlinear receptive fields ofvisual neurons by convolutional neural network.
Sci Rep. 2019 Mar 7;9(1):3791.
(2) Nishiyama M, Matsui T, Murakami T, Hagihara
KM, Ohki K.
Cell-Type-Specific Thalamocortical Inputs
Constrain Direction Map Formation in Visual
Cortex.
Cell Rep. 2019 Jan 29;26(5):1082-1088.e3.
(3) Hayashi A, Yoshida T, Ohki K.
Cell Type Specific Representation of Vibro-tactile
Stimuli in the Mouse Primary Somatosensory
Cortex.
Front Neural Circuits. 2018 Dec 20;12:109.
(4) Matsui T, Murakami T, Ohki K.
Mouse optical imaging for understanding
resting-state functional connectivity in humanfMRI.
Commun Integr Biol. 2018 Oct
21;11(4):e1528821.
(5) Sonoda K, Matsui T, Bito H, Ohki K.
Astrocytes in the mouse visual cortex reliably
respond to visual stimulation.
Biochem Biophys Res Commun. 2018 Nov
10;505(4):1216-1222.

23

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

Lecturer
Yoshito Masamizu, Ph.D.

Research Associate
Yasuhiro R. Tanaka, M.D., Ph.D.
Teppei Ebina, Ph.D.

Homepage

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

Introduction and Organization

Research activities

The Department of Cellular and Molecular Physiology
succeeded the former ‘Second Department of
Physiology’, and belongs to the Department of
Physiology. We participate in the teaching ofphysiology at undergraduate school and graduate
school.
The present members include the above staff, 1secretary staff, 5 technical staff, 4 postdoctoral
researchers, 4 graduate students.

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

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

(1) Establishment of two-photon calcium imaging in
the motor cortex of common marmosets during
upper-limb movement tasks.
In vivo two-photon functional imaging has revealed

24

the cellular mechanisms underlying a variety of brain
functions in rodents and other small animals. Whensuch imaging is combined with a genetically encoded
calcium indicator, it allows the detection of long-term
plasticity and stability in the activity of individual
neurons during motor learning and sensory experiencein rodents, and can do so in a layer- and cell
type-specific manner. Thus, two-photon calcium
imaging has the potential to be a powerful tool for
revealing the principles of the long- and short-term
spatiotemporal organization of the neuronal networks
underlying action, cognition, and perception. However,cortical organization and functioning in primates ismore complex than in rodents. Non-human primate
research is therefore indispensable in gaining an
understanding of neuronal computation in the humanbrain.
We have extended the technique of two-photon
calcium imaging, which we established in a
non-human primate, the common marmoset, in ananesthetized state (Sadakane et al., 2015), to record
neuronal activity in the cerebral cortex of behaving
marmosets. We developed protocols to train
head-fixed common marmosets (Callithrix jacchus) toperform upper-limb movement tasks. We developed anovel behavioral apparatus, which restrains the
marmoset in a chair, and trained the animal to control
a two-dimensional manipulandum to move a cursor ona monitor. After 2–5 months of training sessions,head-fixed marmosets can control the manipulandum
to move the cursor to a target on the screen. We
conducted two-photon calcium imaging of layer 2/3
neurons in the motor cortex during this motor task
performance, and detected task-relevant activity frommultiple neurons at cellular and subcellular
resolutions. In a two-target reaching task, someneurons showed direction-selective activity over the
training days. In a short-term force-field adaptationtask, some neurons changed their activity when theforce field was on. Two-photon calcium imaging inbehaving marmosets will become a fundamental
technique for determining the spatial organization of
the cortical dynamics underlying action and cognition.
(2) Establishment of in vivo wide-field calcium
imaging of axonal boutons in the mouse neocortex atsynaptic resolution.

In vivo wide-field imaging of neural activity with ahigh spatio-temporal resolution is a challenge inmodern neuroscience. Although two-photon imaging
is very powerful, high-speed imaging of the activity of
individual synapses is limited to a field ofapproximately 200 μm on a side because theexcitation laser should be sequentially scanned within
an imaging field. Wide-field one-photon epifluorescence imaging can reveal neuronal activity over a
field of ≥ 1 mm2 at a high speed, but is not able toresolve a single synapse. To achieve a highspatio-temporal resolution, we combined anultra-high-definition (UHD) camera with spinningdisk one-photon confocal laser microscopy (SDCLM).
In SDCLM, a rotating Nipkow disk divides an
excitation laser beam into a thousand of light sources
via a series of pinholes, and parallel scan by the lightsources enables to image a wide field at high speed. In
addition, SDCLM has a three-dimensional resolution
because the pinholes reject out-of-focus fluorescence.
The combination of the UHD camera and SDCLM
allowed us to image a 1 mm2 field with a pixel
resolution of ~0.2 μm at 60 fps. When we imaged
motor cortical layer 1 in a behaving head-restrainedmouse, calcium transients were detected in thousandsof presynaptic boutons of thalamocortical axons
expressing a genetically-encoded calcium indicator.
The effects of out-of-focus fluorescence changes on
calcium transients in individual boutons appeared
minimal. Axonal boutons with highly correlated
activity were detected over the 1 mm2 field, and were
probably distributed on multiple axonal arbors
originating from the same thalamic neuron. This new
microscopy with the UHD camera should serve toclarify the activity and plasticity of widely distributed
cortical synapses.
(3) Thalamocortical axonal activity in motor cortex
exhibits layer-specific dynamics during motor
learning.
Through motor learning, animals acquire the skilled
movements needed to efficiently accomplish theirgoals in everyday life. In motor circuits, subcorticaland cortical structures are interconnected in real time,with the primary motor cortex (M1) sending motor
outputs to the spinal cord. Within M1, motor learning
results in dynamic changes to the representation of

25

well-learned movement in a subset of layer 2/3 (L2/3),
as well as in layer 5 (L5) neurons, including crossed
corticostriatal neurons and corticospinal neurons. The
dynamics of the neuronal ensemble in M1 during
motor learning require interactions with the basal
ganglia, cerebellum, and thalamus. Thus, tounderstand how motor circuits generate appropriate
goal-directed behaviors through learning, it isnecessary to clarify the dynamics of neuronal activity
transmitting the signals from subcortical structures to
M1.
Here we conducted two-photon calcium imaging ofthalamocortical axonal activity in the motor cortex ofmice learning a self-initiated lever-pull task. Layer 1(L1) axons came to exhibit activity at lever-pull
initiation and termination, while layer 3 (L3) axons
did so at lever-pull initiation. L1 population activity
had a sequence structure related to both lever-pull
duration and reproducibility. Stimulation of thesubstantia nigra pars reticulata activated more L1 thanL3 axons, whereas deep cerebellar nuclei (DCN)
stimulation did the opposite. Lesions to either thedorsal striatum or the DCN impaired motor learningand disrupted temporal dynamics in both layers. Thus,
layer-specific thalamocortical signals evolve with theprogression of learning, which requires both the basal
ganglia and cerebellar activities. Our results expand
the understanding of TC axonal activity and its
relationship with subcortical structures in the motor
system. First, TC activities in L1 and L3 evolve tostably represent movement during motor leaning.
Second, the time-locked activity and sequencestructure of TC axons accompany the improvement in
the task performance in a layer-specific manner andare related to some aspects of behavior. Finally, theseTC dynamics that evolve during motor learning
require input from the basal ganglia and cerebellum.
(4) Establishment of super-wide-field two-photon
imaging with a micro-optical device moving in
post-objective space.
Living organisms depend on large-scale cellularinteractions.
Inter-layer
andinter-areal
communications are especially crucial for information
processing in the mammalian neocortex. Even within
the same cortical area, different layers receive
synaptic inputs from different areas and send their

output signals in different ways. Therefore, tounderstand the mechanisms of neocortical functions, it
is essential to simultaneously measure the neuralactivity occurring at multiple layers in multiple areas.
A potential way to address this issue in imaging of themouse cerebral cortex is to expand the field of view(FOV) in two-photon laser scanning microscopy(TPLSM) because this microscopy technique allows
detection of the activity of multiple neurons in all
cortical layers and at a cellular resolution. In thecommon optical design of TPLSM, enlarging the FOV
while maintaining the spatial resolution requires thediameter of the objective to be enlarged. When theobjective is redesigned, it is also necessary to redesign
the pre-objective optics, ensuring that a satisfactory
cellular resolution is attained. Recently, two studies
described development of ultra-large-sized objectives,with the FOV in TPLSM having been expanded to 3
mm with an axial resolution of 12 µm, and 5 mm withan axial resolution of 4 µm.
We provided a novel concept to expand the FOV,
which involves using the post-objective space instandard TPLSM; this does not require redesign of theobjective and pre-objective space. So far, thepost-objective space has attracted little attention
because of the short working distances (WDs; < 3mm) of the high numerical aperture (NA) objectives
used for two-photon imaging. Recently, high-NA
objectives with a WD of up to 8 mm have beendeveloped to detect fluorescence within the wholebrain after tissue-clearing processing. We developed amicro-opto-mechanical device that rapidly rotates
within the enlarged post-objective space. The device
rapidly switches the FOV position, without movementof the objective or the sample. Combining this device
with TPLSM enables sequential imaging of multiple
distant (more than 6 mm) areas of the mouse brain,
which can then be stitched together to form a large
continuous image area (1.2 × 3.5 mm) with a cellular
resolution. We also demonstrated the utility of thedevice by studying functional correlations between
two distant motor cortical areas at the levels of single
axonal boutons, single neurons, and the neuronal
population. When imaging the rostral and caudal
motor forelimb areas (RFA and CFA) 2 mm apart, wefound high pairwise correlations in spontaneous
activity between RFA and CFA neurons and between

26

an RFA neuron and its putative axons in CFA. While
mice performed a sound-triggered forelimb-movementtask, the population activity between RFA and CFA
covaried across trials, although the field-averaged
activitywassimilaracrosstrials.
The
micro-opto-mechanical device in the post-objective
space provides a novel and flexible design to clarify
the correlation structure between distant brain areas at
subcellular and population levels.

References
1. Endo K., Ishigaki S., Masamizu Y., Fujioka Y.,
Watakabe A., Yamamori T., Hatanaka N., Nambu
A., Okado H., Katsuno M., Watanabe H.,
Matsuzaki M., and Sobue G. Silencing of FUS in
the common marmoset (Callithrix jacchus) brain
via stereotaxic injection of an adeno-associatedvirus encoding shRNA. Neuroscience Research
130, 56-64 (2018).
2. Ebina T., Masamizu Y., Tanaka Y.R., Watakabe A.,
Hirakawa R., Hirayama Y., Hira R., Terada S.,
Koketsu D., Hikosaka K., Mizukami H., Nambu
A., Sasaki E., Yamamori T., and Matsuzaki M.
Two-photon imaging of neuronal activity in motor
cortex of marmosets during upper-limb movementtasks. Nature Communications 9, 1879 (2018).
3. Yoshida E., Terada S., Tanaka Y.H., Kobayashi K.,
Ohkura M., Nakai J., and Matsuzaki M.
Wide-field
calcium
imagingofmousethalamocortical synapses with an 8 K
ultra-high-definition camera. Scientific Reports 8,8324 (2018).
4. Tanaka Y.H., *Tanaka Y.R., Kondo M., Terada S.,
Kawaguchi Y., and Matsuzaki M. Thalamocorticalaxonal activity in motor cortex exhibits
layer-specific dynamics during motor learning.
Neuron 100, 244-258 (2018).
5. Terada S., Kobayashi K., Ohkura M., Nakai J.,
and Matsuzaki M. Super-wide-field two-photon
imaging with a micro-optical device moving in
post-objective space. Nature Communications 9,3550 (2018).

27

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, 14 graduate
students, and 5 technicians. We teach neurophysiology
for medical undergraduates and for students in the
Master and Ph.D. courses. Our research aims at
elucidating cellular and molecular mechanisms
underlying regulation of synaptic transmission andpostnatal development of neuronal circuits.

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

properties of synaptic transmission. Second, students
record electromyogram (EMG) from humangastrocnemius muscles and learn how the stretch
reflex works.
We accept Free-Quarter students. Students areencouraged to experience patch-clamp recordings
from neurons either in brain slices or in 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-

28

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) and investigate molecular mechanisms ofsynaptic 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
activity-dependent manner, act retrogradely onto
presynaptic cannabinoid receptors and suppress
transmitter release. Since then, we have been
investigating the mechanisms of this retrograde
modulation. We are also interested in elucidating thephysiological significance of this phenomenon
including learning and memory, addiction, andanxiety.
(3) 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) Sakai Y, Kassai H, Nakayama H, Fukaya M,
Maeda T, Nakao K, Hashimoto K, Sakagami H,
Kano M, Aiba A. Hyperactivation of mTORC1
disrupts cellularhomeostasis in cerebellar Purkinjecells. Sci Rep. 2019 Feb 26;9(1):2799. doi:10.
1038/s41598-019-38730-4.
(2) Yoshida K, Kita Y, Tokuoka SM, Hamano F,
Yamazaki M, Sakimura K, Kano M, Shimizu T.
Monoacylglycerol lipase deficiency affects
diet-induced obesity, fat absorption, and feeding
behavior in CB(1) cannabinoid receptor-deficientmice.
FASEB J. 2019 Feb;33(2):2484-2497. doi: 10.
1096/fj.201801203R. Epub 2018 Sep 28.
(3) Hashimotodani Y, Karube F, Yanagawa Y,
Fujiyama F, Kano M. Supramammillary
Nucleus Afferents to the Dentate Gyrus
Co-release Glutamate and GABA and Potentiate
Granule Cell Output. Cell Rep. 2018 Dec 4;25(10):2704-2715.e4. doi:10.1016/j.celrep.2018.
11.016.
(4) Kano M, Watanabe T, Uesaka N, Watanabe M.
Multiple Phases of Climbing Fiber Synapse
Elimination in the Developing Cerebellum.
Cerebellum. 2018 Dec;17(6):722-734. doi: 10.
1007/s12311-018-0964-z. Review.
(5) Kikuchihara S, Sugio S, Tanaka KF, Watanabe T,
Kano M, Yamazaki Y, Watanabe M, Ikenaka K.
Ectopic positioning of Bergmann glia andimpaired cerebellar wiring in Mlc1-overexpressing mice. J Neurochem. 2018 Nov;147(3):344-360.
doi: 10.1111/jnc.14486. Epub 2018 Aug 8.
(6) Sugaya Y, Kano M. Control of excessive neuralcircuit excitability and prevention of epileptic
seizures by endocannabinoid signaling. Cell Mol
Life Sci. 2018 Aug;75(15):2793-2811.
doi:10.1007/s00018-018-2834-8. Epub 2018 May
8.

Functional Biology
2. Pharmacology

30

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 six
outside expert lecturers to cover rapidly developing
fields in pharmacology and related medical sciences.
The laboratory courses include both traditional andadvanced pharmacological experiments. A new
intensive laboratory course for medical students
started in the year 2001, and we participated in 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 novel strategy for visualizing
neurotransmitters
Imaging techniques which visualize neurotransmittersin living neuronal cells are powerful method tounderstand the mechanism underlying synaptictransmission in neuronal circuits. To facilitate thisprocess, we developed a high-throughput screening
system based on 96-well plate format protocol. Afterscreening, we obtained high performance glutamate
indicators showing large fluorescence changes uponglutamate binding. This result indicates that our
screening system should be applicable to develop thefluorescent indicator for other signaling molecules aswell as for glutamate in short periods.
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31

that single hippocampal synapses contain several
release units. Furthermore, we have succeeded in
imaging spatiotemporal dynamics of glutamate in theextrasynaptic space in brain slices and in vivo. This
study demonstrated that bursting synaptic activities
cause glutamate spillover from the synaptic cleft toactivate perisynaptic metabotropic glutamate receptors,
and will provide a basis for the research of
extrasynaptic glutamate transmission that is involvedin many important brain functions. These results
indicate that our glutamate probe is useful to directly
assess synaptic functions including presynaptic
modulation and plasticity.
3) Analysis of supra-molecular assemblies ofsynaptic molecules in central synapse
Recently, nanoscale molecular distribution in synapses
is suggested to be a key determinant of synaptic
function. To reveal the relationship between the nanoscale molecular assemblies and synaptic functions, weare trying to perform a super resolution microscopic
analysis in combination with glutamate imaging.
These advanced imaging 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, Kanemaru K, Suzuki J, Kobayashi K,
Hirose K, Iino M. Inositol 1,4,5-trisphosphate
receptor type 2-independent Ca2+ release from theendoplasmic reticulum in astrocytes. Glia, 67,
113-24 (2019)
2. Onishi T, Sakamoto H, Namiki S, and Hirose K.
The altered supramolecular structure of dopamine
D2 receptors in Disc1-deficient mice. Sci Rep, 26,1692 (2018)
3. Sakamoto H, Ariyoshi T, Kimpara N, Sugao K,
Taiko I, Takikawa K, Asanuma D, Namiki S, andHirose K. Synaptic weight set by Munc13-1
supramolecular assemblies. Nat Neurosci, 21,
41-9 (2018)

32

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

Lecturer
Etsuo A. Susaki, M.D., Ph.D.

Associate
Koji L. Ode, Ph.D.
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 the
Department participate in the courses to provide close
consultation for the students.
For the graduate students, there are series ofseminars on physiology and neuroscience. We also
have research seminars to discuss and stimulate theresearch activities of the graduate students in thedepartment.

Research activities
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 are currently 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.
1) Next-generation mammalian reverse genetics
In the conventional method for production ofgenetically-modified mice, a single line ofgene-targeted ES cells is injected into host embryos

33(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, and aredeveloping technology for the research scheme. In
order to produce bi-allelic gene knockout mice
without crossing, we improved the design of guide
RNAs (gRNAs) used in CRISPR-Cas9 technology anddeveloped the "triple-CRISPR method" which
simultaneously cuts 3 places in a single targeted gene
(Sunagawa et al., Cell Reports 2016). When thistechnique was applied, it succeeded in producing
various kinds of gene knockout mice with extremely
high production rate (almost 100%) in the first
generation. Furthermore, in order to directly produce
knock-in mice without crossing, ~100% ES
cell-derived mice (ES mice) were directly preparedfrom the genome-modified ES cells. We have alreadyshown the efficiency and throughput of the method
which facilitates to create genetically modified micein just about three months and use them for
subsequent analyses (Ode et al., Molecular Cell 2017;
Susaki et al. npj Systems Biology and Applications,2017; Ukai et al. Nature Protocols 2017). Our recent
study reported a devise for ES mouse generation
without manipulator and microscopy for ES cell
injection (Sumiyama et al. PLOS ONE 2019).
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. Therefore,
sleep/wake phenotyping has been a low-throughput
method; for comprehensive studies, a scalable,
non-invasive, fully automated sleep/wake recording
method was needed. For accurate phenotype analysis,
we developed a respiration-based, non-invasive, fully
automated system, the Snappy Sleep Stager (SSS),
which enabled the high-performance analysis (95.3%
accuracy) of sleep/wake phenotypes (Sunagawa et al.,Cell Reports, 2016).
To highlight the regulatory cellular networks in thesleep/wake rhythm, we facilitate an identification of
sleep/wake generating cells in the whole-brain in ahighly-parallelized manner. A concerted effort has
been made especially in the brain, as scientists areaiming to clarify how neural activity is translated into
consciousness and other complex brain activities. One
example of the technologies needed is whole-brain
imaging at single-cell resolution. This imaging
normally involves preparing a highly transparent
sample that minimizes light scattering and thenimaging neurons tagged with fluorescent probes atdifferent slices to produce a 3D representation.
However, limitations in current methods prevent
comprehensive study of the relationship. A new
high-throughput method, CUBIC (Clear, Unobstructed
Brain/Body Imaging Cocktails and Computational
Analysis) is a great leap forward, as it offers
unprecedented rapid whole-brain imaging at single
cell resolution and a simple protocol to clear andtransparentize the brain sample based on the use ofaminoalcohols (Susaki et al., Cell, 2014; Tainaka et al.,Cell 2014). We recently integrated the latest
light-sheet microscopy with swelling-based clearing
protocol (CUBIC-X) and succeeded in generating asingle-cell resolution whole mouse brain atlas(CUBIC-Atlas) (Murakami et al. Nature Neuroscience342018). We also developed the second-generation
CUBIC reagents from the results of >1600
water-soluble chemical screening, of which
performance are sufficiently improved than thefirst-generation reagents (Tainaka et al. Cell Reports2018). Because of its rapid imaging capability ofwhole organ/body, CUBIC offers extraordinary
opportunity of novel discoveries in life science andmedical researches (Watanabe et al., Developmental
Biology 2018; Hasegawa et al. Kidney International
2019; Puelles et al., Kidney International 2019). We,
together with several major laboratories involving
tissue-clearing development, introduced the latest
circumstances
regardingtheclearing-imaging
technology (Mano et al., J Neurosci. 2018).
3) 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 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).
Given these results showing the role of Ca2+ forsleep control, our next challenge is to investigate
molecules that regulate the transition andconsolidation of sleep and awake phases. In thisregard, we reported a phenotype of Chrm1 and Chrm3
double-knockout mice produced by triple-CRISPR
technology, which showed a complete loss of REM
sleep (Niwa et al., Cell Reports 2018). This was thefirst report of essential genes of REM sleep, withindicating that REM sleep is not critical for thesurvival of animals.
Considering that numbers of researches encompass
model mice for sleep, circadian rhythm and relateddisorders, we envisage that our technologies andresearch outcomes will contribute the understandingof such disorders including psychiatric disorders andneurodegenerative disorders. We proposed theperspectives of circadian rhythm, sleep, and human
genetics in future studies (Ode and 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).

References
1. 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.

Kidny

Int.

Advanced online publication (2019)
2. 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)
3. Hasegawa S., Susaki E.A., Tanaka T., Komaba H.,
Wada T., Fukagawa M., Ueda H.R., Nangaku M.
Comprehensive

three-dimensional(CUBIC-kidney)visualizes

abnormalanalysis
renal

sympathetic nerves after ischemia/reperfusion
injury. Kidny Int. 96, 129-138 (2019)
4. UkaiH.,

Sumiyama

Next-generation

K.,

human

Ueda

H.R.

genetics

fororganism-level systems biology. Curr. Opin.
Biotechnol. 58, 137-145 (2019)
5. Mano T., Albanese A., Dodt H.U., Erturk A.,
Gradinaru V., Treweek J.B., Miyawaki A., Chung
K., Ueda H.R. Whole-Brain Analysis of Cells andCircuits by Tissue Clearing and Light-Sheet
Microscopy. J. Neurosci. 38, 9330-9337 (2018)

35

6. Yoshida K., Shi S., Ukai-Tadenuma M., Fujishima
H., Ohno R., Ueda H.R. Leak potassium channels
regulate sleep duration. Proc. Natl. Acad. Sci.
USA 115, E9459-E9468 (2018)stages between mouse and chicken. Dev. Biol. 444
Suppl 1, S325-S336 (2018)
14. Murakami T.C., Mano T., Saikawa S., Horiguchi
S.A., Shigeta D., Baba K., Sekiya H., Shimizu Y.,

7. Ode K.L., Ueda H.R. Lost in clocks: non ‐Tanaka K.F., Kiyonari H., Iino M., Mochizuki H.,

canonical circadian oscillation discovered in

Tainaka K., Ueda H.R. A three-dimensional

Drosophila cells. Mol. Syst. Biol. 14, e8567

single-cell-resolution whole-brain atlas using(2018)CUBIC-X expansion microscopy and tissue

8. Sumiyama K., Matsumoto N., Garçon-Yoshida J.,

clearing. Nat. Neurosci. 21, 625-637 (2018)

Ukai H., Ueda H.R., Tanaka Y. Easy and efficient

15. Udagawa T., Harita Y., Miura K., Mitsui J., Ode

production of completely embryonic-stem-cell-

K.L., Morishita S., Urae S., Kanda S., Kajiho Y.,

derived mice using a micro-aggregation device.

Tsurumi H., Ueda H.R., Tsuji S., Saito A. Oka A.

PLoS One 13, e0203056 (2018)

Amnionless-mediated glycosylation is crucial for

9. Niwa Y., Kanda G.N., Yamada R.G., Shi S.,
Sunagawa G.A., Ukai-Tadenuma M., Fujishimacell surface targeting of cubilin in renal andintestinal cells. Sci. Rep. 8, 2351 (2018)

H., Matsumoto N., Masumoto K., Nagano M.,

16. Shi S., Ueda H.R. Ca2+-Dependent Hyper-

Kasukawa T., Galloway J., Perrin D., Shigeyoshi

polarization Pathways in Sleep Homeostasis andY., Ukai H., Kiyonari H., Sumiyama K., Ueda

Mental Disorders. BioEssays 40, 1700105 (2018)

H.R. Muscarinic Acetylcholine Receptors Chrm1
and Chrm3 Are Essential for REM Sleep. Cell
Rep. 24, 2231-2247 (2018)
10. Tainaka K., Murakami T.C., Susaki E.A., Shimizu
C., Saito R., Takahashi K., Hayashi-Takagi A.,
Sekiya H., Arima Y., Nojima S., Ikemura M.,
Ushiku T., Shimizu Y., Murakami M., Tanaka K.F.,
Iino M., Kasai H., Sasaoka T., Kobayashi K.,
Miyazono K., Morii E., Isa T., Fukayama M.,
Kakita A., Ueda H.R. Chemical Landscape for
Tissue Clearing Based on Hydrophilic Reagents.
Cell Rep. 24, 2196-2210 (2018)
11. Ode K.L., Ueda H.R. Design Principles of
Phosphorylation-Dependent

TimekeepinginEukaryotic Circadian Clocks. Cold Spring Harb.
Perspect. Biol. 10, a028357 (2018)
12. Narumi R. Masuda K. Tomonaga T. Adachi J.,
Ueda H.R., Shimizu Y. Cell-free synthesis ofstable isotope-labeled internal standards fortargeted quantitative proteomics. Synth. Syst.
Biotechnol. 3, 97-104 (2018)
13. Watanabe T. Nakamura R. Takasea Y. Susaki E.A.,
Ueda H.R., Tadokoro R., Takahash Y. Comparisonof the 3-D patterns of the parasympathetic
nervous system in the lung at late developmental

Pathology, Immunology andMicrobiology
1. Pathology

37

Department of Pathology and
Diagnostic Pathology
Professor
Masashi Fukayama, M.D., Ph.D.

Associate 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),
Munetoshi Hinata*, M.D., Ph.D., Sho Yamazawa*, M.D., Ph.D.,
Kento Misumi*, M.D., Ph.D.,
Naoko Yamauchi, M.D., Ph.D., Naohiro Makise, 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, Yasuyuki Morishita, M.T., 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 conjunction with Divisionof Diagnostic Pathology of the University Hospital*.

Our aim is the construction of “pathology as clinicalmedicine” as well as “next-generation pathology
incorporating cutting-edge science and technology”.
Associate professor Dr. Morikawa moved to be adirector of Department of Pathology, NTT
Higashi-Nihon Kanto Hospital. Dr. Makise become an

38

associate of the department and Drs. Yamazawa and
Misumi became associates of the University of Tokyo
Hospital.
Six postgraduate students Ohide, Yasui, Ogawa,Iwasaki, Miyama, and Kawabe) finished the course
and received Ph.D. In the new fiscal year, 2019, four
new students will enter the postgraduate course, andthere will be 20 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 students incollaboration with Department of MolecularPathology, Systemic Pathology for the 2nd grade,
Elective Clinical Clerkship for the 3rd/4th grade, andClinical Clerkship for the 4th grade students. Programsfor postgraduates and junior residents are also
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. Miyazono,
the dean 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 circulating them among
universities.
In February 2018, the University of Tokyo
Hospital was selected as one of the core hospitals to
promote cancer genomic medicine in Japan. In August,the Hospital began advanced medical care (categoryB) named ‘Trial of a multiplex genomic testing by"Todai OncoPanel" for Geneprofiling of malignant
solid tumors’. We serve as members of expert panel tocontribute to the smooth conduct of genomic medicine.
Several types of cancer panel testing will start next
fiscal year which will be covered by public healthinsurance.
We registered 1000 cases of whole slide images(WSI) in the research project of Japanese Society of

Pathology “Database of Pathology-WSI for Development of Artificial Intelligence (AI) Technique andAI-based Support System for Pathology Diagnosis” in2017. We also examined the problems in image
registration in the hospital with the Departments ofRadiology 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 4th grade medical
students, following courses are included; autopsy
pathologic practices with a case presentation forpaired students, surgical pathologic practices using
various tumor sections, and a tour of the pathology
laboratory in-house as well as other hospital.
Clinical clerkship course was not open becauseof the changes in the curriculum. In free quarter
program, we accepted one M0-student and fourM1-students in this fiscal year.
We also set up the lecture series of “Infection/
Immunology/Cancer II” and “Tumor Pathology. We
also provided two intensive exercise courses,“Integration of Neuropathology/Radiology/Clinics”
and “Histochemistry/Immuno-histochemistry/ClinicalElectron Microscopy”.

Research activities
The first major theme is “chronic inflammation andneoplasms”, especially Epstein-Barr virus (EBV)
associated gastric carcinoma (GC) (Drs. Ushiku,
Kunita, Shinozaki-Ushiku and Abe). We have reported
the significance of viral DNA load in EBV-associatedgastric carcinoma (ref.44). Investigation of tumor
immunity characteristic to this type of cancer is inprogress, and a part of the research was reported (ref.
2).
The second theme is to re-evaluate the disease
entities and tumor entities from histopathologic view.

39

We especially focus on gastric cancer and clarified theearly genetic events in gastric carcinogenesis (ref.33),
the significance of newly identified fusion gene
CLDN18-ARHGAPs in diffuse type gastric cancer(ref. 13), the association between cancer of
esophagastric junction and its background mucosal
status (ref. 27). We joined the international multiinstitutional research project to reveal the pathology ofpyloric gland adenoma (ref. 4). Other research
activities include carcinogenesis of bile duct cancer(ref. 43), identification of new subtype of pancreatic
hamartoma (ref. 14), clinicopathologic studies of soft
tissue tumors (ref. 5,16,28) and urothelial carcinoma(ref. 23).

References(Case reports are listed in the section of Diagnostic
Pathology Division)
1. Iwashita T, Nakai Y, Mukai T, Togawa O,
Matsubara S, Hatano Y, Hara A, Tanaka M,
Shibahara J, Fukayama M, Isayama H, Yasuda
I.A 19-Gauge Histology Needle Versus a
19-Gauge Standard Needle in Endoscopic
Ultrasound-Guided Fine-Needle Aspiration for
Solid Lesions: A Multicenter Randomized
Comparison Study (GREATER Study). Dig Dis
Sci. 2018;63(4):1043-1051.
2. Abe H, Saito R, Ichimura T, Iwasaki A,
Yamazawa S, Shinozaki-Ushiku A, Morikawa T,
Ushiku T, Yamashita H, Seto Y, Fukayama M.
CD47 expression in Epstein-Barr virus-associatedgastric carcinoma: coexistence with tumor
immunity lowering the ratio of CD8+/Foxp3+ T
cells. Virchows Arch. 2018;472(4):643-651.
3. Ohki D, Tsuji Y, Shinozaki T, Sakaguchi Y,
Minatsuki C, Kinoshita H, Niimi K, Ono S,
Hayakawa Y, Yoshida S, Yamada A, Kodashima
S, Yamamichi N, Hirata Y, O T, Fujishiro M,
Fukayama M, Koike K. Sessile serrated adenoma
detection rate is correlated with adenoma
detection rate.World J Gastrointest Oncol. 2018;10(3):82-90.
4. Choi WT, Brown I, Ushiku T, Yozu M, Setia N,
Srivastava A, Johncilla M, Pai RK, Gill RM,
Fukayama M, Misdraji J, Lauwers GY. Gastric
pyloric gland adenoma: a multicentre clinic-

pathological study of 67 cases. Histopathology.
2018;72(6):1007-1014.
5. Makise N, Sekimizu M, Kubo T, Wakai S,
Hiraoka N, Komiyama M, Fukayama M, Kawai A,
Ichikawa H, Yoshida A. Clarifying the Distinction
Between Malignant Peripheral Nerve Sheath
Tumor and Dedifferentiated Liposarcoma: A
Critical Reappraisal of the Diagnostic Utility of
MDM2 and H3K27me3 Status. Am J Surg Pathol.
2018;42(5):656-664.
6. Okuno T, Kawai K, Koyama K, Takahashi M,
Ishihara S, Momose T, Morikawa T, Fukayama M,
Watanabe T. Value of FDG-PET/CT Volumetry
After Chemoradiotherapy in Rectal Cancer. Dis
Colon Rectum. 2018;61(3):320-327.
7. Niikura R, Hayakawa Y, Hirata Y, Konishi M,
Suzuki N, Ihara S, Yamada A, Ushiku T,
Fujishiro M, Fukayama M, Koike K. Distinct
Chemopreventive Effects of Aspirin in Diffuse
and Intestinal-Type Gastric Cancer. Cancer Prev
Res (Phila). 2018;11(5):279-286.
8. Kunita A, Baeriswyl V, Meda C, Cabuy E,
Takeshita K, Giraudo E, Wicki A, Fukayama M,
Christofori G. Inflammatory Cytokines Induce
Podoplanin Expression at the Tumor Invasive
Front. Am J Pathol. 2018;188(5):1276-1288.
9. Saito K, Isayama H, Sakamoto Y, Nakai Y,
Ishigaki K, Tanaka M, Watadani T, Arita J,
Takahara N, Mizuno S, Kogure H, Ijichi H,
Tateishi K, Tada M, Hasegawa K, Fukayama M,
Kokudo N, Koike K. A phase II trial of
gemcitabine, S-1 and LV combination (GSL)
neoadjuvant chemotherapy for patients withborderline resectable and locally advanced
pancreatic cancer. Med Oncol. 2018;35(7):100.
10. Yoshida A, Makise N, Wakai S, Kawai A,
Hiraoka N. INSM1 expression and its diagnostic
significance in extraskeletal myxoid chondrosarcoma. Mod Pathol. 2018;31(5):744-752.
11. Nakai Y, Gonoi W, Hagiwara A, Nishioka Y, Abe
H, Shindoh J, Hasegawa K. MRI Detection of
Intratumoral Fat in Colorectal Liver Metastases
After Preoperative Chemotherapy. AJR Am J
Roentgenol. 2018;210(5):W196-W204.
12. Kunita A, Morita S, Irisa TU, Goto A, Niki T,
Takai D, Nakajima J, Fukayama M. Micro
RNA-21 in cancer-associated fibroblasts supports

40lung adenocarcinoma progression. Sci Rep. 2018;
8(1):8838.
13. Tanaka A, Ishikawa S, Ushiku T, Yamazawa S,
Katoh H, Hayashi A, Kunita A, Fukayama M.
Frequent CLDN18-ARHGAP fusion in highly
metastatic diffuse-type gastric cancer withrelatively early onset. Oncotarget. 2018;9(50):29336-29350.
14. Tanaka M, Ushiku T, Ikemura M, Takazawa Y,
Igari T, Shimizu M, Yamaguchi H, Fukushima N,
Sakuma K, Arita J, Sakamoto Y, Hasegawa K,
Watadani T, Nakai Y, Koike K, Fukayama M.
Pancreatic Lipomatous Hamartoma: A Hitherto
Unrecognized Variant. Am J Surg Pathol. 2018;
42(7):891-897.
15. Tsukui D, Kanda H, Shinozaki-Ushiku A, Tateishi
S, Takeshima Y, Nagafuchi Y, Sasaki O, Iwasaki
Y, Harada H, Shibuya M, Sumitomo S, Shoda H,
Kubo K, Fujio K, Nakamura F, Kurokawa M,
Fukayama M, Yamamoto K. Polymorphic
lymphoproliferative disorders in patients withrheumatoid arthritis are associated with a better
clinical outcome. Mod Rheumatol. 2018;28(4):621-625.
16. Makise N, Sekimizu M, Kubo T, Wakai S,
Watanabe SI, Kato T, Kinoshita T, Hiraoka N,
Fukayama M, Kawai A, Ichikawa H, Yoshida A.
Extraskeletal
osteosarcoma:
MDM2
andH3K27me3 analysis of 19 cases suggest disease
heterogeneity. Histopathology. 2018;73(1):147156.
17. 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. Blood
Vessel Invasion Is a Strong Predictor of
Postoperative Recurrence in Endometrial Cancer.
Int J Gynecol Cancer. 2018;28(5):875-881.
18. Kawazoe Y, Shimamoto K, Yamaguchi R,
Shintani-Domoto Y, Uozaki H, Fukayama M, Ohe
K. Faster R-CNN-Based Glomerular Detection in
Multistained Human Whole Slide Images J.
Imaging. 2018;4(7):91(1-19).
19. Fujiwara N, Nakagawa H, Enooku K, Kudo Y,
Hayata Y, Nakatsuka T, Tanaka Y, Tateishi R,
Hikiba Y, Misumi K, Tanaka M, Hayashi A,

Shibahara J, Fukayama M, Arita J, Hasegawa K,
Hirschfield H, Hoshida Y, Hirata Y, Otsuka M,
Tateishi K, Koike K. CPT2 downregulation
adapts HCC to lipid-rich environment andpromotes carcinogenesis via acylcarnitine
accumulation in obesity. Gut 2018;67(8):14931504.
20. Tainaka K, Murakami TC, Susaki EA, Shimizu C,
Saito R, Takahashi K, Hayashi-Takagi A, Sekiya
H, Arima Y, Nojima S, Ikemura M, Ushiku T,
Shimizu Y, Murakami M, Tanaka KF, Iino M,
Kasai H, Sasaoka T, Kobayashi K, Miyazono K,
Morii E, Isa T, Fukayama M, Kakita A, Ueda HR.
Chemical Landscape for Tissue Clearing Based on
Hydrophilic Reagents. Cell Rep. 2018;24(8):2196-2210.e9.
21. 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. 2018. [Epub ahead of print]
22. Karasaki T, Qiang G, Anraku M, Sun Y,
Shinozaki-Ushiku A, Sato E, Kashiwabara K,
Nagayama K, Nitadori JI, Sato M, Murakawa T,
Kakimi K, Fukayama M, Nakajima J. High CCR4
expression in the tumor microenvironment is apoor prognostic indicator in lung adenocarcinoma.
J Thorac Dis. 2018;10(8):4741-4750.
23. Miyama Y, Morikawa T, Miyakawa J, Koyama Y,
Kawai T, Kume H, Fukayama M. The prognostic
value of PD-L1 expression in upper tract
urothelial carcinoma varies according to platelet
count. Cancer Med. 2018;7(9):4330-4338.
24. 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.
2018. [Epub ahead of print]
25. Ito K, Sakamoto Y, Isayama H, Nakai Y,
Watadani T, Tanaka M, Ushiku T, Akamatsu N,
Kaneko J, Arita J, Hasegawa K, Kokudo N. The

41

Impact of MDCT and Endoscopic Transpapillary
Mapping Biopsy to Predict Longitudinal SpreadofExtrahepatic
Cholangiocarcinoma.
J
Gastrointest Surg. 2018;22(9):1528-1537.
26. Hiroyoshi J, Yamashita S, Tanaka M, Hayashi A,
Ushiku T, Kaneko J, Akamatsu N, Arita J,
Sakamoto Y, Hasegawa K. Contrast-enhanced
intraoperative ultrasound in the resection ofcolorectal liver metastases with intrabiliary
growth. Clin J Gastroenterol. 2018;11(5):348-353.
27. Urabe M, Ushiku T, Shinozaki-Ushiku A, Iwasaki
A, Yamazawa S, Yamashita H, Seto Y, Fukayama
M. Adenocarcinoma of the esophagogastricjunction and its background mucosal pathology: A
comparative analysis according to Siewert
classification in a Japanese cohort. Cancer Med.
2018;7(10):5145-5154.
28. Makise N, Sekimizu M, Konishi E, Motoi T,
Kubo T, Ikoma H, Watanabe SI, Okuma T,
Hiraoka N, Fukayama M, Kawai A, Ichikawa H,
Yoshida A. H3K27me3 deficiency defines asubset of dedifferentiated chondrosarcomas withcharacteristic clinicopathological features. Mod
Pathol. 2018. [Epub ahead of print]
29. Karakawa A, Taoka K, Kaburaki T, Tanaka R,
Shinozaki-Ushiku A, Hayashi H, MiyagiMaeshima A, Nishimura Y, Uekusa T, Kojima Y,
Fukayama M, Kurokawa M, Aihara M. Clinicalfeatures and outcomes of secondary intraocularlymphoma. Br J Haematol. 2018;183(4):668-671.
30. Li Z, Maeda D, Kudo-Asabe Y, Tamura D, Nanjo
H, Hayashi A, Ikemura M, Fukayama M, Goto A.
MED12 is frequently mutated in ovarian and otheradnexal leiomyomas. Hum Pathol. 2018;81:89-95.
31. Toya T, Ogura M, Toyama K, Yoshimi A,
Shinozaki-Ushiku A, Honda A, Honda K, Hosoya
N, Murakami Y, Kawashima H, Nannya Y, Arai S,
Nakamura F, Shinoda Y, Nangaku M, Miyagawa
K, Fukayama M, Moriya-Saito A, Katayama I,
Ogura T, Kurokawa M. Prognostic factors ofErdheim-Chester disease: a nationwide survey inJapan. Haematologica. 2018;103(11):1815-1824.
32. 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. BHLHA15-

positive Secretory Precursor Cells Can Give Riseto Tumors in Intestine and Colon in Mice.
Gastroenterology. 2018; pii: S0016-5085(18)35272-7.
33. 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. 2018. [Epub ahead of print]
34. Kinoshita Y, Takashi Y, Ito N, Ikegawa S, Mano
H, Ushiku T, Fukayama M, Nangaku M,
Fukumoto S. Ectopic expression of Klotho infibroblast growth factor 23 (FGF23)-producing
tumors that cause tumor-induced rickets/
osteomalacia (TIO). Bone Rep. 2018;10:100192.
35. 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 ß-catenin expression isassociated with histological progression and overt
diabetes emergence in NAFLD patients. J
Gastroenterol. 2018;53(12):1261-1275.
36. Sekimizu M, Yoshida A, Mitani S, Asano N,
Hirata M, Kubo T, Yamazaki F, Sakamoto H,
Kato M, Makise N, Mori T, Yamazaki N, Sekine
S, Oda I, Watanabe SI, Hiraga H, Yonemoto T,
Kawamoto T, Naka N, Funauchi Y, Nishida Y,
Honoki K, Kawano H, Tsuchiya H, Kunisada T,
Matsuda K, Inagaki K, Kawai A, Ichikawa H.
Frequent mutations of genes encoding vacuolar
H+ -ATPase components in granular cell tumors.
Genes Chromosomes Cancer 2018. [Epub aheadof print]
37. Fukayama M, Kunita A, Kaneda A. GastritisInfection-Cancer Sequence of Epstein-Barr VirusAssociated Gastric Cancer. Adv Exp Med Biol.
2018;1045:437-457.
38. Nishioka Y, Shindoh J, Inagaki Y, Gonoi W,
Mitsui J, Abe H, Yoshioka R, Yoshida S,
Fukayama M, Tsuji S, Hashimoto M, Hasegawa K,
Kokudo N. Host MICA Polymorphism as a
Potential Predictive Marker in Response to42

Chemotherapy for Colorectal Liver Metastases.
Dig Dis. 2018;36(6):437-445.
39. Mizuno S, Nakai Y, Tanaka M, Ushiku T, Arita J,
Hasegawa K, Fukayama M, Koike
K. Reappraisal of the usefulness of percutaneoustranshepatic cholangioscopy for indeterminate
distal biliary strictures. J Gastroenterol Hepatol.
2019. [Epub ahead of print]
40. Kinoshita H, Hayakawa Y, Konishi M, Hata M,
Tsuboi M, Hayata Y, Hikiba Y, Ihara S,
Nakagawa H, Ikenoue T, Ushiku T, Fukayama M,
Hirata Y, Koike K. Three types of metaplasia
model through Kras activation, Pten deletion, orCdh1 deletion in the gastric epithelium. J Pathol.
2019;247(1):35-47.
41. 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.
42. 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, Mano H.
Fusion Kinases Identified by Genomic Analysesof Sporadic Microsatellite Instability-High
Colorectal Cancers. Clin Cancer Res. 2019;25(1):378-389.
43. Tanaka M, Shibahara J, Ishikawa S, Ushiku T,
Morikawa T, Shinozaki-Ushiku A, Hayashi A,
Misumi K, Tanaka A, Katoh H, Sakuma K,
Kokudo T, Inagaki Y, Arita J, Sakamoto Y,
Hasegawa K, Fukayama M. EVI1 expression isassociatedwithaggressive
behavior
inintrahepatic cholangiocarcinoma. Virchows Arch.
2019;474(1):39-46.
44. Nakayama A, Abe H, Kunita A, Saito R, Kanda T,
Yamashita H, Seto Y, Ishikawa S, Fukayama M.
Viral loads correlate with upregulation of PD-L1
and worse patient prognosis in Epstein-Barr
Virus-associated gastric carcinoma. PLoS One
2019;14(1):e0211358.
45. Bains S, Eguchi T, Warth A, Yeh YC, Nitadori JI,
Woo KM, Chou TY, Dienemann H, Muley T,
Nakajima J, Shinozaki-Ushiku A, Wu YC, Lu S,

Kadota K, Jones DR, Travis WD, Tan KS,
AdusumilliPS.
Procedure-Specific
Risk
Prediction for Recurrence in Patients Undergoing
Lobectomy or Sublobar Resection for Small (≤2cm) Lung Adenocarcinoma: An International
Cohort Analysis. J Thorac Oncol. 2019;14(1):72-86.
46. 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. Interleukin-13 receptor α2 is a novel marker
and potential therapeutic target for humanmelanoma. Sci Rep. 2019;9(1):1281.
47. 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. [Epubahead of print]
48. Kobayashi H, Makise N, Ushiku T, Ito N, Koga
M, Shinoda Y, Tanaka S. Infiltrative nature oftumor-induced osteomalacia lesions in bone:
Correlation
betweenradiologicalandhistopathological features. J Orthop Sci. 2019.
[Epub ahead of print]

43

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;from September 2018)

Assistant Professors
Masato Morikawa, M.D., Ph.D.; Yoko Katsuno, Ph.D.;
Kei Takahashi, Ph.D. (Medical Scientist Training Program; from July 2018)

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
2019, the Department consists of a professor, two
associate professors, three assistant professors,
technical assistants, and some research fellows,
including five graduate students, a master course
student, and five 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 at 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

44

growth, differentiation, and apoptosis of various cells.
From 2015, our research is mainly supported by aGrant-in-Aid for Scientific Research (S) on“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 2018.
1) Chronic TGF-β exposure drives stabilized EMT,
tumor stemness, and cancer drug resistance
It is well known that human tumor tissues include
cancer-initiating cells and their heterogeneousprogeny in a stromal tumor microenvironment. Uponstimulation with TGF-β, normal epithelial cells aswell as cancer cells undergo a partial or complete
epithelial-to-mesenchymal transition (EMT), which is
now known to intimately contribute to progression ofvarious types of cancers. The process of EMT isreversible, because cells, which have undergone apartial or complete EMT, can revert to epithelial-likecells after removal of TGF-β. Importantly, we havefound that chronic TGF-β treatment, which mimicked
the state of in vivo carcinomas, promoted stable EMT
in mammary epithelial cells as well as carcinoma
cells; this was in clear contrast to the reversible EMT
induced by a short-period treatment with TGF-β. We
have also found that in the cells with stabilized EMT
phenotype, enhanced generation of stem cells andresistance to anticancer drugs could be observed.
Moreover, chronic TGF-β treatment enhanced mTOR
signaling activities. A novel mTOR inhibitor
RapaLink1 suppressed the generation of cancerinitiating cells, sphere forming ability, cell survival,
andchemoresistance.
Moreover,RapaLink1
efficiently suppressed tumor formation in mousemodels. These findings suggest a critical role ofmTOR in the stabilization of stem-cell like propertiesof breast cancer cells, and that mTOR inhibition is an
important treatment strategy to target cancer-initiating
cells (Katsuno et al. Science Signaling 2019).

2) Palbociclib augments activin-Smad-induced
cytostasis in estrogen receptor-positive breast cancer
Inhibitors for CDK4 and CDK6, including
palbociclib, are currently known as effective
therapeutic options for hormone receptor (HR)positive, human EGF receptor 2 (HER2)-negativeadvanced breast cancer. Palbociclib targets the cyclin
D-CDK4/6-RB tumor suppressor protein axis;
however, only little is known about the clinicalimportance of other target proteins of palbociclib. We
studied the functions of Smad proteins as targets ofpalbociclib. In the luminal-type breast cancer cell line
T47D, palbociclib inhibited cell cycle progression,cooperatively
withactivin-Smad2
signaling.
Palbociclib accelerated the binding of Smad2 to the
genome by suppressing the phosphorylation of theSmad2 linker region induced by CDK4/6. We also
demonstrated that cyclin G2 plays a critical role inSmad2-dependent cytostasis. Analysis of the Smad2
ChIP-seq data of T47D cells and the triple-negative
breast cancer Hs578T cells revealed that palbociclib
enhanceddistinct
Smad2-mediatedbiological
functions depending on cell type, and that it
stimulated the binding of Smad2 to target regions on
the genome without affecting its binding profiles.
Palbociclib thus shows tumor-suppressive effects
through augmentation of the cytostatic effects by theactivin-Smad2 signaling pathway, while it may alsoenhance the tumor-promoting effects in certain breast
cancer cells (Harada et al. Cancer Science 2019).
3)
Decreased betaglycan/TGFBR3 expression
enhances the metastatic abilities of renal cell
carcinoma cells
Although TGF-β regulates the tumor-forming andmigratory abilities in various types of cancers, it is notknown how the loss of the components of TGF-βsignaling pathway affects these functions in clear-cell
renal cell carcinoma (ccRCC) cells. We studied therole of TGF-β type III receptor (betaglycan, also
known as TGFBR3) in ccRCC cells. Analysis of
public datasets revealed that expression of betaglycan
is decreased in ccRCC tissues, and decreased
betaglycan expression is correlated with poor
prognosis of ccRCC patients. Orthotopic inoculation
experiments using nude mice showed that decreased
betaglycan expression in ccRCC cells resulted in45enhancement of primary tumor formation and lungmetastasis. In the presence of betaglycan, TGF-β2
decreased the cancer-initiating cell population of
ccRCC cells, expressing aldehyde dehydrogenase(ALDH). Loss of betaglycan also accelerated themigration of ccRCC cells in vitro and induced theexpression of several mesenchymal markers, which
could be observed in a TGF-β-independent manner.
Downregulation of betaglycan induced lamellipodium
formation mediated by FAK-PI3K signaling, andcontributed to TGF-β-independent migration of
ccRCC cells. These findings indicated that loss ofbetaglycan endows ccRCC cells with metastatic
abilities through TGF-β-dependent and independent
pathways (Nishida et al. Oncogene 2018).
4) Pancreatic tumor microenvironment confers highly
malignant properties on pancreatic cancer cells.
Although tumor microenvironments play criticalroles in progression of cancer, only little is known
how different microenvironments affect distinct
characteristics of cancer cells. We studied thefunctions of pancreatic tumor microenvironment onpancreatic cancer cells by using mouse models. After
serial inoculations (three cycles) of human pancreaticcancer cells, such as SUIT-2 and PANC-1 cells,
distinct cancer cell lines could be established: thesecell lines were termed 3P cells (obtained from theorthotopic tumor model) and 3sc cells (obtained fromthe subcutaneous tumor model). When these cells
were re-inoculated, 3P cells (and 3sc cells lessprominently) showed higher tumorigenic activity thanthe parental cells. 3P cells showed decreased
expression of E-cadherin and high invasive ability,
suggesting that these cells acquired mesenchymal
characteristics. RNA-sequence analysis revealed that
distinct signaling pathways were activated in thesecell lines; interestingly, in addition to mesenchymal
characteristics, 3P cells acquired a cancer stem
cell-like phenotype. Among the genes related to thecancer stem cell-related phenotype, genes expressed in
3P cells, including NESTIN, may serve as new targets
for cancer therapy (Takahashi et al. Oncogene 2018).

References
1. Kawasaki, N., Isogaya, K., Dan, S., Yamori, T.,
Takano, H., Yao, R., Morishita, Y., Taguchi, L.,
Morikawa, M., Heldin, C.H., Noda, T., Ehata, S.,
Miyazono, K., and Koinuma, D. (2018) TUFT1interacts with RABGAP1 and regulates mTORC1
signaling. Cell Discovery 4, 1, doi:10.1038/
s41421-017-0001-2
2. Sundqvist, A., Morikawa, M., Ren, J., Vasilaki, E.,
Kawasaki, N., Kobayashi, M., Koinuma, D.,
Aburatani, H., Miyazono, K., Heldin, C.H., vanDam, H., and ten Dijke, P. (2018) JUNB governs afeed-forward network of TGF- signaling that
aggravates breast cancer invasion. Nucleic Acids
Research 46 (3), 1180-1195.
3. Komuro, A., Raja, E., Iwata, C., Soda, M.,
Isogaya, K., Yuki, K., Ino, Y., Morikawa, M.,
Todo, T., Aburatani, H., Suzuki, H., Ranjit, M.,
Natsume, A., Mukasa, A., Saito, N., Okada, H.,
Mano, H., Miyazono, K., and Koinuma, D. (2018)
Identification of a novel fusion gene HMGA2EGFR in glioblastoma. International Journal ofCancer 142 (8), 1627-1639.
4. Nishida, J., Miyazono, K., and Ehata, S. (2018)
DecreasedTGFBR3/betaglycan
expression
enhances the metastatic abilities of renal cell
carcinoma cells through TGF--dependent and-independent mechanisms. Oncogene 37 (16),2197-2212.
5. Takahashi, K., Ehata, S., Koinuma, D., Morishita,Y., Soda, M., Mano, H., and Miyazono, K. (2018)
Pancreatic tumor microenvironment confers
highly malignant properties on pancreatic cancer
cells. Oncogene 37 (21), 2757-2772.
6. Kawasaki, N., Miwa, T., Hokari, S., Sakurai, T.,
Ohmori, K., Miyauchi, K., Miyazono, K., andKoinuma, D. (2018) Long noncoding RNANORAD regulates transforming growth factor-
signalingandepithelial-to-mesenchymaltransition-like phenotype. Cancer Science 109 (7),2211-2220.

46

7. Katsuno, Y., Qin, J., Oses-Prieto, J., Wang, H.,
Jackson-Weaver, O., Zhang, T., Lamouille, S., Wu,
J., Burlingame, A., Xu, J., and Derynck, R. (2018)
Arginine methylation of SMAD7 by PRMT1 in
TGF--induced epithelial-mesenchymal transitionand epithelial stem-cell generation. The Journalof Biological Chemistry 293 (34), 13059-13072.
8. Tainaka, K., Murakami, T. C., Susaki, E. A.,
Shimizu, C., Saito, R., Takahashi, K., HayashiTakagi, A., Sekiya, H., Arima, Y., Nojima, S.,
Ikemura, M., Ushiku, T., Shimizu, Y., Murakami,M., Tanaka, K. F., Iino, M., Kasai, H., Sasaoka, T.,
Kobayashi, K., Miyazono, K., Morii, E., Isa, T.,
Fukayama, M., Kakita, A., and Ueda, H. R. (2018)
Chemical landscape for tissue clearing based onhydrophilic reagents. Cell Reports 24 (8),2196-2210.
9. Miyazono, K., Katsuno, Y., Koinuma, D., Ehata,S., and Morikawa, M. (2018) Intracellular andextracellular TGF-signaling in cancer: Some
recent topics. Frontiers of Medicine 12 (4),387-411.

Pathology, Immunology andMicrobiology
2. Microbiology

48

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 24 members; 1 professor (Dr. Hatakeyama),
1 senior lecturer (Dr. Kamiya), 2 research associates(Drs. Takahashi and Hayashi), 1 project research
associate (Dr. Fujii), 3 post-doctoral fellows (Drs.
Nishikawa, Kikuchi, and Ooki), 2 academic assistants(Ms. Nakano and Komatsu), 12 graduate school
students (Mr. and Ms. Nojima, Ben, Lu, Knight, Wada,
Imai, Tahmina, Marrero, Wu, Suzuki, Wu, Hikawa),
and 2 research students (Mr. Lin and Ms. Pricillia).

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

49

1. Inverse regulation of co-activator functions of
YAP and TAZ through tyrosine phosphorylation status of Parafibromin
The Hippo signaling pathway plays a key role in organ
size determination and tissue homeostasis. A uniquefeature of the Hippo signaling is that it mediates
contact inhibition of cell proliferation by sensing celldensity thereby acting as a tumor suppressor. 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 phosphorylates the transcription
co-activator Yes-associated protein (YAP) and thetranscriptional 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.
Parafibromin is the human (mammalian) orthologueof 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-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.
2. Virulence of a Helicobacter pylori cagA-positive
strain isolated from a non-human primate
The C-terminal region of CagA contains multiple
Glu-Pro-Ile-Tyr-Ala(EPIYA)
motifs.
The
EPIYA-repeat region is composed of various
combinations of four distinct EPIYA segments,
EPIYA-A, -B, -C, and -D, which are defined by theamino acid sequence surrounding each of the EPIYA
motifs. The two major CagA subtypes are Western
CagA and East Asian CagA. Western CagA contains
EPIYA-A, EPIYA-B, and EPIYA-C segments(ABC-type CagA), whereas East Asian CagA contains
EPIYA-A, EPIYA-B, and EPIYA-D segments(ABD-type CagA). In addition, the C-terminal regionof CagA contains a 16-amino-acid sequence termed
the CagA multimerization (CM) sequence.
Upon delivery into gastric epithelial cells via typeIVsecretion,
CagA
undergoestyrosine
phosphorylation by Src family kinases or c-Abl kinase
at the EPIYA motif. CagA binds to the pro-oncogenic
proteintyrosine
phosphataseSHP2
via
tyrosine-phosphorylated EPIYA-C or EPIYA-D
segment and thereby aberrantly activates thephosphatase activity, which has been considered toplay an important role in gastric carcinogenesis.
ABD-type CagA binds to SHP2 100-fold morestrongly than ABC-type CagA due to the difference inthe pTyr+5 residue between the EPIYA-C andEPIYA-D segments. CagA also binds topartitioning-defective
1b(PAR1b)/microtubule
affinity-regulating kinase 2 (MARK2) via the CM
sequence in a tyrosine phosphorylation-independent
manner. Through complex formation, CagA inhibits
kinase activity of PAR1b, resulting in induction ofjunctional and polarity defects.
In the present study, we isolated an H. pylori strain(Hp_TH2099) naturally infecting the stomach of ahoused macaque, which indicates a zoonotic feature of

50

H. pylori infection. Whole genome sequence analysis
revealed that Hp_TH2099 belongs to the hpAsia2
cluster and possesses ABC-type Western CagA, whichcontains hitherto unreported variations in both
EPIYA-C segment and CM sequences. Hp_TH2099
CagA lost PAR1b-binding activity due to the CMvariations. Hp_TH2099 CagA also contained two
unique amino substitutions in the EPIYA-C segment,
one at the pTyr-2 position and the pther at the pTyr+5
position. Whereas pTyr+5 variation in the EPIYA-C
segment potentiated SHP2-binding affinity, pTyr-2
variation dampened CagA tyrosine phosphorylationand thus impeded CagA-SHP2 complex formation. As
opposed to the H. pylori standard strain, infection ofmouse ES cell-derived gastric organoids with
Hp_TH2099 failed to elicit CagA-dependent epithelial
destruction. Thus, the macaque-isolated H. pylori
showed low virulence due to attenuated CagA activity
through multiple substitutions in the sequences
involved in binding with SHP2 and PAR1b.

Publications
1.

2.

Tang, C., Takahashi-Kanemitsu, A., Kikuchi, I.,
Ben, C., Hatakeyama, M. Transcriptional
Co-activator Functions of YAP and TAZ Are
Inversely Regulated by Tyrosine Phosphorylation
Status of Parafibromin. iScience 1:1-15 (2018)
Hashi, K., Imai, C., Yahara, K., Tahmina, K.,
Hayashi, T., Azuma, T., Miyabe-Nishiwaki, T.,
Sato, H., Matsuoka, M., Niimi, S., Okamoto, M.,
Hatakeyama, M. Evaluating the origin andvirulence of a Helicobacter pylori cagA-positive
strain isolated from a non-human primate. Sci.
Rep. 8(1), Article number: 15981 (2018)

51

Department of Infection Control
and Prevention
Professor
Kyoji Moriya, 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, five research associates, 11
laboratory technicians, and two office assistants. For
isolation and identification of microorganisms fromclinical 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
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 technique

52

on 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) Mechanism of multi-drug resistant microorganisms11) Epidemiology of Clostridioides difficile infection

Publications
1. Morita K, Honda A, Koya J, Toyama K, Ikeda M,
Misawa Y, et al. Three cases of Candida
fermentati fungemia following hematopoietic
stem cell transplantation. Journal of infection andchemotherapy : official journal of the Japan
Society of Chemotherapy. 2018;24(7):576-8.
2. Aoki K, Harada S, Yahara K, Ishii Y, Motooka D,
Nakamura S, et al. Molecular Characterization of
IMP-1-Producing Enterobacter cloacae Complex
Isolates in Tokyo. Antimicrobial agents andchemotherapy. 2018;62(3).
3. Araoka H, Baba M, Okada C, Kimura M, Sato T,
Yatomi Y, et al. First evidence of bacterialtranslocation from the intestinal tract as a route of
Helicobacter cinaedi bacteremia. Helicobacter.
2018;23(1).
4. Araoka H, Baba M, Okada C, Kimura M, Sato T,
Yatomi Y, et al. Risk Factors for Recurrent
Helicobacter cinaedi Bacteremia and the Efficacy

of Selective Digestive Decontamination With
Kanamycin to Prevent Recurrence. Clinicalinfectious diseases: an official publication of the
Infectious Diseases Society of America. 2018;
67(4):573-8.
5. Ohki D, Tsuji Y, Shinozaki T, Sakaguchi Y,
Minatsuki C, Kinoshita H, et al. Sessile serrated
adenoma detection rate is correlated withadenoma detection rate. World journal ofgastrointestinal oncology. 2018;10(3):82-90.
6. Yokoyama A, Kage H, Ohama Y, Sato T,
Miyashita N, Noguchi S, et al. Mycobacterium
heckeshornense lung infection diagnosed bymatrix-assisted laser desorption ionization-time offlight mass spectrometry (MALDI-TOF MS).
Journal of infection and chemotherapy : official
journal of the Japan Society of Chemotherapy.
2018;24(9):763-5.
7. Enooku K, Kondo M, Fujiwara N, Sasako T,
Shibahara J, Kado A, et al. Hepatic IRS1 andss-catenin expression is associated withhistological progression and overt diabetes
emergence in NAFLD patients. Journal ofgastroenterology. 2018;53(12):1261-75.
8. Minatsuki C, Yamamichi N, Inada KI, Takahashi
Y, Sakurai K, Shimamoto T, et al. Expression of
Gastric Markers Is Associated with Malignant
Potential of Nonampullary Duodenal Adenocarcinoma. Digestive diseases and sciences. 2018;
63(10):2617-25.
9. Matsuda R, Yamamichi N, Shimamoto T, Sumida
H, Takahashi Y, Minatsuki C, et al. Gastroesophageal Reflux Disease-Related Disorders of
Systemic Sclerosis Based on the Analysis of 66
Patients. Digestion. 2018;98(4):201-8.
10. Horita S, Simsek E, Simsek T, Yildirim N, Ishiura
H, Nakamura M, et al. SLC4A4 compound
heterozygous mutations in exon-intron boundary
regions presenting with severe proximal renal
tubular acidosis and extrarenal symptoms
coexisting with Turner's syndrome: a case report.
BMC medical genetics. 2018;19(1):103.
11. Ikeda M, Mizoguchi M, Oshida Y, Tatsuno K,
Saito R, Okazaki M, et al. Clinical andmicrobiological characteristics and occurrence ofKlebsiella pneumoniae infection in Japan.
International journal of general medicine. 2018;

53

11:293-9.
12. Nakano T, Moriya K, Koike K, Horie T. Hepatitis
C virus core protein triggers abnormal porphyrin
metabolism in human hepatocellular carcinoma
cells. PloS one. 2018;13(6):e0198345.
13. Okushin K, Tsutsumi T, Ikeuchi K, Kado A,
Enooku K, Fujinaga H, et al. Helicobacter pylori
infection and liver diseases: Epidemiology andinsights into pathogenesis. World journal ofgastroenterology. 2018;24(32):3617-25.
14. Sato S, Aoyama T, Uejima Y, Furuichi M,
Suganuma E, Takano T, et al. Pyogenic liverabscess due to hypervirulent Klebsiellapneumoniae in a 14-year-old boy. Journal of
infection and chemotherapy : official journal of
the Japan Society of Chemotherapy. 2019;25(2):137-40.
15. Ando T, Noguchi S, Enokida T, Yamato A, Kage
H, Yamauchi Y, et al. Infectious Aneurysm Caused
by Citrobacter koseri in an Immunocompetent
Patient. Internal medicine (Tokyo, Japan). 2019;58(6):813-6.
16. 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. Journal ofgastroenterology and hepatology. 2019;34(5):9218.

Pathology, Immunology andMicrobiology
3. Immunology

55

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 2018, special lectures for undergraduate
students were given by internationally recognizedscientists, Dr. Shimon Sakaguchi (Osaka Univ.), Dr.
Hajime Karasuyama (Tokyo Medical and Dental Univ.),
Dr. Hiroshi Kawamoto (Kyoto Univ.), and Dr.
Tadatsugu Taniguchi (The Univ. of Tokyo).

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

56

is to develop epoch-making strategies for the treatmentof immune disorders such as autoimmune diseases andsevere infectious diseases.
1) Osteoimmuology
The bone marrow is a primary lymphoid organ thatplays a critical role in immune cell development. The
crucial stromal cell types that support hematopoietic
cell development in the bone marrow have not beenclarified. We reported the crucial role of osteoblasts insupporting lymphoid lineage development within thebone marrow microenvironment (Terashima et al.,Immunity. 2016). The mice genetically ablated forosteoblasts exhibited a marked reduction of the numberof common lymphoid progenitor cells in the bonemarrow and mature lymphocytes in the periphery. Our
results showed that osteoblasts play a pivotal role inmaintenance of common lymphoid progenitors throughthe production of IL-7. Furthermore, using a mousemodel of sepsis, we showed that sepsis rapidly ablated
osteoblasts, which reduced the common lymphoidprogenitor number and thereby resulted in peripheral
lymphopenia. This study demonstrates a reciprocalinteraction between the immune and bone systems, inwhich acute inflammation induces a defect in bonecells resulting in lymphopenia-associated immunedeficiency, 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
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

57

of RANKL inhibition with a small-molecule compoundin bone metastasis (Nakai et al., Bone Res. 2019).
These findings provided a new paradigm forphysiological interaction between bone and immune
system.
2) Lymphocyte development and lymphoid tissue
microenvironment
Thymus is the primary lymphoid organ that supports
development of useful T cells (positive selection) andeliminates self-reactive T cells (negative selection).
The microenvironment of the thymus is mainlycomposed of thymic epithelial cells (TECs) 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
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., Nature
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 have

58

identified 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. Narita T, Nitta T, Nitta S, Okamura T, Takayanagi
H. Mice lacking all of the Skint family genes. Int
Immunol, 30(7):301-309 (2018)
2. Inoue M, Okamoto K, Terashima A, Nitta T,
Muro R, Negishi-Koga T, Kitamura T,
Nakashima T, Takayanagi H. Arginine methylation controls the strength of c-family cytokine
signaling in T cell maintenance. Nat Immunol,
19(11):1265-1276.(2018)
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.
AutoregulationofOsteocyte
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

60

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., Takashi 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 assistantprofessor) 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 are provided in thecentralized Clinical Radiology Service Department incooperation with radiology technologists and nurses.
In the section of Diagnostic Radiology, all CT and
MRI examinations are monitored and reported bydiagnostic radiologists. Diagnostic radiologists, gastroenterologists, cardiologists, and neurosurgeons
mainly perform interventional procedures.
In the section of Nuclear Medicine, two cyclotronsand several remote or processor-controlled automateddevices are installed, which facilitate standardized
procedures in the PET tracer production and theimplementation of GMP in PET related work. There
are two SPECT rooms and four PET rooms. These
nuclear imaging procedures are chiefly performed andreported 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 outstanding
feature. Stereotactic radiation therapy for small lungor liver tumors has been carried out.

61

In the 9th floor of the new inpatient building, there
are 12 beds in the Radiology ward, which are usuallyused 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 forradionuclide (RN) therapy in the same floor. In
addition, four beds are allotted 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 and nuclear
medicine. Professor, associate professors and lecturers
as well as specialists assigned as part time lecturers
take part in the education. A series of lectures about
fundamentals of radiology and related sciences are
given to the fourth-year students. As bed-side-learning(Clinical Clerkship, CC) curriculum, small groups ofthe sixth-year students are taking part in mini-lecturesand practice to learn basics of diagnostic radiology,
advanced medical techniques of Radiation Oncology
and Nuclear Medicine. They will learn detailed
principles of image constructions in various kinds ofimaging 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 expansion of its application.
Multi-row detector helical computed tomography(MDCT) enables us to take tomographic images in athree-dimensional (3D) fashion. Using the dataacquired by MDCT, various kinds of diseases inalmost all parts of the body, from cerebral diseases tomusculoskeletal diseases, can be displayed in 3D
images. New 3D software developed in our

departments is now widely used in the field of thegastrointestinal tract, lung, and central nervous system.
In addition, we have opened a new laboratory section
named Image Computing and Analysis Laboratory
with invitation of a new staff from the Faculty ofEngineering, the University of Tokyo. This section
will contribute to development of novel software
including convolutional neural network to abstract
clinically useful information from the 3D imaging
data more sophisticatedly. In the field of magnetic
resonance (MR) imaging, MR digital subtraction
angiography, perfusion imaging, and diffusion tensor
imaging are the foci of research. These techniques areaggressively applied to the investigation of vascularand neoplastic 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 the otheris reduction of injuries due to radiation exposure in
vitro and in vivo. This group pushes forward studies
mainly on a brain tumor, head and neck cancer,
esophageal cancer, uterine cervical cancer, prostatecancer in conformity with recent EBM in the clinicalstudy, and was active in studies of the physicalengineering traditionally and took a main role in thehighly precise radiation therapy of our country until
now. With the purpose of achieving precise external
irradiation, a new linear accelerator with multileaf
collimator systems was developed and installed,which is utilized mainly for non-coplanar radiation
therapy in many patients especially with brain tumor
or head and neck tumor. Dynamic conical conformal
radiotherapy for metastatic brain tumors using theaccelerator is under evaluation. In addition to gamma
knife radiosurgery, this new accelerator basedstereotactic radiotherapy for brain diseases has been
undergone, and stereotactic radiotherapy (SRT) for
body tumors, such as head and neck cancer, prostatecancer, rectal cancer and lung cancer, has been
investigated (intensity modulation radiation therapy;
IMRT) for the reduction of the adverse radiation
damage. A new technology to track mobile tumors,
represented by lung tumors is under investigation incollaboration with accelerator makers.
Nuclear Medicine group promotes clinical researchon functional imaging by the application of62radioisotope-labeled tracer technology, combinedwith molecular biology. In particular, emission
tomography (PET and SPECT) is applied for theevaluation of cerebral blood flow and metabolism inpatients with dementia, epilepsy, and cerebrovasculardiseases. Cerebral blood flow, glucose metabolism andneural synaptic functions are measured for theunderstanding of normal and pathophysiological statesof CNS disorders, using a variety of positron-emitterradiotracer, such as [F-18] FDG,. The study ofdementia using SPECT and the standard brain atlas
has made it possible to categorize the type of dementia.
Evaluation of dopaminergic function by SPECT isvery important in 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 bycomparing blood flow and receptor binding potential(BP) under various tasks and at rest. For the precise
localization of activated brain function, computer
processing and reconstruction of composite images offunction and anatomy is an essential subject forinvestigation. At present, whole body FDG-PET is oneof the most effective tool for exploring metastatic
lesions of cancer patients. Combination display of
SPECT/PET with CT/MRI would be a routine job andanatomo-functional images would play an importantrole in the clinical management of the patients.

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PEG-poly(L-lysine)-based polymeric micelle
MRI contrast agent: Feasibility study of a
Gd-micelle contrast agent for MR lymphography.
J Magn Reson Imaging 47(1): 238-45, 2018
Akai H, Yasaka K, Nojima M, Kunimatsu A,
Inoue Y, Abe O, Ohtomo K, Kiryu S.
Gadoxetate disodium-induced tachypnoea andthe effect of dilution method: a proof-of-concept
study in mice.
Eur Radiol 28(2): 692-7, 2018
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Inoue Y, Abe O, Ohtomo K, Kiryu S.
The inhibitory effect of gadoxetate disodium on
hepatic transporters: a study using indocyanine
green.
Eur Radiol 28(10): 4128-33, 2018
Akai H, Yasaka K, Kunimatsu A, Nojima M,
Kokudo T, Kokudo N, Hasegawa K, Abe O,
Ohtomo K, Kiryu S.
Predicting prognosis of resected hepatocellular
carcinoma by radiomics analysis with random
survival forest.
Diagn Interv Imaging 99(10): 643-51, 2018
Amemiya S, Yamashita H, Takao H, Abe O.
Integrated multi-echo denoising strategy
improves identification of inherent language
laterality.
Magn Reson Med: Epub ahead of print, 2018
Andica C, Hagiwara A, Hori M, Kamagata K,
Koshino S, Maekawa T, Suzuki M, Fujiwara H,
Ikeno M, Shimizu T, Suzuki H, Sugano H, Arai
H, Aoki S.
Review of Synthetic MRI in Pediatric brains:
Basic Principle of MR Quantification, Its
Features, Clinical Applications, and Limitations.
J Neuroradiol: Epub ahead of print, 2019
Aoki S, Yamashita H, Haga A, Ota T, Takahashi
W, Ozaki S, Nawa K, Imae T, Abe O, Nakagawa
K. Stereotactic body radiotherapy for centrallylocated lung tumors with 56 Gy in sevenfractions: A retrospective study.
Oncol Lett 16(4): 4498-506, 2018
Aoki S, Yamashita H, Haga A, Nawa K, Imae T,
Takahashi W, Abe O, Nakagawa K.
Flattening filter-free technique in volumetricmodulated arc therapy for lung stereotactic bodyradiotherapy: A clinical comparison with theflattening filter technique.
Oncol Lett 15(3): 3928-36, 2019
Benner S, Aoki Y, Watanabe T, Endo N, Abe O,
Kuroda M, Kuwabara H, Kawakubo Y, Takao H,
Kunimatsu A, Kasai K, Bito H, Kakeyama M,
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Neurochemical evidence for differential effectsof acute and repeated oxytocin administration.
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Development of a markerless tumor-tracking
algorithm using prior four-dimensional conebeam computed tomography.
J Radiat Res 60(1): 109-15, 2019
Boonrod A, Hagiwara A, Hori M, Fukunaga I,
Andica C, Maekawa T, Aoki S.
Reduced visualization of cerebral infarction on
diffusion-weighted images with short diffusion
times.
Neuroradiology 60(9): 979-82, 2018
Chougar L, Hagiwara A, Maekawa T, Hori M,
Andica C, Iimura Y, Sugano H, Aoki S.
Limitation of neurite orientation dispersion anddensity imaging for the detection of focal corticaldysplasia with a “transmantle sign”.
Phys Med 52: 183-4, 2018
Chougar L, Hagiwara A, Takano N, Andica C,
Cohen-Adad J, Warntjes M, Maekawa T, Hori M,
Koshino S, Nakazawa M, Abe O, Aoki S.
Venous signal on synthetic MRI.
Magn Reson Med Sci: in press, 2019
Fujita S, Nakazawa M, Hagiwara A, Ueda R,
Horita M, Maekawa T, Irie R, Andica C,
Kunishima Kumamaru K, Hori M, Aoki S.
Estimation of Gadolinium-based Contrast Agent
Concentration Using Quantitative Synthetic MRI
and Its Application to Brain Metastases: A
Feasibility Study.
Magn Reson Med Sci: Epub ahead of print, 2019
Gondo T, Kurihara M, Sugiyama Y, Mano T,
Mori H, Hayashi T, Tsuji S.
Longitudinally extensive vasogenic edema
following spinal cord infarction.
Neurol Clin Neurosci 6(5): 143-5, 2018
Goto M, Yamashita F, Kawaguchi A, Abe O,
Aoki S, Miyati T, Gomi T, Takeda T.
The Effect of Single-Scan and Scan-PairIntensity Inhomogeneity Correction Methods on
Repeatability of Voxel-Based Morphometry With
Multiple Magnetic Resonance Scanners.
J Comput Assist Tomogr 42(1): 111-6, 2018
Goto M, Kamagata K, Hatano T, Hattori N, Abe
O, Aoki S, Hori M, Gomi T.
Depressive symptoms in Parkinson's disease are
related to decreased left hippocampal volume:
correlation with the 15-item shortened version of
the Geriatric Depression Scale.

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Acta Radiol 59(3): 341-5, 2018
Goto M, Abe O, Aoki S, Kamagata K, Hori M,
Miyati T, Gomi T, Takeda T.0
Combining Segmented Grey and White Matter
Images Improves Voxel-based Morphometry for
the Case of Dilated Lateral Ventricles.
Magn Reson Med Sci 17(4): 293-300, 2018
Haga A, Takahashi W, Aoki S, Nawa K,
Yamashita H, Abe O, Nakagawa K.
Classification of early stage non-small cell lungcancers on computed tomographic images into
histological types using radiomic features:interobserver delineation variability analysis.
Radiol Phys Technol 11(1): 27-35, 2018
Hagiwara A, Hori M, Kamagata K, Warntjes M,
Matsuyoshi D, Nakazawa M, Ueda R, Andica C,
Koshino S, Maekawa T, Irie R, Takamura T,
Kumamaru KK, Abe O, Aoki S.
Myelin Measurement: Comparison Between
Simultaneous Tissue Relaxometry, Magnetization Transfer Saturation Index, and T1w/T2w
Ratio Methods.
Sci Rep 8(1): 10554, 2018
Hagiwara A, Hori M, Cohen-Adad J, Nakazawa
M, Suzuki Y, Kasahara A, Horita M, Haruyama T,
Andica C, Maekawa T, Kamagata K, Kumamaru
KK, Abe O, Aoki S.
Linearity, Bias, Intrascanner Repeatability, andInterscanner Reproducibility of Quantitative
Multidynamic Multiecho Sequence for Rapid
Simultaneous Relaxometry at 3 T: A Validation
Study With a Standardized Phantom and Healthy
Controls.
Invest Radiol 54(1): 39-47, 2019
Hagiwara A, Otsuka Y, Hori M, Tachibana Y,
Yokoyama K, Fujita S, Andica C, Kamagata K,
Irie R, Koshino S, Maekawa T, Chougar L, Wada
A, Takemura MY, Hattori N, Aoki S.
Improving the Quality of Synthetic FLAIR
Images with Deep Learning Using a Conditional
Generative
Adversarial
Networkfor
Pixel-by-Pixel Image Translation.
AJNR Am J Neuroradiol 40(2): 224-30, 2019
Haneda J, Hagiwara A, Hori M, Wada A,
Fukunaga I, Murata K, Kamagata K, Fujita S,
Maekawa T, Irie R, Takamura T, Suzuki M,
Kunishima Kumamaru K, Aoki S.

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A Comparison of Techniques for Correcting
Eddy-current and Motion-induced Distortions in
Diffusion-weighted Echo-planar Images.
Magn Reson Med Sci: Epub ahead of print, 2018
Haradome H, Woo J, Nakayama H, Watanabe
HN, Ogawa M, Moriyama M, Sugitani M,
Takayama T, Abe O.
Characteristicsof
Hepatic
Schwannoma
Presenting as an Unusual Multi-cystic Mass on
Gadoxetic Acid Disodium-enhanced MR
Imaging.
Magn Reson Med Sci 17(1): 95-9, 2018
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 Superimpositionof Thin Basement Membrane Syndrome.
Intern Med 58(3): 411-4, 2019
Hiroyoshi J, Arita J, Gonoi W, Akamatsu N,
Kaneko J, Hasegawa K.
Significance of Glisson's capsule invasion inpatients with colorectal liver metastases
undergoing resection.
Am J Surg S0002-9610(18)31280-7, 2019
Irie R, Kamagata K, Kerever A, Ueda R,
Yokosawa S, Otake Y, Ochi H, Yoshizawa H,
Hayashi A, Tagawa K, Okazawa H, Takahashi K,
Sato K, Hori M, Arikawa-Hirasawa E, Aoki S.
The Relationship between Neurite Density
Measured with Confocal Microscopy in a
Cleared Mouse Brain and Metrics Obtained from
Diffusion Tensor and Diffusion Kurtosis Imaging.
Magn Reson Med Sci 17(2): 138-44, 2018
Ishida M, Gonoi W, Shirota G, Okuma H,
Yamazawa S, Hinata M, Hayashi A, Fukayama
M, Abe O.
Diffusely decreased liver attenuation on
post-mortem computed tomography: comparison
with ante-mortem computed tomography andautopsy findings.
J Forens Radiol Image 16: 1-4, 2019
Kakeda S, Watanabe K, Katsuki A, Sugimoto K,
Igata N, Ueda I, Igata R, Abe O, Yoshimura R,
Korogi Y.
Relationship between interleukin (IL)-6 andbrain morphology in drug-naive, first-episodemajor depressive disorder using surface-based

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morphometry.
Sci Rep 8(1): 10054, 2018
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 white matter integrity in drugnaive patients with major depressive disorder: adiffusion tensor imaging study of 17 genetic lociassociated with depressive symptoms.
Neuropsychiatr Dis Treat 15: 375-83, 2019
Kamiya K, Okada N, Sawada K, Watanabe Y,
Irie R, Hanaoka S, Suzuki Y, Koike S, Mori H,
Kunimatsu A, Hori M, Aoki S, Kasai K, Abe O.
Diffusional kurtosis imaging and white matter
microstructure modeling in a clinical study ofmajor depressive disorder.
NMR Biomed 31(7): e3938, 2018
《 Japanese Chapter of ISMRM 2018 Ogawa
Seiji Prize 受賞》
Katano A, Takahashi W, Yamashita H, Yamamoto
K, Ando M, Yoshida M, Saito Y, Abe O,
Nakagawa K.
Radiotherapy alone and with concurrent
chemotherapy for nasopharyngeal carcinoma: A
retrospective study.
Medicine (Baltimore) 97(18): e0502, 2018
Katsura M, Sato J, Akahane M, Kunimatsu A,
Abe O.
Current and Novel Techniques for Metal Artifact
Reduction at CT: Practical Guide forRadiologists.
Radiographics 38(2): 450-61, 2018
Katsura M, Sato J, Akahane M, Tajima T, Furuta
T, Mori H, Abe O.
Single-energy metal artifact reduction techniquefor reducing metallic coil artifacts on
post-interventional cerebral CT and CT
angiography.
Neuroradiology 60(11): 1141-50, 2018
Kida S, Nakamoto T, Nakano M, Nawa K, Haga
A, Kotoku J, Yamashita H, Nakagawa K.
Cone Beam Computed Tomography Image
Quality
Improvement
Using
a
Deep
Convolutional Neural Network.
Cureus 10(4): e2548, 2018
Kodama S, Mano T, Kakumoto T, Ishiura H,
Hagiwara A, Kamiya K, Hayashi T, Tsuji S.

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43)

Ketotic hyperglycemia-related seizure withreversible white matter lesion: Metabolic
implication of its reversibility based on magnetic
resonance spectroscopy study.
J Neurol Sci 390: 20-1, 2018
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: Epub ahead of print, 2018
Kunimatsu A, Kunimatsu N, Kamiya K,
Watadani T, Mori H, Abe O.
Comparison between Glioblastoma and PrimaryCentral Nervous System Lymphoma Using MR
Image-based Texture Analysis.
Magn Reson Med Sci 17(1): 50-7, 2018
Kunimatsu A, Kunimatsu N, Yasaka K, Akai H,
Kamiya K, Watadani T, Mori H, Abe O.
Machine Learning-based Texture Analysis ofContrast-enhanced MR Imaging to Differentiate
between Glioblastoma and Primary Central
Nervous System Lymphoma.
Magn Reson Med Sci 18(1): 44-52, 2019
Kunimatsu N, Kunimatsu A, Miura K, Mori I,
Nawano S.
Differentiation between solitary fibrous tumorsand schwannomas of the head and neck: anapparent diffusion coefficient histogram analysis.
Dentomaxillofac Radiol 48(3): 20180298, 2019
Maekawa T, Hori M, Murata K, Feiweier T,
Fukunaga I, Andica C, Hagiwara A, Kamagata K,
Koshino S, Abe O, Aoki S.
Changes in the ADC of diffusion-weighted MRI
with the oscillating gradient spin-echo (OGSE)
sequence due to differences in substrateviscosities.
Jpn J Radiol 36(7): 415-20, 2018
Maekawa T, Hori M, Murata K, Feiweier T,
Andica C, Fukunaga I, Koshino S, Hagiwara A,
Kamiya K, Kamagata K, Wada A, Abe O, Aoki S.
Choroid plexus cysts analyzed using diffusionweighted imaging with short diffusion-time.
Magn Reson Imaging: Epub ahead of print, 2018
Maekawa T, Hagiwara A, Hori M, Andica C,
Haruyama T, Kuramochi M, Nakazawa M,

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Koshino S, Irie R, Kamagata K, Wada A, Abe O,
Aoki S.
Effect of Gadolinium on the Estimation of
Myelin and Brain Tissue Volumes Based on
Quantitative Synthetic MRI.
AJNR Am J Neuroradiol 40(2): 231-7, 2019
Miyano R, Kurihara M, Orimo K, MAno T,
Kaburaki T, Ranaka R, Nishijima H, Ikemura M,
Takahashi M, Mori H, Mutoh T, Hamada M,
Hayashi T, Toda T.
Severe visual impairment and subclinicalencephalitis preceding clinical signs ofchondritis in relapsing polychondritis.
Neurol Clin Neurosci 7(2): 75-7, 2019
Miyatake S, Sacha Schneeberger S, Koyama N,
Yokochi K, Ohmura K, Shiina M, Mori H,
Koshimizu E, Imagawa E, Uchiyama Y,
Mitsuhashi S, Frith MC, Fujita A, Satoh M,
Taguri M, Tomono Y, Takahashi K, Doi H,
Takeuchi H, Nakashima M, Mizuguchi T, Takata
A, Miyake N, Saitsu H, Tanaka F, Ogata K,
Hennet T, Matsumoto N.
Biallelic COLGALT1 variants are associatedwith cerebral small vessel disease.
Ann Neurol 84(6): 843-53, 2018
Mizuno S, Isayama H, Nakai Y, Yoshikawa T,
Ishigaki K, Matsubara S, Yamamoto N, Ijichi H,
Tateishi K, Tada M, Hayashi N, Koike K.
Prevalence of pancreatic cystic lesions is
associated with diabetes mellitus and obesity: An
analysis of 5296 individuals who underwent a
preventive medical examination.
Pancres 46(6): 801-5, 2017
Mizuno S, Nakai Y, Isayama H, Yoshikawa T,
Saito K, Takahara N, Kogure H, Tada M,
Hayashi N, Koike K.
Visceral adiposity and high adiponectin levels
are associated with the prevalence of pancreaticcystic lesions.
Int J Obes 43(1): 169-75, 2019
Naganawa S, Enooku K, Tateishi R, Akai H,
Yasaka K, Shibahara J, Ushiku T, Abe O,
Ohtomo K, Kiryu S.
Imaging prediction of nonalcoholic steatohepatitis using computed tomography texture analysis.
Eur Radiol 28(7): 3050-8, 2018
Nakada T, Kikuta S, Mori H, Shimizu Y,

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Nishijima H, Kondo K, Yamasoba T.
Low CT Attenuation Values of Sinonasal Benign
Tumours Relative to the Brainstem Identify
Schwannomas.
ORL J Otorhinolaryngol Relat Spec 80(1): 41-50,
2018
Nakai Y, Gonoi W, Hagiwara A, Nishioka Y, Abe
H, Shindoh J, Hasegawa K.
MRI Detection of Intratumoral Fat in Colorectal
Liver
Metastases
After
Preoperative
Chemotherapy.
AJR Am J Roentgenol 210(5): W196-204, 2018
Nakao T, Hanaoka S, Nomura Y, Sato I, Nemoto
M, Miki S, Maeda E, Yoshikawa T, Hayashi N,
Abe O.
Deep neural network-based computer-assisted
detection of cerebral aneurysms in MR
angiography.
J Magn Reson Imaging 47(4): 948-53, 2018
Nishioka Y, Shindoh J, Inagaki Y, Gonoi W,
Mitsui J, Abe H, Yoshioka R, Yoshida S,
Fukayama M, Tsuji S, Hashimoto M, Hasegawa
K, Kokudo N.
Host MICA Polymorphism as a Potential
Predictive Marker in Response to Chemotherapy
for Colorectal Liver Metastases.
Dig Dis 36(6):437-445, 2018
Nomura Y, Hayashi N, Hanaoka S, Takenaga T,
Nemoto M, Miki S, Yoshikawa T, Abe O.
Can the spherical gold standards be used as analternative to painted gold standards for thecomputerized detection of lesions using
voxel-based classification?
Jpn J Radiol 37(3): 264-73, 2019
Mami Ogita, Kenji Sekiguchi, Keiko Akahane,
Ryoko Ito, Chiori Haga, Satoru Arai, Yasushi
Ishida, Jiro Kawamori1
Damage to sebaceous gland and the efficacy ofmoisturizer after whole breast radiotherapy: arandomized controlled trial.
BMC Cancer 19(1): 125, 2019
Okumura A, Mori H, Chong PF, Kira R, Torisu H,
Yasumoto S, Shimizu H, Fujimoto T,
Tanaka-Taya K, and the Acute Flaccid Myelitis
Collaborative Study.
Serial MRI Findings of Acute Flaccid Myelitis
during an Outbreak of Enterovirus D68 Infection

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in Japan.
Brain Dev: Epub ahead of print, 2018
Okumura A, Mori H.
Acute flaccid myelitis: an emerging clinicalentity.
Dev Med Child Neurol 61(3): 290-1, 2019
Onishi H, Marino K, Yamashita H, Terahara A,
Onimaru R, Kokubo M, Shioyama Y, Kozuka T,
Matsuo Y, Aruga T, Hiraoka M.
Case Series of 23 Patients Who Developed Fatal
Radiation Pneumonitis After Stereotactic Body
Radiotherapy for Lung Cancer.
Technol
Cancer
Res
Treat
17:
1533033818801323, 2018
Onishi H, Yamashita H, Shioyama Y, Matsumoto
Y, Takayama K, Matsuo Y, Miyakawa A,
Matsushita H, Aoki M, Nihei K, Kimura T,
Ishiyama H, Murakami N, Nakata K, Takeda A,
Uno T, Nomiya T, Takanaka T, Seo Y, Komiyama
T, Marino K, Aoki S, Saito R, Araya M, Maehata
Y, Tominaga L, Kuriyama K.
Stereotactic Body Radiation Therapy for Patientswith Pulmonary Interstitial Change: High
Incidence of Fatal Radiation Pneumonitis in a
Retrospective Multi-Institutional Study.
Cancers (Basel) 10(8): E257, 2018
Sakai N, Tabei K, Sato J, Imae T, Suzuki Y,
Takenaka S, Yano K, Abe O.
Radiation dose reduction with frame rate
conversion in X-ray fluoroscopic imaging
systems with flat panel detector: basic study andclinical retrospective analysis.
Eur Radiol 29(2): 985-92, 2019
Sakatani T, Amano Y, Sato J, Nagase T.
Air embolism after CT-guided percutaneous lungbiopsy.
Jpn J Clin Oncol 48(7): 699-700, 2018
Sawayanagi S, Yamashita H, Ogita M, Kiritoshi
T, Nakamoto T, Abe O, Nakagawa K.
Volumetric and dosimetric comparison of organs
at risk between the prone and supine positions inpostoperative radiotherapy for prostate cancer.
Radiat Oncol 13(1): 70, 2018
Shioyama Y, Onishi H, Takayama K, Matsuo Y,
Takeda A, Yamashita H, Miyakawa A, Murakami
N, Aoki M, Matsushita H, Matsumoto Y,
Shibamoto Y; Japanese Radiological Society

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Multi-Institutional SBRT Study Group (JRSSBRTSG).
Clinical Outcomes of Stereotactic Body
Radiotherapy for Patients With Stage I SmallCell Lung Cancer: Analysis of a Subset of theJapanese Radiological Society Multi-Institutional
SBRT Study Group Database.
Technol
Cancer
Res
Treat
17:
1533033818783904, 2018
Sugawara H, Suzuki S, Katada Y, Ishikawa T,
Fukui R, Yamamoto Y, Abe O.
Measurement of Vascular Diameter in Computed
Tomography Angiography With Reduced Iodine
Load: Comparison of Virtual Monochromatic
Imaging in Dual-Energy Computed Tomography
and Conventional Polychromatic Scan In Vitro.
J Comput Assist Tomogr 42: 919-24, 2018
Sugawara H, Suzuki S, Katada Y, Ishikawa T,
Fukui R, Yamamoto Y, Abe O.
Comparison of full-iodine conventional CT and
half-iodine virtual monochromatic imaging:
advantages and disadvantages.
Eur Radiol 29(3): 1400-7, 2019
Sugimoto K, Kakeda S, Watanabe K, Katsuki A,
Ueda I, Igata N, Igata R, Abe O, Yoshimura R,
Korogi Y.
Relationship between white matter integrity andserum inflammatory cytokine levels in drugnaive patients with major depressive disorder:
diffusion tensor imaging study using tract-based
spatial statistics.
Transl Psychiatry 8(1): 141, 2018
Taniguchi G, Fuse H, Okamura Y, Mori H,
Kondo S, Kasai K, Takahashi Y, Tanaka K.
Improvement in anti-N-methyl-d-aspartate receptor antibody-mediated temporal lobe epilepsy
with amygdala enlargement without immunetherapy.
Epilepsy Behav Case Rep 10: 96-8, 2018
Tsuchiya T, Shiraishi K, Nakagawa K, Kim JR,
Kanegasaki S.
Identification of the active portion of the CCL3
derivative reported to induce antitumor abscopal
effect.
Clin Transl Radiat Oncol 10: 7-12, 2018
Ueda I, Kakeda S, Watanabe K, Sugimoto K,
Igata N, Moriya J, Takemoto K, Katsuki A,

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Yoshimura R, Abe O, Korogi Y.
Brain structural connectivity and neuroticism inhealthy adults.
Sci Rep 8(1): 16491, 2018
Wada A, Tsuruta K, Irie R, Kamagata K,
Maekawa T, Fujita S, Koshino S, Kumamaru K,
Suzuki M, Nakanishi A, Hori M, Aoki S.
Differentiating Alzheimer’s Disease fromDementia with Lewy Bodies Using a Deep
Learning Technique Based on Structural Brain
Connectivity.
Magn Reson Med Sci: Epub ahead of print, 2018
Yamaguchi N, Mano T, Ohtomo R, Ishiura H,
Almansour MA, Mori H, Kanda J, Shirota Y,
Taira K, Morikawa T, Ikemura M, Yanagi Y,
Murayama S, Shimizu J, Sakurai Y, Tsuji S,
Iwata A.
An Autopsy Case of Familial Neuronal
Intranuclear Inclusion Disease with Dementia
and Neuropathy.
Intern Med 57(23): 3459-62, 2018
Yamashita H.
Editorial on comparison between stereotactic
body radiotherapy and surgery in early stage
NCSLC by Scotti et al.
J Thorac Dis 11(Suppl 3): S275-9, 2019
Yasaka K, Akai H, Abe O, Kiryu S.
Deep Learning with Convolutional Neural
Network for Differentiation of Liver Masses at
Dynamic Contrast-enhanced CT: A Preliminary
Study.
Radiology 286(3): 887-96, 2018
Yasaka K, Akai H, Abe O, Ohtomo K, Kiryu S.
Quantitative computed tomography texture
analyses for anterior mediastinal masses:
Differentiation between solid masses and cysts.
Eur J Radiol 100: 85-91, 2018
Yasaka K, Akai H, Kunimatsu A, Kiryu S, Abe O.
Deep learning with convolutional neural networkin radiology.
Jpn J Radiol 36(4): 257-72, 2018
Yasaka K, Akai H, Kunimatsu A, Abe O, Kiryu S.
Liver Fibrosis: Deep Convolutional Neural
Network for Staging by Using Gadoxetic
Acid-enhanced Hepatobiliary Phase MR Images.
Radiology 287(1): 146-55, 2018
Yasaka K, Akai H, Kunimatsu A, Abe O, Kiryu S.

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Deep learning for staging liver fibrosis on CT: apilot study.
Eur Radiol 28(11): 4578-85, 2018
Yasaka K, Abe O.
Deep learning and artificial intelligence inradiology: Current applications and future
directions.
PLoS Med 15(11): e1002707, 2018
Yasaka K, Akai H, Kunimatsu A, Kiryu S, Abe O.
Factors associated with the size of the adhesio
interthalamica based on 3.0-T magnetic
resonance images.
Acta Radiol 60(1): 113-9, 2019
Yoshida Y, Sakane T, Isogai J, Suzuki Y, Miki S,
Nomura Y, Nakajima J
Computer-assisted detection of metastatic lungtumors on computed tomography
Asian Cardiovasc Thorac Ann 27(3): 199-207,
2019

Radiology and Biomedical
Engineering
2. Biomedical Engineering

70

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

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

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

71

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,
we demonstrate that the cellular mitochondria playa critical role in this process. Cultured humanpulmonary artery ECs were exposed to controlledlevels of shear stress in a flow-loading device andthe changes 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 proteinof the caveolae, abolished the shear-stress-induced
mitochondrial ATP generation, resulting in the lossof the ATP release and influx of Ca2+ into the cells.

These results suggest the novel role of themitochondria in transducing the shear stress into ATP
generation: the ATP generation leads to ATP release in
the caveolae, triggering purinergic Ca2+ signaling.
Thus, exposure of ECs to shear stress seems toactivate mitochondrial ATP generation throughcaveola- or caveolin-1-mediated mechanisms.
Moreover, we report that the plasma membrane
itself differentiates between shear stress and stretch byundergoing transitions in its lipid phases. Shear stressdecreased the lipid order of human pulmonary artery
EC plasma membranes, thereby causing a transition
from the liquid-ordered phase to the liquid-disorderedphase in some areas, along with an increase inmembrane fluidity. In contrast, uniaxial stretching andhypotonic swelling increased the membrane lipid
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. Yamamoto K, Imamura H, and Ando J. Shearstress augments mitochondrial ATP generationthat triggers ATP release and Ca2+ signaling invascular endothelial cells. Am. J. Physiol. Heart

73

Circ. Physiol. 315:H1477-H1485, 2018.
2. Yamamoto K and Ando J. Emerging role ofplasma membranes in vascular endothelial
mechanosensing. Circ. J. 82:2691-2698, 2018.
3. Yamamoto K and Ando J. Mechanosensing via
plasma membranes. Seitai no kagaku. 69:237-241,
2018.

74

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, 11 PhD students, 4 master course students
and one technical staff, as of FY2018.

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 mechanism including intramolecularspirocyclization. In FY2018, we have succeeded todevelop new fluorescence probes for detecting
enzyme activity in living tissue and for detecting
antioxidants in living cells. Further, we performed

application of our previously reported fluorescenceprobes for cancer detection.
As a fluorescence probe for detecting enzyme
activity, we previously reported SPiDER-Gal, ahighly functionalized fluorescent probe for detecting
-galactosidase activity in living samples withsingle-cell resolution. However, its hydrolysis productshows green fluorescence emission, and a red-shifted
analogue has been awaited to be developed for use incombination with green fluorescent protein (GFP).
Therefore, we designed and synthesized a red-shifted
fluorogenic substrate for -galactosidase, SPiDERRed-Gal, based on a siliconrhodol derivative and acarboxylic group as the intramolecular nucleophile.
LacZ-positive cells (-galactosidase-expressing cells)
were successfully labeled with SPiDER-Red-Gal at
single-cell resolution in living Drosophila tissues andmouse brain slices, which enabled us to visualize
different cell types in combination with GFP markers
in (Reference 1). This was the collaboration work on
our campus.
As a fluorescence probe for detecting anti-oxidants
in living cells, we focused on hydropolysulfides,
which is one of reactive sulfur species, and developed
a new type of fluorescent probe that reversibly andselectively reacts to hydropolysulfides. The probe
enables live-cell visualization and quantification ofendogenous hydropolysulfides without interference

75

from intrinsic thiol species such as glutathione.
Additionally, real-time reversible monitoring offluctuation of intrinsic hydropolysulfides has beenachieved with a temporal resolution on the order of
seconds. These results reveal the probe’s versatility as
a new fluorescence imaging tool to understand thefunction of hydropolysulfides (Reference 2).
As for application of cancer-imaging probes, weapplied gGlu-HMRG, a fluorescence probe for-glutamyltransferase (GGT), to mouse model ofpara-aortic lymph node metastasis of colorectal cancer.
As a result, we observed that the GGT activity ofmetastatic lymph nodes (mLNs) was high, whereasthat of non-metastatic lymph nodes and colorectal
cancer cell lines was low. We found that GGTexpression was induced under conditions of hypoxia
or low nutritional status, and utilized this feature toachieve detection of mLNs with gGlu-HMRG. These
results suggested that GGT appears to be a promising
candidate enzyme for fluorescence imaging of mLNs
(Reference 3).
Further, in collaboration with pathologists at
Toranomon Hospital, we applied gGlu-HMRG to theclinical specimens of papillary thyroid carcinoma. As
a result, it was demonstrated that thyroid cancer,
especially papillary carcinoma, can be rapidly
detected with gGlu-HMRG (Reference 4).
In collaboration with medical doctors at Hokkaido
University, we also applied EP-HMRG, a fluorescenceprobe for dipeptidylpeptidase IV (DPPIV), to clinicalspecimens of head and neck squamous cell carcinoma.
As a result, it was shown that EP-HMRG is valid tovisualize head and neck squamous cell carcinoma(Reference 5).
We also performed several collaboration works(Reference 6-9).

3.

4.

5.

6.

7.

8.

References
1. H. Ito, Y. Kawamata, M. Kamiya, K. TsudaSakurai, S. Tanaka, T. Ueno, T. Komatsu, K.
Hanaoka, S. Okabe, M. Miura, Y. Urano,
Red-Shifted Fluorogenic Substrate for Detectionof lacZ-Positive Cells in Living Tissue with
Single-Cell Resolution, Angew. Chem. Int. Ed.,57 (2018) 15702-15706.
2. K. Umezawa, M. Kamiya, Y. Urano, A Reversible

9.

Fluorescent Probe for Real-Time Live-Cell
Imaging and Quantification of Endogenous
Hydropolysulfides, Angew. Chem. Int. Ed., 57(2018) 9346-9350.
H. Kubo, K. Hanaoka, Y. Kuriki, T. Komatsu, T.
Ueno, R. Kojima, M. Kamiya, Y. Murayama, E.
Otsuji, Y. Urano, Rapid detection of metastatic
lymph nodes of colorectal cancer with a gammaglutamyl transpeptidase-activatable fluorescenceprobe, Sci. Rep., 8 (2018) 17781.
R. Hino, N. Inoshita, T. Yoshimoto, M. Ogawa, D.
Miura, R. Watanabe, K. Watanabe, M. Kamiya, Y.
Urano, Rapid detection of papillary thyroid
carcinoma by fluorescence imaging using a
γ-glutamyltranspeptidase-specific probe: a pilot
study, Thyroid Research, 11 (2018) 16.
T. Mizushima, S. Ohnishi, Y. Shimizu, Y.
Hatanaka, K.C. Hatanaka, Y. Kuriki, M. Kamiya,
A. Homma, K. Yamamoto, S. Ono, Y. Urano, N.
Sakamoto, Rapid detection of superficial head andneck squamous cell carcinoma by topicallyspraying fluorescent probe targeting dipeptidyl
peptidase-IV, Head & Neck, 40 (2018) 14661475.
Y. Inagaki, T. Kokudo, M. Kamiya, S.-n. Uno, M.
Sato, J. Kaneko, N. Kokudo, Y. Urano, K.
Hasegawa, A novel liver-specific fluorescent anticancer drug delivery system using indocyanine
green, Sci. Rep., 9 (2019) 3044.
Y. Moriizumi, K.V. Tabata, R. Watanabe, T. Doura,
M. Kamiya, Y. Urano, H. Noji, Hybrid cell reactor
system from Escherichia coli protoplast cells andarrayed lipid bilayer chamber device, Sci. Rep., 8(2018) 11757.
H. Tabe, K. Sukenobe, T. Kondo, A. Sakurai, M.
Maruo, A. Shimauchi, M. Hirano, S.-n. Uno, M.
Kamiya, Y. Urano, M. Matsushita, S. Fujiyoshi,
Cryogenic Fluorescence Localization Microscopyof Spectrally Selected Individual FRET Pairs in a
Water Matrix, J. Phys. Chem. B, 122 (2018) 69066911.
T. Hirasawa, R.J. Iwatate, M. Kamiya, S. Okawa,
M. Fujita, Y. Urano, M. Ishihara, Spectraldifferential-based unmixing for multispectral
photoacoustic imaging, Appl. Opt., 57 (2018)
2383-2393.

76

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.

77

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78

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. Koki ARIYOSHI, Shintaro HARA, Takashi
ISOYAMA, Itsuro SAITO, Toshiya ONO, Yusuke
ABE, High Pressure-type Rotary Blood Pump
with a New Principle. Advanced Biomedical
Engineering, 2018; 7: 141-145, DOI:10.14326/abe.
7.141.

Neuroscience
1. Basic Neuroscience80

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

Associate
Tomoko Wakabayashi, Ph.D.
Tomoki Kuwahara, Ph.D.
Kaoru Yamada, Ph.D.

Homepage

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

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

40th or 42nd residues (Aβ40 and Aβ42, respectively),
Dr. Iwatsubo has performed a systematic immunohistochemical studies on autopsied brain tissues frompatients with AD, Down syndrome and familial AD,
and demonstrated that Aβ42, that most readily form
amyloid fibrils in vitro, is the initially andpredominantly deposited species in human cerebral
β-amyloidosis (Iwatsubo et al. Neuron 1994, Ann
Neurol 1995). Dr. Iwatsubo’s group then establishedcelllar models expressing mutant forms of presenilin(PS) genes linked to familial AD (FAD), and using
their original highly-sensitive ELISA quantitation
system, his group has clearly shown that an increasein the production of Aβ42 is the pathogenic
mechanism leading to FAD (Tomita et al. Proc Natl
Acad Sci USA, 1997). These findings have provided afirm basis for the currently prevailing β-amyloid
hypothesis. They then focused on the mechanisms ofγ-secretase complex that cleaves the C terminus of Aβ,
and set out to cell biological studies using RNAinterference on the formation and function of theγ-secretase complex harboring PS as the catalytic
center, associated with three additional membraneproteins. They demonstrated that APH-1 and Nicastrin
serve as the “stabilizing” co-factor of PS, whereas
PEN-2 is the component that confers proteolytic
activity to this complex. They also showed that PS,
APH-1, nicastrin and PEN-2 are the essential set ofproteins that comprise the γ-secretase complex(Takasugi et al. Nature, 2003). This study ishighlighted as a milestone work that elucidated the

81mechanistic roles of protein cofactors in the formationand function of γ-secretase (see reviews; Iwatsubo
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).

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

References
1) Kidana K, Tatebe T, Ito K, Hara N, Kakita A, Saito
T, Ouchi Y, Ikeuchi T, Makino M, Saido TC,
Akishita M, Iwatsubo T, Hori Y, Tomita T: Loss ofkallikrein-related peptidase 7 derived fromastrocytes exacerbates amyloid pathology in
Alzheimer disease model mouse. EMBO Mol Med
pii: e8184, 2018
2) Fujimoto T, Kuwahara T, Eguchi T, Sakurai M,
Komori T, Iwatsubo T: Parkinson's diseaseassociated mutant LRRK2 phosphorylates Rab7L1
and modifies trans-Golgi morphology. Biochem
Biophys Res Commun 495:1708-1715, 20183) Yamada K, Iwatsubo T: Activity-dependent
pathway determines extracellular α-synuclein
levels. Mol Neurodegener 13:9, 20184) Matsumoto T, Matsukawa K, Watanabe N, KishinoY, Kunugi H, Ihara R, Wakabayashi T, Hashimoto
T, Iwatsubo T: Self-assembly of FUS through its
low-complexity domain contributes to neurodegeneration. Hum Mol Genet 27: 1353-1365,
20185) Iwatsubo T, Iwata A, Suzuki K, Ihara R, Arai H,

Ishii K, Senda M, Ito K, Ikeuchi T, Kuwano R,
Matsuda H, Sun CK, Beckett LA, Petersen RC,
Weiner MW, Aisen PS, Donohue MC: Japaneseand North American Alzheimer’s Disease
Neuroimaging Initiative studies: harmonization
for international trials. Alzheimers Dementia 14:
1077-1087, 20186) Eguchi T, Kuwahara T, Sakurai M, Komori T,
Fujimoto T, Ito G, Yoshimura SI, Harada A,
Fukuda M, Koike M, Iwatsubo T: LRRK2 and its
substrate Rab GTPases are sequentially targeted
onto stressed lysosomes and maintain their
homeostasis. Proc Natl Acad Sci USA 115:E9115E9124, 2018
7) Mann DMA, Davidson YS, Robinson AC, Allen N,
Hashimoto T, Richardson A, Jones M, Snowden JS,
Pendleton N, Potier MC, Laquerriere A, Prasher V,
Iwatsubo T, Strydom A: Patterns and severity ofvascular amyloid in Alzheimer's disease associatedwith duplications and missense mutations in APPgene, Down syndrome and sporadic Alzheimer's
disease. Acta Neuropathol 136:569-587, 20188) Ihara R, Iwata A, Suzuki K, Ikeuchi T, Kuwano R,
Iwatsubo T: Clinical and cognitive characteristics
of preclinical Alzheimer’s disease in the Japanese
ADNI cohort. Alzheimers Dementia: Translational Research & Clinical Interventions 4:645651, 20189) Iwata A, Iwatsubo T, Ihara R, Suzuki K,
Matsuyama Y, Arai H, Ishii K, Senda M, Ito K,
Ikeuchi T, Kuwano R, Matsuda H: Effects ofgender, educational background, and renal
function on cognitive and functional decline inJapanese patients with mild cognitive impairment.
Alzheimers Dementia: Translational Research &Clinical Interventions 4:765-774, 2018

83

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

Assistant Professor
Hajime Fujii, Ph.D., Masayuki Sakamoto, 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, four
assistant professors, three postdoctoral scholar, one
technical staff member, six Ph.D. graduate students,
one rotating medical student, two technical assistants
and two administrative assistants.

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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

85

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) indeveloping mouse excitatory cortical neurons anddiscovered that L-type VGCCs play critical roles inneural development 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

86

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).
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
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

87

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 determinedthat protein-protein interaction was key to determining
the physical distance between the synaptic vesicles in
the active zone and the voltage-gated calcium
channels in its vicinity, the opening of which triggers
their release (Kiyonaka et al., Nat. Neurosci. 2007).

Publications by lab members(January 2018- December 2018)
1, Okuno H, Minatohara K, Bito H.
Inverse synaptic tagging: An inactive synapsespecific mechanism to capture activity-induced
Arc/arg3.1 and to locally regulate spatial
distribution of synaptic weights.
Semin Cell Dev Biol. 2018 May;77:43-50. doi:
10.1016/j.semcdb.2017.09.025.
2, Steward O, Matsudaira Yee K, Farris S, Pirbhoy
PS, Worley P, Okamura K, Okuno H, Bito H.
Delayed Degradation and Impaired Dendritic
Delivery of Intron-Lacking EGFP-Arc/Arg3.1
mRNA in EGFP-Arc Transgenic Mice.
Front Mol Neurosci. 2018 Jan 31; 10:435. doi:
10.3389/fnmol.2017.00435. eCollection 2017.
3, Yamazaki H, Sasagawa Y, Yamamoto H, Bito H,
Shirao T.
CaMKIIβ is localized in dendritic spines as bothdrebrin-dependent and drebrin-independent pools.
J Neurochem. 2018 Jul; 146(2):145-159. doi: 10.
1111/jnc.14449.
4, Kamijo S, Ishii Y, Horigane SI, Suzuki K, Ohkura
M, Nakai J, Fujii H, Takemoto-Kimura S, Bito H.
A Critical Neurodevelopmental Role for L-Type
Voltage-Gated Calcium Channels in Neurite
Extension and Radial Migration.
J Neurosci. 2018 Jun 13; 38(24):5551-5566. doi:
10.1523/JNEUROSCI.2357-17.2018.
5, El-Boustani S, Ip JPK, Breton-Provencher V,

88

6,

7,

8,

9,

Knott GW, Okuno H, Bito H, Sur M.
Locally coordinated synaptic plasticity of visualcortex neurons in vivo.
Science. 2018 Jun 22; 360(6395):1349-1354. doi:
10.1126/science.aao0862.
Nishiguchi KM, Fujita K, Tokashiki N,
Komamura H, Takemoto-Kimura S, Okuno H,
Bito H, Nakazawa T.
Retained Plasticity and Substantial Recovery of
Rod-Mediated Visual Acuity at the Visual Cortex
in Blind Adult Mice with Retinal Dystrophy.
Mol Ther. 2018 Oct 3; 26(10):2397-2406. doi:
10.1016/j.ymthe.2018.07.012
Benner S, Aoki Y, Watanabe T, Endo N, Abe O,
Kuroda M, Kuwabara H, Kawakubo Y, Takao H,
Kunimatsu A, Kasai K, Bito H, Kakeyama M,
Yamasue H.
Neurochemical evidence for differential effects ofacute and repeated oxytocin administration.
Mol Psychiatry. 2018 Sep 27. doi: 10.1038/s
41380-018-0249-4
Sonoda K, Matsui T, Bito H, Ohki K.
Astrocytes in the mouse visual cortex reliably
respond to visual stimulation.
Biochem Biophys Res Commun. 2018 Nov 10;505(4):1216-1222. doi: 10.1016/j.bbrc.2018.10.
027.
Attardo A, Lu J, Kawashima T, Okuno H,
Fitzgerald JE, Bito H, Schnitzer MJ.
Long-Term Consolidation of Ensemble Neural
Plasticity Patterns in Hippocampal Area CA1.
Cell Rep. 2018 Oct 16; 25(3):640-650.e2. doi: 10.
1016/j.celrep.2018.09.064.

Neuroscience
2. Integrative Medical Neuroscience90

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., Yuki Kawakubo, Ph.D.

Homepage

http://childpsy.umin.jp/

Introduction and Organization
Recently, mental problems of child and adolescentor 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.

Education
In the year of 2018, we had 6 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
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 2018 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

91・Investigation on clinical evaluation and psychological education for adults with developmental
disordersPublications
1. Owada K, Kojima M, Yassin W, Kuroda M,
Kawakubo Y, Kuwabara H, Kano Y, Yamasue H.
Computer-analyzed facial expression as asurrogate marker for autism spectrum social core
symptoms. PLoS One. 2018; 13(1): e0190442.
2. Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Kasai K, Kakiuchi
C. Novel rare variations in genes that regulate
developmental change in N-methyl-d-aspartate
receptor in patients with schizophrenia. Hum
Genome Var. 2018; 5: 17056.
3. Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Ohashi Y, Iwamoto
K, Kasai K, Kakiuchi C. Mutations of the glycinecleavage system genes possibly affect thenegative symptoms of schizophrenia throughmetabolomic profile changes. Psychiatry Clin
Neurosci. 2018; 72(3): 168-179.
4. Todokoro A, Tanaka SC, Kawakubo Y, Yahata N,
Ishii-Takahashi A, Nishimura Y, Kano Y, Ohtake F,
Kasai K. Deficient neural activity subserving
decision-making during reward waiting time inintertemporal choice in adult attention-deficit
hyperactivity disorder. Psychiatry Clin Neurosci.
2018; 72(8): 580-590.
5. Tanaka SC, Yahata N, Todokoro A, Kawakubo Y,
Kano Y, Nishimura Y, Ishii-Takahashi A, Ohtake F,
Kasai K. Preliminary evidence of altered neural
response during intertemporal choice of losses inadult attention-deficit hyperactivity disorder. Sci
Rep. 2018; 8(1): 6703.
6. Sakakibara E, Takizawa R, Kawakubo Y,
Kuwabara H, Kono T, Hamada K, Okuhata S,
Eguchi S, Ishii-Takahashi A, Kasai K. Genetic
influences on prefrontal activation during a verbal
fluency task in children: A twin study usingnear-infrared spectroscopy. Brain Behav. 2018;
8(6): e00980.
7. Kano Y, Matsuda N, Nonaka M, Fujio M, Kono T,

Kaido T. Sensory phenomena and obsessivecompulsive symptoms in Tourette syndrome
following deep brain stimulation: Two casereports. J Clin Neurosci. 2018; 56: 199-201.
8. Shaw P, Ishii-Takahashi A, Park MT, Devenyi GA,
Zibman C, Kasparek S, Sudre G, Mangalmurti A,
Hoogman M, Tiemeier H, von Polier G, Shook D,
Muetzel R, Chakravarty MM, Konrad K, Durston
S, White T: A multicohort, longitudinal study of
cerebellar development in attention deficit
hyperactivity disorder. J Child Psychol Psychiatry.
2018; 59(10): 1114-1123.
9. Okada N, Yahata N, Koshiyama D, Morita K,
Sawada K, Kanata S, Fujikawa S, Sugimoto N,
Toriyama R, Masaoka M, Koike S, Araki T, Kano
Y, Endo K, Yamasaki S, Ando S, Nishida A,
Hiraiwa-Hasegawa M, Kasai K. Abnormal
asymmetries in subcortical brain volume in earlyadolescentswithsubclinicalpsychotic
experiences. Transl Psychiatry. 2018; 8(1): 254.

Neuroscience
3. Clinical Neuroscience93

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.

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

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

Naohiro Okada, M.D., Ph.D.

Yoshihiro Satomura, M.D., Ph.D.

Akira Wada, M.D., Ph.D.

Tomoko Ando, M.D.

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

Oji Tomoatsu, MD.

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 psychiatric social workers. In 2018, 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 440 patientswith various psychiatric disorders were admitted in
2018. 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.

94

Education

Publications

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

1. Ando S, Usami S, Matsubayashi T, Ueda M,
Koike S, Yamasaki S, Fujikawa S, Sasaki T,
Hiraiwa-Hasegawa M, Patton G, Kasai K, Nishida
A: Age relative to school class peers andemotional well-being in 10-year-olds. PLoS One.
2019 Mar 26;14(3):e0214359.
2. Iwashiro N, Takano Y, Natsubori T, Aoki Y,
Yahata N, Gonoi W, Kunimatsu A, Abe O, Kasai
K, Yamasue H: Neuropsychiatr Dis Treat.
Aberrant attentive and inattentive brain activity toauditory negative words, and its relation topersecutory delusion in patients with schizophrenia. 2019 Feb 14;15:491-502. doi: 10.2147/
NDT.S194353.
3. Morishima R, Ando S, Araki T, Usami S,
Kanehara A, Tanaka S, Kasai K: The course ofchronic and delayed onset of mental illness andthe risk for suicidal ideation after the Great East
Japan Earthquake of 2011: A community-based
longitudinal study. Psychiatry Res. 2018 Dec 29;
273:171-177. doi: 10.1016/j.psychres.2018.12.151.
PMID: 30654301
4. Tanaka T, Nishimura F, Kakiuchi C, Kasai K,
Kimura M, Haruno M. Interactive effects of
OXTR and GAD1 on envy-associated behaviors
and neural responses. PLoS One. 2019 Jan 11;14(1):e0210493.
doi:
10.1371/journal.pone.
0210493. eCollection 2019. PMID: 30633779
5. Okada N, Yahata N, Koshiyama D, Morita K,
Sawada K, Kanata S, Fujikawa S, Sugimoto N,
Toriyama R, Masaoka M, Koike S, Araki T, Kano
Y, Endo K, Yamasaki S, Ando S, Nishida A,
Hiraiwa-Hasegawa M, Edden RAE, Barker PB,
Sawa A, Kasai K: Neurometabolic and functional
connectivity basis of prosocial behavior in earlyadolescence. Sci Rep 2019 Jan 24;9(1):732. doi:
10.1038/s41598-018-38355-z. PMID: 30679738
6. Yamashita M, Yoshihara Y, Hashimoto R, Yahata
N, Ichikawa N, Sakai Y, Yamada T, Matsukawa N,
Okada G, Tanaka SC, Kasai K, Kato N, Okamoto
Y, Seymour B, Takahashi H, Kawato M, Imamizu
H: A prediction model of working memory acrosshealth and psychiatric disease using whole-brain
functional connectivity. Elife. 2018 Dec 10;7. pii:
e38844. doi: 10.7554/eLife.38844. [Epub ahead of

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

95

print] PMID: 30526859
7. Iijima Y, Okumura Y, Yamasaki S, Ando S,
Nakanishi M, Koike S, Endo K, Morimoto Y,
Kanata S, Fujikawa S, Yamamoto Y, Furukawa TA,
Hiraiwa-Hasegawa M, Kasai K, Nishida A:
Response inhibition and anxiety in adolescents:
Results from a population-based community
sample. J Affect Disord. 2018 Dec 10;246:89-95.
doi: 10.1016/j.jad.2018.12.010.PMID: 30578951
8. Ishishita Y, Kunii N, Shimada S, Ibayashi K, Tada
M, Kirihara K, Kawai K, Uka T, Kasai K, Saito N:
Deviance detection is the dominant component ofauditory contextual processing in the lateralsuperior temporal gyrus: A human ECoG study.
Hum Brain Mapp. 2019 Mar;40(4):1184-1194.
doi: 10.1002/hbm.24438. Epub 2018 Oct 24.
PMID: 30353997
9. Murata Y, Bundo M, Sunaga F, Kasai K, Iwamoto
K: DNA methylation profiling in a neuroblastoma
cell line exposed to the antipsychotic perospirone.
Pharmacopsychiatry. 2019 Feb;52(2):63-69.
10. Satomura Y, Sakakibara E, Takizawa R, Koike S,
Nishimura Y, Sakurada H, Yamagishi M, Shimojo
C, Kawasaki S, Okada N, Matsuoka J, Kinoshita
A, Jinde S, Kondo S, Kasai K: Severity-dependentand -independent brain regions of major depresssive disorder: A long-term longitudinal nearinfrared spectroscopy study. J Affect Disord. 2019
Jan 15;243:249-254. doi: 10.1016/j.jad.2018.09.
029. Epub 2018 Sep 17. PMID: 30248636
11. Morita K, Miura K, Fujimoto M, Shishido E,
Shiino T, Takahashi J, Yamamori H, Yasuda Y,
Kudo N, Hirano Y, Koshiyama D, Okada N, Ikeda
M, Onitsuka T, Ozaki N, Kasai K, Hashimoto R:
Abnormalities of eye movement are associatedwith work hours in schizophrenia. Schizophr Res.
2018 Dec; 202:420-422. doi: 10.1016/j.schres.
2018.06.064. Epub 2018 Jul 13. PMID: 30017461
12. Koshiyama D, Fukunaga M, Okada N, Morita K,
Nemoto K, Yamashita F, Yamamori H, Yasuda Y,
Fujimoto M, Kelly S, Jahanshad N, Kudo N,
Azechi H, Watanabe Y, Donohoe G, Thompson
PM, Kasai K, Hashimoto R: Role of frontal whitematter and corpus callosum on social function inschizophrenia. Schizophr Res. 2018 Dec;202:
180-187. doi: 10.1016/j.schres.2018.07.009. Epub
2018 Jul 10. PMID: 30005932

13. Kushima et al., Comparative analyses of copynumber variation in autism spectrum disorder andschizophrenia reveal etiological overlap andbiological insights. Cell Rep. 2018 Sep 11;24(11):2838-2856. doi: 10.1016/j.celrep.2018.08.022.
PMID: 30208311
14. Koshiyama D, Kirihara K, Tada M, Nagai T,
Fujioka M, Ichikawa E, Ohta K, Tani M, Tsuchiya
M, Kanehara A, Morita K, Sawada K, Matsuoka J,
Satomura Y, Koike S, Suga M, Araki T, Kasai K:
Auditory gamma oscillations predict global
symptomatic outcome in the early stages ofpsychosis: A longitudinal investigation. Clin
Neurophysiol. 2018 Nov;129(11):2268-2275. doi:
10.1016/j.clinph.2018.08.007. Epub 2018 Aug 30.
PMID: 30216911
15. Okada N, Yahata N, Koshiyama D, Morita K,
Sawada K, Kanata S, Fujikawa S, Sugimoto N,
Toriyama R, Masaoka M, Koike S, Araki T, Kano
Y, Endo K, Yamasaki S, Ando S, Nishida A,
Hiraiwa-Hasegawa M, Kasai K: Abnormal
asymmetries in subcortical brain volume in earlyadolescentswithsubclinicalpsychotic
experiences. Transl Psychiatry. 2018 Nov 28;8(1):254. doi: 10.1038/s41398-018-0312-6. PMID:
30487578
16. Fujikawa S, Ando S, Nishida A, Usami S, Koike S,
Yamasaki S, Morimoto Y, Toriyama R, Kanata S,
Sugimoto N, Sasaki T, Furukawa TA, HiraiwaHasegawa M, Kasai K: Disciplinary slapping is
associated with bullying involvement regardlessof warm parenting in early adolescence. J Adolesc.
2018 Oct; 68:207-216. doi: 10.1016/j.adolescence.
2018.07.018. Epub 2018 Aug 18.
17. Koshiyama D, Kirihara K, Tada M, Nagai T,
Fujioka M, Ichikawa E, Ohta K, Tani M, Tsuchiya
M, Kanehara A, Morita K, Sawada K, Matsuoka J,
Satomura Y, Koike S, Suga M, Araki T, Kasai K:
Electrophysiological evidence for abnormal
glutamate-GABA association following psychosis
onset. Transl Psychiatry. 2018 Oct 8;8(1):211. doi:
10.1038/s41398-018-0261-0. PMID: 30297786
18. Nakamura Y, Okada N, Kunimatsu A, Kasai K,
Koike S: Anatomical templates of the midbrain
ventral tegmental area and substantia nigra for
Asian populations. Front Psychiatry. 2018 Aug
28;9:383.
doi:
10.3389/fpsyt.2018.00383.

96

eCollection 2018. PMID: 30210369
19. Taniguchi G, Fuse H, Okamura Y, Mori H, Kondo
S, Kasai K, Takahashi Y, Tanaka K: Improvement
in anti-N-methyl-d-aspartate receptor antibodymediated temporal lobe epilepsy with amygdala
enlargement without immunotherapy. Epilepsy
Behav Case Rep. 2018 Aug 3;10:96-98. doi:
10.1016/j.ebcr.2018.07.005. eCollection 2018.
PMID: 30181951
20. Morita S, Taniguchi G, Tamune H, Kumakura Y,
Kondo S, Kasai K: A case of interictal dysphoric
disorder comorbid with interictal psychosis: Partof the same spectrum or separate entities?
Epilepsy Behav Case Rep. 2018 Aug 3;10:102105. doi: 10.1016/j.ebcr.2018.07.007. eCollection
2018. PMID: 30191125
21. Imamura K, Furukawa TA, Matsuyama Y,
Shimazu A, Kuribayashi K, Kasai K, Kawakami
N: Differences in the Effect of internet-based
cognitive behavioral therapy for improving
nonclinical depressive symptoms among workers
by time preference: randomized controlled trial. J
Med Internet Res. 2018 Aug 10;20(8):e10231.
doi: 10.2196/10231. PMID: 30097419
22. Tamune H, Taniguchi G, Morita S, Kumakura Y,
Kondo S, Kasai K: Emotional stimuli-provokedseizures potentially misdiagnosed as psychogenic
non-epileptic attacks: A case of temporal lobe
epilepsy with amygdala enlargement Epilepsy
Behav Case Rep 2018 Aug 3;10:102-105. doi:
10.1016/j.ebcr.2018.07.007. eCollection 2018.
PMID: 30191125
23. Suga M, Kawakubo Y, Nishimura Y, Hashimoto K,
Yumoto M, Kasai K: Lack of correlation between
phonetic magnetic mismatch field and plasmad-serine levels in humans. Clin Neurophysiol.
2018 Jul;129(7):1444-1448. doi: 10.1016/j.clinph.
2018.04.603. Epub 2018 Apr 24. PMID:
29735418
24. Nishida A, Ando S, Yamasaki S, Koike S,
Ichihashi K, Miyakoshi Y, Maekawa S, Nakamura
T, Natsubori T, Ichikawa E, Ishigami H, Sato K,
Matsunaga A, Smith J, French P, Harima H, Kishi
Y, Fujita I, Kasai K, Okazaki Y: A randomized
controlled trial of comprehensive early intervention care in patients with first-episode psychosis
in Japan: 1.5-year outcomes from the J-CAP study.

J Psychiatr Res. 2018 Jul;102:136-141. doi: 10.
1016/j.jpsychires.2018.04.007. Epub 2018 Apr 8.
PMID: 29653344
25. Kamiya K, Okada N, Sawada K, Watanabe Y, Irie
R, Hanaoka S, Suzuki Y, Koike S, Mori H,
Kunimatsu A, Hori M, Aoki S, Kasai K, Abe O:
Diffusional kurtosis imaging and white matter
microstructure modeling in a clinical study ofmajor depressive disorder. NMD Biomed 2018
Jul;31(7):e3938. doi: 10.1002/nbm.3938. Epub
2018 May 30.
26. Ando S, Nishida A, Usami S, Koike S, Yamasaki
S, Kanata S, Fujikawa S, Furukawa TA, Fukuda
M, Sawyer SM, Hiraiwa-Hasegawa M, Kasai K:
Help-seeking intention for depression in earlyadolescents: Associated factors and sex
differences. J Affect Disord 238: 359-365, 2018.
[Jun 7, 2018; doi: 10.1016/j.jad.2018.05.077]
27. Sakakibara E, Takizawa R, Kawakubo Y,
Kuwabara H, Kono T, Hamada K, Okuhata S,
Eguchi S, Ishii-Takahashi A, Kasai K: Genetic
influences on prefrontal activation during a verbal
fluency task in children: A twin study usingnear-infrared spectroscopy. Brain Behav. 2018
Jun;8(6):e00980. doi: 10.1002/brb3.980. Epub
2018 Apr 24. PMID: 30106245
28. Koshiyama D, Kirihara K, Tada M, Nagai T,
Fujioka M, Koike S, Suga M, Araki T, Kasai K:
Association between mismatch negativity andglobal functioning is specific to duration deviancein early stages of psychosis. Schizophr Res 2018;
195:378-384. [May 2018]
29. Tanaka SC, Yahata N, Todokoro A, Kawakubo Y,
Kano Y, Nishimura Y, Ishii-Takahashi A, Ohtake F,
Kasai K: Preliminary evidence of altered neural
response during intertemporal choice of losses inadult attention-deficit hyperactivity disorder. Sci
Rep. 2018 Apr 30;8(1):6703. doi: 10.1038/
s41598-018-24944-5. PMID: 29712945
30. Morimoto Y, Yamasaki S, Ando S, Koike S,
Fujikawa S, Kanata S, Endo K, Nakanishi M,
Hatch SL, Richards M, Kasai K, HiraiwaHasegawa M, Nishida A. Purpose in life andtobacco use among community-dwelling mothersof early adolescents. BMJ Open. 2018;8(4):e020586. [Apr 20, 2018]31. Sugawara H, Murata Y, Ikegame T, Sawamura R,

97

Shimanaga S, Takeoka Y, Saito T, Ikeda M,
Yoshikawa A, Nishimura F, Kawamura Y,
Kakiuchi C, Sasaki T, Iwata N, Hashimoto M,
Kasai K, Kato T, Bundo M, Iwamoto K: DNA
methylation analyses of the candidate genes
identified by a methylome-wide association study
revealed common epigenetic alterations in
schizophrenia and bipolar disorder. Psychiatry
Clin Neurosci. 2018;72(4):245-254. [Apr, 2018]32. Nishioka M, Bundo M, Ueda J, Katsuoka F, Sato
Y, Kuroki Y, Ishii T, Ukai W, Murayama S10,
Hashimoto E, Nagasaki M, Yasuda J, Kasai K,
Kato T, Iwamoto K. Identification of somatic
mutations in postmortem human brains by wholegenome sequencing and their implications forpsychiatric disorders. Psychiatry Clin Neurosci.
2018;72(4):280-294. [Apr, 2018]
33. Nishioka M, Bundo M, Ueda J, Yoshikawa A,
Nishimura F, Sasaki T, Kakiuchi C, Kasai K, Kato
T, Iwamoto K. Identification of somatic mutations
in monozygotic twins discordant for psychiatricdisorders. NPJ Schizophr 2018;4(1):7. [Apr 13,
2018]

98

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

Associate Professor
Jun Shimizu, M.D., Ph.D.

LecturerAtsushi Iwata, M.D., Ph.D.
Kaori Sakuishi, 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,

99

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 offunctionally glycosylated α-DG may be crucial forbrain 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 ofneurodegeneration in PD. We also identified genetic
factors responsible for the individual difference of theeffects of 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. We identified that
ALS patients with multiple rare deleterious variants incausative genes for ALS have earlier ages at onset. On
the basis of the findings that mutations in COQ2 areassociated with familial as well as sporadic multiple
system atrophy, we are conducting an investigatorinitiated clinical trial using coenzyme Q10 for patientswith multiple system atrophy. We also identified
expanded intronic TTTCA and TTTTA repeats in three
independent genes in patients with benign adultfamilial myoclonic epilepsy, which postulate a new
disease mechanism in epilepsy. (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
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.,

100

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., Ikenaga C., Uchio
N., Taira K., 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 visualized globotriaosylceramide distribution within peripheral nerve of
Fabry’s disease patient in non-labeled manner.
Recently we also applied this technique to observe lipid
accumulation in rimmed vacuoles from inclusion body
myositis patients. We also developed a new opticalsensor device detecting biomarkers for Alzheimer’s
disease using nanoimprint lithography (NIL)-based
two-dimensional photonic crystal (2D-PhC). In a pilot
study quantifying Aβ in CSF and serum samples, oursensor achieved higher sensitivity than conventional
ELISA. We also developed a novel preanalyticalsample handling protocol for high sensitivity
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: Yamaguchi N, Mano T, Ohtomo R, Ishiura H,
Almansour MA, Mori H, Kanda J, Shirota Y, Taira
K, Morikawa T, Ikemura M, Yanagi Y, Murayama
S, Shimizu J, Sakurai Y, Tsuji S, Iwata A. An
Autopsy Case of Familial Neuronal Intranuclear
Inclusion Disease with Dementia and Neuropathy.
Intern Med. 2018 Dec1;57(23):3459-3462.
2: Yoshikawa K, Kuwahara M, Saigoh K, Ishiura H,
Yamagishi Y, Hamano Y, Samukawa M, Suzuki H,
Hirano M, Mitsui Y, Tsuji S, Kusunoki S. The
novel de novo mutation of KIF1A gene as the cause
for Spastic paraplegia 30 in a Japanese case.
eNeurologicalSci. 2018 Nov 22;14:34-37.
3: Uenaka T, Satake W, Cha PC, Hayakawa H, Baba
K, Jiang S, Kobayashi K, Kanagawa M, Okada Y,
Mochizuki H, Toda T. In silico drug screening byusing genome-wide association study data
repurposed dabrafenib, an anti-melanoma drug, for
Parkinson's disease. Hum Mol Genet. 2018 Nov
15;27(22):3974-3985.
4: Tokushige SI, Matsuda SI, Oyama G, Shimo Y,
Umemura A, Sasaki T, Inomata-Terada S, Yugeta
A, Hamada M, Ugawa Y, Tsuji S, Hattori N, Terao
Y. Effect of subthalamic nucleus deep brain
stimulation on visual scanning. Clin Neurophysiol.
2018 Nov;129(11):2421-2432.
5: Nagase M, Yamamoto Y, Mitsui J, Tsuji S.
Simultaneous detection of reduced and oxidized
forms of coenzyme Q10 in human cerebral spinal
fluid as a potential marker of oxidative stress. J
Clin Biochem Nutr. 2018 Nov;63(3):205-210.
6: Tsuchida T, Mano T, Koshi-Mano K, Bannai T,
Matsubara T, Yamashita S, Ushijima T, Nagata K,

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Murayama S, Toda T, Tsuji S, Iwata A. Methylation
changes and aberrant expression of FGFR3 in
Lewy body disease neurons. Brain Res. 2018 Oct
15;1697:59-66.
7: Kurihara M, Sasaki T, Ishiura H, Tsuji S. HIV
Dementia with a Decreased Cardiac (123)Imetaiodobenzylguanidine Uptake Masquerading
as Dementia with Lewy Bodies. Intern Med. 2018
Oct 15;57(20):3007-3010.
8: Kurihara M, Bannai T, Otsuka J, Kawabe
Matsukawa M, Terao Y, Shimizu J, Tsuji S. Optic
neuropathy and decorticate-like posture aspresenting symptoms of Bickerstaff's brainstem
encephalitis: A case report and literature review.
Clin Neurol Neurosurg. 2018 Oct;173:159-162.
9: Ishigaki K, Ihara C, Nakamura H, Mori-Yoshimura
M, Maruo K, Taniguchi-Ikeda M, Kimura E,
Murakami T, Sato T, Toda T, Kaiya H, Osawa M.
National registry of patients with Fukuyama
congenital muscular dystrophy in Japan.
Neuromuscul Disord. 2018 Oct;28(10):885-893.
10: Nakamoto FK, Okamoto S, Mitsui J, Sone T,
Ishikawa M, Yamamoto Y, Kanegae Y, Nakatake Y,
Imaizumi K, Ishiura H, Tsuji S, Okano H. The
pathogenesis
linkedtocoenzyme
Q10
insufficiency in iPSC-derived neurons frompatients with multiple-system atrophy. Sci Rep.
2018 Sep 21;8(1):14215.
11: Hamaguchi T, Hirota Y, Takeuchi T, Nakagawa Y,
Matsuoka A, Matsumoto M, Awano H, Iijima K,
Cha PC, Satake W, Toda T, Ogawa W. Treatment ofa case of severe insulin resistance as a result of a
PIK3R1 mutation with a sodium-glucose
cotransporter 2 inhibitor. J Diabetes Investig. 2018
Sep;9(5):1224-1227.
12: Koh K, Ishiura H, Beppu M, Shimazaki H,
Ichinose Y, Mitsui J, Kuwabara S, Tsuji S,
Takiyama Y; Japan Spastic Paraplegia ResearchConsortium. Novel mutations in the ALDH18A1
gene in complicated hereditary spastic paraplegiawith cerebellar ataxia and cognitive impairment. J
Hum Genet. 2018 Sep;63(9):1009-1013.
13: Koh K, Ishiura H, Tsuji S, Takiyama Y. JASPAC:
Japan Spastic Paraplegia Research Consortium.
Brain Sci. 2018 Aug 13;8(8). pii: E153.
14: Imae R, Manya H, Tsumoto H, Osumi K, Tanaka T,
Mizuno M, Kanagawa M, Kobayashi K, Toda T,

Endo T. CDP-glycerol inhibits the synthesis of thefunctional O-mannosyl glycan of α-dystroglycan. J
Biol Chem. 2018 Aug 3;293(31):12186-12198.
15: Cen Z, Jiang Z, Chen Y, Zheng X, Xie F, Yang X,
Lu X, Ouyang Z, Wu H, Chen S, Yin H, Qiu X,
Wang S, Ding M, Tang Y, Yu F, Li C, Wang T,
Ishiura H, Tsuji S, Jiao C, Liu C, Xiao J, Luo W.
Intronic pentanucleotide TTTCA repeat insertionin the SAMD12 gene causes familial cortical
myoclonic tremor with epilepsy type 1. Brain.
2018 Aug 1;141(8):2280-2288.
16: Kodama S, Mano T, Kakumoto T, Ishiura H,
Hagiwara A, Kamiya K, Hayashi T, Tsuji S. Ketotic
hyperglycemia-related seizure with reversible
white matter lesion: Metabolic implication of its
reversibility based on magnetic resonancespectroscopy study. J Neurol Sci. 2018 Jul 15;390:
20-21.
17: Tokushige SI, Terao Y, Matsuda S, Furubayashi T,
Sasaki T, Inomata-Terada S, Yugeta A, Hamada M,
Tsuji S, Ugawa Y. Does the Clock Tick Slower or
Faster in Parkinson's Disease? - Insights Gained
From the Synchronized Tapping Task. Front
Psychol. 2018 Jul 11;9:1178.
18: Sudo A, Chihara N, Takenaka Y, Nakamura T,
Ueda T, Sekiguchi K, Toda T. Paraneoplastic
NMOSD associated with EG junction adenocarcinoma expressing unprotected AQP4. Neurol
Neuroimmunol Neuroinflamm. 2018 Jul 9;5(5):e482.
19: Horikawa Y, Hosomichi K, Enya M, Ishiura H,
Suzuki Y, Tsuji S, Sugano S, Inoue I, Takeda J. No
novel, high penetrant gene might remain to befound in Japanese patients with unknown MODY.
J Hum Genet. 2018 Jul;63(7):821-829.
20: Horita S, Simsek E, Simsek T, Yildirim N, Ishiura
H, Nakamura M, Satoh N, Suzuki A, Tsukada H,
Mizuno T, Seki G, Tsuji S, Nangaku M. SLC4A4
compound heterozygous mutations in exon-intron
boundary regions presenting with severe proximal
renal tubular acidosis and extrarenal symptoms
coexisting with Turner's syndrome: a case report.
BMC Med Genet. 2018 Jun 18;19(1):103.
21: Higuchi Y, Okunushi R, Hara T, Hashiguchi A,
Yuan J, Yoshimura A, Murayama K, Ohtake A,
Ando M, Hiramatsu Y, Ishihara S, Tanabe H,
Okamoto Y, Matsuura E, Ueda T, Toda T,

102

Yamashita S, Yamada K, Koide T, Yaguchi H,
Mitsui J, Ishiura H, Yoshimura J, Doi K, Morishita
S, Sato K, Nakagawa M, Yamaguchi M, Tsuji S,
Takashima H. Mutations in COA7 cause
spinocerebellar ataxia with axonal neuropathy.
Brain. 2018 Jun 1;141(6):1622-1636.
22: Misawa S, Kuwabara S, Sato Y, Yamaguchi N,
Nagashima K, Katayama K, Sekiguchi Y, Iwai Y,
Amino H, Suichi T, Yokota T, Nishida Y, Kanouchi
T, Kohara N, Kawamoto M, Ishii J, Kuwahara M,
Suzuki H, Hirata K, Kokubun N, Masuda R,
Kaneko J, Yabe I, Sasaki H, Kaida KI, Takazaki H,
Suzuki N, Suzuki S, Nodera H, Matsui N, Tsuji S,
Koike H, Yamasaki R, Kusunoki S; JapaneseEculizumab Trial for GBS (JET-GBS) Study Group.
Safety and efficacy of eculizumab in GuillainBarré syndrome: a multicentre, double-blind,randomised phase 2 trial. Lancet Neurol. 2018 Jun;
17(6):519-529.
23: Tsuchiya M, Hara Y, Okuda M, Itoh K, Nishioka R,
Shiomi A, Nagao K, Mori M, Mori Y, Ikenouchi J,
Suzuki R, Tanaka M, Ohwada T, Aoki J, Kanagawa
M, Toda T, Nagata Y, Matsuda R, Takayama Y,
Tominaga M, Umeda M. Cell surface flip-flop ofphosphatidylserine is critical for PIEZO1mediated myotube formation. Nat Commun. 2018
May 24;9(1):2049.
24: Kanagawa M, Toda T. Ribitol-phosphate-a newly
identified posttranslational glycosylation unit inmammals: structure, modification enzymes andrelationship to human diseases. J Biochem. 2018
May 1;163(5):359-369.
25: Sudo A, Kanagawa M, Kondo M, Ito C, Kobayashi
K, Endo M, Minami Y, Aiba A, Toda T. Temporal
requirement of dystroglycan glycosylation during
brain development and rescue of severe corticaldysplasia via gene delivery in the fetal stage. Hum
Mol Genet. 2018 Apr 1;27(7):1174-1185.
26: Ishiura H, Doi K, Mitsui J, Yoshimura J,
Matsukawa MK, Fujiyama A, Toyoshima Y, Kakita
A, Takahashi H, Suzuki Y, Sugano S, Qu W,
Ichikawa K, Yurino H, Higasa K, Shibata S, Mitsue
A, Tanaka M, Ichikawa Y, Takahashi Y, Date H,
Matsukawa T, Kanda J, Nakamoto FK,
Higashihara M, Abe K, Koike R, Sasagawa M,
Kuroha Y, Hasegawa N, Kanesawa N, Kondo T,
Hitomi T, Tada M, Takano H, Saito Y, Sanpei K,

Onodera O, Nishizawa M, Nakamura M, Yasuda T,
Sakiyama Y, Otsuka M, Ueki A, Kaida KI, Shimizu
J, Hanajima R, Hayashi T, Terao Y, Inomata-Terada
S, Hamada M, Shirota Y, Kubota A, Ugawa Y, Koh
K, Takiyama Y, Ohsawa-Yoshida N, Ishiura S,
Yamasaki R, Tamaoka A, Akiyama H, Otsuki T,
Sano A, Ikeda A, Goto J, Morishita S, Tsuji S.
Expansions of intronic TTTCA and TTTTA repeats
in benign adult familial myoclonic epilepsy. Nat
Genet. 2018 Apr;50(4):581-590.
27: Tohnai G, Nakamura R, Sone J, Nakatochi M,
Yokoi D, Katsuno M, Watanabe H, Watanabe H, Ito
M, Li Y, Izumi Y, Morita M, Taniguchi A, Kano O,
Oda M, Kuwabara S, Abe K, Aiba I, Okamoto K,
Mizoguchi K, Hasegawa K, Aoki M, Hattori N,
Onodera O, Naruse H, Mitsui J, Takahashi Y, Goto
J, Ishiura H, Morishita S, Yoshimura J, Doi K, Tsuji
S, Nakashima K, Kaji R, Atsuta N, Sobue G;
Japanese Consortium for Amyotrophic Lateral
Sclerosis Research (JaCALS). Frequency andcharacteristics of the TBK1 gene variants inJapanese patients with sporadic amyotrophic
lateral sclerosis. Neurobiol Aging. 2018 Apr;64:
158.e15-158.e19.
28: Nishihara R, Kobayashi K, Imae R, Tsumoto H,
Manya H, Mizuno M, Kanagawa M, Endo T, Toda
T. Cell endogenous activities of fukutin and FKRP
coexist with the ribitol xylosyltransferase, TMEM5.
Biochem Biophys Res Commun. 2018 Mar 18;
497(4):1025-1030.
29: Endo H, Sekiguchi K, Shimada H, Ueda T, Kowa
H, Kanda F, Toda T. Low signal intensity in motor
cortex on susceptibility-weighted MR imaging iscorrelated with clinical signs of amyotrophic
lateral sclerosis: a pilot study. J Neurol. 2018 Mar;
265(3):552-561.
30: Tanabe H, Higuchi Y, Yuan JH, Hashiguchi A,
Yoshimura A, Ishihara S, Nozuma S, Okamoto Y,
Matsuura E, Ishiura H, Mitsui J, Takashima R,
Kokubun N, Maeda K, Asano Y, Sunami Y, Kono
Y, Ishigaki Y, Yanamoto S, Fukae J, Kida H, Morita
M, Tsuji S, Takashima H. Clinical and genetic
features of Charcot-Marie-Tooth disease 2F andhereditary motor neuropathy 2B in Japan. J
Peripher Nerv Syst. 2018 Mar;23(1):40-48.
31: Komaki R, Ueda T, Tsuji Y, Miyawaki T, Kusuhara
S, Hara S, Toda T. [Retinal vasculopathy with103

cerebral leukoencephalopathy carrying TREX1
mutation
diagnosedbytheintracranialcalcification: a case report]. Rinsho Shinkeigaku.
2018 Feb 28;58(2):111-117.
32: Udagawa T, Harita Y, Miura K, Mitsui J, Ode KL,
Morishita S, Urae S, Kanda S, Kajiho Y, Tsurumi
H, Ueda HR, Tsuji S, Saito A, Oka A. Amnionlessmediated glycosylation is crucial for cell surface
targeting of cubilin in renal and intestinal cells. Sci
Rep. 2018 Feb 5;8(1):2351.
33: Sasaki T, Shirota Y, Kodama S, Togashi N,
Sugiyama Y, Tokushige SI, Inomata-Terada S,
Terao Y, Ugawa Y, Toda T, Hamada M. Modulationof motor learning by a paired associative
stimulation protocol inducing LTD-like effects.
Brain Stimul. 2018 Nov - Dec;11(6):1314-1321.
34: Nishioka Y, Shindoh J, Inagaki Y, Gonoi W, Mitsui
J, Abe H, Yoshioka R, Yoshida S, Fukayama M,
Tsuji S, Hashimoto M, Hasegawa K, Kokudo N.
Host MICA Polymorphism as a Potential
Predictive Marker in Response to Chemotherapy
for Colorectal Liver Metastases. Dig Dis. 2018;36(6):437-445.
35: Kurihara M, Ishiura H, Sasaki T, Otsuka J, Hayashi
T, Terao Y, Matsukawa T,Mitsui J, Kaneko J,
Nishiyama K, Doi K, Yoshimura J, Morishita S,
Shimizu J,Tsuji S. Novel De Novo KCND3
Mutation in a Japanese Patient with Intellectual
Disability, Cerebellum. 2018 Apr;17(2):237-242.
36: Uchio N, Taira K, Ikenaga C, Unuma A, Kadoya
M, Kubota A, Toda T, Shimizu J. Granulomatous
myositis induced by anti–PD-1 monoclonal
antibodies Neurol Neuroimmunol Neuroinflamm
April 2018 5:e464
37: Uchio N, Taira K, Ikenaga C, Kadoya M, Unuma
A, Yoshida K, Nakatani-Enomoto S, Hatanaka Y,
Sakurai Y, Shiio Y, Kaida K, Kubota A, Toda T,
Shimizu J. Inflammatory myopathy withmyasthenia gravis: Thymoma association andpolymyositis pathology. Neurol Neuroimmunol
Neuroinflamm. 2018 Dec 24;6(2):e535.
38: Iwata A, Iwatsubo T, Ihara R, Suzuki K,
Matsuyama Y, Tomita N, Arai H, Ishii K, Senda M,
Ito K, Ikeuchi T, Kuwano R, Matsuda H, for the
Alzheimer’s Disease Neuroimaging Initiative, andthe Japanese ADNI. Effects of sex, educational
background, and CKD grading on cognitive andfunctional decline in Japanese ADNI study.
Alzheimers Dement (NY) TRCI, 4, 765-774, 2018.
39: Ohtomo R, Banna T, Ohtomo G, Shindo A,
Tomimoto H, Tsuj S, Iwata A. Therapeutic effect ofcilostazol towards chronic cerebral hypoperfusion
in mice: Implication from gene expression analysis.
Neurosci Lett, 662, 247-252, 2018.
40: Iwatsubo T, Iwata A, Suzuki K, Ihara R, Arai H,
Ishii K, Senda M, Ito K, Ikeuchi T, Kuwano R,
Matsuda H; Japanese Alzheimer’s diseaseneuroimaging initiative, Chung-Kai Sun, Laurel
Beckett, Paul Aisen, Michael Donohue;
Alzheimer’s disease neuroimaging initiative.
Japanese and north American Alzheimer’s diseaseneuroimaging initiative studies: Harmonization forinternational trials. Alzheimers Dement, 14(8),1077-1087, 2018
41: Matsumoto L, Suzuki K, Mizuno Y, Ohike Y, Ozeki
A, Ono S, Takanashi M, Sawaki D, Suzuki T,
Yamazaki T, Tsuji S, Iwata A. Association of
subclinical carotid atherosclerosis with immediate
memory and other cognitive functions. Geriatr
Gerontol Int, 18(1), 65-71, 2018
42: Nagata K, Mano T, Murayama S, Saido TC, Iwata
A. DNA methylation level of the neprilysin
promoter in Alzheimer’s disease brains. Neurosci
Lett, 670, 8-13, 2018
43: Ihara R, Iwata A, Suzuki K, Ikeuchi T, Kuwano R,
Iwatsubo T, the Japanese Alzheimer’s Disease
Neuroimaging Initiative. Clinical and Cognitive
Characteristics of Preclinical Alzheimer’s Diseasein the Japanese Alzheimer’s Disease Neuroimaging Initiative Cohort. Alzheimers Dement(NY) TRCI, 4, 645-651, 2018
44: Iwata A, Iwatsubo T, Ihara R, Suzuki K,
Matsuyama Y, Tomita N, Arai H, Ishii K, Senda M,
Ito K, Ikeuchi K, Kuwano R, Matsuda H, for the
Alzheimer’s Disease Neuroimaging Initiative, andthe Japanese Alzheimer’s Disease Neuroimaging
Initiative. Effects of sex, educational background,and CKD grading on cognitive and functional
decline in Japanese ADNI study. Alzheimers
Dement (NY) TRCI, 4, 765-774, 2018

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.

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

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

Shota Tanaka, M.D.

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

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

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

Mariko Kawashima, M.D.

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

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

Tsuguto Takizawa, 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 13 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research, and education. The staffs include
a professor/chairman, an associate professor, a lecturerand 10 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 2018 to March
2019, 18,239 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 2017, 891 patients wereadmitted to the neurosurgery ward. 445 surgicalprocedures and 169 gamma knife procedures were
performed in 2018. Our practice covers a wide varietyof neurosurgical diseases including malignant andbenign brain tumors, hemorrhagic and thromboembolic
cerebrovascular diseases, spinal disorders, epilepsy,
pain and movement disorders.

105

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.
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) 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,106

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.
3) 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 thenovel treatment for intractable epilepsy. Since ourfacility was the first in Japan to provide vagus nerve
stimulation therapy, we evaluated its efficacy andsafety in epilepsy treatment. We established a new
intraoperative monitoring method of vagus-nerve
evoked potential. Efficacy evaluation and developmentof surgical instruments were promoted for novel
function-preserving techniques, multiple subpial
transection and multiple hippocampal transection.
Basic and clinical research on gamma knife treatmentof epilepsy has been performed as well. For the purposeof more precise localization of epileptic foci andelucidation of epileptogenesis, we are now developing
novel types of intracranial eletrodes.
4) 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.
5) Clinical applications of the functional brain
imaging and operative simulation using threedimensional computer graphics for neurosurgery
Our department intensively utilizes various kinds offunctional and metabolic imaging modalities including
magnetoencephalography, functional MRI, and diffusion tensor imaging-based tractography for presurgicalbrain mapping. Combining the results of the multimodalities enables to visualize all cortical andsubcortical networks of the motor, language and othercognitive functions in each patient. Furthermore, we
succeeded to import the combined information into a
neuronavigation system (functional neuronavigation),
which quickly and accurately indicates the eloquent
brain areas. We could develop virtual reality operative
simulation using multi-modal fusion threedimensional computer graphics. Then, it was possible
to precisely examine surgical strategy.
6) 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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K., Nishikawa T., Tanaka T., Hata K., Kawai K.,
Imai H., Saito N., Kobayashi H., Tanaka S.,
Ikemura M., Ushiku T., Nozawa H. Surgicalmanagement for a huge presacral teratoma and ameningocele in an adult with Currarino triad: acase report. Surgical case reports 4(1):9, 2018
2. Fujimoto S., Takai K., Nakatomi H., Kin T., Saito
N. Three-dimensional angioarchitecture andmicrosurgical treatment of arteriovenous fistulas at
the craniocervical junction. J Clin Neurosci
53:140-146, 2018
3. Funato K., Hayashi T., Echizen K., Negishi L.,
Shimizu N., Koyama-Nasu R., Nasu-Nishimura Y.,
Morishita Y., Tabar V., Todo T., Ino Y., Mukasa A.,
Saito N., Akiyama T. SIRT2-mediated inactivationof p73 is required for glioblastoma tumorigenicity.
EMBO reports 19(11), 2018
4. Hasegawa H., Hanakita S., Shin M., Kawashima
M., Kin T., Takahashi W., Suzuki Y., Shinya Y.,
Ono H., Shojima M., Nakatomi H., Saito N.
Integration of rotational angiography enables
better dose planning in Gamma Knife radiosurgery
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5. Hasegawa H., Hanakita S., Shin M., KawashimaM., Takahashi W., Ishikawa O., Koizumi S.,
Nakatomi H., Saito N. Comparison of the Longterm Efficacy and Safety of Gamma Knife
Radiosurgery for Arteriovenous Malformations in
Pediatric and Adult Patients. Neurol Med Chir
(Tokyo) 58(6):231-239, 2018
6. Hasegawa H., Hanakita S., Shin M., Koga T.,
Takahashi W., Nomoto A. K., Sakuramachi M.,
Saito N. Single-Fractionated Stereotactic Radiosurgery for Intracranial Meningioma in Elderly
Patients: 25-Year Experience at a Single Institution.
Operative neurosurgery (Hagerstown, Md)
14(4):341-350, 2018
7. Hasegawa H., Hanakita S., Shin M., Sugiyama T.,
Kawashima M., Takahashi W., Nomoto A. K.,
Shojima M., Nakatomi H., Saito N. Does
Advanced Age Affect the Outcomes of Stereotactic
Radiosurgery
forCerebral
Arteriovenous
Malformation? World Neurosurg 109:e715-e723,

2018
8. Hasegawa H., Hanakita S., Shin M., Sugiyama T.,
Kawashima M., Takahashi W., Shojima M.,
Ishikawa O., Nakatomi H., Saito N. A Comprehensive Study of Symptomatic Late RadiationInduced Complications After Radiosurgery for
Brain Arteriovenous Malformation: Incidence,
Risk Factors, and Clinical Outcomes. World
Neurosurg 116:e556-e565, 2018
9. Hasegawa H., Shin M., Kondo K., Hanakita S.,
Mukasa A., Kin T., Saito N. Role of endoscopictransnasal surgery for skull base chondrosarcoma:
a retrospective analysis of 19 cases at a single
institution. J Neurosurg 128(5):1438-1447, 2018
10. Hasegawa H., Shin M., Kondo K., Saito N.
Reconstruction of Dural Defects in Endoscopic
Transnasal Approaches for Intradural Lesions
Using Multilayered Fascia with a Pressure-Control
Spinal Drainage System. World Neurosurg 114:
e1316-e1324, 2018
11. Ibayashi K., Kunii N., Matsuo T., Ishishita Y.,
Shimada S., Kawai K., Saito N. Decoding SpeechWith Integrated Hybrid Signals Recorded From the
Human Ventral Motor Cortex. Frontiers inneuroscience 12:221, 2018
12. Ishii K., Nagaoka A., Kishida Y., Okazaki H.,
Yagishita S., Ucar H., Takahashi N., Saito N.,
Kasai H. In Vivo Volume Dynamics of Dendritic
Spines in the Neocortex of Wild-Type and Fmr1
KO Mice. eNeuro 5(5), 2018
13. Ishikawa O., Tsutsumi K., Yoshikawa G., Saito A.,
Tsunoda S., Kondo E., Sato K., Omura T., Saito N.
Thrombectomy using a method to Directly Insert
an Aspiration Catheter into a 6-Fr sheathintroducer placed into the brachial Artery. Journalof Neuroendovascular Therapy (JNET) 12: 456462, 2018
14. Ishikawa O., Tanaka M., Konno K., Hasebe T.,
Horikawa A., Iijima A., Saito N., Takahashi K.
Swine model of in-stent stenosis in the iliac artery
evaluating the serial time course. Exp Anim
67(4):501-508, 2018
15. Kapeller C., Ogawa H., Schalk G., Kunii N., Coon
W. G., Scharinger J., Guger C., Kamada K. Realtime detection and discrimination of visual
perception using electrocorticographic signals. J
Neural Eng 15(3):036001, 2018

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16. Kawasaki T., Shin M., Kimura Y., Umitsu Y.,
Matsumura G., Yokochi F., Okiyama R., Taniguchi
M., Arai N. Topographic anatomy of thesubthalamic nucleus localized by high-resolution
human brain atlas superimposing digital images ofcross-sectioned surfaces and histological images of
microscopic sections from frozen cadaveric brains.
J Clin Neurosci 53:193-202, 2018
17. Koizumi S., Kimura T., Shojima M., Inoue T.
Initial Attempt to Select Patients for MechanicalThrombectomy Using Noncontrast Computed
Tomography and Symptom-Based Criteria: SingleCenter Experience. World Neurosurg 112:e581e587, 2018
18. Koizumi S., Yamaoka Y., Matsuo T., Kimura T.,
Inoue T. Changes in Blood Flow Velocity of the
MiddleCerebral
ArteryAfter
Carotid
Endarterectomy:
Daily
Assessment
withTranscranial Color-Coded Sonography. World
Neurosurg 110:e710-e714, 2018
19. Komuro A., Raja E., Iwata C., Soda M., Isogaya K.,
Yuki K., Ino Y., Morikawa M., Todo T., Aburatani
H., Suzuki H., Ranjit M., Natsume A., Mukasa A.,
Saito N., Okada H., Mano H., Miyazono K.,
Koinuma D. Identification of a novel fusion gene
HMGA2-EGFR in glioblastoma. Int J Cancer
142(8):1627-1639, 2018
20. Lo B. W. Y., Fukuda H., Miyawaki S., Koyanagi M.
Short review of randomized controlled trials(RCTs) for Surgical Neurology International: Two
important RCT articles for 2018 - Part I. Surg
Neurol Int 9:138, 2018
21. Maruyama K., Watanabe E., Kin T., Saito K.,
Kumakiri A., Noguchi A., Nagane M., Shiokawa Y.
Smart Glasses for Neurosurgical Navigation by
Augmented Reality. Operative neurosurgery(Hagerstown, Md) 15(5):551-556, 201822. Miyawaki S., Shinya Y., Imai H., Hongo H., Ono
H., Takenobu A., Nakatomi H., Teraoka A., Saito
N. Response to Letter to the Editor Regarding"Genetic Analysis of Ring Finger Protein 213(RNF213)c.14576G>A
in
Intracranial
Atherosclerosis of the Anterior and Posterior
Circulations". J Stroke Cerebrovasc Dis 27(10):2894-2895, 201823. Nejo T., Tanaka S., Ikemura M., Nomura M.,
Takayanagi S., Shin M., Ushiku T., Shibahara J.,

Saito N., Mukasa A. Maffucci syndrome
complicated by three different central nervous
system tumors sharing an IDH1 R132C mutation:case report. J Neurosurg:1-6, 201824. Okano A., Ogiwara H. Long-term follow-up for
patients with infantile hydrocephalus treated bychoroid plexus coagulation. J Neurosurg Pediatr
22(6):638-645, 2018
25. Okazaki H., Hayashi-Takagi A., Nagaoka A.,
Negishi M., Ucar H., Yagishita S., Ishii K.,
Toyoizumi T., Fox K., Kasai H. Calcineurinknockout mice show a selective loss of small
spines. Neurosci Lett 671:99-102, 2018
26. Ono H., Inoue T., Tanishima T., Tamura A., Saito
I., Saito N. High-flow bypass with radial artery
graft followed by internal carotid artery ligation forlarge or giant aneurysms of cavernous or cervicalportion: clinical results and cognitive performance.
Neurosurg Rev 41(2):655-665, 2018
27. Ota T., Nishiyama Y., Koizumi S. Impact of onsetto-groin puncture time within three hours on
functional outcomes in mechanical thrombectomy
for acute large-vessel occlusion. Interv
Neuroradiol 24(2):162-167, 2018
28. Otani R., Mukasa A., Shin M., Omata M.,
Takayanagi S., Tanaka S., Ueki K., Saito N.
Brachyury gene copy number gain and activationof the PI3K/Akt pathway: association withupregulation of oncogenic Brachyury expression inskull base chordoma. J Neurosurg 128(5):14281437, 2018
29. Otani R., Uzuka T., Higuchi F., Matsuda H.,
Nomura M., Tanaka S., Mukasa A., Ichimura K.
IDH-mutatedastrocytomas
with
19q-loss
constitute a subgroup that confers better prognosis.
Cancer Sci 109(7):2327-2335, 201830. Sato I., Higuchi A., Yanagisawa T., Murayama S.,
Kumabe T., Sugiyama K., Mukasa A., Saito N.,
Sawamura Y., Terasaki M., Shibui S., Takahashi J.,
Nishikawa R., Ishida Y., Kamibeppu K. Employment status and termination among survivors ofpediatric brain tumors: a cross-sectional survey.
Int J Clin Oncol 23(5): 801-811, 201831. Sato M., Tateishi K., Murata H., Kin T., Suenaga J.,
Takase H., Yoneyama T., Nishii T., Tateishi U.,
Yamamoto T., Saito N., Inoue T., Kawahara N.
Three-dimensional multimodality fusion imaging

109

as an educational and planning tool for deep-seatedmeningiomas. Br J Neurosurg 32(5):509-515,
2018
32. Shin M., Shojima M., Kondo K., Hasegawa H.,
Hanakita S., Ito A., Kin T., Saito N. Endoscopic
Endonasal Craniofacial Surgery for Recurrent
Skull Base Meningiomas Involving the
Pterygopalatine Fossa, the Infratemporal Fossa, theOrbit, and the Paranasal Sinus. World Neurosurg
112:e302-e312, 201833. Shojima M., Morita A., Nakatomi H., Tominari S.
Size is the Most Important Predictor of Aneurysm
Rupture Among Multiple Cerebral Aneurysms:
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Cerebral Aneurysm Study Japan. Neurosurgery
82(6):864-869, 201834. Shono N., Kin T., Nomura S., Miyawaki S., Saito
T., Imai H., Nakatomi H., Oyama H., Saito N.
Microsurgery Simulator of Cerebral Aneurysm
Clipping with Interactive Cerebral Deformation
Featuring a Virtual Arachnoid. Operative
neurosurgery (Hagerstown, Md) 14(5):579-589,
2018
35. Sone D., Ikemura M., Saito Y., Taniguchi G., Kunii
N. Marked accumulation of oligodendroglia-likecells in temporal lobe epilepsy with amygdala
enlargement
andhippocampal
sclerosis.
Neuropathology 38(2):154-158, 2018
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M. Microsurgical and Endovascular Treatments ofSpinal Extradural Arteriovenous Fistulas with orwithout Intradural Venous Drainage. World
Neurosurg 111:e819-e829, 201837. Torazawa S., Shin M., Hasegawa H., Otani R.,
Ueki K., Saito N. Endoscopic Transnasal Resectionof Solitary Fibrous Tumor in the Optic Canal.
World Neurosurg 116:127-132, 2018
38. Umekawa M., Hasegawa H., Shin M., Kawashima
M., Nomura S., Nakatomi H., Saito N.
Radiosurgery-Induced Anterior Inferior Cerebellar
Artery Pseudoaneurysm Treated with Trapping andBypass. World Neurosurg 116:209-213, 2018
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Rapaka S., Mihalef V., Fu W., Qiao A., Jain K.,
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Ashton N., Revell A., Aristokleous N., Houston J.
G., Tsuji M., Ishida F., Menon P. G., Browne L. D.,
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Al-Smadi Y. M., Tran J. S., Marsden A. L.,
Vaippummadhom S., Einstein G. A., Brown A. G.,
Debus K., Niizuma K., Rashad S., Sugiyama S. I.,
Owais Khan M., Updegrove A. R., Shadden S. C.,
Cornelissen B. M. W., Majoie C., Berg P., Saalfield
S., Kono K., Steinman D. A. Real-World
Variability in the Prediction of Intracranial
Aneurysm Wall Shear Stress: The 2015
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Cardiovascular engineering and technology
9(4):544-564, 2018

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

111

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

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

Homepagehttps://plaza.umin.ac.jp/prm/

Introduction and Organization
Department of Preventive Medicine is the oldest
laboratory in the University of Tokyo, established by
Masanori Ogata in 1885. Ever since, for more than 130
years, the laboratory has been a hub to importantresearch leading to disease prevention and developed
and produced core human resources in public healthadministration. The philosophy of the Department toPreventive Medicine has not changed throughout its
history, but its focus of research has changed from time
to time, like infectious diseases and occupational healthto name a few, to meet the expectations of the society.
Eventually, in response to the completion of the Human
Genome Project and the recent advancement inmolecular biology, the laboratory had changed its nameto the Department of Molecular Preventive Medicine.
Under Professor Koji Matsushima, the 8th director of
the laboratory, research was actively conducted toclarify inflammation/immune phenomenon with focus
on cytokines in disease background, and its clinicalapplication for secondary/tertiary prevention. In
December 2018, Professor Shumpei Ishikawa became
the 9th director, and in April 2019, he changed the nameof the department back to Preventive Medicine.
Currently, our lab includes (besides the professor andthe assistant professor) 7 students (2 are from outsideof UTokyo), 2 technical staffs, 7 technical assistants, 1
visiting researcher, 1 research student, 1 collaboration
researcher, and 1 assistant clerk. Also, 2 collaborative
researchers from private companies have joined ourlaboratory.

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

Research activities
In Department of Molecular Preventive Medicine,
we conduct research based on genome science andinformation science to explore the appropriate points ofintervention for various health issues, in particular,
cancer prevention and treatment. Cancer andinflammation/immune diseases are complex systems
comprised of numerous types of cells. We aim toelucidate the dynamics of such complex systems bycollecting extensive data at genome-level, as well as toexplore specific phenomena which may serve asintervenable preventive/therapeutic targets, and toevaluate their significance in the related diseases. In
addition, we are developing bioinformatics technology

112

to extract essential information from massive andmulti-dimensional biological data, e.g., genome
sequence and images, for human interpretation bytechniques such as dimensionality reduction andvisualization.
Our current primary focus areas of research are as
follow:
1. Immune Repertoire Analysis to Reveal
Internal/External
ImmuneEnvironment
Profiles in Individuals
Antigen receptor genes of human lymphocyte
undergo somatic hypermutation to acquire extensive
diversity. The entire set of antigen receptors inlymphocyte population is called immune repertoire,
and its profiling in individuals has now become
possible thanks to the advancement in genome analysis
technology such as next-generation sequencing (NGS).
Immune repertoires are considered to reflect immune
history affected by external factors, e.g., pathogens andfoods that the individual has encountered, and byinternal factors, e.g., self-antigens and cancer antigens.
In the department of Molecular Preventive Medicine,
we are trying 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 use information analysis
technique such as deep learning to analyze information
related to cancer prevention and treatment. Also, we areapplying the obtained immune repertoire data to design
antibodies and use them in cancer treatment andprevention.
2. Cancer
Genome Analysis
toExploreCarcinogenic Factors and Point of Intervention
We are combining human clinical cancer tissues with
NGS to achieve a comprehensive understanding of thecancer genome. Whole cancer genome sequencing will
provide numerous information, such as the driver genes,
which would serve direct therapeutic targets, and thegenetic background of an individual related tocarcinogenic predispositions. It also enables mutation

signature analysis to reveal environmental factors
which are also possible carcinogenic predispositions.
The obtained information is processed as a whole by
the combination of bioinformatics and experimental
validation to explore the appropriate points ofintervention for cancer prevention and treatment,
which are crucial for health in our country. We haveidentified RHOA driver mutation in diffuse-type
gastric adenocarcinoma by cancer genome sequencing
and showed that its mutation signature differs from theintestinal-type gastric adenocarcinoma, suggesting thatcarcinogenic factors are different in these two types ofcancer. We are looking at cancer tissues as a whole, byapplying genomics point of view, i.e., single-cell
analysis, to cancer cells, immune cells, and vascularstroma cells that comprise cancer tissue, to elucidate
carcinogenic and progression factors and points ofintervention from higher dimensions.
3. Contribution to Elimination of Medical Care
Disparities by Histopathological Image Analysis
As the volume of available biomedical information
is growing rapidly, technology to extract essential
abstract information by compressing dimensions of anenormous amount of biological data is extremely
important in our society. In the department of
Molecular Preventive Medicine, deep neural network is
applied to extract essential information of cancer fromcancer histopathological images. Our goal is to develop
tools to achieve a uniform pathological diagnosis andto help eliminate regional medical care disparities. We
are developing algorithms using deep learning forclinical application, and our unique analyticaltechnique has lead to achievement in an international
competition (Camelyon 17). Our current focus is on thedevelopment of contents which would seamlessly
connect routine lab tests performed in small clinics andcancer genome medicine given in large core hospitals
by integrated analysis of histopathological informationand cancer genome information.
4. Genome Screening of Gut Microbial Metabolites
which are Safe and Highly Effective in Disease
Prevention/Treatment
Identification of anticancer- or anti-inflammatorymicrobial metabolites will lead to the development ofsafe preventive medicine/health food, which in turn

113

enables individuals to pursue evidence-based dietarycontrol and results in significant disease prevention
effect. The interaction between gut microbiota andhuman host cells leads to the production of various
metabolites, which affect our immunity andcarcinogenic environment. We have developed ascreening library that represents the diverse hostmicrobial interaction by inserting shRNAs formetabolic genes and microbial cDNAs into a virus
library. We are using this unique library for functional
genome screening in GI cancer to identify highlyeffective anticancer natural metabolites. In addition, by
elucidating its synthetic pathway at the same time,large-scale ex vivo production of such metabolites may
become possible.

Publications
None (since 1 December 2018）

114

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. (seconded to Harvard University until Dec 2018)
Taeko Oguma, M.D., Ph.D. (until Dec 2018; Project Research Associate from Jan 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.
In the academic year of 2018, the Department
consists of 6 faculty members above listed, 2 project
researchers (part-time), 2 supporting staff members,

115

17 graduate students (13 in PhD program, 1 in
temporary supervised program, 3 in professional
degree course), 17 part-time lecturers, and 31 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).
These studies have been published in health policy
and health services research journals. We havecontinued a collaborative study on a system of
HIV/AIDS care with the introduction of highly active
anti-retroviral therapy (HAART) in developing
countries, since such a system involves medical,
behavioral, social, and economic 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
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) epidemiological116

study on incidence and survival rate of children withcerebral palsy.

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Dietary Environment in Relation to Difficulty of
Shopping for Elderly Living at Home-. Bulletin ofSocial Medicine 35(1): 19-28, 2018.
3. Hasegawa J, Ikeda T, Toyokawa S, Jojima E,
Satoh S, Ichizuka K, Tamiya N, Nakai A, Fujimori
K, Maeda T, Masuzaki H, Takeda S, Suzuki H,
Ueda S, Ikenoue T. Prevention Recurrence
Committee, Japan Obstetric Compensation
System for Cerebral Palsy: Relevant obstetricfactors associated with fetal heart rate monitoringfor cerebral palsy in pregnant women withhypertensive disorder of pregnancy. Journal of
Obstetrics and Gynaecology Research 44(4): 647654, 2018. doi.org/10.1111/jog.13555.
4. Hamada R, Lee JS, Mori K, Watanabe E, Muto S.
Influence of abdominal obesity and habitual
behaviors on incident atrial fibrillation in
Japanese. Journal of Cardiology 71: 118-124,
2018. doi.org/10.1016/j.jjcc.2017.07.008.
5. Alkebsi L, Ideno Y, Lee JS, Suzuki S,
Nakajima-Shimada J, Ohnishi H, Sato Y, Hayashi
K. Gastroduodenal ulcers and ABO blood group:
the Japan Nurses’ Health Study (JNHS). Journalof Epidemiology 28(1): 34-40, 2018. doi.org/10.
2188/jea.JE20160204.
6. Hara K, Tomio J, Svensson T, Ohkuma R,
Svensson AK, Yamazaki T. Association measuresof claims-based algorithms for common chronic
conditions were assessed using regularly collected
data in Japan. Journal of Clinical Epidemiology
99: 84-95, 2018. doi.org/10.1016/j.jclinepi.2018.
03.004.
7. Sugiyama T, Tamiya N, Watanabe T, Wakui T,

Shibayama T, Moriyama Y, Yamaoka Y, Noguchi
H. Association of care recipients’ care-need levelwith family caregiver participation in health check-ups in Japan. Geriatrics Gerontology International 18(1): 26-32, 2018. doi.org/10.1111/ggi.
13131.
8. Tsujimoto T, Kajio H, Sugiyama T. Favourable
changes in mortality in people with diabetes: US
NHANES 1999-2010. Diabetes, Obesity &Metabolism 20(1): 85-93, 2018. doi.org/10.1111/
dom.13039.
9. Zaitsu M, Yoo BK, Tomio J, Nakamura F,
Toyokawa S, Kobayashi Y. Impact of a direct-toconsumer information campaign on prescription
patterns for overactive bladder. BMC HealthServices Research 18(1):325, 2018. doi.org/10.
1186/s12913-018-3147-1.
10. Zaitsu M, Cuevas AG, Trudel-Fitzgerald C,
Takeuchi T, Kobayashi Y, Kawachi I.
Occupational class and risk of renal cell cancer.
Health Science Reports 1(6):e49, 2018. doi.org/10.
1002/hsr2.49.
11. Zaitsu M, Kaneko R, Takeuchi T, Sato Y,
Kobayashi Y, Kawachi I. Occupational
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Hospital-based matched case-control study withoccupational class. SSM-Population Health 5(1):129-137, 2018. doi.org/10.1016/j.ssmph.2018.06.
001.
12. Tanaka H, Ishikawa KB, Katanoda K. Geographic
Access to Cancer Treatment in Japan: Results
From a Combined Dataset of the Patient Survey
and the Survey of Medical Institutions in 2011.
Journal of Epidemiology 28(11): 470-475, 2018.
doi.org/10.2188/jea. JE20170051.
13. Tanaka H, Miyawaki A, Toyokawa S, Kobayashi
Y. Relationship of relative poverty and social
relationship on mortality around retirement: a
10-year follow -up of the Komo-lse cohort.
Environmental Health and Preventive Medicine
23:64, 2018. doi.org/10.1186/s12199-018-0756-6.
14. 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, 2018.
[Epub ahead of print] doi.org/10.1093/pubmed/
fdy095.

117

15. Fujita A, Hayamizu K, Yoshihara T, Zaitsu M,
Shiraishi F, Arima H, Matsuo K, Shiokawa K,
Hidekazu Setoguchi H, Sasaguri T. Effect of sex
and polymorphisms of CYP2B6 and UGT1A9 on
the difference between the target-controlled
infusion predicted and measured plasma propofol
concentration. JA Clinical Reports 4(1): 59, 2018.
doi.org/10.1186/s40981-018-0196-8.
16. Zaitsu M, Kawachi I, Ashida T, Kondo K, Kondo
N. Participation in Community Group Activities
Among Older Adults: Is Diversity of Group
Membership Associated With Better Self-rated
Health? Journal of Epidemiology 28(11):452-457,
2018. doi.org/10.2188/jea.JE20170152.
17. Zaitsu M, Yoshihara T, Nakai H, Kubota S.
Optimal Thermal Control with Sufficient
Nutrition May Reduce the Incidence of Neonatal
Jaundice by Preventing Body-Weight Loss Among
Non-Low Birth Weight Infants Not Admitted to
Neonatal Intensive Care Unit. Neonatology 114(4):348-354, 2018. doi.org/10.1159/000491817.
18. 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, 2018. [Epub ahead of print]
doi./org/10.1093/humrep/dez015.
19. 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, 2018. [Epub ahead of print] doi.org/10.1007/
s10654-019-00490-w.
20. Hino K, Asami Y, Lee JS. Step counts of middleaged and elderly adults for tem months before andafter the release of Pokémon GO in Yokohama,Japan. Journal of Medical Internet Research, 2018.

[Epub ahead of print] doi.org/10.2196/10724.
21. 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 , 2018. [Epub ahead of print]
doi.org/10.1016/j.maturitas.2018.12.010.
22. Zhu D, Chung HF, Pandeya N, Dobson AJ, Cade
JE, Greenwood DC, Crawford SL, Avis NE, GoldEB, Mitchell ES, Woods NF, Anderson D, Brown
DE, Sievert LL, Brunner EJ, Kuh D, Hardy R,
Hayashi K, Lee JS, Mizunuma H, Giles GG,
Bruinsma F, Tillin T, Simonsen MK, Adami HO,
Weiderpass E, Canonico M, Ancelin ML,
Demakakos P, Mishra GD. Relationships between
intensity, duration, cumulative dose, and timing ofsmoking with age at menopause: a pooled analysis
of individual data from 17 observational studies.
PLOS Medicine 15(11): e1002704, 2018. doi.org/
10.1371/journal.pmed.1002704.
23. 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, 2018.
[Epub ahead of print] doi.org/10.1111/jdi.12947.
24. Yasui T, Hayashi K, Okano H, Kamio M,
Mizunuma H, Kubota T, Lee JS, Suzuki S.
Uterine leiomyomata: a retrospective study ofcorrelations with hypertension and diabetes
mellitus from the Japan Nurses' Health Study.
Journal of Obstetrics and Gynaecology (38)8:
1128-1134, 2018. doi.org/10.1080/01443615.2018.
1451987.
25. Hasegawa H, Hanakita S, Shin M, Sugiyama T,
Kawashima M, Takahashi W, Shojima M,
Ishikawa O, Nakatomi H, Saito N. A Comprehensive Study of Symptomatic Late RadiationInduced Complications After Radiosurgery for
Brain Arteriovenous Malformation: Incidence,
Risk Factors, and Clinical Outcomes. World
Neurosurgery 116 (1): e556-e565, 2018. doi.org/
10.1016/j.wneu.2018.05.038.
26. Tsujimoto T, Kajio K, Shapiro MF, Sugiyama T.
Risk of All-Cause Mortality in Diabetic Patients
Taking β-Blockers. Mayo Clinic Proceedings 93

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2017.11.019.
27. Shibahashi K, Sugiyama K, Okura Y, Tomio J,
Hoda H, Hamabe Y. Defining hypotension inpatients with severe traumatic brain injury. World
Neurosurgery120 (1): e667-e674, 2018. doi.org/
10.1016/j.wneu.2018.08.142.
28. Morioka N, Tomio J, Seto T, Yumoto Y, Ogata Y,
Kobayashi Y. Association between local-level
resources for home care and home deaths:
anationwide spatial analysis in Japan. PLoS One
13(8): e0201649, 2018. doi.org/10.1371/journal.
pone.0201649.
29. Kitamura T, Iwami T, Atsumi T, Endo T, Kanna T,
Kuroda Y, Sakurai A, Tasaki O, Tahara Y, Tsuruta
R, Tomio J, Nakata K, Nachi S, Hase M,
Hayakawa M, Hiruma T, Hiasa K, Muguruma T,
Yano T, Shimazu T, Morimura N; special
committee that aims to improve survival after out‐ of ‐ hospital cardiac arrest (OHCA) by
providing evidence‐based therapeutic strategy
and emergency medical system from the Japanese
Association for Acute Medicine (JAAM). The
profile of Japanese Association for Acute
Medicine - out-of-hospital cardiac arrest registryin 2014-2015. Acute Medicine & Surgery 5(3):249-258, 2018. doi.org/10.1002/ams2.340.
30. Maeda E, Ishihara O, Tomio J, Sato A, Terada Y,
Kobayashi Y, Murata K. Caesarean section rates
and local resources for perinatal care in Japan: anationwide ecological study using the National
Database of health insurance claims. Journal of
Obstetrics and Gynaecology Research 44(2):208-216, 2018. doi.org/10.1111/jog.13518.

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
Fumiko Chiba, M.D., Ph.D., Suguru Torimitsu, 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 one of
the most important practices at our department. We
perform medico-legal autopsies for around 120
criminal cases in eastern part of Tokyo every year. We
also perform post-mortem CT at the request of police.
In medico-legal autopsy, we usually examine various
tests such as the pathological, alcohol, toxicological,
and blood type tests. Finally, forensic pathologists inour department diagnose the cause of death. Expert
opinions express the cause of death and forensic
judgment for each case.

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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 ClinicalClerkship 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, Makino Y, Saka K, Fujii Y,Abe H,
Chiba F, Yamaguchi R, Iwase H. Olanzapine‐
Induced Fatal Ketoacidosis with Pneumomediastinum and Subcutaneous Emphysema. J
Forensic Sci. 2018; 27: 245-249.
2. Saitoh H, Ikegaya H, Sakurada K, Inoue H,
Nagasawa S, Sakuma A, Ishii N, Inokuchi G,
Chiba F, Torimitsu S, Iwase H. Usefulness ofhuman herpes simplex virus type 1 genotyping for
tracing the geographical origins of unidentified
cadavers. Future Virology. 2018; 13: 391-398.
3. Nagasawa S, Saitoh H, Kasahara S, Chiba F,122Torimitsu S, Abe H, Yajima D, Iwase H.
Relationship between KCNQ1 (LQT1) and
KCNH2 (LQT2) gene mutateons and sudden
death during illegal drug use. Sci Rep. 2018; 31:
8: 8443.
4. Chiba F, Makino Y, Torimitsu S, Motomura A,
Inokuchi G, Ishii N, Hoshioka Y, Abe H,
Yamaguchi R, Sakuma A, Nagasawa S, Saito H,
Yajima D, Fukui Y, Iwase H. Stature estimation
based on femoral measurements in the modern
Japanese population: a cadaveric study using
multidetector computed tomography. Int J LegalMed. 2018; 132:1485-1491.
5. Chiba F, Makino Y, Torimitsu S, Motomura A,
Inokuchi G, Ishii N, Hoshioka Y, Abe H,
Yamaguchi R, Sakuma A, Nagasawa S, Saito H,
Yajima D, Fukui Y, Iwase H. Sex estimation basedon femoral measurements using multidetector
computed tomography in cadavers in modern
Japan. Forensic Sci Int. 2018; 292: 262.e1-262.e2.
6. Kuwayama K, Nariai M, Miyaguchi H, Iwata T,
Kanamori T, Tsujikawa K, Yamamuro T, Segawa
H, Abe H, Iwase H, Inoue H. Estimation of day ofdeath using micro-segmental hair analysis basedon drug use history: a case of lidocaine use as amarker. Int J Legal Med. 2018 Sep
7. Abe H, Takei C, Sakakura M, Yajima D, Iwase H.
Comprehensive Drug Screening by Thermal
Desorption and Pyrolysis Combined with Direct
Analysis in Real Time-Mass Spectrometry (TDP/DART-MS). Methods Mol Biol. 2018;1810:115124.
8. Kuwayama K, Nariai M, Miyaguchi H, Iwata Y,
Kanamori T, Tsujikawa K, Yamamuro T, Segawa
H, Abe H, Iwase H, Inoue H. Micro-segmental
hair analysis for proving drug-facilitated crimes:
Evidence that a victim ingested a sleeping aid,
diphenhydramine, on a specific day. Forensic Sci
Int. 2018 Jul;288:23-28
9. Kuwayama K, Nariai M, Miyaguchi H, Iwata Y,
Kanamori T, Tsujikawa K, Yamamuro T, Segawa
H, Abe H, Iwase H, Inoue H. Accurate estimationof drug in take day by microsegmental analysis ofa strand of hair by use of internal temporalmarkers. Journal of applied laboratory medicine.
2018; 37-47.
10. Kinoshita H, Tanaka N,Takakura A, Abe H,

Kumihashi M, Jamal M, Ito A , Tsitsui K, Kimura
S, Iwase H, Ameno K. AN AUTOPSY CASE
IDENTIFYING
α-PYRROLIDINOHEXANOPHENONE (α-PHP),A SYNTHETIC CATHINONE. Review of
Albanian Legal Medicine. 2018;Nor.18:53-61
11. Nagano M, Kohsaka S, Ueno T, Kojima S, Saka K,
Iwase H, Kawazu M, Mano H. High-throughput
functional evaluation of variants of unknown
significance in ERBB2. Clin Cancer Res. 2018;24(20): 5112-5122.
12. Shintani-Ishida K, Saka K, Nakamura M, Yoshida
K, Ikegaya H. Experimental study on the
postmortem redistribution of the substituted
phenethylamine, 25B-NBOMe. J Forensic Sci.
2018; 63(2): 588-591.

123

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

Assistant Professor
Katsuya Tanaka, Ph.D., Hidenao Atarashi, M.P.H, Ph.D., Yoshimasa Kawazoe, M.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 ofInterdisciplinary Information Studies. The department
is located on the fourth floor in Administration andResearch Building in the University of Tokyo
Hospital.

124

Teaching activities
Teaching staffs are Professor Kazuhiko Ohe,
Associate Professor Takeshi Imai, Assistant Professor
Katsuya Tanaka, Hidenao Atarashi, Yoshimasa
Kawazoe, Research Associate Shinichiro Yokota andDaisuke Sato.
1). 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 FY2018 are seven 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) analysis of
localization and restructuring of medical humanresources.
In these domains, major research topics are as listed
below.
1) A study on development of large scale ontology
databases of medical terms and concepts anddevelopment of application systems using theontology: This research is to develop a methods tobuild a large scale medical ontology, which is adatabase for hundreds of thousand of clinicalterms and concepts and their relationships. The
medical ontology covers over 6000 diseases andwhole of human anatomical structures using
HOZO ontology describing tool, and the ontology
was converted from the HOZO-proprietary XML
data format into the LOD format. Using the LOD
format, a web application for browsing the disease
ontology was developed and published on the website; http://lodc.med-ontology.jp/
2) Development of Multi-purpose Clinical Data

125

Repository System(MCDRS) and Joining the
University of Tokyo COI (Center of Innovation )Project named “Self Management of Your
Health”: The department joined “Clinical
Outcome Database Project” sponsored by MHLW
in 2014 and developed MCDRS as a system forregistration of clinical case data by clinicalresearchers. The system is now under public
release for other database projects.
On the other hand, the COI project aims toconstruct and deliver an infrastructure for theenhancement of clinical database research and thestandardization of nation-wide health information
systems. The department plays a role of thedevelopment as a sub-project leader. The use of
SS-MIX2 standard and extensive storage system
is key technology for converting venderproprietary database format into the international
standard format and facilitating easy multipurpose secondary use for clinical researches andother 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.

References
1. 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.
2. Yokota S, Tomotaki A, Mohri O, Endo M, Ohe K.
Evaluating the Effectiveness of a Fall Risk
Screening Tool Implemented in an Electronic
Medical Record System. Journal of Nursing Care
Quality. 2018;33(4): E1-E6.
3. Y Kawazoe, K Shimamoto, R Yamaguchi, Y
Shintani-Domoto, H Uozaki, M Fukayama, K
Ohe: Faster R-CNN-BasedGlomerular Detection
inMultistainedHuman
WholeSlideImages.
J.
Imaging 2018,4,91; doi:10.3390/imaging4070091
4. Koike S, Matsumoto M, Kawaguchi H, Ide H,
Atarashi H, Kotani K, Yasunaga H. Board
certification and urban-rural migration ofphysicians in Japan. BMC Health Services
Research. 2018;18(1):615.
5. Yokota S, Shinohara E, Ohe K. Can Staff
Distinguish Falls: Experimental Hypothesis
Verification Using Japanese Incident Reports andNatural Language Processing. Studies in HealthTechnology and Informatics. 2018;250: 159-163.
(14th International Congress on Nursing
Informatics: NI2018, Guadalajara, Mexico.
2018/06/06-08)
6. Ide H, Doi S, Atarashi H, Fujita S, Koike S. The
distance and chance of lifetime geographicalmovement of physicians in Japan: an analysis
using the age-period-cohort model. Human
Resources for Health. 2018;16(1):26.
7. Kawaguchi H, Koike S, Ohe K. Regional
differences in electronic medical record adoption
in Japan: A nationwide longitudinal ecologicalstudy. International Journal of Medical
Informatics. 2018;115. 114-119.
8. Kawaguchi H, Koike S, Sakurai R, Ohe K.
Association between number of institutions withcoronary computed tomography angiography andregional mortality ratio of acute myocardial
infarction: a nationwide ecological study using aspatial Bayesian model. International Journal of
Health Geographics. 2018;17(1):13.
9. Chinzei K, Shimizu A, Mori K, Harada K, Takeda
H, Hashizume M, Ishizuka M, Kato N, Kawamori
R, Kyo S, Nagata K, Yamane T, Sakuma I, Ohe K,
Mitsuishi M.Regulatory Science on AI-based
Medical Devices and Systems. Advanced
Biomedical Engineering. 2018;7:118-123.
10. Yamamoto-Honda R, Takahashi Y, Mori Y,
Yamashita S, Yoshida Y, Kawazu S, Iwamoto Y,
Kajio H, Yanai H, Mishima S, Handa N,
Shimokawa K, Yoshida A, Watanabe H, Ohe K,
Shimbo T, Noda M. Changes in Antidiabetic Drug
Prescription and Glycemic Control Trends inElderly Patients with Type 2 Diabetes Mellitus
from 2005-2013: An Analysis of the National
Center Diabetes Database (NCDD-03). Internal
Medicine. 2018;57(9): 1229-1240.

Internal Medicine
1. Medicine Ⅰ

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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, thesecond professor, the present professor Issei Komuro
was elected in August, 2012. Our department
comprises one professor, 4 lecturers, 2 hospital
lecturers, 15 research assistants, 10 staff members, and
45 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 2018, a total of 1,870 patients were newly
admitted to our hospital ward of 62 beds. The average
duration of hospitalization was 12.1 days.

Because we are an authorized facility for hearttransplantation, the use of left ventricular assist device
in cases of severe heart failure has been increasing. In
2006, the first patient with heart failure from ourdepartment underwent a heart transplant procedure atthe Department of Cardiovascular Surgery. In 2018,16 patients underwent heart transplant (total 111
cases). In March 2014, our facility was also
authorized to perform lung transplantation. Cardiovascular angiography was performed in 1,398 patients,of which 431 patients underwent interventional
procedures. CT coronary angiography and cardiovascular MRI were performed in 481 and 132 patients,
respectively. With regard to arrhythmias, there were
348 cases of catheter ablation, 106 cases of
implantation or replacement of pacemakers and otherspecialized pacemaker devices, including 26 cases of
implantation or replacement of implantablecardioverter-defibrillator and 18 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 and afternoons from Monday to Friday, and approximately
195.1 patients visit each day. The disease profile includes ischemic heart disease, heart failure, arrhythmia. hypertension and peripheral artery disease, There128

are special outpatient clinics for pulmonary hypertension, congenital heart disease, valvular heart disease,cardiomyopathy, and Marfan’s syndrome. The department is also focused on acute cases of coronary
heart disease and aortic disease, as emergent catheterization is available on a 24-hour basis.

and adult 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

Education

Publications (2018)

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

1. Akazawa H. Periodontitis and Diabetes Mellitus:
Be true to your teeth. Int Heart J. 2018;59(4):680-682.
2. Akimoto A, Suzuki JI, Aoyama N, Ikeuchi R,
Watanabe H, Tsujimoto H, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Komuro I. A
Novel Bioabsorbable Sheet That Delivers NF-κB
Decoy Oligonucleotide Restrains Abdominal
Aortic Aneurysm Development in Rats. Int HeartJ. 2018 Sep 26;59(5):1134-1141.
3. Amiya E, Morita H, Ishiura H, Tsuji S, Komuro I.
Authors' reply to the Drs. Finsterer andZarrouk-Mahjoub's comments for our case report.
Int J Cardiol. 2018 Mar 1;254:262.
4. Aoyama N, Suzuki JI, Kobayashi N, Hanatani T,
Ashigaki N, Yoshida A, Shiheido Y, Sato H,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Minabe M, Izumi Y, Isobe M. JapaneseCardiovascular Disease Patients with Diabetes
Mellitus Suffer Increased Tooth Loss in Comparison to Those without Diabetes Mellitus -A
Cross-sectional Study. Intern Med. 2018 Mar 15;
57(6):777-782.
5. Fuji H, Ohmae S, Noma N, Takeiri M, Yasutomi
H, Izumi K, Ito M, Toyomoto M, Iwaki S,
Takemoto K, Seo S, Taura K, Hida S, Aoyama M,
Ishihama Y, Hagiwara M, Takeda N, Hatano E,
Iwaisako K, Uemoto S, Asagiri M. Necrostatin-7
suppresses RANK-NFATc1 signaling and attenuates macrophage to osteoclast differentiation.
Biochem Biophys Res Commun. 2018 Sep 5;503(2):544-549.
6. Fujiwara T, Takeda N, Hara H, Morita H,
Kishihara J, Inuzuka R, Yagi H, Maemura S, Toko
H, Harada M, Ikeda Y, Kumagai H, Nomura S,
Takimoto E, Akazawa H2, Ako J, Komuro I.
Distinct variants affecting differential splicing of
TGFBR1 exon 5 cause either Loeys-Dietz

Research activities
From a research perspective, our interests include
all fields of cardiovascular medicine, ranging frommolecular biology to clinical research, including
genomics. Importantly, our research interests are
aimed at facilitating new diagnostic and treatment
methods for cardiovascular diseases. Our areas ofinterest include the following:
1. Cardiac hypertrophy and heart failure: 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’s syndrome

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syndrome or multiple self-healing squamous
epithelioma. Eur J Hum Genet. 2018 Aug;26(8):1151-1158.
7. Funabashi N, Takaoka H, Ozawa K, Kamata T,
Uehara M, Komuro I, Kobayashi Y. Quantitative
Differentiation of LV Myocardium with andwithout Layer-Specific Fibrosis Using MRI in
Hypertrophic Cardiomyopathy and Layer-Specific
Strain TTE Analysis. Int Heart J. 2018 May 30;
59(3):523-530.
8. Funabashi N, Takaoka H, Ozawa K, Uehara M,
Komuro I, Kobayashi Y. 2D speckle-tracking
TTE-based quantitative classification of left
ventricular myocardium in patients withhypertrophic cardiomyopathy by the presence or
the absence of fibrosis and/or hypertrophy.
"Funabashi N, Takaoka H, Ozawa K, Uehara M,
Komuro I, Kobayashi Y. Heart Vessels. 2018 Sep;
33(9):1046-1051.
9. Funabashi N, Takaoka H, Ozawa K, Kamata T,
Uehara M, Komuro I, Kobayashi Y. Quantitative
Differentiation of LV Myocardium with andwithout Layer-Specific Fibrosis Using MRI in
Hypertrophic Cardiomyopathy and Layer-Specific
Strain TTE Analysis. Int Heart J. 2018 May 30;
59(3):523-530.
10. Hara H, Takeda N, Kondo M, Kubota M, Saito T,
Maruyama J, Fujiwara T, Maemura S, Ito M,
Naito AT, Harada M, Toko H, Nomura S,
Kumagai H, Ikeda Y, Ueno H, Takimoto E,
Akazawa H, Morita H, Aburatani H, Hata Y,
Uchiyama M, Komuro I. Discovery of a Small
Molecule to Increase Cardiomyocytes and Protect
the Heart After Ischemic Injury. JACC
Basic
Transl Sci. 2018 Nov 12;3(5):639-653.
11. Hasumi E, Fujiu K, Kawata T, Komuro I. The
influence of His bundle pacing on tricuspid valvefunctioning using three-dimensional echocardiography. HeartRhythm Case Rep. 2018 Jun
18;4(9):437-438.
12. Hasumi E, Fujiu K, Kojima T, Kinoshita O,
Nawata K, Yamauchi H, Ono M, Komuro I. Novel
extraction technique of retained pacemaker anddefibrillator lead during heart transplantation.
PLoS One. 2018 Sep 6;13(9):e0203172.
13. Ito M, Nomura S. Cardiomyopathy with LMNA
Mutation. Int Heart J. 2018;59(3):462-464.

14. Itoh H, Komuro I, Takeuchi M, Akasaka T, Daida
H, Egashira Y, Fujita H, Higaki J, Hirata KI,
Ishibashi S, Isshiki T, Ito S, Kashiwagi A, Kato S,
Kitagawa K, Kitakaze M, Kitazono T,
Kurabayashi M, Miyauchi K, Murakami T,
Murohara T, Node K, Ogawa S, Saito Y, Seino Y,
Shigeeda T, Shindo S, Sugawara M, Sugiyama S,
Terauchi Y, Tsutsui H, Ueshima K, Utsunomiya K,
Yamagishi M, Yamazaki T, Yo S, Yokote K,
Yoshida K, Yoshimura M, Yoshimura N, Nakao K,
Nagai R; EMPATHY Investigators. Intensive
Treat-to-Target Statin Therapy in High-Risk
Japanese Patients With Hypercholesterolemia andDiabetic Retinopathy: Report of a Randomized
Study Diabetes Care. 2018 Jun;41(6):12
15. Itoh H, Ueshima K, Komuro I. Response toComment on Itoh et al. Intensive Treat-to-Target
Statin Therapy in High-Risk Japanese PatientsWith
Hypercholesterolemia
andDiabetic
Retinopathy: Report of a Randomized Study.
Diabetes Care 2018;41:1275-1284. Diabetes Care.
2018 Nov;41(11):e145-e146.
16. Iwazaki K, Kojima T, Murasawa T, Yokota J,
Tanimoto H, Matsuda J, Fukuma N, Matsubara T,
Shimizu Y, Oguri G, Hasumi E, Kubo H, Chang K,
Fujiu K, Komuro I. A Case of a Cardiac
Resynchronization Therapy-Defibrillator Exhibiting a Lower and Alternately Variable Basic Rate.
Int Heart J. 2018 May 30;59(3):626-629..
17. Kodera S, Kiyosue A, Ando J, Komuro I. Cost
effectiveness of transcatheter aortic valve
implantation in patients with aortic stenosis inJapan. J Cardiol. 2018 Mar;71(3):223-229.
18. Kodera S, Morita H, Kiyosue A, Ando J, Takura T,
Komuro I Cost-effectiveness of PCSK9 inhibitor
plus statin in patients with triple-vessel coronary
artery disease in Japan. Circ J. 2018 Sep 25;
82(10):2602-2608.
19. Kojima T, Fujiu K, Fukuma N, Matsunaga H,
Oshima T, Matsuda J, Matsubara T, Shimizu Y,
Oguri G, Hasumi E, Morita H, Komuro I.
Periprocedural Complications in Patients Undergoing Catheter Ablation of Atrial Fibrillation
Without Discontinuation of a Vitamin K
Antagonist and Direct Oral Anticoagulants. Circ J.
2018 May 25;82(6):1552-1557.
20. Kubota K, Soma K, Uehara M, Inaba T, Saito A,

130

Takeda N, Hatano M, Morita H, Inuzuka R, Hirata
Y, Yao A, Komuro I. Combined Surgical andMedical Therapy for Candida Prosthetic
Endocarditis in a Patient with Repaired Tetralogy
of Fallot. Int Heart J. 2018 Jul 31;59(4):877-880.
21. Minatsuki S, Hatano M, Kiyosue A, Saito A, Maki
H, Takimoto E, Komuro I. Clinically Worsening
Chronic Thromboembolic Pulmonary Hypertension by Riociguat After Balloon Pulmonary
Angioplasty. Int Heart J. 2018 Sep 26;59(5):11861188.
22. Minatsuki S, Kiyosue A, Saito A, Maki H, Hatano
M, Komuro I. Effectiveness of Nitroglycerin in
Managing Subacute Lung Bleeding Induced by
Balloon Pulmonary Angioplasty. Int Heart J. 2018
Jul 31;59(4):899-901.
23. Minatsuki S, Takeda N, Soma K, Katoh M, Maki
H, Hatano M, Takimoto E, Manabe I, Komuro I.
Murine Model of Pulmonary Artery Overflow
Vasculopathy Revealed Macrophage Accumulation in the Lung. Int Heart J. 2019 Mar 20;60(2):451-456.
24. Morita H, Komuro I. Identification of pathogenic
mutations for dilated cardiomyopathy accompanied with unicuspid aortic valve. Circ J. 2018
May 25;82(6):1723.
25. Morita H, Komuro I. Outcomes of Cardiac
Screening in Adolescent Soccer Players. N Engl J
Med. 2018 Nov 22;379(21):2083-4.
26. Morita H, Komuro I. Somatic Activating KRAS
Mutations in Arteriovenous Malformations of theBrain. N Engl J Med. 2018 Apr 19;378(16):1561.
27. Nakanishi K, Daimon M. Early prediction ofcardiotoxicity from cancer chemotherapy: canbaseline strain identify high-risk patients? Circ J,
2018;82(10):2477-2478.
28. Nakao T, Morita H. Thrombospondin-2. Int HeartJ. 2019;60(2):235-237.
29. Nakayama A. Do the Roles of Fats from Different
Depots Differ in the Coronary Artery? Int Heart J.
2018;59(4):671-673.
30. Nitta D, Kinugawa K, Imamura T, Amiya E,
Hatano M, Kinoshita O, Nawata K, Ono M,
Komuro I. A Useful Scoring System For
Predicting Right Ventricular Assist Device
Requirement Among Patients with a Paracorporeal Left Ventricular Assist Device. Int HeartJ. 2018 Sep 26;59(5):983-990.
31. Nomura S, Satoh M, Fujita T, Higo T, Sumida T,
Ko T, Yamaguchi T, Tobita T, Naito AT, Ito M,
Fujita K, Harada M, Toko H, Kobayashi Y, Ito K,
Takimoto E, Akazawa H, Morita H, Aburatani H,
Komuro I. Cardiomyocyte gene programs
encoding morphological and functional signaturesin cardiac hypertrophy and failure. Nat Commun.
2018 Oct 30;9(1):4435.
32. Saito A, Soma K, Kojima T, Inaba T, Yao A,
Komuro I. Diastolic Tricuspid Regurgitation
Related to Atrial Systole With a Bileaflet
Mechanical Valve. Circ J. 2018 Oct 25;82(11):2921-2922.
33. Sato T, Hatano M, Iwasaki Y, Maki H, Saito A,
Minatsuki S, Inaba T, Amiya E, Fujio K,
Watanabe M, Yamamoto K, Komuro I. Prevalenceof primary Sjögren's syndrome in patients
undergoing evaluation for pulmonary arterial
hypertension. PLoS One. 2018 May 15;13(5):e0197297.
34. Soma K, Yao A, Saito A, Inaba T, Ishikawa Y,
Hirata Y, Komuro I. Regular Treatment Strategy
with a Large Amount of Carvedilol for Heart
Failure Improves Biventricular Systolic Failure ina Patient with Repaired Tetralogy of Fallot. Int
Heart J. 2018 Sep 26;59(5):1169-1173.
35. Sugita J, Fujiu K. Systemic Inflammatory StressResponse During Cardiac Surgery. Int Heart J.
2018;59(3):457-459.
36. Tajima T, Morita H, Ito K, Yamazaki T, Kubo M,
Komuro I, Momozawa Y. Blood lipid-related
low-frequency variants in LDLR and PCSK9 areassociated with onset age and risk of myocardial
infarction in Japanese. Sci Rep. 2018 May 25;8(1):8107.
37. Takeda N, Inuzuka R, Morita H, Komuro I.
Response by Takeda et al to Letter Regarding
Article, "Impact of Pathogenic FBN1 Variant
Types on the Progression of Aortic Disease inPatients With Marfan Syndrome. Circ Genom
Precis Med. 2018 Sep;11(9):e002321.
38. Takeda N, Hara H, Fujiwara T, Kanaya T,
Maemura S, Komuro I. TGF-β Signaling-Related
Genes and Thoracic Aortic Aneurysms andDissections. Int J Mol Sci. 2018 Jul 21;19(7).
39. Takeda N, Inuzuka R, Morita H, Komuro I.

131

Response by Takeda et al to Letter Regarding
Article, "Impact of Pathogenic FBN1 Variant
Types on the Progression of Aortic Disease inPatients With Marfan Syndrome Circ Genom
Precis Med. 2018 Sep;11(9):e002321.
40. Tanaka K, Sata M. Possible Roles of Epicardial
Adipose Tissue in the Pathogenesis of Coronary
Atherosclerosis Annals of Nuclear Cardiology,
2018 Volume 4 Issue 1 Pages 5-10
41. Taya M, Amiya E, Hatano M, Maki H, Nitta D,
Saito A, Tsuji M, Hosoya Y, Minatsuki S,
Nakayama A, Fujiwara T, Konishi Y, Yokota K,
Watanabe M, Morita H, Haga N, Komuro I.
Correction to: High-intensity aerobic interval
training can lead to improvement in skeletal
muscle power among in-hospital patients withadvanced heart failure. Heart Vessels. 2018 Jul;33(7):760-761
42. Taya M, Amiya E, Hatano M, Maki H, Nitta D,
Saito A, Tsuji M, Hosoya Y, Minatsuki S,
Nakayama A, Fujiwara T, Konishi Y, Yokota K,
Watanabe M, Morita H, Haga N2, Komuro I1.
High-intensity aerobic interval training can lead to
improvement in skeletal muscle power among
in-hospital patients with advanced heart failure.
Heart Vessels. 2018 Jul;33(7):752-759.
43. Terao C, Yoshifuji H, Matsumura T, Naruse TK,
Ishii T, Nakaoka Y, Kirino Y, Matsuo K, Origuchi
T, Shimizu M, Maejima Y, Amiya E, Tamura N,
Kawaguchi T, Takahashi M, Setoh K, Ohmura K,
Watanabe R, Horita T, Atsumi T, Matsukura M,
Miyata T, Kochi Y, Suda T, Tanemoto K, Meguro
A, Okada Y, Ogimoto A, Yamamoto M, Takahashi
H, Nakayamada S, Saito K, Kuwana M, Mizuki N,
Tabara Y, Ueda A, Komuro I, Kimura A, Isobe M,
Mimori T, Matsuda F. Genetic determinants andan epistasis of LILRA3 and HLA-B*52 in
Takayasu arteritis. Proc Natl Acad Sci U S A.
2018 Dec 18;115(51):13045-13050.
44. Tsuji M, Kodera S, Oshima T, Uehara M, Kiyosue
A, Ando J, Watanabe M, Yamauchi H, Ono M,
Komuro I. Coronary Artery Perforation During
Percutaneous Coronary Intervention in a Patientwith a Prior Modified Bentall Procedure. Int HeartJ. 2018 Jul 31;59(4):848-853.
45. Uchino Y, Watanabe M, Takata M, Amiya E,
Tsushima K, Adachi T, Hiroi Y, Funazaki T,

Komuro I. Effect of Oral Branched-Chain Amino
Acids on Serum Albumin Concentration in Heart
Failure Patients with Hypoalbuminemia: Resultsof a Preliminary Study. Am J Cardiovasc Drugs.
2018 Aug;18(4):327-332.
46. Ueda K, Takimoto E, Lu Q, Liu P, Fukuma N,
Adachi Y, Suzuki R, Chou S, Baur W, Aronovitz
MJ, Greenberg AS, Komuro I, Karas RH.
Membrane-Initiated Estrogen Receptor Signaling
Mediates Metabolic Homeostasis via Central
Activation of Protein Phosphatase 2A. Diabetes.
2018 Aug;67(8):1524-1537.
47. Umei M, Akazawa H. MicroRNAs as biomarkers
for cardiac sarcoidosis: No matter how small. J
Cardiol. 2018 Dec;72(6):449-451.
48. Xu B, Kawata T, Daimon M, Kimura K, Nakao T,
Lee SL, Hirokawa M, Yoshinaga A, Watanabe M,
Komuro I, Yatomi Y. Simple echocardiographic
parameter, right ventricular systolic to diastolicduration ratio predicts one-year outcome inadvanced heart failure. Int Heart J. 2018;59(5):968-975.
49. Xu B, Kawata T, Daimon M, Kimura K, Nakao T,
Lee SC, Hirokawa M, Yoshinaga A, Watanabe M,
Yatomi Y, Komuro I. Prognostic Value of a
Simple Echocardiographic Parameter, the Right
Ventricular Systolic to Diastolic Duration Ratio,
in Patients with Advanced Heart Failure with
Non-Ischemic Dilated Cardiomyopathy. Int HeartJ. 2018 Sep 26;59(5):968-975.
50. Yonenaga A, Hasumi E, Fujiu K, Ushiku A,
Hatano M, Ando J, Morita H, Watanabe M,
Komuro I. Prognostic improvement of acutenecrotizing eosinophilic myocarditis (ANEM)
through a rapid pathological diagnosis andappropriate therapy. Int Heart J. 2018 May 30;
59(3):641-646.

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

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

Assistant Professor
Kousuke Watanabe, 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.

Kunihiko Soma, M.D.,Ph.D.,

Keita Maemura, 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, 22 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133

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
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 2017
1. Primary lung cancer
513
2. Interstitial pneumonia
63
3. Respiratory infections
27
4. Malignancy other than
primary lung cancer
18
5. Non-tuberculous
mycobacterial infections
15
6. COPD
15
7. Sarcoidosis
8
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
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.

134

Research

References

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

1. Sato C, Okuda K, Tamiya H, Yamamoto K,
Hoshina K, Narumoto O, Urushiyama H, Noguchi
S, Amano Y, Watanabe K, Mitani A, Kage H,
Tanaka G, Yamauchi Y, Takai D, Nagase T. Acute
Arterial Thrombosis during Postoperative
Adjuvant Cisplatin-based Chemotherapy forCompletely Resected Lung Adenocarcinoma.
Intern Med. 2018 Feb 15;57(4):557-561.
2. Makita K, Mikami Y, Matsuzaki H, Miyashita N,
Takeshima H, Noguchi S, Horie M, Urushiyama
H, Iikura M, Hojo M, Nagase T, Yamauchi Y.
Mechanism of Periostin Production in Human
Bronchial Smooth Muscle Cells. Int Arch Allergy
Immunol. 2018;175(1-2):26-35.
3. Hiyama N, Ando T, Maemura K, Sakatani T,
Amano Y, Watanabe K, Kage H, Yatomi Y,
Nagase T, Nakajima J, Takai D. Glutamatecysteine ligase catalytic subunit is associated withcisplatin resistance in lung adenocarcinoma. Jpn J
Clin Oncol. 2018 Apr 1;48(4):303-307.
4. Maemura K, Kage H, Isago H, Takeshima H,
Makita K, Amano Y, Takai D, Ohishi N, Nagase T.
Cerebral Arterial Air Embolism after Diagnostic
Flexible Fiberoptic Bronchoscopy: A Case Reportand Review of the Literature. Case Rep Pulmonol.
2018 May 7;2018:7108215.
5. Mitani A, Jo T, Yasunaga H, Sakamoto Y,
Hasegawa W, Urushiyama H, Yamauchi Y, Matsui
H, Fushimi K, Nagase T. Venous thromboembolic
events in patients with lung cancer treated withcisplatin-based versus carboplatin/nedaplatinbased chemotherapy. Anticancer Drugs. 2018 Jul;29(6):560-564.
6. Sakatani T, Amano Y, Sato J, Nagase T. Air
embolism after CT-guided percutaneous lungbiopsy. Jpn J Clin Oncol. 2018 Jul 1;48(7):699700.
7. Kage H, Kohsaka S, Shinozaki-Ushiku A, Ushiku
T, Takai D, Nakajima J, Miyagawa K, Aburatani
H, Mano H, Nagase T. Spontaneous Transformation from EGFR and ALK Wild-Type Lung
Adenocarcinoma to Neuroendocrine Carcinoma. J
Thorac Oncol. 2018 Jul;13(7):e126-e128.
8. Ando T, Kage H, Saito M, Amano Y, Goto Y,
Nakajima J, Nagase T. Early stage non-small cell



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

Takahide Nagase is a GOLD Assembly member.

135lung cancer patients need brain imaging
regardless of symptoms. Int J Clin Oncol. 2018
Aug;23(4):641-646.
9. Saito A, Horie M, Nagase T. TGF-β Signaling inLung Health and Disease. Int J Mol Sci. 2018 Aug
20;19(8). pii: E2460.
10. Urushiyama H, Jo T, Yasunaga H, Michihata N,
Yamana H, Matsui H, Hasegawa W, Hiraishi Y,
Mitani A, Fushimi K, Nagase T, Yamauchi Y.
Effect of Hangeshashin-To (Japanese Herbal
Medicine Tj-14) on Tolerability of Irinotecan:
Propensity Score and Instrumental Variable
Analyses. J Clin Med. 2018 Aug 28;7(9). pii:
E246.
11. Yokoyama A, Kage H, Ohama Y, Sato T,
Miyashita N, Noguchi S, Okugawa S, Yamauchi Y,
MoriyaK,
NagaseT.
Mycobacterium
heckeshornense lung infection diagnosed bymatrix-assisted laser desorption ionization-time offlight mass spectrometry (MALDI-TOF MS). JInfect Chemother. 2018 Sep;24(9):763-765.
12. Jo T, Yasunaga H, Michihata N, Sasabuchi Y,
Hasegawa W, Takeshima H, Sakamoto Y, Matsui
H, Fushimi K, Nagase T, Yamauchi Y. Influenceof Parkinsonism on outcomes of elderly
pneumonia patients. Parkinsonism Relat Disord.
2018 Sep;54:25-29.
13. Watanabe K, Yasumoto A, Amano Y, Kage H,
Goto Y, Yatomi Y, Takai D, Nagase T. Mean
platelet volume and lymphocyte-to-monocyte
ratio are associated with shorter progression-freesurvival in EGFR-mutant lung adenocarcinoma
treated by EGFR tyrosine kinase inhibitor. PLoS
One. 2018 Sep 7;13(9):e0203625.
14. Saito M, Kage H, Ando T, Sawada R, Amano Y,
Goto Y, Shinoda Y, Nagase T. Prevalence of bone
pain decreases as lymph node stage increases innonsmall cell lung cancer patients. Curr Probl
Cancer. 2019 Feb;43(1):86-91.
15. Horie M, Miyashita N, Mattsson JSM, Mikami Y,
Sandelin M, Brunnström H, Micke P, Nagase T,
Saito A. Horie M, Miyashita N, Mattsson JSM,
Mikami Y, Sandelin M, Brunnström H, Micke P,
Nagase T, Saito A. J Pathol. 2018 Oct;246(2):154165.
16. Maemura K, Watanabe K, Ando T, Hiyama N,
Sakatani T, Amano Y, Kage H, Nakajima J,

Yatomi Y, Nagase T, Takai D. Altered editinglevel of microRNAs is a potential biomarker inlung adenocarcinoma. Cancer Sci. 2018 Oct;109(10):3326-3335.
17. Urushiyama H, Jo T, Yasunaga H, Michihata N,
Matsui H, Hasegawa W, Takeshima H, Sakamoto
Y, Hiraishi Y, Mitani A, Fushimi K, Nagase T,
Yamauchi Y. Oral fluorouracil vs vinorelbine plus
cisplatin as adjuvant chemotherapy for stage
II-IIIA non-small cell lung cancer: Propensity
score-matched and instrumental variable analyses.
Cancer Med. 2018 Oct;7(10):4863-4869.
18. Miyashita N, Horie M, Suzuki HI, Yoshihara M,
Djureinovic D, Persson J, Brunnström H,
Lindskog C, Elfving H, Micke P, Saito A, Nagase
T. An Integrative Analysis of Transcriptome andEpigenome Features of ASCL1-Positive Lung
Adenocarcinomas. J Thorac Oncol. 2018 Nov;
13(11):1676-1691.
19. Souma K, Shichino S, Hashimoto S, Ueha S,
Tsukui T, Nakajima T, Suzuki HI, Shand FHW,
Inagaki Y, Nagase T, Matsushima K. Lung
fibroblasts express a miR-19a-19b-20a sub-cluster
to suppress TGF-β-associated fibroblast activationin murine pulmonary fibrosis. Sci Rep. 2018 Nov
9;8(1):16642.
20. Saito A, Horie M, Micke P, Nagase T. The Role of
TGF-β Signaling in Lung Cancer Associated with
Idiopathic Pulmonary Fibrosis. Int J Mol Sci.
2018 Nov 15;19(11). pii: E3611.
21. Noguchi S, Saito A, Nagase T. YAP/TAZ
Signaling as a Molecular Link between Fibrosis
and Cancer. Int J Mol Sci. 2018 Nov 20;19(11).
pii: E3674.
22. Tamiya H, Mitani A, Saito A, Ishimori T, Saito M,
Isago H, Jo T, Yamauchi Y, Tanaka G, Nagase T.
Exosomal MicroRNA Expression Profiling in
Patients with Lung Adenocarcinoma-associated
Malignant Pleural Effusion. Anticancer Res. 2018
Dec;38(12):6707-6714.
23. Hiraishi Y, Yamaguchi S, Yoshizaki T, Nambu A,
Shimura E, Takamori A, Narushima S, Nakanishi
W, Asada Y, Numata T, Suzukawa M, Yamauchi Y,
Matsuda A, Arae K, Morita H, Hoshino T, Suto H,
Okumura K, Matsumoto K, Saito H, Sudo K,
Iikura M, Nagase T, Nakae S. IL-33, IL-25 and
TSLP contribute to development of fungal-

136

associated protease-induced innate-type airway
inflammation. Sci Rep. 2018 Dec 21;8(1):18052.
24. 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 Daikenchu-to: a retrospective cohort study. Int J
Chron Obstruct Pulmon Dis. 2018 Dec 27;14:129139.

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.

Homepage

http://gastro.m.u-tokyo.ac.jp/med/home.html

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, 5 fellows, 69 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 and Clinical Research Building (West) as in theother departments.

Clinical Activities
The Department of Gastroenterology is in chargeof about 80 inpatients on average, which are about
2,800 in total per year. We receive about 110 new
patients in and out of the hospital each week, with anaverage hospital stay of 10.3 days. Resident, juniorand senior staff members bear the responsibility for a

138

medical management of each inpatient, in collaboration with subspecialty groups concerned. The staff
members examine about 5,250 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 2018). Number of treatments forhepatocellular carcinoma treatments, represented by
percutaneous radiofrequency ablation, nearly 300
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 250 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 400 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) 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
training of our department for 1-4 months in the first139

year. 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, 69 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, organoids, or liquid biopsy, we
perform various experiments, in order to eventuallytranslate 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
drainage for acute cholangitis, prevention of postERCP pancreatitis by pancreatic duct stenting, newchemotherapeutic regimens for advanced pancreaticcancer or biliary tract cancer, efficacy of polyglycolicacid 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, Yamada A, Hirata Y, Suzuki H, Nakada A,
Niikura R, Seto M, Okamoto M, Koike K.
Etiology and long-term rebleeding of endoscopic
ulcerative lesions in the small bowel in patientswith obscure gastrointestinal bleeding: A multicenter cohort study. J Gastroenterol Hepatol.
2018;33(7):1327-34.
2. Aoki T, Yamada A, Nagata N, Niikura R, Hirata Y,
Koike K. External validation of the NOBLADS
score, a risk scoring system for severe acute lower
gastrointestinal bleeding. PLoS One. 2018;13(4):e0196514.
3. 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 ss-catenin expression isassociated with histological progression and overt
diabetes emergence in NAFLD patients. J
Gastroenterol. 2018;53(12):1261-75.
4. Fujiwara H, Tateishi K, Kato H, Nakatsuka T,
Yamamoto K, Tanaka Y, Ijichi H, Takahara N,
Mizuno S, Kogure H, Matsubara S, Nakai Y,
Koike K. Isocitrate dehydrogenase 1 mutation
sensitizes intrahepatic cholangiocarcinoma to the
BET inhibitor JQ1. Cancer Sci. 2018;109(11):3602-10.
5. Fujiwara N, Nakagawa H, Enooku K, Kudo Y,
Hayata Y, Nakatsuka T, Tanaka Y, Tateishi R,
Hikiba Y, Misumi K, Tanaka M, Hayashi A,
Shibahara J, Fukayama M, Arita J, Hasegawa K,
Hirschfield H, Hoshida Y, Hirata Y, Otsuka M,

140

Tateishi K, Koike K. CPT2 downregulation adapts
HCC to lipid-rich environment and promotes
carcinogenesis via acylcarnitine accumulation in
obesity. Gut. 2018;67(8):1493-504.
6. Hakuta R, Kogure H, Nakai Y, Yamada A,
Takahara N, Mizuno S, Koike K. Successfulendoscopic lithotripsy using a new digitalcholangioscope through an overtube placed by anenteroscope. Endoscopy. 2018;50(9):E269-e71.
7. Ihara S, Hirata Y, Hikiba Y, Yamashita A, Tsuboi
M, Hata M, Konishi M, Suzuki N, Sakitani K,
Kinoshita H, Hayakawa Y, Nakagawa H, Ijichi H,
Tateishi K, Koike K. Adhesive Interactions
between Mononuclear Phagocytes and Intestinal
Epithelium Perturb Normal Epithelial Differentiation and Serve as a Therapeutic Target in
Inflammatory Bowel Disease. J Crohns Colitis.
2018;12(10):1219-31.
8. Ishibashi R, Niikura R, Obana N, Fukuda S,
Tsuboi M, Aoki T, Yoshida S, Yamada A, Hirata Y,
Koike K. Prediction of the Clinical Outcomes ofSigmoid Volvulus by Abdominal X-Ray: AXISClassification System. Gastroenterol Res Pract.
2018;2018:8493235.
9. Kinoshita H, Hayakawa Y, Niu Z, Konishi M,
Hata M, Tsuboi M, Hayata Y, Hikiba Y, Ihara S,
Nakagawa H, Hirata Y, Wang TC, Koike K.
Mature gastric chief cells are not required for thedevelopment of metaplasia. Am J Physiol
Gastrointest Liver Physiol. 2018;314(5):G583g96.
10. Kishikawa T, Otsuka M, Suzuki T, Seimiya T,
Sekiba K, Ishibashi R, Tanaka E, Ohno M,
Yamagami M, Koike K. Satellite RNA Increases
DNA Damage and Accelerates Tumor Formationin Mouse Models of Pancreatic Cancer. Mol
Cancer Res. 2018;16(8):1255-62.
11. Koike K, Suyama K, Ito H, Itoh H, Sugiura W.
Randomized prospective study showing the noninferiority of tenofovir to entecavir in treatmentnaive chronic hepatitis B patients. Hepatol Res.
2018;48(1):59-68.
12. Minatsuki C, Yamamichi N, Inada KI, Takahashi
Y, Sakurai K, Shimamoto T, Tsuji Y, Shiogama K,
Kodashima S, Sakaguchi Y, Niimi K, Ono S,
Niwa T, Ohata K, Matsuhashi N, Ichinose M,
Fujishiro M, Tsutsumi Y, Koike K. Expression of

Gastric Markers Is Associated with Malignant
Potential of Nonampullary Duodenal Adenocarcinoma. Dig Dis Sci. 2018;63(10):2617-25.
13. Mizutani H, Ono S, Ushiku T, Kudo Y, Ikemura M,
Kageyama N, Yamamichi N, Fujishiro M, Someya
T, Fukayama M, Koike K, Transparencyenhancing technology allows three-dimensional
assessment of gastrointestinal mucosa: A porcine
model. Pathol Int. 2018;68(2):102-8.
14. Nakagawa H, Hayata Y, Kawamura S, Yamada T,
Fujiwara N, Koike K. Lipid Metabolic
Reprogramming in Hepatocellular Carcinoma.
Cancers (Basel). 2018;10(11).
15. Nakagawa H, Hayata Y, Yamada T, Kawamura S,
Suzuki N, Koike K. Peribiliary Glands as the
Cellular Origin of Biliary Tract Cancer. Int J Mol
Sci. 2018;19(6).
16. Nakai Y, Kogure H, Yamada A, Isayama H, Koike
K. Endoscopic management of bile duct stones inpatients with surgically altered anatomy. Dig
Endosc. 2018;30 Suppl 1:67-74.
17. Nakayama C, Yamamichi N, Tomida S, Takahashi
Y, Kageyama-Yahara N, Sakurai K, Takeuchi C,
Inada KI, Shiogama K, Nagae G, Ono S, Tsuji Y,
Niimi K, Fujishiro M, Aburatani H, Tsutsumi Y,
Koike K. Transduced caudal-type homeobox(CDX) 2/CDX1 can induce growth inhibition on
CDX-deficient gastric cancer by rapid intestinal
differentiation. Cancer Sci. 2018;109(12):385364.
18. Niikura R, Hayakawa Y, Hirata Y, Yamada A,
Fujishiro M, Koike K. Long-term proton pumpinhibitor use is a risk factor of gastric cancer after
treatment for Helicobacter pylori: a retrospective
cohort analysis. Gut. 2018;67(10):1908-10.
19. 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. 2018:1-10.
20. Niikura R, Yamada A, Hirata Y, Hayakawa Y,141Takahashi A, Shinozaki T, Takeuchi Y, Fujishiro
M, Koike K. Efficacy of Vonoprazan for
Gastroesophageal Reflux Symptoms in Patientswith Proton Pump Inhibitor-resistant Non-erosive
Reflux Disease. Intern Med. 2018;57(17):244350.
21. Niikura R, Yamada A, Maki K, Nakamura M,
Watabe H, Fujishiro M, Oka S, Esaki M, Fujimori
S, Nakajima A, Ohmiya N, Matsumoto T, Tanaka
S, Koike K, Sakamoto C. Associations between
drugs and small-bowel mucosal bleeding: Multicenter capsule-endoscopy study. Dig Endosc.
2018;30(1):79-89.
22. Okushin K, Tsutsumi T, Ikeuchi K, Kado A,
Enooku K, Fujinaga H, Moriya K, Yotsuyanagi H,
Koike K. Helicobacter pylori infection and liverdiseases: Epidemiology and insights into pathogenesis. World J Gastroenterol. 2018;24(32):3617-25.
23. Saito K, Isayama H, Sakamoto Y, Nakai Y,
Ishigaki K, Tanaka M, Watadani T, Arita J,
Takahara N, Mizuno S, Kogure H, Ijichi H,
Tateishi K, Tada M, Hasegawa K, Fukayama M,
Kokudo N, Koike K. A phase II trial of
gemcitabine, S-1 and LV combination (GSL)
neoadjuvant chemotherapy for patients withborderline resectable and locally advanced
pancreatic cancer. Med Oncol. 2018;35(7):100.
24. Saito T, Nakai Y, Isayama H, Hirano K, Ishigaki
K, Hakuta R, Takeda T, Saito K, Umefune G,
Akiyama D, Watanabe T, Takagi K, Takahara N,
Hamada T, Uchino R, Mizuno S, Mouri D,
Yagioka H, Kogure H, Togawa O, Matsubara S,
Ito Y, Yamamoto N, Tada M, Koike K. A
Multicenter Open-Label Randomized Controlled
Trial of Pancreatic Enzyme Replacement Therapy
in Unresectable Pancreatic Cancer. Pancreas.
2018;47(7):800-6.
25. Sakitani K, Nishizawa T, Arita M, Yoshida S,
Kataoka Y, Ohki D, Yamashita H, Isomura Y,
Toyoshima A, Watanabe H, Iizuka T, Saito Y,
Fujisaki J, Yahagi N, Koike K, Toyoshima O.
Early detection of gastric cancer after
Helicobacter pylori eradication due to endoscopic
surveillance. Helicobacter. 2018;23(4):e12503.
26. Sekiba K, Otsuka M, Ohno M, Kishikawa T,
Yamagami M, Suzuki T, Ishibashi R, Seimiya T,

Tanaka E, Koike K. DHX9 regulates productionof hepatitis B virus-derived circular RNA andviral protein levels. Oncotarget. 2018;9(30):20953-64.
27. Takahara N, Nakai Y, Isayama H, Sasaki T, Saito
K, Oyama H, Kanai S, Suzuki T, Sato T, Hakuta R,
Ishigaki K, Takeda T, Saito T, Mizuno S, Kogure
H, Tada M, Koike K. Second-line chemotherapy
in patients with advanced or recurrent biliary tract
cancer: a single center, retrospective analysis of
294 cases. Invest New Drugs. 2018;36(6):1093102.
28. Takahashi Y, Yamamichi N, Inada KI, Shiogama
K, Sakurai K, Takeuchi C, Mizutani Y, Tsutsumi Y,
Koike K. Nectin1 expression is frequently
decreased in gastric cancers. Pathol Int. 2018;
68(10):557-62.
29. Tanaka Y, Tateishi R, Koike K. Proteoglycans Are
Attractive Biomarkers and Therapeutic Targets in
Hepatocellular Carcinoma. Int J Mol Sci. 2018;19(10).
30. Uchino K, Tateishi R, Nakagomi R, Fujiwara N,
Minami T, Sato M, Enooku K, Nakagawa H,
Asaoka Y, Kondo Y, Shibahara J, Shiina S, Koike
K. Serum levels of ferritin do not affect the
prognosis of patients with hepatocellular
carcinoma undergoing radiofrequency ablation.
PLoS One. 2018;13(7):e0200943.
31. Yamagami M, Otsuka M, Kishikawa T, Sekiba K,
Seimiya T, Tanaka E, Suzuki T, Ishibashi R, Ohno
M, Koike K. ISGF3 with reduced phosphorylation
is associated with constitutive expression ofinterferon-induced genes in aging cells. NPJ
Aging Mech Dis. 2018;4:11.

Internal Medicine
2. Medicine Ⅱ143

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

Lecturer
Noriko Makita, M.D., Ph.D.,
Tetsuhiro Tanaka, 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.,

Yuka Kinoshita, M.D., Ph.D.,

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

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

Hiroshi Nishi, M.D., Ph.D.

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

Tomoko Usui, 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
Department of Urology, we are conducting renaltransplantation and promoting peritoneal dialysis.

144

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

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

Research
In our department there are more than 30 studentsof the graduate school. We have research conferences
to discuss the results of the research with the Professor
and faculty members. As you see in the references
below, our research topics are various and cover every
field of nephrology, hypertension and endocrinology.
We are also actively collaborating with scientists
outside the department and outside the University
including foreign countries. Achievements of ourresearches are published in the world’s leading
journals of nephrology, hypertension and endocrinology.
1. Investigation of mechanism and development oftreatment of chronic kidney diseases: from theviewpoints of hypoxia, oxidative stress, epigenetics, carbonyl stress and endoplasmic reticulum
stress.

2. Investigation of causes of atypical hemolyticuremic syndrome.
3. Roles of renal proximal tubule transport in theregulation of plasma volume and blood pressure.
4. Physiological and pathological significance of
Na-HCO3 cotransporter NBCe1.
5. Investigation on pathogenesis of disorders andtreatments of mineral and bone metabolism
6. Molecular mechanism of G protein-coupled
receptor-mediated signal transduction
7. Development of a new drug and strategy targeting
G protein-coupled receptor.

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
not accept holiday dialysis.
3. Emergency hemodialysis and hemodiafiltration

145

4.

5.
6.
7.
8.
9.

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
syndrome and those functional analyses.
4. Association between factors at the initiation of

5.
6.
7.
8.

renal 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) Kinoshita Y, Takashi Y, Ito N, Ikegawa S, Mano
H, Ushiku T, Fukayama M, Nangaku M,
Fukumoto S. Ectopic expression of Klotho infibroblast growth factor 23 (FGF23)-producing
tumors that cause tumor-induced rickets/
osteomalacia (TIO). Bone Rep. 2018 Dec 31;
10:100192. doi: 10.1016/j.bonr.2018.100192.
eCollection 2019 Jun. PubMed PMID: 30627598;
PubMed Central PMCID: PMC6321977.
(2) Mimura I, Nangaku M. The Lasker Prize award
2018: histones "tail" the story. Kidney Int. 2018
Dec;94(6):1032-1034. doi: 10.1016/j.kint.2018.10.
005. PubMed PMID: 30466557.
(3) de Zeeuw D, Renfurm RW, Bakris G, Rossing P,
Perkovic V, Hou FF, Nangaku M, Sharma K,
Heerspink HJL, Garcia-Hernandez A, Larsson TE.
Efficacy of a novel inhibitor of vascular adhesion
protein-1 in reducing albuminuria in patients withdiabetic kidney disease (ALBUM): a randomised,
placebo-controlled, phase 2 trial. Lancet Diabetes
Endocrinol. 2018 Dec;6(12):925-933. doi: 10.
1016/S2213-8587(18)30289-4. Epub 2018 Nov 6.
PubMed PMID: 30413396.
(4) Hayase N, Doi K, Hiruma T, Inokuchi R,
Hamasaki Y, Noiri E, Nangaku M, Morimura N.
Damage-associatedmolecular
patterns
inintensive care unit patients with acute liver
injuries: A prospective cohort study. Medicine(Baltimore). 2018 Oct;97(41):e12780. doi: 10.
1097/MD.0000000000012780. PubMed PMID:
30313098; PubMed Central PMCID: PMC
6203498.
(5) Hirakawa Y, Miura R, Sasaki Y, Yoshida Y,
Mimura I, Katsura M, Shintani-Domoto Y, Ogawa
M, Hayashi A, Nangaku M. Nutcracker Syndrome146with the Superimposition of Thin Basement
Membrane Syndrome. Intern Med. 2019 Feb 1;
58(3):411-414. doi: 10.2169/internalmedicine.
1433-18. Epub 2018 Sep 12. PubMed PMID:
30210125; PubMed Central PMCID: PMC
6395115.
(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.
2018 Oct;33(5):611-615. doi: 10.1002/jca.21655.
Epub 2018 Sep 6. PubMed PMID: 30188580.
(7) Nakamura Y, Kurata Y, Hamasaki Y, Nangaku M.
Extraperitoneal Placement of a Peritoneal Dialysis
Catheter. Intern Med. 2019 Jan 1;58(1):147-148.
doi: 10.2169/internalmedicine.1396-18. Epub
2018 Aug 24. PubMed PMID: 30146595; PubMed
Central PMCID: PMC6367099.
(8) Hasegawa S, Tanaka T, Nangaku M. Hypoxiainducible factor stabilizers for treating anemia ofchronic kidney disease. Curr Opin Nephrol
Hypertens. 2018 Sep;27(5):331-338. doi: 10.1097/
MNH.0000000000000431. Review. PubMed
PMID: 30067604.
(9) Tanaka S, Sugiura Y, Saito H, Sugahara M,
Higashijima Y, Yamaguchi J, Inagi R, Suematsu
M, Nangaku M, Tanaka T. Sodium-glucose
cotransporter 2 inhibition normalizes glucose
metabolism and suppresses oxidative stress in thekidneys of diabetic mice. Kidney Int. 2018 Nov;
94(5):912-925. doi: 10.1016/j.kint.2018.04.025.
Epub 2018 Jul 16. PubMed PMID: 30021702.
(10)Kanda E, Kashihara N, Matsushita K, Usui T,
Okada H, Iseki K, Mikami K, Tanaka T, Wada T,
Watada H, Ueki K, Nangaku M; ResearchWorking Group for Establishing Guidelines forClinical Evaluation of Chronic Kidney Disease.
Guidelines for clinical evaluation of chronic
kidney disease: AMED research on regulatory
science of pharmaceuticals and medical devices.
Clin Exp Nephrol. 2018 Dec;22(6):1446-1475.
doi: 10.1007/s10157-018-1615-x. PubMed PMID:
30006871.

(11)Toya T, Ogura M, Toyama K, Yoshimi A,
Shinozaki-Ushiku A, Honda A, Honda K, Hosoya
N, Murakami Y, Kawashima H, Nannya Y, Arai S,
Nakamura F, Shinoda Y, Nangaku M, Miyagawa
K, Fukayama M, Moriya-Saito A, Katayama I,
Ogura T, Kurokawa M. Prognostic factors ofErdheim-Chester disease: a nationwide survey inJapan. Haematologica. 2018 Nov;103(11):18151824. doi: 10.3324/haematol.2018.190728. Epub
2018 Jul 5. PubMed PMID: 29976744; PubMed
Central PMCID: PMC6278973.
(12)Horita S, Simsek E, Simsek T, Yildirim N, Ishiura
H, Nakamura M, Satoh N, Suzuki A, Tsukada H,
Mizuno T, Seki G, Tsuji S, Nangaku M. SLC4A4
compound heterozygous mutations in exon-intron
boundary regions presenting with severe proximal
renal tubular acidosis and extrarenal symptoms
coexisting with Turner's syndrome: a case report.
BMC Med Genet. 2018 Jun 18;19(1):103. doi:
10.1186/s12881-018-0612-y. PubMed PMID:
29914390; PubMed Central PMCID: PMC
6006740.
(13)Anusornvongchai T, Nangaku M, Jao TM, Wu
CH, Ishimoto Y, Maekawa H, Tanaka T, Shimizu
A, Yamamoto M, Suzuki N, Sassa R, Inagi R.
Palmitate deranges erythropoietin production via
transcription factor ATF4 activation of unfolded
protein response. Kidney Int. 2018 Sep;94(3):536550. doi: 10.1016/j.kint.2018.03.011. Epub 2018
Jun 7. PubMed PMID: 29887316.
(14)Inoue K, Leung AM, Sugiyama T, Tsujimoto T,
Makita N, Nangaku M, Ritz BR. Urinary Iodine
Concentration and Mortality Among U.S. Adults.
Thyroid. 2018 Jul;28(7):913-920. doi: 10.1089/
thy.2018.0034. PubMed PMID: 29882490.
(15)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. 2018 Feb 3;3(3):677-683. doi: 10.1016/j.ekir.2018.01.013.
eCollection 2018 May. PubMed PMID:
29854976; PubMed Central PMCID: PMC
5976819.
(16)Saito H, Tanaka T, Tanaka S, Higashijima Y,
Yamaguchi J, Sugahara M, Ito M, Uchida L,
Hasegawa S, Wakashima T, Fukui K, Nangaku M.
Persistent expression of neutrophil gelatinase-147

associated lipocalin and M2 macrophage markers
and chronic fibrosis after acute kidney injury.
Physiol Rep. 2018 May;6(10):e13707. doi: 10.
14814/phy2.13707. PubMed PMID: 29845768;
PubMed Central PMCID: PMC5974714.
(17)Nangaku M. Introduction: Kidney Disease andCardiovascular Disease. Semin Nephrol. 2018
May;38(3):207. doi: 10.1016/j.semnephrol.2018.
03.001. PubMed PMID: 29753397.
(18)Shinozaki-Ushiku A, Higashihara T, Ikemura M,
Sato J, Nangaku M, Ushiku T, Fukayama M.
Glomeruloid hemangioma associated withTAFRO syndrome. Hum Pathol. 2018 Dec;82:
172-176. doi: 10.1016/j.humpath.2018.04.011.
Epub 2018 Apr 25. PubMed PMID: 29702119.
(19)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. 2018;139(3):243-253. doi: 10.1159/
000488219. Epub 2018 Apr 3. PubMed PMID:
29614509.
(20)Hirakawa Y, Mizukami K, Yoshihara T,
Takahashi I, Khulan P, Honda T, Mimura I,
Tanaka T, Tobita S, Nangaku M. Intravital
phosphorescence lifetime imaging of the renal
cortex accurately measures renal hypoxia. KidneyInt. 2018 Jun;93(6):1483-1489. doi: 10.1016/j.kint.
2018.01.015. Epub 2018 Mar 30. PubMed PMID:
29606399.
(21)Yamamura T, Nozu K, Ueda H, Fujimaru R,
Hisatomi R, Yoshida Y, Kato H, Nangaku M,
Miyata T, Sawai T, Minamikawa S, Kaito H,
Matsuo M, Iijima K. Functional splicing analysis
in an infantile case of atypical hemolytic uremic
syndrome caused by digenic mutations in C3 and
MCP genes. J Hum Genet. 2018 Jun;63(6):755759. doi: 10.1038/s10038-018-0436-9. Epub 2018
Mar 19. PubMed PMID: 29556035.
(22)Fukasawa C, Ooishi S, Kumagai T, Koshiisi M,
Sueki Y, Nakajima K, Mitsumori T, Yoshida Y,
Kato H, Nangaku M, Miyata T, Kirito K.
[Atypical hemolytic uremic syndrome in anelderly patient successfully treated witheculizumab]. Rinsho Ketsueki. 2018;59(2):182186. doi: 10.11406/rinketsu.59.182. Japanese.
PubMed PMID: 29515071.

(23)Fujisawa M, Kato H, Yoshida Y, Usui T, Takata
M, Fujimoto M, Wada H, Uchida Y, Kokame K,
Matsumoto M, Fujimura Y, Miyata T, Nangaku M.
Clinical characteristics and genetic backgroundsof Japanese patients with atypical hemolytic
uremic syndrome. Clin Exp Nephrol. 2018 Oct;22(5):1088-1099.
doi:
10.1007/s10157-0181549-3. Epub 2018 Mar 6. Erratum in: Clin Exp
Nephrol. 2019 Apr 23;:. PubMed PMID:
29511899; PubMed Central PMCID: PMC
6437120.
(24)Mimura I, Hirakawa Y, Kanki Y, Nakaki R,
Suzuki Y, Tanaka T, Aburatani H, Nangaku M.
Genome-wide analysis revealed that DZNep
reduces tubulointerstitial fibrosis via downregulation of pro-fibrotic genes. Sci Rep. 2018
Feb 28;8(1):3779. doi: 10.1038/s41598-01822180-5. PubMed PMID: 29491489; PubMed
Central PMCID: PMC5830881.
(25)Usui T, Hanafusa N, Yasunaga H, Nangaku M.
Association of dialysis with in-hospital disability
progression and mortality in community-onset
stroke. Nephrology (Carlton). 2018 Feb 22. doi:
10.1111/nep.13242. [Epub ahead of print]
PubMed PMID: 29468787.
(26)Kashihara N, Nangaku M, Ito S, Nishiyama A,
Harris D. The Sendai declaration for theeradication of kidney disease. Clin Exp Nephrol.
2018 Feb;22(1):1-2. doi: 10.1007/s10157-0181535-9. PubMed PMID: 29372473.
(27)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. 2018 Jan 17;8(1):8. doi: 10.1186/s13613018-0355-0. PubMed PMID: 29344743; PubMed
Central PMCID: PMC5772346.
(28)Tojo A, Hatakeyama S, Nangaku M, Ishimitsu T.
H(+)-ATPase blockade reduced renal gluconeogenesis and plasma glucose in a diabetic rat model.
Med Mol Morphol. 2018 Jun;51(2):89-95. doi:
10.1007/s00795-017-0175-6. Epub 2018 Jan 9.
PubMed PMID: 29318388; PubMed Central
PMCID: PMC5960008.

148(29)Kato H, Nangaku M, Okada H, Kagami S.
Controversies of the classification of TMA andthe terminology of aHUS. Clin Exp Nephrol. 2018
Aug;22(4):979-980. doi: 10.1007/s10157-0171524-4. Epub 2017 Dec 27. PubMed PMID:
29282571.
(30)Kanda E, Usui T, Kashihara N, Iseki C, Iseki K,
Nangaku M. Importance of glomerular filtration
rate change as surrogate endpoint for the future
incidence of end-stage renal disease in general
Japanese population: community-based cohort
study. Clin Exp Nephrol. 2018 Apr;22(2):318-327.
doi: 10.1007/s10157-017-1463-0.
Epub 2017
Sep 7. PubMed PMID: 28884361; PubMed
Central PMCID: PMC5838149.
(31)Kato H, Nangaku M, Hirakata H, Wada T,
Hayashi T, Sato H, Yamazaki Y, Masaki T,
Kagimura T, Yamamoto H, Hase H, Kamouchi M,
Imai E, Mizuno K, Iwasaki M, Akizawa T,
Tsubakihara Y, Maruyama S, Narita I. Erratum to:
Rationale and design of oBservational clinicalResearch In chronic kidney disease patients withrenal anemia: renal proGnosis in patients with
Hyporesponsive anemia To Erythropoiesisstimulating agents, darbepoetiN alfa (BRIGHTEN
Trial). Clin Exp Nephrol. 2018 Feb;22(1):85-86.
doi: 10.1007/s10157-017-1461-2. PubMed PMID:
28875480.
(32)Horie S, Oya M, Nangaku M, Yasuda Y, Komatsu
Y, Yanagita M, Kitagawa Y, Kuwano H,
Nishiyama H, Ishioka C, Takaishi H, Shimodaira
H, Mogi A, Ando Y, Matsumoto K, Kadowaki D,
Muto S. Guidelines for treatment of renal injury
during cancer chemotherapy 2016. Clin Exp
Nephrol. 2018 Feb;22(1):210-244. doi:
(33)10.1007/s10157-017-1448-z. Review. PubMed
PMID: 28856465; PubMed Central PMCID:
PMC5805816.
(34)Komaru Y, Inokuchi R, Ueda Y, Nangaku M, Doi
K. Use of the anion gap and intermittent
hemodialysis following continuous hemodiafiltration in extremely high dose acute-on-chronic
lithium poisoning: A case report. Hemodial Int.
2018 Jan;22(1):E15-E18. doi: 10.1111/hdi.12583.
Epub 2017 Aug 10. PubMed PMID: 28796408.
(35)Usui T, Kanda E, Iseki C, Iseki K, Kashihara N,
Nangaku M. Observation period for changes inproteinuria and risk prediction of end-stage renal
disease in general population. Nephrology(Carlton). 2018 Sep;23(9):821-829. doi: 10.1111/
nep.13093. Epub 2018 Mar 2. PubMed PMID:
28635004; PubMed Central PMCID:
PMC
6120455.

149

Department of Diabetes andMetabolic Diseases
Professor
Toshimasa Yamauchi, M.D., Ph.D. (since July 2018)

Lecturer
Hironori Waki, M.D., Ph.D. (since Nov 2018)

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

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

Yukiko Okazaki, M.D., Ph.D.,

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

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

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

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

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

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, andtake care of 576 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 [since Jun 2018]),
Department of Clinical Nutrition Therapy (Associate
Professor: Dr. Naoto Kubota), Department of
Molecular Sciences on Diabetes (Project AssistantProfessor: Dr. Takayoshi Sasako [since Aug 2018]),
Laboratoryfor
Advanced
Researchon
Pathophysiology of Metabolic Diseases (Project
Associate Professor: Dr. Miki Okada-Iwabu, Project
Associate Professor: Dr. Masato Iwabu [since Nov
2018]), Genomic Research Support Center (Project
Associate Professor: Dr. Nobuhiro Shojima),
Ubiquitous Health Informatics (Project Associate
Professor: Dr. Kayo Waki), Department of ClinicalLaboratory (Lecturer: Dr. Makoto Kurano), Division
for Health Service Promotion, The University ofTokyo (Assistant Professor: Drs. Sachiko Okazaki andTomohide Yamada [until Dec 2018]) and Center for
Epidemiology and Preventive Medicine (Project150

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 15 students of Graduate Schoolin our division. With all these 56 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 166 patients perday (total 40,597 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
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

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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
1. Adachi T, Imanishi N, Ogawa Y, Furusawa Y,
Izumida Y, Izumi Y, Suematsu M: Survey on
patients with undiagnosed diseases in Japan:
potential patient numbers benefiting from Japan's
initiative on rare and undiagnosed diseases(IRUD). Orphanet J Rare Dis. 2018 Nov 20;13(1):208.
2. Buse JB, Carlson AL, Komatsu M, Mosenzon O,
Rose L, Liang B, Buchholtz K, Horio H,
Kadowaki T: Fast-acting insulin aspart versus
insulin aspart in the setting of insulin degludectreated type 1 diabetes: Efficacy and safety from arandomized double-blind trial.Diabetes Obes.
Metab. 20:2885-2893, 2018
3. 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.
4. Haneda M, Kadowaki T, Ito H, Sasaki K, Hiraide
S, Ishii M, Matsukawa M, Ueno M: Safety andefficacy of teneligliptin in patients with type 2
diabetes mellitus and impaired renal function:
Interim report from post-marketing surveillance.
Diabetes Ther. 9:1083-1097, 2018
5. Kadowaki T, Inagaki N, Kondo K, Nishimura K,
Kaneko G, Maruyama N, Nakanishi N, Watanabe
Y, Gouda M, Iijima H: Long-term safety andefficacy of canagliflozin as add-on therapy toteneligliptin in Japanese patients with type 2
diabetes. Diabetes Obes.Metab. 2018 Jan; 20(1)77-84.

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6. Kadowaki T, Haneda M, Ito H, Ueno M,
Matsukawa M, Yamakura T, Sasaki K, Kimura M,
Iijima H : Safety and efficacy of long-term
treatment with teneligliptin:：Interim analysis of apost-marketing surveillance of more than 10,000
Japanese patients with type 2 diabetes mellitus.
Expert Opin Pharmacother. 2018 Feb;19(2):83-91.
7. Kadowaki T, Inagaki N, Kondo K, Nishimura K,
Kaneko G, Maruyama N, Nakanishi N, Gouda M,
Iijima H, Watanabe Y : Efficacy and safety ofteneligliptin added to canagliflozin monotherapy
in Japanese patients with type 2 diabetes mellitus:
A multicentre,
randomized,
double-blind,placebo-controlled, parallel-group comparative
study. Diabetes Obes Metab. 2018 Feb;20(2):453457
8. Kadowaki T, Sasaki K, Ishii M, Matsukawa M,
Ushirogawa Y: Efficacy and safety of teneligliptin
40 mg in type 2 diabetes: A pooled analysis of
two phase III clinical studies.Diabetes Ther. 9:623-636, 2018
9. Kadowaki T, Haneda M, Ito H, Sasaki K, Hiraide
S, Matsukawa M, Ueno M: Relationship of eating
patterns and metabolic parameters, andteneligliptin treatment: Interim results from postmarketing surveillance in Japanese type 2
diabetes patients.Adv. Ther. 35:817-831, 2018
10. Kadowaki T, Sarai N, Hirakawa T, Taki K,
Iwasaki K, Urushihara H: Persistence of oral
antidiabetic treatment for type 2 diabetes
characterized by drug class, patient characteristics
and severity of renal impairment: A Japanesedatabase analysis. Diabetes Obes. Metab. 20:
2830-2839, 2018
11. 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.
2018 Nov 9.
12. 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.
13. Kubota T, Inoue M, Kubota N, Takamoto I,
Mineyama T, Iwayama K, Tokuyama K, Moroi M,
Ueki K, Yamauchi T, Kadowaki T. Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype
macrophage activation in obesity. Nat. Commun.
9:4863, 2018.
14. Nohara A, Ohmura H, Okazaki H, Ogura M,
Kitagawa K, Koseki M, Sato K, Tsukamoto K,
Yamashita S; Japan Atherosclerosis Society
Working Group on Statement for Appropriate Useof PCSK9 Inhibitors: Statement for Appropriate
Clinical Use of PCSK9 Inhibitors. J Atheroscler
Thromb. 25(8):747-750, 2018.
15. Okada-Iwabu M, Iwabu M, Yamauchi T,
Kadowaki T. Structure and Function Analysis of
Adiponectin Receptors toward Development ofNovel Antidiabetic Agents Promoting Healthy
Longevity. Endocr. J. 65, 971-977,2018 Oct 3.
16. Ota S, Horisaki R, Kawamura Y, Ugawa M, Sato I,
Hashimoto K, Kamesawa R, Setoyama K,
Yamaguchi S, Fujiu K, Waki K, Noji H. Ghost
cytometry. Science. 2018 Jun 15;360(6394):12461251. doi: 10.1126/science.aan0096
17. Pinto S, Waki K, Chiovato L, De Cata P, Dagliati
A, Tibollo V, Ruvolo G, Bellazzi R. SmartphoneBased
Self-Managementof
Non-InsulinDependent Diabetes: A Japanese System at Use
by an Italian Patients' Cohort. J Diabetes Sci
Technol. 2018 Jul;12(4):903-904. doi: 10.1177/
1932296818763884.
18. Suzuki R, Eiki J, Moritoyo T, Furihata K, Wakana
A, Ohta Y, Tokita S, Kadowaki T. Effect ofshort-term treatment with sitagliptin orglibenclamide on daily glucose fluctuation in
drug-naïve Japanese patients with type 2 diabetes
mellitus. Diabetes Obes Metab 20:2274-2281,
2018
19. Taira M, Imamura M, Takahashi A, Kamatani Y,
Yamauchi T, Araki SI, Tanaka N, van Zuydam NR,
Ahlqvist E, Toyoda M, Umezono T, Kawai K,
Imanishi M, Watada H, Suzuki D, Maegawa H,
Babazono T, Kaku K, Kawamori R; SUMMIT
Consortium, Groop LC, McCarthy MI, Kadowaki

153T, Maeda S: A variant within the FTO confers
susceptibility to diabetic nephropathy in Japanesepatients with type 2 diabetes. PLoS One 13:
e0208654, 2018
20. Ueda K, Takimoto E, Lu Q, Liu P, Fukuma N,
Adachi Y, Suzuki R, Chou S, Baur W, Aronovitz
MJ, Greenberg AS, Komuro I, Karas RH.
Membrane-Initiated Estrogen Receptor Signaling
Mediates Metabolic Homeostasis via Central
Activation of Protein Phosphatase 2A. Diabetes
67:1524-1537, 2018
21. Yamada T, Shojima N, Noma H, Yamauchi T,
Kadowaki T. Weekly Versus Daily Dipeptidyl
Peptidase 4 Inhibitor Therapy for Type 2
Diabetes: Systematic Review and Meta-analysis.
Diabetes Care. 2018 Apr;41(4):e52-e55.
22. Yamada T, Kamata R, Ishinohachi K, Shojima N,
Ananiadou S, Nom H, Yamauchi T, Kadowaki T.
Biosimilar vs originator insulins: Systematic
review and meta-analysis. Diabetes Obes Metab.
2018 Jul;20(7):1787-1792.
23. Yamada T, Shojima N, Noma H, Yamauchi T,
Kadowaki T. Sodium-glucose co-transporter-2
inhibitors as add-on therapy to insulin for type 1
diabetes mellitus: Systematic review and metaanalysis of randomized controlled trials. Diabetes
Obes Metab. 2018 Jul;20(7):1755-1761.
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26. GBD 2017 Population and Fertility Collaborators(incl. Yamada t). Population and fertility by age
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27. GBD 2017 Risk Factor Collaborators (incl.
Yamada T). Global, regional, and national

comparative risk assessment of 84 behavioural,environmental and occupational, and metabolicrisks or clusters of risks for 195 countries andterritories, 1990-2017: a systematic analysis for
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Global, regional, and national incidence,prevalence, and years lived with disability for 354
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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 three lecturers and 7 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155

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. Allogeneic hematopoietic
stem cell transplant for the elderly are performed
under the admission of the ethical committee ofthe Faculty of Medicine. Cord blood cells are also
used as a source of hematopoietic 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, (7)regulation of hematopoiesis. Translational research todevelop novel methods for diagnosis and treatment
based on basic research is also performed. Everyeffort has been made to achieve the highest quality inboth clinical and basic medical research. The ultimate
aims of our research are the application of
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, Kurokawa M. Role of ASXL1 mutation in
impaired hematopoiesis and cellular senescence.
Oncotarget, 2018. doi: 10.18632/oncotarget.
26423. eCollection 2018
2. Chiba A, Toya T, Mizuno H, Tokushige J,
Nakamura F, Nakazaki K, Kurokawa M. Chronic
myelogenous leukemia presenting with central
nervous system infiltration, successfully treatedwith central nervous system-directed chemotherapy followed by allogeneic stem cell transplantation. Int J Hematol, 108(6):640-646, 2018.

156

3. 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, Osaki
Y, Izumi N, Imawari M. Lusutrombopag Reduces
Need for Platelet Transfusion in Patients With
Thrombocytopenia Undergoing Invasive Procedures. Clin Gastroenterol Hepatol, pii: S15423565(18)31324-7, 2018.
4. Dumas PY, Mansier O, Prouzet-Mauleon V, Koya
J, Villacreces A, Brunet de la Grange P, LuquePaz D, Bidet A, Pasquet JM, Praloran V, Salin F,
Kurokawa M, Mahon FX, Cardinaud B, Lippert E.
MiR-10a and HOXB4 are overexpressed in
atypical myeloproliferative neoplasms. BMC
Cancer, 18(1):1098, 2018.
5. Karakawa A, Taoka K, Kaburaki T, Tanaka R,
Shinozaki-Ushiku A, Hayashi H, MiyagiMaeshima A, Nishimura Y, Uekusa T, Kojima Y,
Fukayama M, Kurokawa M, Aihara M. Clinicalfeatures and outcomes of secondary intraocularlymphoma. Br J Haematol, 183(4):668-671,
2018
6. Ebisawa K, Koya J, Nakazaki K, Arai S,
Nakamura F, Kurokawa M. Usefulness ofpresepsin for early detection of infections inpatients with hematologic disorders. Clin Chim
Acta, 486:374-380, 2018.
7. Toya T, Ogura M, Toyama K, Yoshimi A,
Shinozaki-Ushiku A, Honda A, Honda K, Hosoya
N, Murakami Y, Kawashima H, Nannya Y, Arai S,
Nakamura F, Shinoda Y, Nangaku M, Miyagawa
K, Fukayama M, Moriya-Saito A, Katayama I,
Ogura T, Kurokawa M. Prognostic factors ofErdheim-Chester disease: a nationwide survey inJapan. Haematologica, 103(11):1815-1824, 2018.
8. Matsuda A, Kawabata H, Tohyama K, Maeda T,
Araseki K, Hata T, Suzuki T, Kayano H, Shimbo
K, Usuki K, Chiba S, Ishikawa T, Arima N,
Nohgawa M, Ohta A, Miyazaki Y, Nakao S,
Ozawa K, Arai S, Kurokawa M, Mitani K,
Takaori-Kondo A; Japanese National ResearchGroup on Idiopathic Bone Marrow Failure
Syndromes. Interobserver concordance of assessments of dysplasia and blast counts for the
diagnosis of patients with cytopenia: From theJapanese central review study. Leuk Res, 74:137143, 2018.
9. Senda N, Miyagaki T, Oka T, Itoigawa A,
Kikuchi K, Kobayashi T, Nakamura F, Kurokawa
M, Sugaya M, Sato S. Case of extranodal naturalkiller/T-cell lymphoma, nasal type, accompanied
by Epstein-Barr virus-positive nasopharyngeal
carcinoma. J Dermatol, 2018. doi: 10.1111/13468138.14701. Epub ahead of print
10. Taoka K, Arai S, Kataoka K, Hosoi M, Miyauchi
M, Yamazaki S, Honda A, Aixinjueluo W,
Kobayashi T, Kumano K, Yoshimi A, Otsu M,
Niwa A, Nakahata T, Nakauchi H, Kurokawa M.
Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic
leukemia and therapeutic drug identification,
including liposomal clodronate. Sci Rep. 8(1):15855, 2018.
11. 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, 2018. doi: 10.1038/
s41409-018-0371-6. Epub ahead of print
12. 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. 2018. doi: 10.1111/jgh.14452. Epubahead of print
13. Yasunaga M, Taoka K, Nakagawa H, Yamada A,
Abe H, Jona M, Nishikawa M, Nakazaki K,
Yatomi Y, Fukayama M, Koike K, Kurokawa M.
Eculizumab treatment for ischemic enteritis
accompanied with paroxysmal nocturnal hemoglobinuria: a case report and literature review.
Ann Hematol, 97(8):1513-1515, 2018.
14. Yoshinaga N, Kanda J, Aisa Y, Hagiwara S, MoriT, Fukuda T, Ishida Y, Hashimoto H, Iwato K,
Kanda Y, Kurokawa M, Nakazawa H, Ota S,
Uchida N, Ichinohe T, Atsuta Y, Takaori-Kondo
A. Impact of HIV Infection on Transplant
Outcomes after Autologous Peripheral Blood
Stem Cell Transplantation: A Retrospective Study

157

of Japanese Registry Data. Biol Blood Marrow
Transplant, 24(8):1596-1601, 2018.
15. Toyama K, Yasumoto A, Nakamura F, Arai S,
Kurokawa M. The Development of Acute
Systemic Multiple Thrombosis after Achieving
Remission during Systemic Glucocorticoid
Therapy for Acquired Hemophilia A. Intern Med,
57(15):2237-2241, 2018.
16. Suzuki Y, Honda A, Nakazaki K, Mizuno H,
Ikemura M, Shinozaki-Ushiku A, Nakamura F,
Fukayama M, Kurokawa M. Histologicaltransformation of MALT lymphoma to plasma
cell leukemia after rituximab-containing therapy.
Ann Hematol, 97(7):1297-1298, 2018.
17. Morita K, Honda A, Koya J, Toyama K, Ikeda M,
Misawa Y, Okugawa S, Nakamura F, Moriya K,
Kurokawa M. Three cases of Candida fermentati
fungemia following hematopoietic stem celltransplantation. J Infect Chemother, 24(7):576578, 2018.
18. Tsukui D, Kanda H, Shinozaki-Ushiku A, Tateishi
S, Takeshima Y, Nagafuchi Y, Sasaki O, Iwasaki
Y, Harada H, Shibuya M, Sumitomo S, Shoda H,
Kubo K, Fujio K, Nakamura F, Kurokawa M,
Fukayama M, Yamamoto K. Polymorphic
lymphoproliferative disorders in patients withrheumatoid arthritis are associated with a better
clinical outcome. Mod Rheumatol, 28(4):621625, 2018.
19. Furuya G, Abe H, Shinozaki-Ushiku A,
Yamashita A, Ihara S, Hirata Y, Chiba A, Fujioka
Y, Kurokawa M, Koike K, Fukayama M.
Extranodal NK/T-cell lymphoma of the nasal
cavity developed in a patient with intestinal
Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder. Pathol Res Pract, 214(7):1051-1055, 2018.
20. Morita K, Koya J, Toya T, Nakamura F,
Kurokawa M. Philadelphia chromosome-negative
acute promyelocytic leukemia manifesting after
long-term imatinib treatment for chronic myeloid
leukemia: a case report and literature review. Ann
Hematol, 97(6):1105-1109, 2018.
21. Osumi T, Tsujimoto SI, Nakabayashi K,
Taniguchi M, Shirai R, Yoshida M, Uchiyama T,
Nagasawa J, Goyama S, Yoshioka T, Tomizawa
D, Kurokawa M, Matsubara Y, Kiyokawa N,

Matsumoto K, Hata K, Kato M. Somatic MECOM
mosaicism in a patient with congenital bonemarrow failure without a radial abnormality.
Pediatr Blood Cancer. 65(6):e26959, 2018.
22. Suzuki Y, Koya J, Ebisawa K, Abe H, ShinozakiUshiku A, Nakamura F, Kurokawa M. Sequential
development of monoclonal B cell lymphocytosisderived small lymphocytic lymphoma and plasma
cell leukemia. Ann Hematol, 97(5):917-919,
2018.
23. Masamoto Y, Kurokawa M. Targeting chronic
myeloid leukemia stem cells: can transcriptional
program be a druggable target for cancers? Stem
Cell Investig. 5:10, 2018.
24. Maki H, Nannya Y, Imai Y, Yamaguchi S,
Kamikubo Y, Ichikawa M, Nakamura F, andKurokawa M. Nonmyelomatous ascites resulting from increased secretion of vascularendothelial growth factor in multiple myeloma.
Internal Medicine, 57(5): 725-727, 2018.
25. Chiba A, Nakamura F, Nakazaki K, andKurokawa M. Cytomegalovirus antigenemia andend-organ disease in Japanese patients treatedwith bendamustine.
Leukemia & Lymphoma, 59(3): 749-751, 2018.
26. Matsuda K, Kazuhiro T, Toya T, Ikemura M,
Nakamura F, and Kurokawa M. Reactivation ofhemophagocytic lymphohistiocytosis triggered byantithymocyte globulin.
Internal Medicine,
57(4): 583-586, 2018.
27. Sakura T, Hayakawa F, Sugiura I, Murayama T,
Imai K, Usui N, Fujisawa S, Yamauchi T, Yujiri
T, Kakihana K, Ito Y, Kanamori H, Ueda Y,
Miyata Y, Kurokawa M, Asou N, Ohnishi K,
Ohtake S, Kobayashi Y, Matsuo K, Kiyoi H,
Miyazaki Y, and Naoe T. High-dose methotrexate therapy significantly improved survival of
adult acute lymphoblastic leukemia: a phase III
study by JALSG. Leukemia, 32(3): 626-632,
2018.
28. Itonaga H, Aoki K, Aoki J, Ishikawa T, Ishiyama
K, Uchida N, Sakura T, Ohashi K, Kurokawa M,
Ozawa Y, Matsuoka K, Yujiri T, Kimura F, Iwato
K, Nawa Y, Hirokawa M, Kato K, Ichinohe T,
Atsuta Y, and Miyazaki Y. Prognostic impact ofdonor source on allogeneic hematopoietic stem
cell transplantation outcomes in adults with

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chronic myelomonocytic leukemia: a nationwide
retrospective analysis in Japan. Biol Blood
Marrow Transplant, 24(4): 840-848, 2018.
29. Arai Y, Kondo T, Shigematsu A, Tanaka J,
Ohashi K, Fukuda T, Hidaka M, Kobayashi N,
Iwato K, Sakura T, Onizuka M, Ozawa Y, Eto T,
Kurokawa M, Kahata K, Uchida N, Atsuta Y,
Mizuta S, and Kako S. Improved prognosis withadditional medium-dose VP16 to CY/TBI inallogeneic transplantation for high risk ALL in
adults.
American Journal of Hematology,
93(1): 47-57, 2018.
30. Miyauchi M, Koya J, Arai S, Yamazaki S, Honda
A, Kataoka K, Yoshimi A, Taoka K, Kumano K,
and Kurokawa M. ADAM8 is an antigen of
TKI-resistant CML cells identified by patientderived induced pluripotent stem cells. Stem
Cell Reports, 10(3): 1115-1130, 2018.
31. Masamoto Y, and Kurokawa M.
Targetingchronic myeloid leukemia stem cells withprostaglandin E1. Stem Cell Investigation. doi:
10.21037/sci.2018.03.05, 2018

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

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

Hospital Lecturer
Shuji Sumitomo，M.D., Ph.D. (Rheumatology)

Research Associate
Yukiko Iwasaki, M.D., Ph.D. (Rheumatology)
Hiroaki Harada, M.D., Ph.D. (Allergology)
Oh Sasaki, M.D., Ph.D. (Allergology)
Yumi Tsuchida，M.D., Ph.D. (Rheumatology)
Toshihiko Komai, M.D., Ph.D. (Rheumatology)
Haruka Tsuchiya, M.D., Ph.D. (Rheumatology)

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

Project Research Associate
Shyoko Tateishi, M.D., Ph.D. (Rheumatology)
Mariko Inoue, M.D., Ph.D. (Rheumatology)
Yasuo Nagafuchi，M.D., Ph.D. (Rheumatology)
MIneto Ohta, M.D., Ph.D. (Rheumatology)
Yusuke Takeshima, M.D., Ph.D. (Rheumatology)

The Department of Allergy and Rheumatology
presently consists of 17 staffs mentioned above, who
preside over 3 medical staff, 17 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 and160

systemic 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
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.

References

2018

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. New horizons in clinical immunology: applications of induced pluripotent stem cells for the
analysis of immune disorders.
Shoda H, Natsumoto B, Fujio K.
Immunol Med. 2018;41:12-16.
3. Tofacitinib rapidly ameliorated polyarthropathy ina patient with systemic sclerosis. Komai T, Shoda
H, Hanata N, Fujio K. Scand J Rheumatol. 2018;
47:505-506.
4. Polymorphic lymphoproliferative disorders inpatients with rheumatoid arthritis are associatedwith a better clinical outcome.
Tsukui D, Kanda H, Shinozaki-Ushiku A,
Tateishi S, Takeshima Y, Nagafuchi Y, Sasaki O,
Iwasaki Y, Harada H, Shibuya M, Sumitomo S,
Shoda H, Kubo K, Fujio K, Nakamura F,
Kurokawa M, Fukayama M, Yamamoto K. Mod
Rheumatol. 2018;28:621-625.
5. A gene module associated with dysregulated TCR
signaling pathways in CD4+ T cell subsets inrheumatoid arthritis. Sumitomo S, Nagafuchi Y,
Tsuchida Y, Tsuchiya H, Ota M, Ishigaki K,
Nakachi S, Kato R, Sakurai K, Hanata N, Tateishi
S, Kanda H, Suzuki A, Kochi Y, Fujio K,
Yamamoto K. J Autoimmun. 2018;89:21-29.
6. Splicing variant of WDFY4 augments MDA5
signalling and the risk of clinically amyopathic
dermatomyositis.

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Kochi Y, Kamatani Y, Kondo Y, Suzuki A,
Kawakami E, Hiwa R, Momozawa Y, Fujimoto M,
Jinnin M, Tanaka Y, Kanda T, Cooper RG,
Chinoy H, Rothwell S, Lamb JA, Vencovský J,
Mann H, Ohmura K, Myouzen K, Ishigaki K,
Nakashima R, Hosono Y, Tsuboi H, Kawasumi H,
IwasakiY,
Kajiyama
H,
HoritaT,
Ogawa-Momohara M, Takamura A, Tsunoda S,
Shimizu J, Fujio K, Amano H, Mimori A,
Kawakami A, Umehara H, Takeuchi T, Sano H,
Muro Y, Atsumi T, Mimura T, Kawaguchi Y,
Mimori T, Takahashi A, Kubo M, Kohsaka H,
Sumida T, Yamamoto K.
Ann Rheum Dis. 2018;77:602-611.
7. Rhabdomyolysis Induced by Isoniazid in a Patientwith Rheumatoid Arthritis and End-stage Renal
Disease: A Case Report and Review of the
Literature.
Komai T, Sumitomo S, Teruya S, Fujio K.
Intern Med. 2018;57:2413-2416.
8. HLA-DRB1 Shared Epitope Alleles and Disease
Activity Are Correlated with Reduced T Cell
Receptor Repertoire Diversity in CD4+ T Cells in
Rheumatoid Arthritis. Sakurai K, Ishigaki K,
Shoda H, Nagafuchi Y, Tsuchida Y, Sumitomo S,
Kanda H, Suzuki A, Kochi Y, Yamamoto K,
Fujio K. J Rheumatol. 2018;45:905-914.
9. Egr2-independent, Klf1-mediated induction of
PD-L1 in CD4+ T cells.
Teruya S, Okamura T, Komai T, Inoue M,
Iwasaki Y, Sumitomo S, Shoda H, Yamamoto K,
Fujio K. Sci Rep. 2018;8:7021.
10. Reduction of CD83 Expression on B Cells and the
Genetic Basis for Rheumatoid Arthritis. TsuchidaY, Sumitomo S, Ota M, Tsuchiya H, Nagafuchi Y,
Shoda H, Fujio K, Ishigaki K, Yamaguchi K,
Suzuki A, Kochi Y, Yamamoto K. Arthritis
Rheumatol. 2018;70:1695-1696.
11. Transforming Growth Factor-β and Interleukin-10
Synergistically Regulate Humoral Immunity via
Modulating Metabolic Signals.Komai T, Inoue M,
Okamura T, Morita K, Iwasaki Y, Sumitomo S,
Shoda H, Yamamoto K, Fujio K. Front Immunol.
2018;9:1364.
12. Reevaluation of Pluripotent Cytokine TGF-β3 in
Immunity. Komai T, Okamura T, Inoue M,

Yamamoto K, Fujio K.
Int J Mol Sci. 2018;19. pii: E2261.
13. Retro-odontoid Pseudotumor Associated with
Sjögren Syndrome and Systemic Lupus
Erythematosus Serology.
Yamada S, Nagafuchi Y, Fujio K.
J Rheumatol. 2018;45:1424-1425.
14. Transcriptome analysis of peripheral blood frompatients with rheumatoid arthritis: a systematic
review. Sumitomo S, Nagafuchi Y, Tsuchida Y,
Tsuchiya H, Ota M, Ishigaki K, Suzuki A, Kochi
Y, Fujio K, Yamamoto K. Inflamm Regen. 2018;
38:21.
15. Factors associated with discontinuation of
glucocorticoids after starting biological diseasemodifying antirheumatic drugs in rheumatoid
arthritis patients. Inoue M, Kanda H, Tateishi S,
Fujio K. Mod Rheumatol. 2018:1-15. [Epubahead of print]
16. Molecular and functional heterogeneity of IL-10producing CD4+ T cells. Brockmann L, Soukou S,
Steglich B, Czarnewski P, Zhao L, Wende S,
Bedke T, Ergen C, Manthey C, Agalioti T,
Geffken M, Seiz O, Parigi SM, Sorini C, Geginat
J, Fujio K, Jacobs T, Roesch T, Izbicki JR, Lohse
AW, Flavell RA, Krebs C, Gustafsson JA,
Antonson P, Roncarolo MG, Villablanca EJ,
Gagliani N, Huber S. Nat Commun. 2018;9:5457.

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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. Yoshitaka Wakabayashi, M.D, Ph.D (-Jan. 2019).

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

Introduction and Organization
The Department of Infectious Diseases has been
one of the leading academic organizations specialized
for internal medicine, in particular, infectious disease
medicine in Japan since 1998, when the Departmentsof Internal Medicine, established in 1890, wererearranged into new ones according to subspecialty ofinternal medicine. Our department has been chiefly
engaged in clinical, educational and research activities
for infectious diseases including bacterial, fungal andviral infections of all organs including HIV infection,
tuberculosis and viral hepatitis. Our department islocated on 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

163

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.

Members
Kyoji Moriya, Shu Okugawa, Shintaro Yanagimoto,
Keita Tatsuno, Mahoko Ikeda, Yoshitaka Wakabayashi,
Koh Okamoto

References
1. Sato S, Aoyama T, Uejima Y, Furuichi M,
Suganuma E, Takano T, et al. Pyogenic liverabscess due to hypervirulent Klebsiellapneumoniae in a 14-year-old boy. J InfectChemother. 2019;25(2):137-40.
2. Ando T, Noguchi S, Enokida T, Yamato A, Kage
H, Yamauchi Y, et al. Infectious Aneurysm Caused
by Citrobacter koseri in an Immunocompetent
Patient. Intern Med. 2019;58(6):813-6.
3. Yokoyama A, Kage H, Ohama Y, Sato T,
Miyashita N, Noguchi S, et al. Mycobacterium
heckeshornense lung infection diagnosed bymatrix-assisted laser desorption ionization-time offlight mass spectrometry (MALDI-TOF MS). JInfect Chemother. 2018;24(9):763-5.
4. Yamamoto S, Ikeda M, Fujimoto F, Okamoto K,
Wakabayashi Y, Sato T, et al. Bilateral Candida
endophthalmitis accompanying Candida lusitaniae
bloodstream infection: A case report. J InfectChemother. 2018;24(2):147-9.
5. Okushin K, Tsutsumi T, Ikeuchi K, Kado A,
Enooku K, Fujinaga H, et al. Helicobacter pylori
infection and liver diseases: Epidemiology andinsights into pathogenesis. World J Gastroenterol.
2018;24(32):3617-25.
6. Okamoto K, Hatakeyama S, Sugita C, Ogura K,
Ueda R, Kouda H, et al. Nasal diphtheria (chronic
carriage) caused by nontoxigenic Corynebacterium diphtheriae. J Infect Chemother. 2018;24(9):759-62.
7. Okamoto K, Hatakeyama S. Tuberculous

164

Peritonitis. N Engl J Med. 2018;379(12):e20.
8. Nakano T, Moriya K, Koike K, Horie T. Hepatitis
C virus core protein triggers abnormal porphyrin
metabolism in human hepatocellular carcinoma
cells. PLoS One. 2018;13(6):e0198345.
9. Morita K, Honda A, Koya J, Toyama K, Ikeda M,
Misawa Y, et al. Three cases of Candida
fermentati fungemia following hematopoietic
stem cell transplantation. J Infect Chemother.
2018;24(7):576-8.
10. Ikeda M, Mizoguchi M, Oshida Y, Tatsuno K,
Saito R, Okazaki M, et al. Clinical and microbiological characteristics and occurrence ofKlebsiella pneumoniae infection in Japan. Int J
Gen Med. 2018;11:293-9.
11. Enooku K, Kondo M, Fujiwara N, Sasako T,
Shibahara J, Kado A, et al. Hepatic IRS1 andss-catenin expression is associated withhistological progression and overt diabetes
emergence in NAFLD patients. J Gastroenterol.
2018;53(12):1261-75.
12. Araoka H, Baba M, Okada C, Kimura M, Sato T,
Yatomi Y, et al. Risk Factors for Recurrent
Helicobacter cinaedi Bacteremia and the Efficacy
of Selective Digestive Decontamination With
Kanamycin to Prevent Recurrence. Clin Infect Dis.
2018;67(4):573-8.

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

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

Homepage

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

Introduction and Organization
The Department of Stress Science andPsychosomatic Medicine is one of 11 divisions of the
Department of Internal Medicine, the University ofTokyo. It covers eating disorder, panic disorder, andvarious psychosomatic diseases such as chronicheadache, irritable bowel syndrome, functional
dyspepsia, hypertension, diabetes mellitus, andhyperthyroidism. Our teaching staff consists of one
associate professor, two associates, and 5 adjunctprofessors, and other members are 3 senior residents,
9 graduate students, and 4 researchers.

Clinical activities
Our department is responsible for both outpatient
clinic and inpatient ward. The ward is managed as apart of the Division of General Internal Medicine, andsenior residents, an associate, and the associate
professor attend it every day and provide close sideby-side instruction to junior residents. The weekly
professor’s round is scheduled on Thursday morning.
During 2018 April to 2019 March, overall 1,781
patients (60 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 2018 April to 2019
March, the numbers of the new outpatients and of theoverall outpatients in our department were 247 and
4,896, respectively.

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

Research activities
Targeting stress-related diseases such as not only
those covered by our department but also otherlifestyle-related disease, and cancers, we areinvestigating their pathophysiology and psycho-

166

pathology through assessing bio-psycho-behavioral
time-series data, various questionnaire data, andautonomic nervous function. We are also actively
conducting basic as well as clinical research on
eating-related substances.
Some representative research methods are as
follows:
1) Ecological momentary assessment (EMA):
Investigation on neurobehavioral basis of stressrelated diseases such as tension-type headache,eating disorders, insomnia, and panic disorderusing portable computers for real-time assessmentof subjective symptoms in combination withambulatory monitors such as electrocardiogramand actigraphy.
2) Neuroendocrinological and neuroimmunologicalstudies in anorexia nervosa patients: multidisciplinary investigation on energy metabolism
during a refeeding phase; changes in various
substances such as neuropeptides before and after
treatment; relationship between bone metabolism
and various makers; and exploration of biomarkers
for evaluating treatment efficacy.
3) Psycho-oncology: Development of a new questionnaire for evaluating depressive mood in cancer
patients.
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. Shibayama O, Yoshiuchi K, Inagaki M, Matsuoka Y,
Yoshikawa E, Sugawara Y, Akechi T, Wada N,
Imoto S, Murakami K, Ogawa A, Uchitomi Y.
Long-term influence of adjuvant breast radiotherapy
on cognitive function in breast cancer patientstreated with conservation therapy. International
Journal of Clinical Oncoloy 24:68-77, 2019.
2. Ogino K, Takahashi H, Nakamura T, Kim J, Kikuchi
H, Nakahachi T, Ebishima K, Yoshiuchi K, Ando T,

Sumiyoshi T, Stickley A, Yamamoto Y, Kamio Y.
Negatively skewed locomotor activity is related to
autistic traits and behavioral problems in typicallydeveloping children and those with autism spectrum
disorders. Front Hum Neurosci 12:518, 2018
3. Takahashi H, Nakamura T, Kim J, Kikuchi H,
Nakahachi T, Ishitobi M, Ebishima K, Yoshiuchi K,
Ando T, Stickley A, Yamamoto Y, Kamio Y.
Acoustic hyper-reactivity and negatively skewed
locomotor activity in children with autism spectrum
disorders: an exploratory study. Frontiers in
Psychiatry 9:355, 2018
4. Yasui H, Iwase S, Ariyoshi K, Nojima M, Yoshiuchi
K. Decline of physical activity in terminally illpatients could be useful for predicting short-term
survival. Am J Hosp Palliat Care 35:749-735, 2018
5. Shimizu E, Nakamura T, Kim J, Yoshiuchi K,
Yamamoto Y. Application of empirical mode
decomposition to mother and infant physicalactivity: synchronization of circadian rhythms is
associated with maternal mental health. Methods Inf
Med 51: 152-157, 2018.

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. Yoshikawa N, Masuda A, Sato T, Jona M, Maki H,
Masamoto Y, Sone S, Okazaki H, Kurokawa M,
Yatomi Y: Evaluation of the clinical utility ofhematopoietic progenitor cell (HPC) measurement
obtained by a multi-item hematology analyzer.
Rinsho Byori 66:144-51, 2018
2. Masuda R, Iijima T, Kondo R, Itoda Y,
Matsuhashi M, Hashimoto S, Kohira T,
Kobayashi N, Okazaki H: Preceding haemorrhagic shock as a detrimental risk factor for
respiratory distress after excessive allogeneic
blood transfusion. Vox Sang 113:51-59, 2018

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
4) effect of ovarian steroid hormones on bonemetabolism, and 5) effects of endocrine disrupters on
the reproductive system.

References published in 2018
1. Matsumoto L, Hirota Y, Saito-Fujita T, Takeda N,
Tanaka T, Hiraoka T, et al. HIF2α in the uterine
stroma permits embryo invasion and luminal
epithelium detachment. The jounal of clinicalinvestigation. 2018;128(7):3186-3197.
2. Yamamoto N, Hirata T, Izumi G, Nakazawa A,
Fukuda S, Neriishi K, et al. A survey of public
attitudes towards third-party reproduction in
Japan in 2014.A survey of public attitudes
towards third-party reproduction in Japan in 2014.
PLoS One. 2018 Oct 31;13(10).
3. Takahashi N, Harada M, Tanabe R, Takayanagi A,
Izumi G, Oi N, et al. Factors associated with

173

successful pregnancy in women of late
reproductive age with uterine fibroids who
undergo embryo cryopreservation before surgery.
The journal of obstetrics and gynaecology
research. 2018;44(10):1956-1962.
4. Ono Y, Nagai M, Yoshino O, Koga K, Nawaz A,
Hatta H, et al. CD11c+ M1-like macrophages(MΦs) but not CD206+ M2-like MΦ are involvedin folliculogenesis in mice ovary. Scientificreports. 2018;8(1):8171.
5. Takahashi N, Koga K, Arakawa I, Harada M, Oda
K, et al. A Potential Role for Development ofendometrioma
after
cervicalconization.
Gynecological endocrinology. 2018;34(4): 341-4.

174

Department of
Gynecologic Oncology
Professor
Yutaka Osuga

Associate Professor
Katsutoshi Oda

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 in bothclinical and research activities, as well as teachingactivities, with 19 associates of the University of Tokyo
Hospital. For the clinical aspect, they are engaged within-patient and out-patient care.

Activities(1) Oncology research
In our division, the pathogenesis of cervical cancer,
endometrial cancer, and ovarian cancer have been
investigated these two decades.
Cervical cancer is associated with a subset of highrisk HPVs. The most prevalent of these, types 16 and18, together account for more than 70% of cases. HPV
infections are very common among young sexuallyactive women, and the majority of infections aretransient and cleared by their immune system within ashort period, with 70% of infections deleted in 1 year
and 90% in 2 years.
Studies of virus neutralization by antibody are
prerequisite for development of a prophylactic vaccine
strategy against HPVs. To determine whether neutralizing anti-bodies (NAs) against HPV16 is responsible
for a higher regression rate of low-grade cervicalintraepithelial neoplasia (CIN1), we investigated an

association between the presence of the NAs and thefate of the HPV16-related CIN1. The incidence of thepresence of the NAs in the women with a nonpathological cervix (85.7%) was significantly higher
than in the CIN1 cases (21.5%), the CIN2/3 cases(15.7%), and the cervical cancer cases (0%) (p<0.0001).
The regression of the CIN1 lesion was closely
associated with the presence of the NAs (p=0.0002).
The presence of the NAs was associated with low-level
copy number of the viral DNA relative to the NAnegative group (p=0.05). The presence of the NAs
against HPV16 was associated with a higher regression
rate of HPV-related CIN1 lesions. The NAs seem tohave a role in deterring HPV-related cervical lesions
from progressing to CIN2/3 by inhibiting the infection
with de novo replicated HPV. Then we designed aplacebo-controlled trial in healthy adults to evaluate thesafety and immunogenicity of a synthetic peptide
consisting of the aa 108-120 of HPV16 L2 (L2108/120) region, because this region contains a crossneutralization epitope against genital HPV.. A total of
13 volunteers were given nasal inoculations with 0.1(n=5) or 0.5mg (n=5) doses of the peptides or placebo(n=3) without adjuvant at weeks 0, 4, and 12. Sera werecollected before inoculation and at 6, 16 and 36 weeks.
The inoculation caused no serious local and systemic
complications. The inoculation generated anti-L2
antibodies binding to both HPV16 and 52 L1/L2capsids in four of the five recipients in the 0.5mg group.
Sera of the four recipients showed neutralizing
activities against HPV16 and 52. Serological responses

175

to the peptides were not found in the 0.1mg group andthe placebo group recipients. This study suggests theL2-108/120 peptide is tolerable in humans and has thepotential as a broad-spectrum prophylactic vaccine
against genital HPV.
In endometrial cancer, we identified novel mutations
in PIK3CA and AKT1, and reported that inhibiting the
Phosphatidylinositol 3-kinase (PI3K) / Akt pathway
showed anti-tumor effect in endometrial cancer cells.
We have identified other candidate molecular targets inendometrial cancer. For example, high expression ofsurvivin, an anti-apoptotic protein, is associated withpoor prognosis. We found that survivin inhibitor,
YM155, dose-dependently and significantly increased
the apoptotic cell population in all endometrial cancer
cell lines examined. In addition, we elucidated that thehistone methyltransferase EZH2, a key epigenetic
modifier, is significantly overexpressed in endometrial
cancers, and that EZH2 inhibitor suppressed
endometrial cancer cell growth. We also investigatedmolecular biomarkers to predict the prognosis and/or
drug sensitivity in endometrial cancer, using genomewide analyses in clinical samples. Of note, extensive
chromosomal instability was an independent poor
prognostic factor in endometrial cancer.
In ovarian cancer, we also investigated genomewide analyses, including whole-exome sequencing andgene expression array, in high-grade serous and clear
cell carcinomas. As well, we examined various types ofmolecular-targeted drugs in ovarian cancer cell lines.
For example, we identified a subgroup in ovarian clear
cell carcinomas, which is associated with prognosis andchemosensitivity. We reported several moleculartargets in ovarian clear cell carcinomas. Targeting thePI3K pathway showed anti-tumor effect throughinduction of wild-type TP53. We further identified that
MDM2, a negative regulator of TP53, is frequently
overexpressed and that MDM2 inhibitor induced TP53mediated apoptosis in ovarian clear cell carcinomas.
We also reported a role of the dysregulation of
epigenetic modifier in carcinogenesis and ovariancancer progression. For example, histone methyltransferase WHSC1 was overexpressed in ovarian clear
cell carcinoma. Overexpression of WHSC1 wasinvolved in the proliferation of cancer cells.

(2) Clinical oncology
In our department, more than 150 patients withgynecological cancer are treated every year. And also,
we play an important role in clinical trials of JCOG
(Japan Clinical Oncology Group) and JGOG (Japanese
Gynecologic Oncology Group). For example, we
conducted a non-randomized confirmatory phase III
trial (JCOG1101) in Japan to evaluate the efficacy ofmodified radical hysterectomy in patients with tumor
diameter 2 cm or less FIGO Stage IB1 uterine cervicalcancer, for which the current standard is radical
hysterectomy. This study began in January 2013 and a
total of 240 patients will be accrued from 44
institutions within 5 years. The primary endpoint is 5year survival. The secondary endpoints are overall
survival, relapse-free survival, local relapse-freesurvival, percent completion of modified radical
hysterectomy, percent local relapse, percent
pathological parametrial involvement, days until selfurination and residual urine disappearance, blood loss,
operation time, percent post-operative radiation
therapy, adverse events and severe adverse events.
In addition, we have performed a lot of singleinstitution analyses in clinical setting. For example, toevaluate the efficacy and toxicity of systematic
lymphadenectomy and postoperative radiotherapy(PORT) in the treatment of endometrial cancer (EC), a
total of 256 patients with EC between 2000 and 2008
were retrospectively analyzed. Surgery included
systematic pelvic and aortic lymphadenectomy,
whereas pelvic lymphadenectomy alone was performed
to preoperative stage I patients with superficial
myometrial invasion and G1 endometrioid adenocarcinoma. PORT was administered to 67 patients withpositive lymph nodes, deep myometrial invasion, or
adnexal/peritoneal metastases. Prior to PORT, 37
patients with adnexal/peritoneal involvement or aortic
node metastases were treated with chemotherapy.
Surgery was undergone in 247 patients, including with
215 pelvic lymphadenectomy and 126 aortic
lymphadenectomy. Five-year survival was 97.0% forstage I, 83.3% for stage II, 84.1% for stage III, and45.2% for stage IV. In PORT group, 13 (19%) wererecurred including one (1.5%) intrapelvic recurrence,and five-year survival was 96.7% for intermediate-risk
group and 85.3% for high-risk group. Among thepatients who had received lymphadenectomy, 19

176(8.8%) experienced severe (more than grade 3) ileus
and 18 (8.4%) developed severe lymphocystitis. The
frequency of severe ileus in PORT group was
significantly higher than that in non-PORT group(14/65 vs. 5/150, P<0.0001). The rates of adverse
effects were irrespective of aortic lymphadenectomy.
This study suggested that surgery with systematic
lymphadenectomy followed by PORT was associatedwith good prognosis but increased rates of ileus inpatients with EC. PORT subsequent to lymphadenectomy should limit to relatively high-risk patients.

References published in 2018
(1) Ogishima J, et al.The oncogene KRAS promotes
cancer cell dissemination by stabilizing spheroid
formation via the MEK pathway. BMC Cancer.
2018 Dec 3;18(1):1201.
(2) Chuwa AH, et al. Kaempferol, a natural dietaryflavonoid,
suppresses
17β-estradiol-induced
survivin expression and causes apoptotic cell
death in endometrial cancer. Oncol Lett. 2018
Nov;16(5):6195-6201.
(3) Yoshida M, et al. Intraperitoneal neutrophils
activated by KRAS-induced ovarian cancer exert
antitumor effects by modulating adaptive
immunity. Int J Oncol. 2018 Oct;53(4):1580-1590.
(4) Sato M, et al. Blood Vessel Invasion Is a Strong
Predictor of Postoperative Recurrence inEndometrial Cancer. Int J Gynecol Cancer. 2018
Jun;28(5):875-881.
(5) Nakamura H, et al. Therapeutic significance oftargeting survivin in cervical cancer andpossibility of combination therapy with TRAIL.
Oncotarget. 2018 Feb 5;9(17):13451-13461.
(6) Sato M, et al. Detachment from the primary siteand suspension in ascites as the initial step inmetabolic reprogramming and metastasis to theomentum in ovarian cancer. Oncol Lett. 2018
Jan;15(1):1357-1361.

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 are taking part inboth the clinical and research activities, as well as theteaching activities, with 19 associates of the
University of Tokyo Hospital. For the clinical aspect,they are engaged with in-patient and out-patient careincluding the activities in the delivery units.

Activities
The clinical service for perinatology in the
University of Tokyo Hospital consists of out-patient
clinic and the Delivery Unit. [See Delivery Unit of the
University of Tokyo Hospital]
By the advance of the techniques for prenatal
diagnosis of fetal growth and congenital malformations, the area of fetal medicine is enlarging. Strictmeasurement of fetal growth during pregnancy has
made possible the accurate diagnosis of fetal growth
restriction. New techniques like fetal blood sampling
and three-dimensional ultrasonography have been
introduced into clinical service. 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, we are challenging toestablish objective evaluation of labor progress which
can contribute to safer labor management. Pregnancy

complicated with adenomyosis are associated withvariety of adverse perinatal events, such as second
trimester miscarriage, preeclampsia, and placental
malposition. We are challenging to establish clinicalmanagement contributing to the improvement ofclinical outcomes in pregnancy with adenomyosis.
Recurrent pregnancy loss (RPL) is a condition
when a woman has two or more clinical pregnancy
losses. Our “special clinic for RPL” opens once a
week. About 200 new couples with RPL visit us in ayear. The patients are checked several risk factors of
RPL, such as anatomical, chromosomal, hormonal,
biological, or autoimmune factors. To RPL womenwith autoimmune factors, especially with antiphospholipid antibodies, anti-coagulation therapy is
performed. For low risk group, low dose aspirin isadministered. Heparin injection is performed for highrisk group, for instance, patients with successive
intrauterine fetal death during the second or third
trimester of pregnancy, or those with beta-2glycoprotein I dependent anticardiolipin antibody.
Causative factor is not detectable in a half of thewomen with RPL. Supportive care rather thanpharmacological intervention is important for those
women. In our clinic, mental stress in RPL women isevaluated using K6 scale. We are investigating therelationship of their mental status with the outcome inthe subsequent pregnancy.
The reconstruction of the inpatient’s wards forobstetrics and NICU/GCU/PICU unit was completed
on June, 2019. The new perinatal medical center

178

restarted as one of the largest facility in Japan and isaccommodated with full capacity to treat with allmaternal and fetal diseases. We provide advanced
medical care for more patients.

References published in 2018
1: Nagamatsu T, Fujii T, Schust DJ, Tsuchiya N,
Tokita Y, Hoya M, Akiba N, Iriyama T, Kawana
K, Osuga Y, Fujii T. Tokishakuyakusan, a
traditional Japanese medicine (Kampo) mitigates
iNKT cell-mediated pregnancy loss in mice. Am J
Reprod Immunol. 2018 Oct;80(4):e13021.
2: Katoh Y, Seyama T, Mimura N, Furuya H,
Nakayama T, Iriyama T, Nagamatsu T, Osuga Y,
Fujii T. Elevation of maternal serum sFlt-1 in
pregnancy with mirror syndrome caused by fetal
cardiac failure. Oxf Med Case Reports. 2018 Mar
28;2018(3):omx112.
3: Hoya M, Nagamatsu T, Fujii T, Schust DJ, Oda H,
Akiba N, Iriyama T, Kawana K, Osuga Y, Fujii T.
Impact of Th1/Th2 cytokine polarity induced byinvariant NKT cells on the incidence of pregnancy
loss in mice. Am J Reprod Immunol. 2018
Mar;79(3).
4: Sayama S, Takeda N, Iriyama T, Inuzuka R,
Maemura S, Fujita D, Yamauchi H, Nawata K,
Bougaki M, Hyodo H, Shitara R, Nakayama T,
Komatsu A, Nagamatsu T, Osuga Y, Fujii T.
Peripartum type B aortic dissection in patientswith Marfan syndrome who underwent aortic root
replacement: a case series study. BJOG. 2018
Mar;125(4):487-493.
5: Hashimoto A, Iriyama T, Sayama S, Nakayama T,
Komatsu A, Miyauchi A, Nishii O, Nagamatsu T,
Osuga Y, Fujii T. Adenomyosis and adverse
perinatal outcomes: increased risk of second
trimester miscarriage, preeclampsia, and placental
malposition. J Matern Fetal Neonatal Med. 2018
Feb;31(3):364-369.
6: Toshimitsu M, Kamei Y, Ichinose M, Seyama T,
Imada S, Iriyama T, Fujii T. Atomoxetine, aselective norepinephrine reuptake inhibitor,
improves short-term histological outcomes after
hypoxic-ischemic brain injury in the neonatal
male rat. Int J Dev Neurosci. 2018 Nov;70:34-45.
7: Seyama T, Kamei Y, Iriyama T, Imada S, Ichinose

M, Toshimitsu M, Fujii T, Asou H. Pretreatment
with magnesium sulfate attenuates white matterdamage by preventing cell death of developing
oligodendrocytes. J Obstet Gynaecol Res. 2018
Apr;44(4):601-607.

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 functions, and molecular biologicalmethods are utilized to accomplish this purpose. Basic
researches are currently performed and we arerevealing many interesting findings annualy. We
specifically focus on the role of inflammation andtranscription machinery in these issues.
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 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 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 relatively younger generation might
be a heavy burden for patinets and we have alreadyestablished the primary care system for these women.

References published in 2018
1. Miyashita M, Koga K, Takeuchi A, Makabe T,
Taguchi A, Urata Y, et al. Expression of Nerve
Injury-Induced Protein1 (Ninj1) in Endometriosis.
Reproductive sciences. 2018:1933719118806395.
2. Fukuda S, Hirata T, Neriishi K, Nakazawa A,
Takamura M, Izumi G, et al. Thoracic
endometriosis syndrome: Comparison between
catamenial pneumothorax or endometriosis-related pneumothorax and catamenial hemoptysis.
European journal of obstetrics, and reproductive
biology. 2018;225:118-123.
3. Isono W, Wada-Hiraike O, Kawamura Y, Fujii T,
Osuga Y, Kurihara H. Administration of Oral
Contraceptives Could Alleviate Age-Related
Fertility Decline Possibly by Preventing Ovarian
Damage in a Mouse Model. Reproductive
sciences. 2018;25(9):1413-1423.

180

4. Neriishi K, Hirata T, Fukuda S, Izumi G,
Nakazawa A, Yamamoto N, et al. Long-term
dienogest administration in patients withsymptomatic adenomyosis. The journal ofobstetrics and gynaecology research. 2018;44(8):1439-1444.
5. Akino N, Wada-Hiraike O, Terao H, Honjoh H,
Isono W, Fu H, et al. Activation of Nrf2 might
reduce oxidative stress in human granulosa cells.
Molecular and cellular endocrinology. 2018; 15;
470:96-104.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

182

Department ofPediatrics, Department ofDevelopmental 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., , Youichirou Hirata, M.D., Ph.D.,
Mitsuteru Hiwatari, M.D., Ph.D., (Department of Cell Therapy and Transplantation
Medicine), Hikorou Matsui M.D., Ph. D.

Associate
Hiroko Asakai, M.D, Moe Hidaka, M.D., Kenichirou Hayashi, M.D., Chiharu Irisa, M.D.,
Yuu Kakimoto, M.D., Sho-ichirou Kanda, M.D., Ph.D., ., Yuichi Mitani, M.D.,
Takayuki Mori, M.D., Hiroshi Mutoh, M.D., Riki Nishimura, M.D.,Ph.D.,
Ryo Nakagawa, M.D., PhD. , Katsutoshi Nakano, M.D., Atsushi Satou, M.D. Ph.D.,
Konomi Shimoda, M.D., Takahiro Shindo,M.D.., Satoshi Takenaka, M.D.,
Hiroki Takehara, M.D, Susumu Urata, M.D.,(As of March 31, 2019)

Homepage

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

Introduction and Organization
The former Department of Pediatrics developed into
Department of Pediatrics and Department of Developmental Pediatrics, which comprise subgroups of theGroup of Reproductive, Developmental and Aging
Medicines, Graduate School of Medicine, The University of Tokyo.
Our staff consists of 1 professor, 3 associate
professors, 5 lecturers, 18 associate professors, 14senior residents, 2 research fellow, and graduate
students on March 31, 2014.
The outpatient clinic of our department is locatedon the second floor of the outpatient clinic building.
The inpatient ward and conference rooms are locatedon the second floor of the inpatient clinic building A.
Offices are on the second and third floors of the East
Research Building. Our laboratories are located on thesecond, third and fourth floors of the Research
Building of Internal Medicine and on the second andthird floors of the East Research Building.

Clinical activities
We have specialized outpatient clinics covering allpediatric fields in addition to general pediatrics. In

183

July, 2008, the capacity of the pediatric and pediatricsurgery ward was increased to 100 beds, including 9
beds in the neonatal intensive care unit (NICU), 15
beds in the growing care unit (GCU) and 6 beds in thepediatric intensive care unit (PICU), and our institution is going to fulfill the designation as children’s
hospital affiliated to the university hospital. In
NICU, we are taking care of small premature babies
weighing from 400g to 4,000g often associated withcongenital disorders requiring invasive interventions.
A variety of patients with diseases, such ashematological/oncological disorders (acute leukemia,
neuroblastoma, rhabdomyosarcoma, hepatoblastoma,
brain tumors, etc.), cardiac disorders (congenital heartdiseases and Kawasaki disease), neuromuscular disorders, immunological/allergic disorders (common
variable immunodeficiency, chronic granulomatous
disease and bronchial asthma), renal and urinary tract
diseases (nephrotic syndrome, chronic glomeluronephritis, purpura nephritis and renal and/or urinary
tract anomalies), endocrinological disorders, metabolic disorders and psychosomatic diseases are admitted
in the wards. Approximately 10 patients received
hematopoietic stem cell transplantation every year.
There are patients with severe combined immunodeficiency, aplastic anemia-myelodysplastic syndrome,
relapse/refractory acute lymphoblastic leukemia, acute
myeloid leukemia and high-risk neuroblastoma.
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 with thepatients and help their mothers, providing enormous
comfort to both the patients and their mothers. Various
activities are scheduled for the patients in the hospitalsuch as the 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 clinicalclerjship in the inpatient ward for 2 weeks. During
bedside learning, teaching sessions on variety ofpediatric fields are held every day. We also offer anelective clinical clerkship course for selected students
in their third year. In the outpatient learning of theforth year students, students take histories andperform physical examinations of patients under thesupervision of the teaching staff. During the period,
students visit the local pediatric clinic or hospitals inand around Tokyo. On the last day of clinical learning,
the Professor and an Associate Professor evaluate thestudents’ achievements.

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 and epidemiology. The main subjects of research during the lastyear are listed as follows.
① Hematology/Oncology
group:
To
exploremolecular mechanisms of pediatric malignancies,
we performed target capture sequencing, wholetranscriptome sequencing and genome-wide
methylation analysis in T cell acute lymphoblastic
leukemia (T-ALL), pancreatoblastoma (PBL) andneuroblastoma (NBL) using next-generation
sequencing and array based technologies. Subsequently.
② Nephrology group: Our aim is to reveal themolecular mechanism of pediatric kidney diseases.
We identified novel causative mutations on several
proteinuric diseases including pediatric nephrotic
syndrome.
③ Endocrinology and Metabolism group: We are
analyzing genes and mechanisms involved in
endocrinology and bone diseases. We analyzed
the function of the novel gene identified in a rarecongenital disease using model animals and iPS
cells. We also analyzed the responsible gene forhereditary rickets and found novel mutations andetiology.
④ Cardiology group: We performed genome-wide

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association studies for congenital heart disease andstudies to develop a novel treatment for Kawasaki
disease using mouse models.
⑤ Neurology Group: The pathogenetic mechanism ofacute encephalopathy as well as congenital CNS
anomalies such as tuberous sclerosis is investigated. Regarding congenital cytomegalovirus
infection, an important and common cause ofperinatal brain injury, diagnostic method andtreatment are being investigated.
⑥ Neonatology group: Epigenetic changes in cord
blood and postnatal peripheral blood of pretermand SGA infants are investigated using
epigenome-wide methylation analysis. Influenceof microbiome on neonatal immune function is
also investigated. Neonatal brain function has been
investigated using near infra-red spectro-scopy(NIRS) with researchers of Department of
Education. A clinical trial of formula suppliedwith biotin has been conducted with groups of theother Universities. Cytokine profiles have been
investigated in order to elucidate pathophysiologyof several diseases in perinatal period.

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Ariffin H, Chen J, Takita J, Yasuda T, Mano H,
Johansson B, Yang JJ, Yeoh AE, Hayakawa F,
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Department of Pediatric Surgery
Associate Professor
Jun Fujishiro, M.D., Ph.D.

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

Research Associate
Miho Watanabe, M.D.,Ph.D.
Shohei Takami, M.D.

Homepage

Noriko Hoshino, M.D., Ph.D.

Chizue Uotani, M.D., Ph.D.

Tsubasa Goshima, 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. Nakajo took office as a professor in 1985. Prof.
Nakajo has developed original operative procedures,such as a radical operation for umbilical hernia, andan anti-reflex valve for biliary atresia. These original
operative procedures have since been inherited byother 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. 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.
The present staff includes one associate professor andchief, one lecturer, and five research associates. Morethan 20 members of our department shoulder theclinical work as pediatric surgeons.

Clinical activities
Staff members higher than the level of research
associate take charge of the outpatient clinic from
Monday through Friday. The pediatric surgical190

outpatient clinic takes place in the same location as
the pediatric outpatient clinic, and we closelycooperate with pediatricians to diagnose and treat
patients. We also have specialized outpatient clinics,
liver and biliary tract clinics, a tumor clinic, and aspina bifida clinic. Recently, a second-opinion clinic
opened to provide careful detailed explanations, andthis has received a favorable reception.
Our ward was transferred to the hospital's second floorof B wing from the second floor of south of the A
wing on January 2018. Other pediatric surgicalpatients also are admitted to this ward. We have 16
beds in the ward, and about 400 patients a year are
hospitalized within it. Most operation cases are
inguinal hernia, but we manage other cases such as
respiratory surgery disease, neonatal digestive organ
obstructions, infant malignant tumors such as Wilms'
tumor and neuroblastoma, biliary tract diseases suchas biliary tract dilatation and biliary atresia,
respiratory anomalies such as tracheal stenosis andlung cysts, gastrointestinal anomalies, and urologicaldisorders including hydronephrosis and vesicoureteral
reflux.
We work with other pediatric surgery teams at otherinstitutions who perform endoscopic surgery (laparoscopic surgery/thoracoscopic surgery). We havedeveloped an endoscopic surgery technique forpediatric diseases not covered by insurance, for cases
requiring advanced medical care. Furthermore, we
surgically manage seriously ill, mentally andphysically handicapped infants, as well as patientswith intractable nervous system diseases, to improvetheir quality of life, and we cooperate withpediatricians (neonatologists) to treat patients withprenatal diagnoses.

Education
We expose first and second year students to our dailyclinical work, as well as to our research work, during
the “Free Quarter” and “Research Lab Visit” courses.
These students are guided to be concerned withclinical areas, and are in charge of parts of various
research projects. The students hold a results
announcement party at the end of training. For M2
students, general pediatric surgery and neonatal
surgery instruction is provided by the associate

professor and the lecturer.
An education program is also provided for M3 and M4
students for five days.
The bedside education of pediatric surgery consists ofparticipation in clinical conferences, attendance at
operations, and small group lectures concerning
neonatal surgery; pediatric surgical oncology;
pediatric hepatobiliary surgery; and pediatricemergency medicine, which includes the practice ofperforming cardiac massage and intra-tracheal
intubation using mannequins for practice.
Additionally, we take charge of the core surgicalcurriculum during the “super-rotation” postgraduate
training. We offer a program in which each resident
can learn basic knowledge about pediatric surgicaldisease and surgery and hemodynamic and respiratory
evaluation, as well as basic surgical techniques andpatient management strategies.

Research activities
A low-invasive operation study group first establishedunder the direction of Professor Iwanaka has been
continued since its inception, and has aimed its
research at understanding the safety and efficiency ofendoscopic surgical techniques in children. This study
group also works to develop training tools andinstruments for pediatric endoscopic surgery.
In addition, we have initiated joint research efforts todevelop anastomotic suture reinforcement and surgicaldevices, such as clips and staples, by the use of
bioabsorbable materials.
The subject of trypsin activation in the intestine of
inflammatory bowel disease and the study of cellbiological analysis, a new therapeutic method for
lymphangioma, and analysis of medical big data such
as NCD (National Clinical Database) are also being
evaluated in ongoing research.

References(1) Fujishiro J, Suzuki K, Watanabe M, Uotani C,
Takezoe T, Takamoto N, Hayashi K. Outcomes of
Alagille syndrome following the Kasai operation: asystematic review and meta-analysis. Pediatr Surg
Int . 34(10) 2018 PMID: 30073479(2) Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Postoperative Small Bowel

191

(3)

(4)

(5)

(6)

(7)

(8)

(9)

Obstruction Following Laparoscopic or Open
Fundoplication in Children: A Retrospective
Analysis Using a Nationwide Database. World J
Surg. 42(12) 2018. PMID: 30014291
Ishimaru T, Deie K, Sakai T, Satoh H, Nakazawa A,
Harada K, Takazawa S, Fujishiro J, Sugita N,
Mitsuishi M, Iwanaka T. Development of a Skill
Evaluation System for the Camera Assistant Using
an Infant-Sized Laparoscopic Box Trainer. J
Laparoendosc Adv Surg Tech A. 28(7) 2018. PMID:
29893626
Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Clinical features andpractice patterns of gastroschisis: a retrospective
analysis using a Japanese national inpatient database.
Pediatr Surg Int. 34(7) 2018. PMID: 29770842
Imagawa K, Hayashi H, Sabu Y, Tanikawa K,
Fujishiro J, Kajikawa D, Wada H, Kudo T, Kage M,
Kusuhara H, Sumazaki R. Clinical phenotype andmolecular analysis of a homozygous ABCB11
mutation responsible for progressive infantile
cholestasis. J Hum Genet. 63(5) 2018. PMID:
29507376
Takazawa S, Ishimaru T, Harada K, Deie K, Hinoki
A, Uchida H, Sugita N, Mitsuishi M, Iwanaka T,
Fujishiro J. Evaluation of Surgical Devices Using an
Artificial Pediatric Thoracic Model: A Comparison
Between Robot-Assisted Thoracoscopic Suturing
Versus Conventional Video-Assisted Thoracoscopic
Suturing. J Laparoendosc Adv Surg Tech A. 28(5)2018. PMID: 29406817
Ishimaru T, Sugiyama M, Arai M, Satoh K, Uotani
C, Takahashi M, Takami S, Katoh R, Goshima T,
Fujishiro J. A questionnaire-based comparative
study of postoperative quality of life between
laryngotracheal separation and tracheoesophageal
diversion. Ann Pediatr Surg. 14(2) 2018.
Fujiogi M, Tanaka Y, Amano H, Deie K, Suzuki K,
Kawashima H, Murase N, Uchida H. A newlaparoscopic triangle fixation technique forgastrostomy: a safe and effective procedure for
reduction of the wound infection rate. Nagoya
journal of medical science. 80 2018.
Fujishiro J, Sugiyama M, Ishimaru T, Watanabe M,
Satoh K, Hoshino N, Uotani C, Kutsukake M,
Hirata Y, Oka A. Direct hyperbilirubinemia in
infants with congenital heart disease. Pediatr Int.

60(2) 2018. PMID: 29178522(10) Amano H, Tanaka Y, Tainaka T, Hinoki A,
Kawashima H, Kakihara T, Morita K, Uchida H.
The impact of body weight on stapled anastomosis
in pediatric patients. J Pediatr Surg. 53(10) 2018.
PMID: 29792281(11) Amano H, Uchida H, Tanaka Y, Tainaka T, Mori M,
Oguma E, Kishimoto H, Kawashima H, Arakawa Y,
Hanada R, Koh K. Excellent prognosis of patientswith intermediate-risk neuroblastoma and residual
tumor post-chemotherapy. J Pediatr Surg. 53(9)2018. PMID: 29195808(12) Kanamori Y, Watanabe T, Yorifuji T, Masue M,
Sasaki H, Nio M. Congenital hyperinsulinism
treated by surgical resection of the hyperplastic
lesion which had been preoperatively diagnosed by
18F-DOPA PET examination in Japan: a nationwide
survey. Pediatr Surg Int. 34
2018. PMID:
30076450(13) Tomonaga K, Tahara K, Watanabe T, Ohno M,
Ogawa K, Kutsukake M, Fujino A, Hishiki T,
Kinjyo K, Horikawa R, Katsumata N, Kanamori Y.
A case of congenital hyperthyroidism (autonomous
thyroid adenoma: AA) with a somatic activating
gene mutation in the thyroid-stimulating hormone
receptor (TSHR). J Pediatr Surg Case Reports. 38
2018.
(14) Ishimaru T, Kawashima H, Tainaka T, Suzuki K,
Takami S, Kakihara T, Katoh R, Aoyama T, Uchida
H, Iwanaka T. Laparoscopically Assisted
Anorectoplasty for Intermediate-Type Imperforate
Anus: Comparison of Surgical Outcomes with the
Sacroperineal Approach. J Laparoendosc Adv Surg
Tech A. 2018. PMID: 30277838(15) Suzuki K, Komura M, Terawaki K, Kodaka T,
Gohara T, Komura H, Nakayama Y. Engineeringand repair of diaphragm using biosheet, acollagenous connective tissue membrane, in rabbit.
J Pediatr Surg. 53(2) 2018. PMID: 29241962

Reproductive, Developmental andAging Sciences
3. Aging Sciences

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Department of Geriatric Medicine
Department of Aging Research
Professor
Masahiro Akishita, MD, PhD.

Associate Professor
Sumito Ogawa, MD, PhD.

Lecturer
Yasuhiro Yamaguchi, MD, PhD.

Taro Kojima, MD, PhD.

Masaki Ishii, MD, PhD.

Research Associate
Yumi Kameyama, MD, PhD.

Mitsutaka Yakabe, MD, PhD.

Tsuyoshi Hashizume, 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
the elderly 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, andbone metabolism, besides geriatrics.
The main objective of our research is to elucidate
the pathophysiology of aging process and tounderstand elderly patients from viewpoints of basic
aging science using molecular biology technique andclinical aspects using the recent advancement oftechnology 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
made in weekly professor's round.
Specialized services are provided to out-patientson a daily basis in all areas of internal medicine.

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

194

studies one or two cases, through which the student
learns the techniques of interrogation and physicalexamination, interpretation of laboratory tests, andactual medical procedures. Interpretation of theresults of geriatric assessment is studied throughlectures in a case-oriented manner with an emphasis
placed on the multidisciplinary basis of geriatricpatients.

Research
Various studies have been done over a wide rangeof field, such as clinical observational studies orbasic 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 disorder in 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. Hashizume T, Son BK, Kojima T, Nanao-Hamai
M, Asari Y, Umeda-Kameyama Y, Ogawa S,
Akishita M. Sex difference in the association ofandrogens with aortic calcification. Geriatr
Gerontol Int, 18:1137-1138, 2018
2. Imaeda J, Son BK, Uchiyama E, Tanaka T,
Taniguchi S, Unyaporn S, Miyoshi Y, Tanaka T,
Iijima K, Otsuki T. The Architectural Factors inContinuity of Living for the Elderly After Falls
andFractures.
The
12thInternational
Symposium on Architectural Interchanges in
Asia, 420-424, 2018
3. Inoue H, Yamashita T, Akao M, Atarashi H,
Ikeda T, Okumura K, Koretsune Y, Shimizu W,
Tsutsui H, Toyoda K, Hirayama A, Yasaka M,
Yamaguchi T, Akishita M, Hasebe N, Kario K,
Mizokami Y, Nagata K, Nakamura M, Terauchi
Y, Yamamoto T, Teramukai S, Kimura T,
Kaburagi J, Takita A. Prospective observational
study in elderly patients with non-valvular atrial
fibrillation: Rationale and design of the All
Nippon AF In the Elderly (ANAFIE) Registry. J
Cardiol. 2018; 72:300-306. doi:10.1016/j.jjcc.
2018.02.018.
4. Nomura K, Kojima T, Ishii S, Yonekawa T,
Akishita M, Akazawa M. Identifying drug
substances of screening tool for older persons'appropriate prescriptions for Japanese. BMC
Geriatr.. 2018;18:154. doi:10.1186/s12877-0180835-y.
5. Ogawa N, Mori T, Fujishima I, Wakabayashi H,
Itoda M, Kunieda K, Shigematsu T, Nishioka S,
Tohara H, Yamada M, Ogawa S. Ultrasonography to measure swallowing muscle massand quality in older patients with sarcopenic
dysphagia. J. Am. Med. Dir. Assoc. 19(6): 516522, 2018

195

6. Peng LN, Chou MY, Liang CK, Lee WJ, Kojima
T, Lin MH, Loh CH, Chen LK. Association
between serum activin A and metabolic
syndrome in older adults: Potential of activin A
as a biomarker of cardiometabolic disease. Exp
Gerontol. 2018 Oct 1; 111:197-202. doi:10.1016/
j.exger.2018.07.020.
7. Tanaka T, Takahashi K, Akishita M, Iijima K.
Can bioelectrical impedance analysis using ahome-use device properly estimate sarcopenia incommunity-dwelling older adults? Geriatr
Gerontol Int. 2018;18:1579-1580. doi: 10.1111/
ggi.13538.
8. Tomita N, Kojima T, Ishiki A, Ueda J, Numasaki
M, Okinaga S, Akishita M, Arai H. Could
problem lists summarize comprehensive geriatricassessments? A nationwide cross-sectional
survey on geriatricians' attitudes towards
problem lists. Geriatr Gerontol Int. 2019 Feb;
19(2):159-164. doi: 10.1111/ggi.13574.
9. Shibasaki K, Ogawa S, Yamada S, Ouchi Y,
Akishita M. The role of autonomic nervous
activity, as measured by heart rate variability, on
the effect of mortality in frail elderly with low
blood pressure in long-term care. Geriatr
Gerontol Int. 18(8): 1153-1158, 2018
10. Shibasaki K, Asahi T, Mizobuchi K, Akishita M,
Ogawa S. Rehabilitation strategy for hip fracture
focused on behavioral psychological symptoms
of dementia for the elderly with cognitive
impairment. PLOS ONE. 13: e0200143, 2018
11. Shibasaki K, Yamada S, Akishita M, Ogawa S.
Plasma Leptin Concentration and Sympathetic
Nervous Activity in Older Adults with PhysicalDysfunction. J Endocr Soc. 2:1040-1049,2018
12. Shimada H, Lee S, Akishita M, Kozaki K, Iijima
K, Nagai K, Ishii S, Tanaka M, Koshiba H,
Tanaka T, Toba K. Effects of golf training on
cognition in older adults: a randomised
controlled trial. J Epidemiol Community Health.
2018;72(10):944-950.
13. Tanaka T, Matsumoto H, Son BK, Imaeda S,
Uchiyama E, Taniguchi S, Nishino A, Miura T,
Tanaka T, Otsuki T, Nishide K, Iijima K, Okata
J.
Environmental
andphysicalfactors
predisposing middle-aged and older Japanese

adults to falls and fall-related fractures in thehome. Geriatr Gerontol Int 18:1372-1377, 2018
14. Toyoshima K, Araki A, Tamura Y, Morimoto S,
Ogawa S, Kozaki K, Ebihara S, Hanyu H, Arai H,
Kuzuya M, Iijima K, Sakurai T, Suzuki T, Toba
K, Arai H, Akishita M, Rakugi H, Yokote K, Ito
H, Awata S. Development of the Dementia
Assessment Sheet for Community-based Integrated Care System 8-items, a short version of
the Dementia Assessment Sheet for Communitybased Integrated Care System 21-items, for theassessment of cognitive and daily functions.
Geriatr. Gerontol. Int. 18:1458-1462,2018
15. Yakabe M, Ogawa S, Ota H, Iijima K, Eto M,
Ouchi Y, Akishita M. Inhibition of interleukin-6
decreases atrogene expression and ameliorates
tail suspension-induced skeletal muscle atrophy.
PLOS ONE. 19; 13(1): e0191318, 2018
Reaearch letter
1. Nishimoto M, Tanaka T, Hirano H, Kikutani T,
Watanabe Y, Ohara Y, Huruya H, Iijima K.
Health literacy and oral health behaviors
decrease the risk of oral frailty in Japabeseelderly. Innovation in Aging. 2018; 2 (suppl_1):
719.doi.org/10.1093/geroni/igy023.2660.
2. Tanaka T, Akishita M, Suthutvoravut U, Iijima
K. Polypharmacy asa a predictor of sarcopenia,
Disability, and Mortality among CommunityDwelling Older Adults. Innovation in Aging.
2018; 2 (suppl_1): 988. doi.org/10.1093/geroni/
igy031.3653.
3. Tanaka T, Takahashi K, Suthutvoravut U,
Nishimoto M, Fujisaki M, Yoshizawa Y,
Akishita M, Iijima K. S Frailty as a predictor of
5-year disability and mortality in physically nonfrail adults. Innovation in Aging. 2018; 2(suppl_1): 960-961. doi.org/10.1093/geroni/igy
031.3560.
4. Yamanaka T, Hirota Y, Noguchi-Watanabe M,
Tamai A, Eto M, Iijima K, Akishita M. Changes
in attitude of medical students toward home careduring a required 2-week home care clinicalclerkship program. Geriatr Gerontol Int. 2018;
18:655-656. doi: 10.1111/ggi.13268.

196

Review article
1. kishita M, Kozaki K, Iijima K, Tanaka
T,Shibasaki K, Ogawa S, Arai H. Chapter 1
Definitions and diagnosis of sarcopenia. Geriatr.
Gerontol. Int. 18 Suppl 1: 7-12, 2018.
2. Imaeda J, Son BK, Uchiyama E, Tanaka
T,Taniguchi S, Unyaporn S, Miyoshi Y, Tanaka
T, Iijima K, Otsuki T. The Architectural Factors
in Continuity of Living for the Elderly After
Falls and Fractures. The 12th International
Symposium on Architectural Interchanges in
Asia, 420-424, 2018
3. Jeon B, Tamiya N, Yoshie S, Iijima K, Ishizaki
T.Potentially avoidable hospitalizations, nonpotentially avoidable hospitalizations, and inhospital deaths among residents of long-termcare facilities. Geriatr Gerontol Int. 18(8):12721279, 2018. doi: 10.1111/ggi.13458.
4. Kojima T. Needs for actions against polypharmacy in older people with frailty. Ann
Geriatr Med Res 2018; 22(3): 111-116. doi: 10.
4235/agmr.2018.22.3.111
5. Shimada H, Lee S, Akishita M, Kozaki K, Iijima
K, Nagai K, Ishii S, Tanaka M, Koshiba H,
Tanaka T, Toba K. Effects of Golf Training on
Cognition in Older Adults: A Randomised
Controlled Trial. Journal Epidemiol Community
Health. 72(10):944-950, 2018. doi: 10.1136/jech2017-210052.
6. Shimokata H, Shimada H, Satake S, Endo N,
Shibasaki K, Ogawa S, Arai H. Chapter 2
Epidemiology of sarcopenia. Geriatr Gerontol Int.
2018 May;18 Suppl 1:13-22. doi: 10.1111/ggi.
13320.
7. Tanaka T, Matsumoto H, Son BK, Imaeda S,
Uchiyama E, Taniguchi S, Nishino A, Miura T,
Tanaka T, Otsuki T, Nishide K, Iijima K, Okata
J.
Environmental
andphysicalfactors
predisposing middle-aged and older Japanese
adults to falls and fall-related fractures in thehome. Geriatr Gerontol Int. 18(9):1372-1377,
2018. doi: 10.1111/ggi.13494.
8. Tanaka T, Takahashi K, Akishita M, Iijima K.
Can bioelectrical impedance analysis using ahome-use device properly estimate sarcopenia incommunity-dwelling elderly adults? Geriatr

Gerontol Int. 18(11):1579-1580, 2018. doi: 10.
1111/ggi.13538.
9. Toyoshima K, Araki A, Tamura Y, Iritani O,
Ogawa S, Kozaki K, Ebihara S, Hanyu H, Arai H,
Kuzuya M, Iijima K, Sakurai T, Suzuki T, Toba
K, Arai H, Akishita M, Rakugi H, Yokote K, Ito
H, Awata S. Development of the Dementia
Assessment Sheet for Community ‐ based
Integrated Care System 8‐items, a short versionof the Dementia Assessment Sheet forCommunity ‐ based Integrated Care System
21‐items, for the assessment of cognitive anddaily functions. Geriatr Gerontol Int. 18(10):1458-1462, 2018. doi: 10.1111/ggi.13512.

Surgical Sciences
1. Surgery

198

Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Sato, Masaaki
Nagayama, Kazuhiro
Kitano, Kentaro
Karasaki, Takahiro
Shinohara, Yoshikazu

Homepage

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

History
Study on thoracic surgery has begun since 1916
when symposium on lung surgery was held at annual
meeting of Japan Surgical Society. Clinical and basic
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 Karasaki T), who are certificated as

199

members of the Japanese Board of General Thoracic
Surgery, are in charge of the Department of Thoracic
Surgery, University of Tokyo Hospital. They
specialize in surgical treatment for diseases of therespiratory and the mediastinal organs and the chest
wall, except for diseases of the esophagus andmammary glands.
Lung cancer is the leading cause of cancer death inour country: In 2016, Ministry of Health, Labour andWelfare documented that number of deaths frommalignant neoplasms was approximately 380 thousandout of 1.3 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.
We also treat patients with advanced, unresectable
NSCLC and those with recurrent NSCLC
postoperatively by an immunotherapy. We registered
the patients from 2012 to 2018 to perform acell-transfer therapy with activated autologous
gammadelta T-lymphocytes which has been approvedby the Ministry of Health, Labour and Welfare.
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 24 lung transplants(including 3 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. We haveconducted clinical studies on the immunotherapy with

200

adopted gammadelta- T-cell for the treatment of thepatients with unresectable or recurrent NSCLC.
The following are the major themes under research:(1) Minimally invasive surgeries for thoracic
malignant neoplasms.
(2) Navigation techniques for finding out small
pulmonary lesions through thoracoscopy.
(3) Imaging analysis of lung lung adenocarcinoma(4) Global analysis of oncogenes and suppressor
genes associated with lung cancer.
(5) Application of new fluorescent agents fordiagnosis of lung cancer.
(6) Immunotherapy for lung cancer.
(7) Analysis on mechanisms of acute or chronic
rejection of the allogeneic lung and trachea after
allogeneic transplantation.
(8) Regeneration of the de-cellularized allogeneic
lung with autologous cell seeding(9) Research on extracorporeal membranous oxygenation for bridge use to lung transplantation

Selected publications (2018)
1. Yanagiya M, Nitadori JI, Nagayama K, Anraku M,
Sato M, Nakajima J. Prognostic significance of thepreoperative neutrophil-to-lymphocyte ratio forcomplete resection of thymoma. Surg Today. 2018
Apr; 48(4):422-430.
2. Hino H, Karasaki T, Yoshida Y, Fukami T, Sano A,
Tanaka M, Furuhata Y, Ichinose J, Kawashima M,
Nakajima J. Risk factors for postoperativecomplications and long-term survival in lung cancer
patients older than 80 years. Eur J Cardiothorac Surg.
2018 May 1;53 (5):980-986.
3. Matsumoto K, Sato S, Okumura M, Niwa H, Hida
Y, Kaga K, Date H, Nakajima J, Usuda J, Suzuki
M, Souma T, Tsuchida M, Miyata Y, Nagayasu T.
Frequency of cerebral infarction after pulmonary
resection: a multicenter, retrospective study inJapan. Surg Today. 2018 May;48(5):571-572
4. Hiyama N, Ando T, Maemura K, Sakatani T,
Amano Y, Watanabe K, Kage H, Yatomi Y,
Nagase T, Nakajima J, Takai D. Glutamatecysteine ligase catalytic subunit is associated withcisplatin resistance in lung adenocarcinoma. Jpn J
Clin Oncol. 2018 Apr 1;48(4):303-307

5. Ando T, Kage H, Saito M, Amano Y, Goto Y,
Nakajima J, Nagase T. Early stage non-small celllung cancer patients need brain imaging regardlessof symptoms. Int J Clin Oncol. 2018 Aug;23(4):641-646.
6. Hiyama N, Sasabuchi Y, Jo T, Hirata T, Osuga Y,
Nakajima J, Yasunaga H. The three peaks in age
distribution of females with pneumothorax: anationwide database study in Japan. Eur J
Cardiothorac Surg. 2018 Sep 1;54(3):572-578
7. Hino H, Nitadori JI, Ohno K, Kishimoto S,
Takahashi M, Kakizaki M, Arai T, Nishimura T,
Nakajima J. An Unusual Invasive Ectopic
Thymoma in the Thyroid and Anterior
Mediastinum. Ann Thorac Surg. 2018 Aug;106(2):e65-e67
8. Sato M, Murayama T, Nakajima J. Thoracoscopic
stapler-based "bidirectional" segmentectomy for
posterior basal segment (S10) and its variants. J
Thorac Dis. 2018 Apr;10(Suppl 10):S1179-S1186
9. Wang L, Anraku M, Sato M, Nitadori JI,
Nagayama K, Kitano K, Nakajima J. Impact of the
8th Edition of the UICC-TNM Classification on
Clinical Stage 0-IA Lung Adenocarcinoma: Does
the New Classification Predict Postoperative
Prognosis More Precisely than the Previous One?
Ann Thorac Cardiovasc Surg. 2018 Oct 19;24(5):223-229
10. Kunita A, Morita S, Irisa TU, Goto A, Niki T,
Takai D, Nakajima J, Fukayama M. Micro
RNA-21 in cancer-associated fibroblasts supports
lung adenocarcinoma progression. Sci Rep. 2018
Jun 11;8(1):8838
11. Hino H, Nitadori JI, Kawata M, Murata T, Seki A,
Arai T, Nishimura T, Nakajima J. Combined
operation for thymoma with myasthenia gravis
and coronary artery disease in an octogenarian.
Geriatr Gerontol Int. 2018 Jun;18(6):975-977
12. Kage H, Kohsaka S, Shinozaki-Ushiku A, Ushiku
T, Takai D, Nakajima J, Miyagawa K, Aburatani
H, Mano H, Nagase T. Spontaneous Transformation from EGFR and ALK Wild-Type Lung
Adenocarcinoma to Neuroendocrine Carcinoma. J
Thorac Oncol. 2018 Jul;13(7):e126-e128
13. Sato M, Kuwata T, Kitamura A, Misawa K,
Imashimizu K, Yamanashi K, Ikeda M, Koike T,
Kobayashi M, Kosaka S, Fukai R, Isowa N,

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Nagayama K, Aoyama A, Date H, Nakajima J.
The role of virtual-assisted lung mapping in theresection of ground glass nodules. J Thorac Dis.
2018 May;10(5):2638-2647
14. Maemura K, Watanabe K, Ando T, Hiyama N,
Sakatani T, Amano Y, Kage H, Nakajima J,
Yatomi Y, Nagase T, Takai D. Altered editing levelof microRNAs is a potential biomarker in lungadenocarcinoma. Cancer Sci. 2018 Oct;109(10):3326-3335
15. Nakajima J. Lung cancer surgery for
octogenarians: an option for select patients only? J
Thorac Dis. 2018 Jun;10(Suppl 17):S1920-S1922
16. Karasaki T, Qiang G, Anraku M, Sun Y,
Shinozaki-Ushiku A, Sato E, Kashiwabara K,
Nagayama K, Nitadori JI, Sato M, Murakawa T,
Kakimi K, Fukayama M, Nakajima J. High CCR4
expression in the tumor microenvironment is apoor prognostic indicator in lung adenocarcinoma.
J Thorac Dis. 2018 Aug;10(8):4741-4750
17. Sato M, Kobayashi M, Kojima F, Tanaka F,
Yanagiya M, Kosaka S, Fukai R, Nakajima J.
Effect of virtual-assisted lung mapping inacquisition of surgical margins in sublobar lungresection. J Thorac Cardiovasc Surg. 2018 Oct;156(4):1691-1701.
18. Kawashima M, Sato M, Murakawa T, Anraku M,
Konoeda C, Hosoi A, Kakimi K, Nakajima J. Roleof Toll-like Receptor 4 Expressed by Fibroblastsin Allograft Fibrosis in Mouse Orthotopic
Tracheal Transplantation. Transplant Proc. 2018
Dec;50(10):3863-3872.

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Department of
Cardiac Surgery
Professor
Minoru Ono, M.D.

Associate Professor
Yasutaka Hirata, M.D.

Project Associate Professor
Kan Nawata, 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.

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

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Professor, two Associate Professor and three Lecturer
and seven Associates.

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 350,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There areeight Board-certified surgeons, each of whom has his
own subspecialty among adult cardiac, thoracic aortic
or congenital heart disease. We are famous for offpump coronary 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 2019, 118 cases ofheart transplantation including 12 pediatric patientsand 321 cases of ventricular assist device (VAD)
implantation including 195 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 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 Regular ClinicalClerkship, in which he/she is required to learn
preoperative patient evaluation and management,
surgical treatment and postoperative care, based onparticipatory practice. There are also fifteen small keylectures on cardiovascular surgery. Hands-on practiceis provided during the Advanced Clinical Clerkshipone-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 of

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regenerative medicine to end-stage heart failure, 4)
mechanism analysis of right heart failure anddevelopment of effective pharmacological therapy, 5)development of versatile suture device, 6) clinicalresearch for new drug for spinal cord ischemia, 7)
clinical research to test the safety and efficacy ofartificial pancreas during open heart surgery.

References
1. Shibata M, Itatani K, Hayashi T, Honda T,
Kitagawa A, Miyaji K, Ono M. Flow Energy Loss
as a Predictive Parameter for Right Ventricular
Deterioration Caused by Pulmonary Regurgitation
After Tetralogy of Fallot Repair. Pediatr Cardiol.
2018 Apr; 39(4):731-742.
2. Miyazaki T, Sato S, Kondo T, Kusaka M, Gotoh M,
Saiki Y, Ono M, Kokudo N, Enosawa S, Satoh S,
Soeda E, Furukawa H, Kobayashi E, Nagayasu T.
National survey of de novo malignancy after solidorgan transplantation in Japan. Surg Today 2018
Jun; 48(6): 618-624.
3. Naito N, Takewa Y, Kishimoto S, Iizuka K,
Mizuno T, Tsukiya T, Ono M, Tatsumi E:
Preclinical animal study of the NIPRO-ventricularassist device for use in pediatric patients. J Artif
Organs 2018 Jun; 21(2): 156-163.
4. Saito A, Kumamaru H, Ono M, Miyata H,
Motomura N.: Propensity-matched analysis of aside-clamp versus an anastomosis assist device incases of isolated coronary artery bypass grafting.
Eur J Cardiothorac Surg 2018 Nov 1; 54(5): 889895.
5. Yoshitake S, Kinoshita O, Nawata K, Hoshino Y,
Itoda Y, Kimura M, Yamauchi H, Ono M.: Noveldriveline route for prevention from driveline
infection: Triple tunnel method. J Cardiol. 2018
Oct; 72(4): 363-366.
6. Tsuji M, Kodera S, Oshima T, Uehara M, Kiyosue
A, Ando J, Watanabe M, Yamauchi H, Ono M,
Komuro I.: Coronary Artery Perforation During
Percutaneous Coronary Intervention in a Patientwith a Prior Modified Bentall Procedure. Int HeartJ. 2018 Jul 31; 59(4): 848-853.
7. Takeda N, Inuzuka R, Maemura S, Morita H,
Nawata K, Fujita D, Taniguchi Y, Yamauchi H,
Yagi H, Kato M, Nishimura H, Hirata Y, Ikeda Y,

Kumagai H, Amiya E, Hara H, Fujiwara T,
Akazawa H, Suzuki JI, Imai Y, Nagai R, Takamoto
S, Hirata Y, Ono M, Komuro I.: Impact ofPathogenic FBN1 Variant Types on the
Progression of Aortic Disease in Patients With
Marfan Syndrome. Circ Genom Precis Med. 2018
Jun; 11(6):e002058. doi: 10.1161/ CIRCGEN. 117.
002058.
8. Yoshitake S, Kinoshita O, Nawata K, Hoshino Y,
Itoda Y, Kimura M, Yamauchi H, Ono M. Singlecenter experience of the bridge-to-bridge strategy
using the Nipro paracorporeal ventricular assist
device. J Artif Organs 2018 Dec; 21(4): 405-411.
9. Akiyama D, Nishimura T, Sumikura H, Iizuka K,
Mizuno T, Tsukiya T, Takewa Y, Ono M, Tatsumi
E.: Accurate Method of Quantification of Aortic
Insufficiency During Left Ventricular Assist
Device Support by Thermodilution Analysis: Proofof Concept and Validation by a Mock Circulatory
System. Artif Organs. 2018 Oct; 42(10): 954-960.
10. Nitta D, Kinugawa K, Imamura T, Amiya E,
Hatano M, Kinoshita O, Nawata K, Ono M,
Komuro I.: A Useful Scoring System For
Predicting Right Ventricular Assist Device
Requirement Among Patients with a Paracorporeal
Left Ventricular Assist Device. Int Heart J. 2018
Sep 26; 59(5): 983-990.
11. Hasumi E, Fujiu K, Kojima T, Kinoshita O,
Nawata K, Yamauchi H, Ono M, Komuro I.: Novel
extraction technique of retained pacemaker anddefibrillator lead during heart transplantation.
PLoS One. 2018 Sep 6; 13(9): e0203172.
eCollection 2018.
12. Komae H, Ono M, Shimizu T: Cell Sheet-Based
Vascularized Myocardial Tissue Fabrication. Eur
Surg Res. 2018 Sep 21; 59(3-4): 276-285.
13. Lee Y, Ohno T, Uemura Y, Osanai A, Miura S,
Taketani T, Fukuda S, Ono M, Takamoto S: Impact
of Complete Revascularization on Long-Term
Outcomes After Coronary Artery Bypass Graftingin Patients With Left Ventricular Dysfunction. Circ
J. 2018 Dec 25;83(1):122-129.
14. Kawashima D, Maeba S, Saito M, Ono M:
Postinfarction ventricular septal rupture closure
without ventriculotomy. Asian Cardiovasc Thorac
Ann. 2018 Oct; 26(8): 628-631.

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15. 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.
16. 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.
PMID: 30374810
17. Ando T, Noguchi S, Enokida T, Yamato A, Kage
H, Yamauchi Y, Okazaki A, Wakabayashi Y,
Moriya K, Yamauchi H, Ono M, Nagase T.:
Infectious Aneurysm Caused by Citrobacter koseri
in an Immunocompetent Patient. Intern Med. 2019
Mar 15; 58(6): 813-816.
18. Nunoda S, Sasaoka T, Sakata Y, Ono M, Sawa Y,
Isobe M; Heart Transplantation Committee of theJapanese Circulation Society: Survival of Heart
Transplant Candidates in Japan. Circ J. 2019 Feb
25; 83(3): 681-683.
19. 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.
20. Yanagie H, Fujihara M, Sakurai Y, Mouri K,
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
21. Kadowaki H, Amiya E, Hoshino Y, Tamura M,
Uehara M, Nakayama A, Nawata K, Domoto Y,
Saeki T, Ono M, Komuro I.: Enormous Aneurysmin Coronary Artery Fistula With Immunoglobulin
G4-Related Disease. Can J Cardiol. 2019 Feb;
35(2): 230.e1-230.e3.

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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
Masato Nishida M.D., Ph.D.

Koichi Yagi M.D., Ph.D.

Kotaro Wakamatsu M.D., Ph.D.
Yasuhiro Okumura M.D., Ph.D.
Sayuri Iitaka M.D.

Takako Wakeda M.D., Ph.D.
Masayuki Takegami M.D.
Kota Itamoto M.D.

Homepage

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

207

which often extend to the terminal stage. We believethat patient care encompassing the entire lifespanprovides a wealth of valuable information concerning
the appropriateness of current treatment strategy, theestablishment of new surgical designs, the development of new basic research activities which can muchcontribute to clinical fields, and indications ofdesirable modes of terminal care.
Fostering good surgeons as well as scientists whomeet both clinical and academic needs has always
been the guiding principle of our Department.

Educational Activities:
The new system of clinical clerkship for medical
students has begun from 2013. During those periods,
the students are educated strictly and gently by staffs.
Clinical exercises, e.g., blood sampling, injection, andligation, etc., are performed. They can attend theoperations as an assistant.
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)
radicalesophagectomy with extended lymphadenectomy has

been applied, which shows less pulmonary
complications, shorter postoperative hospital stay andbetter QOL after surgery. To develop this surgicalprocedure, we and other surgeons sharing same will
established the Japanese Society for Nontransthoracic
Radical Esophagectomy in 2016. New methods ofendoscopic/ laparoscopic full-thickness resection,
non-exposed endoscopic wall-inversion surgery(NEWS) has been developed for submucosal gastrictumor as a collaboration of endoscopy andlaparoscopy, and now NEWS is applied for somegastric cancer. Elimination of the pulmonary
complications after esophagectomy and the detectionof minute metastasis for the establishment 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,

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where the radiologists and endoscopists as well as
surgeons attend together and have discussions frankly.
Generally, elective surgery is scheduled on Tuesday，
Wednesday and Thursday. The statistics shows 180
gastric and 70 esophageal cancer surgeries are
performed a year, respectively. Hernia surgery is also
performed. Laparoscopic sleeve gastrectomy formorbid obesity has started in June 2016, and thenumber of cases is steadily increasing. All residents
and medical personnel work many extra hours withhigh motivation whenever it is necessary for the goodof the patients.

References
1) Sugawara K, Yamashita H, Seto Y.Reply to"Nodal skip metastasis may undermine thepredictive power of topographic pN classificationin esophageal squamous cell carcinoma".Surgery.
2018 Jul 16. pii: S0039-6060(18)30308-8. doi: 10.
1016/j.surg.2018.06.001.
2) Mori K, Ino K, Yoshimura S, Aikou S, Yagi K,
Nishida M, Mitsui T, Okumura Y, Yamagata Y,
Yamashita H, Nomura S, Seto Y. Mediastinoscopic view of the bronchial arteries in a series ofsurgical cases evaluated with three-dimensional
computed tomography.Esophagus. 2018 Jul;15(3):173-9.
3) Zhang CD, Yamashita H, Zhang S, Seto Y.
Reevaluation of laparoscopic versus open distal
gastrectomy for early gastric cancer in Asia: A
meta-analysis of randomized controlled trials.Int J
Surg. 2018 May 31;56:31-43. doi: 10.1016/j.
ijsu.2018.05.733. [Epub ahead of print] Review.
4) Shimizu N, Oki E, Tanizawa Y, Suzuki Y, Aikou
S, Kunisaki C, Tsuchiya T, Fukushima R, Doki Y,
Natsugoe S, Nishida Y, Morita M, Hirabayashi N,
Hatao F, Takahashi I, Choda Y, Iwasaki Y, Seto
Y. Effect of early oral feeding on length of
hospital stay following gastrectomy for gastriccancer: a Japanese multicenter, randomized
controlled trial.Surg Today. 2018 May 2. doi:
10.1007/s00595-018-1665-4. [Epub ahead ofprint]
5) Urabe M, Yamashita H, Nishida M, Seto Y. Giant
Brunner's gland adenoma of the duodenum
manifested by melena.ANZ J Surg. 2018 Apr 25.

doi: 10.1111/ans.14491. [Epub ahead of print] No
abstract available.
6) Mitsui T, Yamashita H, Aikou S, Niimi K,
Fujishiro M, Seto Y. Non-exposed endoscopic
wall-inversion surgery for gastrointestinal stromal
tumor.Transl Gastroenterol Hepatol. 2018 Mar 16;
3:17. doi: 10.21037/tgh.2018.03.02. eCollection
2018.
7) Wakamatsu K, Lo Menzo E, Szomstein S, Seto Y,
Chalikonda S, Rosenthal RJ. Feasibility of
Laparoscopic Resection of Gastrointestinal
Stromal Tumor of the Stomach.J Laparoendosc
Adv Surg Tech A. 2018 May;28(5):569-73.
8) Yoshimura S, Mori K, Yamagata Y, Aikou S,
Yagi K, Nishida M, Yamashita H, Nomura S, Seto
Y. Quality of life after robot-assisted transmediastinal radical surgery for esophageal cancer.
Surg Endosc. 2018 May;32(5):2249-54.
9) Urabe M, Yamashita H, Uemura Y, Tanabe A,
Yagi K, Aikou S, Seto Y. Non-linear association
between long-term outcome and preoperative
neutrophil-to-lymphocyte ratio in patients undergoing curative resection for gastric cancer: aretrospective analysis of 1335 cases in atetrachotomous manner.Jpn J Clin Oncol. 2018
Apr 1;48(4):343-9.
10) Wakamatsu K, Perez Quirante F, Montorfano L,
Lo Menzo E, Seto Y, Rosenthal RJ. Laparoscopic
treatment of gastroparesis: a single center
experience. Surg Obes Relat Dis. 2018 Feb; 14(2):200-5.
11) Okumura T, Seto Y, Aikou S, Moriyama M,
Sekine S, Hashimoto I, Shibuya K, Hojo S,
Yoshioka I, Nagata T, Fujii T. Mediastinoscopic
salvage esophagectomy for recurrent esophageal
squamous cell carcinoma after definitive
chemoradiotherapy in a previously pneumonectomized patient. Asian J Endosc Surg. 2018
Nov 8. doi: 10.1111/ases.12658. [Epub ahead ofprint]
12) 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. 2018 Sep 27. doi: 10.1002/
jpen.1446. [Epub ahead of print]

20913) Urabe M, Ushiku T, Shinozaki-Ushiku A, Iwasaki
A, Yamazawa S, Yamashita H, Seto Y, Fukayama
M. Adenocarcinoma of the esophagogastricjunction and its background mucosal pathology: A
comparative analysis according to Siewert
classification in a Japanese cohort. Cancer Med.
2018 Oct; 7(10):5145-5154. doi: 10.1002/cam4.
1763. Epub 2018 Sep 21.
14) Yamashita H, Yagi K, Seto Y. How should we
define the no. 3b lesser curvature lymph node?
Gastric Cancer. 2017;20(3):558-9.
15) Mori A, Seto Y, Ushijima T. LINC00162 confers
sensitivity to 5-Aza-2'-deoxycytidine via modulation of an RNA splicing protein, HNRNPH1.
Zong L, Hattori N, Yasukawa Y, Kimura K,
Oncogene. 2019 doi: 10.1038/s41388-019-0792-8.
[Epub ahead of print]

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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 and 1
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

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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 (2017-2018)
1. Yang PC, Akamatsu N, Hasegawa K, et al. Twenty
years of Milan criteria: how far do we go.
Hepatobiliary Surg Nutr. 2016;5(6):488.
2. Aoki T, Matsushita H, Hoshikawa M, et al.
Adjuvant combination therapy with gemcitabine
and autologous gammadelta T-cell transfer inpatients with curatively resected pancreatic cancer.
Cytotherapy. 2017;19(4):473.
3. Arita J, Sakamoto Y, Hasegawa K, et al.
Assessment of preoperative liver function basedon indocyanine green clearance. Proc Natl Acad
Sci U S A. 2017;66(2):675.
4. Gupta R, Togashi J, Akamatsu N, et al. Impact ofincidental/misdiagnosed intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma on the outcomes of livertransplantation: an institutional case series andliterature review. Surg Today. 2017;47(8):908.
5. Hasegawa K, Yamamoto S, Inoue Y, et al.
Hepatocellular Carcinoma With Bile Duct Tumor
Thrombus: Extrahepatic Bile Duct Preserving or
Not? Reply. Ann Surg. 2017;266(6):e63.
6. Ikegami T, Ueda Y, Akamatsu N, et al.
Asunaprevir and daclatasvir for recurrent hepatitis
C after liver transplantation: A Japanese multicenter experience. Clin Transplant. 2017;31(11).
7. Ishizawa T, Lim C, Kokudo N. Reply to "Liver

Malignancies in Segment VII: The Role ofRobot-assisted Surgery". Ann Surg. 2017;265(6):E81.
8. Ito K, Akamatsu N, Kokudo N. Reply. Liver
Transpl. 2017;23(4):563.
9. Kaibori M, Kon M, Kitawaki T, et al. Comparisonof anatomic and non-anatomic hepatic resection
for hepatocellular carcinoma. J Hepatobiliary
Pancreat Sci. 2017;24(11):616.
10. Kaibori M, Yoshii K, Yokota I, et al. Impact ofAdvanced Age on Survival in Patients Undergoing Resection of Hepatocellular Carcinoma:
Report of a Japanese Nationwide Survey. Ann
Surg. 2017.
11. Kawaguchi Y, Hasegawa K, Okura N, et al.
Influence of outflow-obstructed liver volume andvenous communication development: A threedimensional volume study in living donors. Liver
Transpl. 2017;23(12):1531.
12. Kawaguchi Y, Nomura Y, Nagai M, et al. Livertransection using indocyanine green fluorescenceimaging and hepatic vein clamping. Br J Surg.
2017;104(7):898.
13. Kawaguchi Y, Sakamoto Y, Ito D, et al. Statin use
is associated with a reduced risk of hepatocellular
carcinoma recurrence after initial liver resection.
Biosci Trends. 2017;11(5):574.
14. Kiryu S, Akai H, Nojima M, et al. Impact ofhepatocellular carcinoma heterogeneity on
computed tomography as a prognostic indicator.
2017;7(1):12689.
15. Kobayashi K, Hasegawa K, Kokudo T, et al.
Extended Segmentectomy II to Left Hepatic Vein:
Importance of Preserving Umbilical Fissure Vein
to Avoid Congestion of Segment III. J Am Coll
Surg. 2017;225(3):e5.
16. Kobayashi K, Mori K, Arita J, et al. Safety andefficacy of venous reconstruction in liverresection using cryopreserved homologous veins.
J Surg Oncol. 2017;24(9):511.
17. Kobayashi Y, Kawaguchi Y. Portal vein territory
identification using indocyanine green fluorescence imaging: Technical details and short-term
outcomes. 2017;116(7):921.
18. Kobayashi Y, Sakamoto Y. Vascular anatomy of
the jejunal mesentery and complications
associated with division of the first jejunal venous

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trunk during pancreaticoduodenectomy. 2017.
19. Kokudo T, Hasegawa K, Kokudo N. Reply.
Hepatology. 2017.
20. Kokudo T, Hasegawa K, Matsuyama Y, et al.
Liver resection for hepatocellular carcinoma
associated with hepatic vein invasion: A Japanesenationwide survey. Hepatology. 2017;66(2):510.
21. Lim C, Shinkawa H, Hasegawa K, et al. Salvage
liver transplantation or repeat hepatectomy forrecurrent hepatocellular carcinoma: An intent-totreat analysis. Liver Transpl. 2017;23(12):1553.
22. Maki H, Aoki T, Ishizawa T, et al. Intraductal
papillary neoplasm originating from ananomalous bile duct. Clin J Gastroenterol. 2017;10(2):174.
23. Masuda K, Kaneko J, Kawaguchi Y, et al.
Diagnostic accuracy of indocyanine green
fluorescence imaging and multidetector row
computed tomography for identifying hepatocellular carcinoma with liver explant correlation.
Hepatol Res. 2017;47(12):1299.
24. Mihara Y, Matsuura K, Sakamoto Y, et al.
Production of pancreatic progenitor cells fromhuman induced pluripotent stem cells using athree-dimensional suspension bioreactor system. J
Tissue Eng Regen Med. 2017;11(11):3193.
25. Mise Y, Hasegawa K, Satou S, et al. How Has
Virtual Hepatectomy Changed the Practice ofLiver Surgery?: Experience of 1194 Virtual
Hepatectomy Before Liver Resection and Living
Donor Liver Transplantation. Ann Surg. 2017.
26. Miyata Y, Ishizawa T, Kamiya M, et al.
Intraoperative imaging of hepatic cancers using
gamma-glutamyltranspeptidase-specificfluorophore enabling real-time identification andestimation of recurrence. Sci Rep. 2017;7(1):3542.
27. Mizuno H, Koya J, Fujioka Y, et al. Extranodal
NK/T cell lymphoma in a living donor livertransplant recipient. Ann Hematol. 2017;96(6):1051.
28. Nakagawa H, Suzuki N, Hirata Y, et al. Biliary
epithelial injury-induced regenerative response by
IL-33 promotes cholangiocarcinogenesis fromperibiliary glands. 2017;114(19):E3806.
29. Nishioka Y, Shindoh J, Yoshioka R, et al. ClinicalImpact of Preoperative Chemotherapy on Micro-

scopic Cancer Spread Surrounding Colorectal
Liver Metastases. Ann Surg Oncol. 2017;24(8):2326.
30. Notake T, Kobayashi A, Shinkawa H, et al.
Nomogram predicting long-term survival after the
diagnosis of intrahepatic recurrence of hepatocellular carcinoma following an initial liverresection. Int J Clin Oncol. 2017;22(4):715.
31. Ohtomo K, Xia J, Inagaki Y, et al. Combination of
Cinobufacini
andDoxorubicin
Increases
Apoptosis of Hepatocellular Carcinoma Cells
through the Fas- and Mitochondria-MediatedPathways. Sci Rep. 2017;45(7):1537.
32. Sakamoto Y, Kokudo N, Kawaguchi Y, et al.
Clinical Anatomy of the Liver: Review of the 19th
Meeting of the Japanese Research Society ofClinical Anatomy. Liver Cancer. 2017;6(2):146.
33. Sakamoto Y, Kokudo N, Watadani T, et al.
Proposal of size-based surgical indication criteria
for liver hemangioma based on a nationwide
survey in Japan. J Hepatobiliary Pancreat Sci.
2017;24(7):417.
34. Shinkawa H, Hasegawa K, Arita J, et al. Impact of
Sustained Virological Response to Interferon
Therapy on Recurrence of Hepatitis C VirusRelated Hepatocellular Carcinoma. Ann Surg
Oncol. 2017;24(11):3196.
35. Shirata C, Kaneko J, Inagaki Y, et al. Nearinfrared photothermal/photodynamic therapy withindocyanine green induces apoptosis of hepatocellular carcinoma cells through oxidative stress.
Sci Rep. 2017;7(1):13958.
36. Tanaka M, Ishikawa S, Ushiku T, et al. EVI1
modulates oncogenic role of GPC1 in pancreatic
carcinogenesis. Oncotarget. 2017;8(59):99552.
37. Tani K, Ishizawa T, Sakamoto Y, et al. SurgicalApproach to "Right Hepatic Core": Deepest
Region Surrounded by Major Portal Pedicles andRight Hepatic Vein. Dig Surg. 2017.
38. Tani K, Shindoh J, Takamoto T, et al. Kinetic
Changes in Liver Parenchyma After Preoperative
Chemotherapy for Patients with Colorectal Liver
Metastases. J Gastrointest Surg. 2017;21(5):813.
39. Ueda Y, Ikegami T, Akamatsu N, et al. Treatment
with sofosbuvir and ledipasvir without ribavirinfor 12 weeks is highly effective for recurrent
hepatitis C virus genotype 1b infection after living

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donor liver transplantation: a Japanese multicenter
experience. J Gastroenterol. 2017;52(8):986.
40. Yamashita S, Sakamoto Y, Yamamoto S, et al.
Efficacy of Preoperative Portal Vein Embolization
Among Patients with Hepatocellular Carcinoma,
Biliary Tract Cancer, and Colorectal Liver
Metastases: A Comparative Study Based onSingle-Center Experience of 319 Cases. Ann Surg
Oncol. 2017;24(6):1557.
41. Arita J, Akamatsu N, Kaneko J, et al. Proximal
total splenic artery embolization for refractory
hepatic encephalopathy. J Surg Oncol. 2018;11(2):156.
42. Hoshikawa M, Aoki T, Matsushita H, et al. NK
cell and IFN signatures are positive prognostic
biomarkers for resectable pancreatic cancer.
Biochem Biophys Res Commun. 2018;495(2):2058.
43. Igaki H. A systematic review of publications on
charged particle therapy for hepatocellular
carcinoma. J Surg Oncol. 2018;23(3):423.
44. Ito K, Kawaguchi Y, Sakamoto Y, et al. Predictorsof Postoperative Non-Chylous Massive Discharge
after Pancreaticoduodenectomy for Pancreatic
Ductal Adenocarcinoma. Dig Surg. 2018;35(3):252.
45. Kaibori M, Yoshii K, Hasegawa K, et al. Treatment Optimization for Hepatocellular Carcinoma
in Elderly Patients in a Japanese Nationwide
Cohort. Ann Surg. 2018.
46. Kawaguchi Y, Fuks D, Kokudo N, et al. Difficultyof Laparoscopic Liver Resection: Proposal for a
New Classification. Ann Surg. 2018;267(1):13.
47. Kobayashi Y, Omichi K, Kawaguchi Y, et al.
Intraoperative real-time tissue elastographyduring laparoscopic hepatectomy. HPB (Oxford).
2018;20(1):93.
48. Kokudo T, Kokudo N, Hasegawa K. Negative
phase 3 study of (90)Y microspheres versus
sorafenib in HCC. Lancet Oncol. 2018;19(2):e68.
49. Mizumoto M, Okumura T, Hasegawa K, et al.
Partial TIPE ALPPS for Perihilar Cancer. Int J
Clin Oncol. 2018;267(2):e18.
50. 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.
51. 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.
52. 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.
53. Shirata C, Hasegawa K, Kokudo T, et al. SurgicalSite Infection after Hepatectomy for Hepatocellular Carcinoma. Dig Surg. 2018;35(3):204.
54. 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.
55. 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.
56. 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.
57. 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):4070-4080.
58. Kobayashi K, Kawaguchi Y, Arita J, et al.
Parenchyma-sparing
liver
resectionforhepatocellular carcinoma in left lateral section isassociated with better liver volume recovery. HPB(Oxford). 2018;20(10):949-955
59. Takemura N, Aoki T, Hasegawa K, et al.
Hepatectomy for hepatocellular carcinoma after
perioperative management of portal hypertension.
Br J Surg 2019 (in press)
60. Matsumura M, Yamashita S, Ishizawa T, et al.
Oncological benefit of complete metastasectomy
for simultaneous colorectal liver and lungmetastases. Am J Surg 2019 (in press)

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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.

Associate
Yoshiyuki Akiyama, M.D., Ph.D., Keina Nozaki, M.D., Kotaro Takemura, M.D.,
Ituki Yoshimura, M.D., Takahiro Oshina, M.D., Yoko Hirai, M.D., Yuriko Sugihara, M.D.,
Takeru Morishige, M.D., Ibuki Tsuru, M.D., Hiroki Ko, M.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. The total number of inpatientswas about 14,437 from January 2018 to December
2018. Elective operations are performed on Tuesday,
Wednesday, Thursday and Friday. 1,519 operations
were performed in 2018. The numbers of main
operations are adrenalectomy 16, nephrectomy 25,
partial nephrectomy 36, nephroureterectomy 28,
radical cystectomy 18, radical prostatectomy 130,transurethral resection of the bladder tumor (TUR-Bt)
168, transurethral resection of the prostate (TUR-P) 11,
laparoscopic surgery 52, and Robot assisted surgery

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168 (radical prostatectomy 130, partial nephrectomy
29, radical cystectomy 9).
At the weekly professor’s round on Wednesday, dataof all in patients are presented and appropriate
treatment strategies are recommended for them. On
Wednesday evening, a clinical conference is held for
discussing cases with difficult problems in detail andthe best treatment is chosen for each case.
In out-patient clinic, services are provided from
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 14,437 patientdays from January 2018 to December 2018.

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. Yamada D, Kume H, Miyazaki H, Tanaka M,
Takata M, Uemura Y, Morikawa T, Enomoto Y,
Suzuki M, Nishimatsu H, Nakagawa T, Fujimura
T, Fukuhara H, Igawa Y and Homma Y. A
prospective randomized controlled study on the
Suppression of Prostate Cancer by Naftopidil(SNAP). Preventive Medicine and Community
Health, 1(1) , 1-6, 2018.
2. Takizawa A, Kawai K, Kawahara T, Kojima T,
Maruyama S, Shinohara N, Akamatsu S, Kamba T,
Nakamura T, Ukimura O, Jikuya R, Kishida T,
Kakimoto K, Nishimura K, Harabayashi T,
Nagamori S, Yamashita S, Arai Y, Sawada Y,
Sekido N, Kinoshita H, Matsuda T, Nakagawa T,
Homma Y, Nishiyama H. The usefulness of
testosterone
administrationinidentifying
false-positive elevation of serum human chorionicgonadotropin in patients with germ cell tumor. J
Cancer Res Clin Oncol, 144, 109-115, 2018.
3. Azuma T, Matayoshi Y, Sato Y, Nagase Y. Effectof dutasteride on castration‑resistant prostatecancer. Mol Clin Oncol, 8, 133-136, 2018.
4. Takizawa A, Kawai K, Kawahara T, Kojima T,
Maruyama S, Shinohara N, Akamatsu S, Kamba T,
Nakamura T, Ukimura O, Jikuya R, Kishida T,
Kakimoto K, Nishimura K, Harabayashi T,
Nagamori S, Yamashita S, Arai Y, Sawada Y,
Sekido N, Kinoshita H, Matsuda T, Nakagawa T,
Homma Y, Nishiyama H. The usefulness of
testosterone
administrationinidentifying
false-positive elevation of serum human chorionicgonadotropin in patients with germ cell tumor. J
Cancer Res Clin Oncol, 144, 109-15, 2018.
5. Kamei J, Ito H, Aizawa N, Hotta H, Kojima T,
Fujita Y, Ito M, Homma Y and Igawa Y.
Age-related changes in function and gene
expression of the male and female mouse bladder.
Scientific Reports, 8, 2089, 2018.
6. Ikebe T, Okuno R, Sasaki M, Kanda Y, Otsuka H,
Kawahara R, Ohya H, Suzuki M, Uchida K,
Nihonmatsu H, Ohnishi M. Molecular characterization and antibiotic resistance of Streptococcus
dysgalactiae subspecies equisimilis isolated frompatients with streptococcal toxic shock syndrome.
J Infect Chemother, 24, 117-122, 2018.

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7. Urakami S, Inoshita N, Oka S, Miyama Y,
Nomura S, Arai M, Sakaguchi K, Kurosawa K,
Okaneya T. Clinicopathological characteristics ofpatients with upper urinary tract urothelial cancer
with loss of immunohistochemical expression of
the DNA mismatch repair proteins in universal
screening. Int J Urol, 25, 151-156, 2018.
8. Akiyama Y, Maeda D, Morikawa T, Niimi A,
Nomiya A, Yamada Y, Igawa Y, Goto A,
Fukayama M, Homma Y. Digital quantitative
analysis of mast cell infiltration in interstitial
cystitis. Neurourol Urodyn, 37, 650-7, 2018.
9. Matsumoto A, Nakagawa T, Kanatani A, Ikeda M,
Kawai T, Miyakawa J, Taguchi, S, Naito A,
Otsuka M, Nakanishi Y, Suzuki M, Koga F,
Nagase Y, Kondo Y, Okaneya T, Tanaka Y,
Miyazaki H, Fujimura T, Fukuhara H, Kume H,
Igawa Y, Homma Y. Preoperative chronic kidneydisease is predictive of oncological outcome ofradical cystectomy for bladder cancer. World J
Urol, 36, 249-56, 2018.
10. Aruga S, Kuwana N, Shiroki Y, Takahashi S,
Samejima N, Watanabe A, Seki Y, Igawa Y andHomma Y. Effect of cerebrospinal fluid shunt
surgery on lower urinary tract dysfunction in
idiopathic normal pressure hydrocephalus.
Neurourol Urodyn, 37, 1053-1059, 2018.
11. Kamei J, Yazawa S, Yamamoto S, Kaburaki N,
Takahashi S, Takeyama M, Koyama M, Homma Y,
Arakawa S, Kiyota H. Risk factors for surgicalsite infection after transvaginal mesh placement ina nationwide Japanese cohortNeurourol Urodyn,
37, 1074-1081, 2018.
12. Niimi A, Igawa Y, Aizawa N, Honma T, Nomiya
A, Akiyama Y, Kamei J, Fujimura T, Fukuhara H
and Homma Y. Diagnostic value of urinary
CXCL10 as a biomarker for predicting Hunnertype interstitial cystitis. Neurourol Urodyn, 37,
1113-1119, 2018.
13. Chen L , Azuma T(equally first author) , Yu W ,Zheng X, Luo L, Chen L. B7-H1 Maintains the
Polyclonal T-Cell Response by Protecting
Dendritic Cells from Cytotoxic T Lymphocyte
Destruction.Proc Natl Acad Sci U S A, 115,
3126-3131, 2018.
14. Takada I, Tsuchiya M, Yanaka K, Hidano S,
Takahashi S, Kobayashi T, Ogawa H, Nakagawa S,

Makishima M. Ess2 bridges transcriptional
regulators and spliceosomal complexes via
distinct interactingdomains. Biochem Biophys
Res Commun, 2, 597-604, 2018.
15. 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, 37, 1441-1447,
2018.
16. Fujisaki A, Shigeta M, Shimoinaba M, Yoshimura
Y. Influence of adequate pelvic floor muscle
contraction on the movement of the coccyx during
pelvic floor muscle training. J Phys Ther Sci, 30,
544-548, 2018.
17. Kitamura T, Suzuki M, Koyama Y, Shigehara K.
Long-term persistence of human papillomavirus
in the skin of the glans penis of elderly men above
80 years of age. Int J STD AIDS, 29, 552-556,
2018.
18. Sugihara T, Yasunaga H, Matsui H, Ishikawa A,
Fujimura T, Fukuhara H, Fushimi K, Homma Y,
Kume H. A skill degradation in laparoscopic
surgery after a long absence: assessment based on
nephrectomy case. Mini-invasive surgery, 2, 11,
2018.
19. Kinjo M, Sekiguchi Y, Yoshimura Y, Nutahara K.
Long-term Persistence with Mirabegron versus
Solifenacin in Women with Overactive Bladder:
Prospective, Randomized Trial. Low Urin Tract
Symptoms, 10, 148-152, 2018.
20. 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, 2018.
21. Otsuka M, Taguchi S, Nakagawa T, Morikawa T,
Maekawa S, Miyakawa J, Matsumoto A,
Miyazaki H, Fujimura T, Fukuhara H, Kume H,
Igawa Y, Homma Y. Clinical significance ofrandom bladder biopsy in primary T1 bladdercancer. Mol Clin Oncol, 8, 665-70, 2018.

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22. Makino K, Nakagawa T, Ito E, Kasahara I, Murata
T, Fujimura T, Fukuhara H, Homma Y.
Oncological and peri-surgical outcomes of radical
prostatectomy for non-metastatic prostate cancer
with prostate-specific antigen level of 50 ng/mL
or greater. Jpn J Clin Oncol, 48, 485-90, 2018.
23. Aizawa N, Fujimori Y, Kobayashi J, Nakanishi O,
Hirasawa H, Kume H, Homma Y, Igawa Y.
KPR-2579, a novel TRPM8 antagonist, inhibits
hyperactivity of the primary bladder afferent
nerves induced by acetic acid in rats. Neurourol
Urodyn, 37, 1633-1640, 2018.
24. 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. Blood vessel
invasion is a strong predictor of postoperative
recurrence in endometrial cancer. International
Journal of Gynecological Cancer, 28(5), 875-881,
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25. Obinata D, Sugihara T, Yasunaga H, Mochida J,
Yamaguchi K, Murata Y, Yoshizawa T, Matsui T,
Matsui H, Sasabuchi Y, Fujimura T, Homma Y,
Takahashi S. Tension-free vaginal mesh surgery
versus laparoscopic sacrocolpopexy for pelvic
organ prolapse: Analysis of perioperative
outcomes using a Japanese national inpatient
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26. Taguchi S, Fukuhara H, Miyakawa J, Morikawa T,
Naito A, Kawai T, Fujimura T, Kume H.
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significanceofneutrophil-tolymphocyte ratio in collecting duct carcinoma.
Jpn J Clin Oncol, 48, 692-694, 2018.
27. Azuma T, Sato Y, Ohno T, Azuma M, Kume H.
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28. Kinjo M, Yoshimura Y, Kitagawa Y, Okegawa T,
Nutahara K. Sexual activity and quality of life inJapanese pelvic organ prolapse patients after
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29. Hakozaki Y, Murata T, Yokoyama M, Matsushima
H, Ogawa M, Masuda T, Hirai Y, Kume H.
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staining for prostate cancer markers including
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30. 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
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31. Otsuka M, Kamasako T, Uemura T, Takeshita N,
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A. Factors predicting biochemical recurrence afterradical prostatectomy among patients with clinicalT3 prostate cancer. Jpn J Clin Oncol, 48, 760-764,
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32. Kotabe K, Kume H et al. Relationship between
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33. Oka S, Inoshita N, Miura Y, Oki R, Miyama Y,
Nagamoto S, Ogawa K, Sakaguchi K, Kondoh C,
Kurosawa K, Urakami S, Takano T, Okaneya T.
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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., Masaya Hiyoshi, M.D.
Shigenobu Emoto, M.D., Ph.D., Koji Murono, 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 571
surgically treated inpatients in the year of 2017. 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

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Kokudo N, Murofushi K, Nakajima T, Oka S,
Sakai Y, Tsuji A, Uehara K, Ueno H, Yamazaki K,
Yoshida M, Yoshino T, Boku N, Fujimori T,
Itabashi M, Koinuma N, Morita T, Nishimura G,
Sakata Y, Shimada Y, Takahashi K, Tanaka S,
Tsuruta O, Yamaguchi T, Yamaguchi N, Tanaka T,
Kotake K, Sugihara K, Japanese Society forCancer of the Colon and Rectum. JapaneseSociety for Cancer of the Colon and Rectum(JSCCR) guidelines 2016 for the treatment ofcolorectal cancer. Int J Clin Oncol. 23(1):1-34,
2018
48. Yoshino T, Oki E, Nozawa H, Eguchi-Nakajima T,
Taniguchi H, Morita S, Takenaka N, Ozawa D,
Shirao K. Rationale and design of the TRUSTY
study: a randomised, multicentre, open-labelphase II/III study of trifluridine/tipiracil plus
bevacizumab versus irinotecan, fluoropyrimidine
plus bevacizumab as second-line treatment inpatients with metastatic colorectal cancer
progressive during or following first-line
oxaliplatin-based chemotherapy. ESMO Open. 3:
e000411, 2018

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Department of Vascular Surgery
Chief of Vascular Surgery
Katsuyuki Hoshina, M.D., Ph.D.

Lecturer
Katsuyuki Hoshina, M.D., Ph.D., Toshio Takayama, M.D., Ph.D.

Assistant Professor
Toshihiko Isaji, M.D., Ph.D.,

Takafumi Akai, M.D., Ph.D.,

Takuro Shirasu, 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 two Lecturer, and three AssistantProfessors. The outpatient office is located on thethird floor of the Outpatient Building. The ward issituated on the eighth floor of the Ward Building. The
administrative office and research laboratories arelocated in the Administration and Research Building.
Current activities of the Department of Vascular
Surgery in clinical practice, education, and research
are summarized as follows.

Clinical activities
The Department of Vascular Surgery has anextensive clinical program in both primary and tertiarycare for vascular problems, and manages patients with
peripheral arterial occlusion, abdominal and thoracoabdominal aortic aneurysms, peripheral aneurysm,
visceral arterial occlusion, carotid artery disease andcommon disorders of the venous circulation such asvaricose veins and venous leg ulcers. State-of-the-art
techniques of percutaneous transluminal angioplasty,
angioscopy and intraoperative ultrasonography areavailable for the treatment of peripheral arterial

disease. And endovascular aneurysm repair was alsoavailable for the treatment of abdominal aortic
aneurysm. The outpatient clinic is open from Monday
through Friday, and twenty-four-hour consultation isavailable for urgent or emergency problems.
Included in the department is the non-invasive
Clinical Vascular Laboratory, which sees over 500
patients per year, with broad reaching expertise inperipheral vascular diagnostic modalities. Also thedepartment has an active angiography program, which
encompasses all aspects of diagnostic and therapeuticintervention in over 500 patients per year and a fullrange of other support and collaborative services.
On Monday, Wednesday and Friday mornings, preand post-surgery conferences are held. Operating days
are Monday, Tuesday and Thursday. The vascularclinical conference is held every Tuesday evening.

Teaching activities
The operative procedure should be the basics ofsurgery. In 2017, the Japanese Board of
Cardiovascular Surgery announced that 30 hours of
Off JT experience will be required for new
cardiovascular specialist applicants. Responding tothis announcement and taking into consideration thesocial request for change in recent years, The JapaneseSociety for Vascular Surgery created the Off JT
working group to create a new framework for Off JT.

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Thus far, there has not been a versatile Off JT systemthat can be used in any institution with young
surgeons. Therefore, in our department, we aimed todevelop a simple and inexpensive Off JT system thatcan be used at any institution with medical students
and young surgeons. We developed a new Off JT
system that is simple and inexpensive and can be used
at any institution with medical students and young
surgeons. The effectiveness and appropriateness of
this system were confirmed by the learning curve,
analysis of the balance of the anastomosis, and scoringby the trainers. In addition, we demonstrated therelationships among time, performance, and skill. We
will set this system as one of the educational methods
for surgeons.
The Department of Vascular Surgery also offers afellowship in vascular surgery for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in vascularsurgery. The Department of Vascular Surgery has a
Vascular Surgery Training Program and provides
broad reaching experience in technical aspects ofvascular surgery, development of surgical judgment,
and increasing knowledge about routine and complex
conditions. In addition, the dedicated staff offers
multiple opportunities for academic development bothalong clinical and basic scientific lines.
In the undergraduate education program, theDepartment of Vascular Surgery plays a role in thesystemic and clinical lectures and the bedside learning
program for 3rd year medical students, in cooperation
with other departments of surgery. In the postgraduate
education program, new residents are trained to
become qualified surgeons in our department. The
Department of Vascular Surgery is involved with theeducation program of the post-graduate education
meeting, which is held monthly. In addition to preand post-surgery clinical conferences, the residents are
expected to attend research conferences and seminars,
which are held periodically.

Research activities
The Department of Vascular Surgery includes major
research laboratories for academic development bothalong clinical and basic scientific lines. The clinicalvascular laboratories are approaching completely non-invasive testing for vascular disorders, analyzing
essential physiologic information about the specificproblems being addressed. The basic vascularlaboratories are actively performing research on
endothelial biology, the mechanism of intimal
hyperplasia, microcirculation, application of genetherapy to vascular surgery and vascular prosthesis
development. Vascular research meeting is held every
month on Saturday morning. The following are themajor themes under research.
1) Navigation system for less invasive vascularsurgery2) Pathophysiology of the development of theaneurysm
3) Pathophysiology of stent restenosis
4) Analyzing the intercellular transmission of thegrowth signal in the vascular smooth muscle cells5) Tissue oxygen dynamics assessed by near infrared
spectroscopy
6) Genome wide-association studies for arteriosclerosis.
7) Pharmacological analysis of microcirculation in
in-vivo model8) Mechanism of arteriogenesis in ischemic limb.
9) Development of a new drug delivery system fortherapeutic angiogenesis10) Hemodynamic analysis after endovascularaneurysm repair11) Introduction of gene into vascular wall cells byelectroporation
12) Application of nano technology for in-vivo genetransfer to vascular wall cells
13) Basic research for arterialization of artificial
organ
14) Development of a new method for evaluation oflimb ischemia
15) Development of a new machine for autoevaluation of in-vivo endothelial function16) Creating strategy for diagnosis of acute aortic
syndrome.
17) Analysis of ambulatory system and muscle
mechanics in claudicants with peripheral arterydisease.
18) Modeling of saccular aneurysm with thecomputational simulation.

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References
1. Akagi D, Hoshina K, Watanabe T, Conte MS.
Drug therapy for abdominal aortic aneurysms
utilizing omega-3 unsaturated fatty acids and theirderivatives. Curr Drug Targets. In press
2. Haga M, Yamamoto S, Okamoto H, Hoshina K,
Asakura T, Watanabe T. Histological Reactions
and the In Vivo Patency Rates of Small Silk
Vascular Grafts in a Canine Model. Ann Vasc Dis.
10: 132-138. 2017
3. Hoshina K, Akai T, Ohshima M, Watanabe T,
Yamamoto S. Theoretical mechanism of
temporary renal function improvement after
abdominal aortic aneurysm surgery: Applications
for clinical imaging and laboratory data. Medicine(Baltimore). 96: e7428. 2017
4. 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. In press
5. Isaji T, Hashimoto T, Yamamoto K, Santana JM,
Yatsula B, Hu H, Bai H, Jianming G, Kudze T,
Nishibe T, Dardik A. Improving the Outcome ofVein Grafts: Should Vascular Surgeons Turn Veins
into Arteries?. Ann Vasc Dis. 10(1): 8-16. 2017
6. Li J, Zhao L, Urabe G, Fu Y, Guo LW. Epigenetic
intervention with a BET inhibitor ameliorates
acute retinal ganglion cell death in mice. Mol Vis.
23: 149-159. 2017
7. Nemoto Y, Hoshina K, Kobayashi M, Kimura M,
Yamamoto S, Watanabe T, Ohshima M.
Morphological Changes and Device Migration
After Stent Graft Insertion - Clinical Applicationof an Image-Based Modeling System and Analysis
With Geometric Parameters. Circ J. In press
8. Nemoto Y, Hosoi Y, Hoshina K, Nunokawa M,
Kubota H, Watanabe T. In Situ Reconstruction
with Extended Debridement in Patients with
Mycotic Abdominal Aortic Aneurysms. Ann Vasc
Dis. 10: 159-163. 2017
9. Protack CD, Foster TR, Hashimoto T, Yamamoto
K, Lee MY, Kraehling JR, Bai H, Hu H, Isaji T,
Santana JM, Wang M, Sessa WC, Dardik A.
Eph-B4 regulates adaptive venous remodeling to
improve arteriovenous fistula patency. ScientificRep. 7(1): 15386. 201710. Suhara M, Hoshina K, Akai A, Isaji T, Akagi D,
Yamamoto K, Miyahara T, Watanabe T. Stenotic
lesion level did not affect outcomes of carotid
endarterectomy. Asian Cardiovasc Thorac Ann.
25: 271-275. 2017
11. Yamamoto K, Hoshina K, Akai A, Isaji T, Akagi
D, Miyahara T, Watanabe T. Results of surgicalinterventions for critical limb ischemia due tovasculitis or collagen-tissue related disease. Int
Angiol. 36(4): 332-339. 201712. Yamamoto K, Hoshina K, Akai A, Isaji T, Akagi
D, Miyahara T, Watanabe T. Results of surgicalinterventions for critical limb ischemia due tovasculitis or collagen-tissue related disease. Int
Angiol. 36: 332-339. 2017
13. Yu Q, Wang B, Chen Z, Urabe G, Glover MS, Shi
X, Guo LW, Kent KC, Li L. Electron-Transfer/
Higher-Energy Collision Dissociation (EThcD)Enabled Intact Glycopeptide/Glycoproteome
Characterization. J Am Soc Mass Spectrom.
28(9): 1751-1764. 2017

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Department ofBreast and Endocrine Surgery
Professor
Yasuyuki Seto M.D., Ph.D.

Lecturer
Masahiko Tanabe M.D., Ph.D.

Kotoe Nishioka M.D., Ph.D.

Associates
Takayoshi Niwa M.D., Ph.D.

Takako Wakeda M.D., Ph.D.

Ayaka Sato M.D., Ph.D.

Kazutaka Otsuji M.D., Ph.D.

Mayumi Harada M.D., Ph.D.

Kanako Hayashi M.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 ourstudies are performed with other good institutions.
1) Hereditary Breast and Ovarian Cancer syndrome2) Precision medicine based on Todai OncoPanel
3) Clinical significance of Ki67 in the area of earlybreast cancer.

2294) 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.

2.

3.

4.

5.

Masahiko Tanabe, Takayo Fukuda, Yoshinori Ito.
The Position of Combination Chemotherapy with
Mitomycin C and Methotrexate in the Treatment ofMetastatic Breast Cancer - Especially Triple Negative Breast Cancer. Oncomedicine 2017; 2: 126-131.
Otsuji K, Sasaki T, Tanaka A, Kunita A, Ikemura M,
Matsusaka K, Tada K, Fukayama M, Seto Y. Use ofdroplet digital PCR for quantitative and automatic
analysis of the HER2 status in breast cancer patients.
Breast Cancer Res Treat. 2017 Feb;162(1):11-18.
Sasahara A, Tominaga K, Nishimura T, Yano M,
Kiyokawa E, Noguchi M, Noguchi M, Kanauchi H,
Ogawa T, Minato H, Tada K, Seto Y, Tojo A, Gotoh
N. An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenanceof breast cancer stem-like cells. Oncotarget. 2017
Apr 11;8(15):24869-24881.
Tada K, Nishioka K, Kikuchi Y, Niwa T, Seto Y.
Post-mastectomy radiation therapy in breast cancer
with 1-3 involved lymph nodes: the Pros.Breast
Cancer. 2017 Jul;24(4):502-504.
Ishibashi Y, Ohtsu H, Ikemura M, Kikuchi Y, Niwa T,
Nishioka K, Uchida Y, Miura H, Aikou S, Gunji T,
Matsuhashi N, Ohmoto Y, Sasaki T, Seto Y, Ogawa T,
Tada K, Nomura S. Serum TFF1 and TFF3 but not
TFF2 are higher in women with breast cancer than inwomen without breast cancer. Sci Rep. 2017 Jul

7;7(1):4846.
6. Kikuchi Y1, Uchida Y2, Shirakawa K3, Kanauchi
H4, Niwa T1, Nishioka K1, Tada K1, Hashimoto M5,
Yasuda H5, Sugiura R5, Kawabata H6, Seto Y1,
Ogawa T. A multicenter, observational study of metastatic breast cancer patients who were treated witheribulin mesylate or taxane-based regimens. Asia
Pac J Clin Oncol. 2018 Mar 1.
7. Ayaka Sato, Masahiko Tanabe, Yumi Tsuboi, Masako Ikemura, Keiichiro Tada, Yasuyuki Seto,
Yoshinori Murakami. Detection of the PIK3CA Mutation in Circulating Tumor DNA as a Possible Predictive Indicator for Poor Prognosis of Early-Stage
Breast Cancer. Journal of Cancer Therapy. Vol.09
No.01(2018)
8. Shien T, Tanaka T, Tanabe M, Okumura Y, Masuda
N, Yoshida A, Arima N, Komoike Y, Tanaka S,
Iwase T, Taguchi T, Nakatsukasa K, Inaji H, Ishitobi
M; Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society. Evaluation of ALDH1 expression in ipsilateral breast
cancer recurrence. Oncol Lett. 2017 Mar;13(3):1071-1077.
9. Tominaga K, Shimamura T, Kimura N, Murayama T,
Matsubara D, Kanauchi H, Niida A, Shimizu S,
Nishioka K, Tsuji EI, Yano M, Sugano S, Shimono Y,
Ishii H, Saya H, Mori M, Akashi K, Tada KI, Ogawa
T, Tojo A, Miyano S, Gotoh N. Addiction to the
IGF2-ID1-IGF2 circuit for maintenance of the breast
cancer stem-like cells. Oncogene. 2017 Mar 2;36(9):1276-1286.
10. Yamamoto M, Sakane K, Tominaga K, Gotoh N,
Niwa T, Kikuchi Y, Tada K, Goshima N, Semba K,
Inoue JI. Intratumoral bidirectional transitions
between epithelial and mesenchymal cells in triplenegative breast cancer. Cancer Sci. 2017 Jun;108(6):1210-1222.

11. Kawazu M, Kojima S, Ueno T, Totoki Y, Nakamura
H, Kunita A, Qu W, Yoshimura J, Soda M, Yasuda T,
Hama N, Saito-Adachi M, Sato K, Kohsaka S, Sai E,
Ikemura M, Yamamoto S, Ogawa T, Fukayama M,
Tada K, Seto Y, Morishita S, Hazama S, Shibata T,
Yamashita Y, Mano H. Integrative analysis of
genomic alterations in triple-negative breast cancer
in association with homologous recombination
deficiency. PLoS Genet. 2017 Jun 21;13(6):e1006853.

Surgical Sciences
2. Sensory and Motor System Medicine

231

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

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

Lecturer
Tomomitsu Miyagaki, M.D., Ph.D.

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

Ayumu Yoshizaki, M.D., Ph.D.

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

Hospital Lecturer
Daisuke Yamada, M.D., Ph.D.

Associate
Tetsuo Toyama, M.D., Ph.D.

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

Asako Yoshizaki, M.D., Ph.D.

Toru Kawai, M.D., Ph.D.

Syunsuke Miura, M.D.

Maasa Kobayashi, M.D., Ph.D.

Tomonori Oka, M.D., Ph.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, threelecturers, two hospital lecturer and seven associatestake part in inpatient and outpatient cares as well as
research and teaching activities. Fifty-two doctors
who basically belong to our department are currently
out in affiliated hospitals mainly engaged in clinicalworks there. Additionally, eight staff members areabroad at present, mainly involved in advanced
research activities in cell biology and molecularbiology.

In the outpatient clinic we see around 200 patients aday. Incisional and excisional biopsies are frequently
performed under local anesthesia at the outpatient
operation facilities belonging to our department.
Clinical and histological discussions by all staff
members including Professor and Associate Professors
are held regularly, which always gives us invaluablelessons.
Concerning the inpatient clinic, there are about ten
staff members under the supervision of the ward-chief.
Surgical operations such as removal of malignancies
and skin grafting that require general anesthesia arealso performed weekly in the central surgical facilities.

Education
We have twenty dermatologists who are studying in
the postgraduate course under the guidance of staff
members of our department.

232

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. Miyagawa T, Kadono T, Saigusa R, Yamada D,
Masui Y, Fujita H, Asano Y, Sato S.
Lymphangiosarcoma of the hip arising in acongenital non-irradiated lymphangioma. J Dtsch
Dermatol Ges. 2017; 15(12):1235-7.
2. Taniguchi T, Miyagawa T, Tamaki Z, Nakamura K,
Yamashita T, Saigusa R, Takahashi T, Toyama T,
Ichimura Y, Yoshizaki A, Tada Y, Sugaya M,
Kadono T, Sato S, Asano Y. A possible implication of reduced levels of LIF, LIFR, and gp130 in
vasculopathy related to systemic sclerosis. Arch
Dermatol Res. 2017; 309(10):833-42.
3. Sakamoto M, Miyagaki T, Kamijo H, Oka T,
Takahashi N, Suga H, Yoshizaki A, Asano Y,
Sugaya M, Sato S. Serum vascular endothelial
growth factor A levels reflect itch severity inmycosis fungoides and Sézary syndrome. J
Dermatol. 2018; 45(1):95-9.
4. Miyagawa T, Kadono T, Masui Y, Yamada D,
Saigusa R, Numajiri H, Omatsu J, Asano Y, SatoS. Nivolumab-induced vitiligo successfully
treated with narrowband UVB phototherapy. Eur J
Dermatol. 2017; 27(6):656-8.

5. Suzuki H, Miyagaki T, Otobe S, Nakajima R, Oka
T, Takahashi N, Kabasawa M, Suga H, Yoshizaki
A, Asano Y, Sato S, Sugaya M. Increased endocan
expression in lesional skin and decreased endocan
expression in sera in atopic dermatitis. J Dermatol.
2017; 44(12):1392-5.
6. Marangoni RG, Masui Y, Fang F, Korman B, Lord
G, Lee J, Lakota K, Wei J, Scherer PE, Otvos L,
Yamauchi T, Kubota N, Kadowaki T, Asano Y,
Sato S, Tourtellotte WG, Varga J. Adiponectin isan endogenous anti-fibrotic mediator and therapeutic target. Sci Rep. 2017; 7(1):4397.
7. Miyagawa T, Kadono T, Saigusa R, Numajiri H,
Omatsu J, Funamizu K, Yamada D, Masui Y,
Asano Y, Sato S. Multiple-opposing rotation flaps
for the scalp defect including hair whorl. J
Dermatol. 2017; 44(11):e302-3.
8. Oka T, Sugaya M, Takahashi N, Nakajima R,
Otobe S, Kabasawa M, Suga H, Miyagaki T,
Asano Y, Sato S. Increased Interleukin-19
Expression in Cutaneous T-cell Lymphoma andAtopic Dermatitis. Acta Derm Venereol. 2017;
97(10):1172-7.
9. Kamijo H, Sugaya M, Takahashi N, Oka T,
Miyagaki T, Asano Y, Sato S. BET bromodomain
inhibitor JQ1 decreases CD30 and CCR4
expression and proliferation of cutaneous T-cell
lymphoma cell lines. Arch Dermatol Res. 2017;309(6):491-7.
10. Saigusa R, Asano Y, Nakamura K, Hirabayashi M,
Miura S, Yamashita T, Taniguchi T, Ichimura Y,
Takahashi T, Yoshizaki A, Miyagaki T, Sugaya M,
Sato S. Systemic Sclerosis Dermal Fibroblasts
Suppress Th1 Cytokine Production via Galectin-9
Overproduction due to Fli1 Deficiency. J Invest
Dermatol. 2017; 137(9):1850-9.
11. Taniguchi T, Asano Y, Nakamura K, Yamashita T,
Saigusa R, Ichimura Y, Takahashi T, Toyama T,
Yoshizaki A, Sato S. Fli1 Deficiency Induces
CXCL6 Expression in Dermal Fibroblasts andEndothelial Cells, Contributing to the Development of Fibrosis and Vasculopathy in Systemic
Sclerosis. J Rheumatol. 2017; 44(8):1198-205.
12. Takahashi T, Asano Y, Shibata S, Tada Y, Sato S.
Serum angiopoietin-2 level as a potential
biomarker in psoriasis vulgaris. J Dermatol. 2017;44(2):205-6.

233

13. Miyagawa T, Asano Y, de Mestier Y, Saigusa R,
Taniguchi T, Yamashita T, Nakamura K,
Hirabayashi M, Miura S, Ichimura Y, Takahashi T,
Yoshizaki A, Miyagaki T, Sugaya M, Sato S.
Serum H-ficolin levels: Clinical association withinterstitial lung disease in patients with systemicsclerosis. J Dermatol. 2017; 44(10):1168-71.
14. Otobe S, Sugaya M, Taniguchi T, Miyagaki T,
Iozumi K, Sato S. Adult T-cell leukemia/
lymphoma with subungual hematomas in all
fingers and toes as the first manifestation. J
Dermatol. 2018; 45(3):378-9.
15. Takahashi N, Sugaya M, Suga H, Oka T,
Kawaguchi M, Miyagaki T, Fujita H, Inozume T,
Sato S. Increased Soluble CD226 in Sera ofPatients with Cutaneous T-Cell Lymphoma Mediates Cytotoxic Activity against Tumor Cells via
CD155. J Invest Dermatol. 2017; 137(8):1766-73.
16. Oka T, Sugaya M, Takahashi N, Takahashi T,
Shibata S, Miyagaki T, Asano Y, Sato S. CXCL17
Attenuates Imiquimod-Induced Psoriasis-like
Skin Inflammation by Recruiting MyeloidDerived Suppressor Cells and Regulatory T Cells.
J Immunol. 2017; 198(10):3897-908.
17. Takahashi T, Asano Y, Taniguchi T, Yoshizaki A,
Sato S. Serum LL-37 levels correlate with theefficacy of i.v. cyclophosphamide pulse for skinsclerosis and interstitial lung disease in systemicsclerosis. J Dermatol. 2017;44(4):468-9.
18. Toyama T, Asano Y, Miyagawa T, Nakamura K,
Hirabayashi M, Yamashita T, Saigusa R, Miura S,
Ichimura Y, Takahashi T, Taniguchi T, Yoshizaki
A, Sato S. The impact of transcription factor Fli1
deficiency on the regulation of angiogenesis. Exp
Dermatol. 2017;26(10):912-8.
19. Taniguchi T, Asano Y, Fukasawa T, Yoshizaki A,
Sato S. Critical contribution of the interleukin6/signal transducer and activator of transcription 3
axis to vasculopathy associated with systemicsclerosis. J Dermatol. 2017;44(8):967-71.
20. Senda N, Miyagaki T, Oka T, Ito Y, Katayama K,
Kamiyama T, Sugaya M, Sato S. Case of mycosis fungoides with gastric and central nervous
system involvement. J Dermatol. 2017;44(7):e166-7.
21. Saigusa R, Asano Y, Yamashita T, Sumida H,
Miyazaki M, Sato S. A case of systemic sclerosis

with linear scleroderma developing after fracture
surgery. Eur J Dermatol. 2017;27(2):200-1.
22. Miyagawa T, Kadono T, Miyazaki M, Sato S.
Multiple molluscum contagiosum lesions in adults
suggesting compromised immune system.
Infection. 2017;45(4):573-4.
23. Takahashi T, Asano Y, Sugawara K, Yamashita T,
Nakamura K, Saigusa R, Ichimura Y, Toyama T,
Taniguchi T, Akamata K, Noda S, Yoshizaki A,
Tsuruta D, Trojanowska M, Sato S. Epithelial Fli1
deficiency drives systemic autoimmunity andfibrosis: Possible roles in scleroderma. J Exp Med.
2017;214(4):1129-51.
24. Miyagaki T, Sugaya M, Oka T, Takahashi N,
Kawaguchi M, Suga H, Fujita H, Yoshizaki A,
Asano Y, Sato S. Placental Growth Factor and
Vascular Endothelial Growth Factor Together
Regulate Tumour Progression via Increased
Vasculature in Cutaneous T-cell Lymphoma. Acta
Derm Venereol. 2017; 97(5):586-92.
25. Toyama T, Asano Y, Taniguchi T, Takahashi T,
Ichimura Y, Tamaki Z, Kagami S, Mitsui H, SatoS. Ethosuximide-induced lupus-scleroderma syndrome with disease-specific autoantibodies. Eur J
Dermatol. 2017; 27(2):196-7.
26. Miyagawa T, Kadono T, Kimura T, Saigusa R,
Yoshizaki A, Miyagaki T, Yamada D, Masui Y,
Fujita H, Sato S. Pazopanib induced a partial
response in a patient with metastatic fibrosarcomatous dermatofibrosarcoma protuberans
without genetic translocations resistant to mesna,
doxorubicin, ifosfamide and dacarbazine chemotherapy and gemcitabine-docetaxel chemotherapy.
J Dermatol. 2017; 44(3):e21-2.
27. Ebata S, Yoshizaki A, Fukasawa T, Nakamura K,
Yamashita T, Miura S, Saigusa R, Ichimura Y,
Takahashi T, Hirabayashi M, Taniguchi T,
Akamata K, Asano Y, Sato S． Unprecedented
success of rituximab therapy for prednisoloneand
immunosuppressant-resistantsystemicsclerosis-associated interstitial lung disease.
Scand J Rheumatol. 2017; 46(3):247-52.
28. Yamashita T, Asano Y, Taniguchi T, Nakamura K,
Saigusa R, Miura S, Toyama T, Takahashi T,
Ichimura Y, Yoshizaki A, Trojanowska M, Sato S.
Glycyrrhizin Ameliorates Fibrosis, Vasculopathy,

234

and Inflammation in Animal Models of Systemic
Sclerosis. J Invest Dermatol. 2017; 137(3):631-40.
29. Takahashi N, Sugaya M, Oka T, Miyagaki T, Sato
S. Alopecia areata, thyroiditis and vitiligo
vulgaris in a Japanese patient with smoldering
type adult T-cell leukemia/lymphoma. J Dermatol.
2017; 44(4):e79-80.

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.,
Takao Numahata, M.D.,

Homepage

Koji Kanayam, M.D.,
Daisuke Mito, M.D.,

Kazuya Imai, 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 (2017)
1. Mashiko T, Wu SH, Kanayama K, Asahi R,
Shirado T, Mori M, Sunaga A, Sarukawa S, Uda H,
Yoshimura K.
Biological Properties and Therapeutic Value of
Cryopreserved Fat Tissue.
Plast Reconstr Surg 141:104-115, 2018. (2018.1)
2. Mori H, Uemura N, Koga H, Okazaki M.
Objective assessment of reconstructed breast
hardness using a durometer.
Breast Cancer. 25: 81-85, 2018. (2018.1)
3. Satoh T, Kurita M, Suga H, Eto H, Ozaki M,
Takushima A, Harii K.
Efficient isolation and culture of endothelial cells

from venous malformation using the Rhoassociated protein kinase inhibitor Y27632.
J Plast Surg Hand Surg. 52(1):60-66, 2018.
(2018.1)
4. Miyamoto S.
Self-citation rate and impact factor in the field ofplastic and reconstructive surgery.
J Plast Surg Hand Surg 52:40-46, 2018.(2018.2)
5. Kagaya Y, Miyamoto S.
A systematic review of near-infrared spectroscopy
in flap monitoring: Current basic and clinicalevidence and prospects.
J Plast Reconstr Aesthet Surg 71:246-257, 2018.
(2018.2)
6. Mashiko T, Takada H, Wu SH, Kanayama K, FengJ, Tashiro K, Asahi R, Sunaga A, Hoshi K,
Kurisaki A, Takato T, Yoshimura K.
Therapeutic effects of a recombinant humancollagen peptide bioscaffold with human adiposederived stem cells on impaired wound healing
after radiotherapy.
J Tissue Eng Regen Med. 12:1186-1194, 2018.
(2018.5)
7. Miyamoto S, Higashino T, Sakuraba M.
Mandibular reconstruction in elderly patients.
J Surg Oncol 117:1744-1751, 2018.(2018.6)
8. Kagaya Y, Arikawa M, Kobayashi E, Kawai A,
Miyamoto S.
Successful Pregnancy and Delivery after
Autologous Abdominal Wall Reconstruction using
Anterolateral-Thigh and Iliotibial-Tract Flap.
Plast Reconstr Surg Glob Open 6:e1819, 2018.
(2018.7)
9. Miura K, Namiki T, Akashi T, Uemura N, Mori H,
Yokozeki H, Okazaki M.
Desmoplastic transformation of a nodular melanoma arising from a speckled lentiginous nevus.
J Dermatol. 45:e230-e231, 2018. (2018.8)
10. Higashino T, Okazaki M, Mori H, Yamaguchi K,
Akita K.
Microanatomy of Sensory Nerves in the Upper
Eyelid: A Cadaveric Anatomical Study.
Plast Reconstr Surg. 142:345-353, 2018. (2018.8)
11. Wu SH, Shirado T, Mashiko T, Feng J, Asahi R,
Kanayama K, Mori M, Chi D, Sunaga A,
Sarukawa S, Yoshimura K.
Therapeutic Effects of Human Adipose-Derived

237

Products on Impaired Wound Healing in
Irradiated Tissue.
Plast Reconstr Surg. 142(2):383-391, 2018.
(2018.8)
12. Kurita M, Araoka T, Hishida T, O'Keefe DD,
Takahashi Y, Sakamoto A, Sakurai M, Suzuki K,
Wu J, Yamamoto M, Hernandez-Benitez R,
Ocampo A, Reddy P, Shokhirev MN, Magistretti P,
Núñez Delicado E, Eto H, Harii K, Izpisua
Belmonte JC.
In vivo reprogramming of wound-resident cells
generates skin epithelial tissue.
Nature. 561(7722):243-247, 2018. (2018.9)
13. Narushima M, Yamasoba T, Iida T, Matsumoto Y,
Yamamoto T, Yoshimatsu H, Timothy S, Pafitanis
G, Yamashita S, Koshima I.
Pure Skin Perforator Flaps: The Anatomical
Vascularity of the Superthin Flap.
Plast Reconstr Surg. 142(3):351e-360e, 2018.
(2018.9)
14. Tanaka K, Yano T, Homma T, Tsunoda A, Aoyagi
M, Kishimoto S, Okazaki M.
A new method for selecting auricle positions inskull base reconstruction for temporal bone cancer.
Laryngoscope. 128 :2605-2610, 2018. (2018.11)

238

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.

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

AssociateFujihara Yuko, D.D.S., Ph.D.

Madoka Sugiyama, D.D.S.

Takato Inokuchi, D.D.S., Ph.D.(until September)
Kosuke Kanke, D.D.S., Ph.D.

Mari Okayasu, D.D.S., Ph.D.

Keigo Kubota, D.D.S., Ph.D.

Asako Taniguchi, D.D.S., Ph.D.

Rika Narita, D.D.S., Ph.D.(from November)

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.
Dental care for the patients who have systemic
disorders or under medical control is another field ofour department. Multidisciplinary treatment teamed bythese 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: Department 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

239

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,and the original artificial bone graft technique in
addition to orthognatic surgery. The original bone
graft is made from patient’s three dimensional imagesof CT data and this technique is now applied forpatients.

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 anomaly2) 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

2406) 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. Fujihara Y, Hikita A, Takato T, Hoshi K. Roles ofmacrophage migration inhibitory factor in
cartilage tissue engineering. J Cell Physiol. 2018
Feb;233(2):1490-1499.
2. Hoshi K, Fujihara Y, Yamawaki T, Harai M,
Asawa Y, Hikita A: Biological aspects oftissue-engineered cartilage, Histochem Cell Biol.

2018 Apr,149(4):375-381.
3. Sugiyama M, Nakatsuka T, Saijo H, Fujihara Y,
Kanno Y, Hikita A, Takato T, Hoshi K: Clinicalfindings of a cantilever iliac bone graft forsecondary correction of cleft lip-nose deformities,
J Craniofac Surg, 2018 May, 29(3):741-746.
4. Mashiko T, Takada H, Wu SH, Kanayama K,
Feng J, Tashiro K, Asahi R, Sunaga A, Hoshi
K,Kurisaki A, Takato T, Yoshimura K:
Therapeutic effects of a recombinant humancollagen peptide bioscaffold with human adiposederived stem cells on impaired wound healing
after radiotherapy. J Tissue Eng Regen Med, 2018
May, 12(5):1186-1194.
5. Ohsato A, Abe M, Ohkubo K, Yoshimasu H,
Zong L, Hoshi K, Takato T, Yanagimoto S,
Yamamoto K: A comparative study of oral healthstatus between international and Japanese University student patients in Japan. Healthcare (Basel),2018 May 22, 6(2), pii:E52.
6. Sato T, Abe T, Ichioka S. Factors impairing cellproliferation in the granulation tissue of pressure
ulcers: Impact of bacterial burden. Wound Repair
Regen. 2018 May, 26(3):284-292.
7. Okayasu M, Susami T, Asahito T, Sakamoto T,
Kurata K, Ishiwata Y, Nagahama K, Takato T,
Saito I. Questionnaire investigation after
orthodontic treatment in patients with unilateralcleft lip and palate: an inter-clinic collaborative
study. Orthodontic Waves 2018 June, 77(2):90-100.
8. Inaki R, Fujihara Y, Kudo A, Misawa M, Hikita A,
Takato T, Hoshi K: Periostin contributes to thematuration and shape retention of tissueengineered cartilage. Sci Rep, 2018 Jul 25, 8(1):11210.
9. Uto S, Nishizawa S, Hikita A, Takato T, Hoshi K:
Application of induced pluripotent stem cells for
cartilage regenerarion in CLAWN miniatuer pig
osteochondral replacement model. Regen Ther,
2018 Aug 22, 9:58-70.
10. Tan S, Chen P, Ji J, Guo S, Yu D, Asakawa T,
Zhou Y, Abe M, Zong L: Genomic subtypes of
GISTs for stratifying patient response to sunitinib
following imatinib-resistance: a pooled-analysis
and systematic review. Disease Markers, 2018
Aug 26; 2018:1368617

241

11. Fujihara Y, Kikuta S, Sugiyama M, Kubota K,
Ishibashi M, Igarashi M, Saijo H, Hoshi K: A caseof cleft lip and palate associated with unilateralchoanal atresia. J Oral Maxillofac Surg Med Path.
2018 Nov, 30:538-541.
12. Susami T, Mori Y, Ohkubo K, Takahashi M,
Hirano Y, Saijo H, Takato T. Changes inmaxillofacial morphology and velopharyngeal
function with two-stage maxillary distractionmandibular setback surgery in patients with cleft
lip and palate. Int J Oral Maxillofac Surg. 2018
Mar;47(3):357-365.
13. Komura M, Komura H, Komuro H, KonishiK,Obana K, Ikebukuro K, Hikita A, Hoshi K, Takato
T: Long-term follow-up of tracheal cartilage
growth promotion by intratracheal injection ofbasic fibroblast growth factor. J Pediatr Surg.
2018 Dec, 53(12):2394-2398.
(Review articles)
1. Abe M, Zong L, Abe T, Hoshi K: A turning pointin therapy for ameloblastomas. Oral Oncol, 2018
May, 80:95-96.
2. Xiao H, Fu J, Abe M, Ji J, Zong L. Prognostic
value of CpG island methylator phenotype ingastric cancer. Cancer Sci. 2018 Aug 28, 109(8):2623-2625.
3. Abe M, Zong L, Abe T, Takeshima H, Ji J,
Ushijima T, Hoshi K: BRAF inhibitor: a novel
therapy for ameloblastoma in mandible. Clin J
Cancer Res. 2018 Dec, 30(6):677-678.
(Patents)
1. Wang J, Suenaga H, Sakuma I, Kobayashi E,
Hoshi K: Surgical navigation system, surgicalnavigation method, and program. (U.S. Patent
Application No. US 15/765,303) (U.S. Patent
Application No. US-2018-0280091-A1)

242

Department ofOrthopaedic Surgery
Professor
Sakae Tanaka, M.D., Ph.D.

Associate Professors
Taku Saito, M.D., Ph.D.

Lecturers
Takehiro Matsubara, M.D., Ph.D.

Jun Hirose, M.D., Ph.D.

Yasushi Oshima, M.D., Ph.D.

Shuji Taketomi, M.D., Ph.D.

Hiroshi Inui, M.D.

Associates
Yutaka Morizaki, M.D.

Yuki Taniguchi, M.D., Ph.D.

Hiroshi Kobayashi, M.D., Ph.D.

Takeyuki Tanaka, M.D.

Keita Okada, M.D., Ph.D.

Yoshitaka Matsubayashi, M.D.

Kousuke Uehara, M.D.

So Kato, M.D.

Chan Sonnho, M.D.

Humihiko Oguchi, M.D.

Kentarou Takagi, M.D.

Kouji Nakajima, M.D.

Kazuaki Hashikura, M.D.

Yuuki Ishibashi, 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

243(OPLL), rheumatoid arthritis, biomechanics, and thedegenerative skeletal disorders such as osteoporosis
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, one associate professors, 5 lecturers, 14
associates, 7 medical staff members, 10 seniorresidents, and 11 part-time teachers.

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 coorporation 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 35,916 patients
visited the outpatient clinic in fiscal 2018.
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.
1,397 operations were performed in fiscal 2016.
These include 332 spine surgeries, 49 surgeries forrheumatoid arthritis patients, 125 hip surgeries, 291
knee surgeries (including 53 computer-assisted ACL
reconstructions, 165 computer-assisted TKA, 25
UKA), 232 hand surgeries, 51 foot and ankle surgeries,

244

46 pediatric surgeries, 111 surgeries for bone and soft
tissue tumor, and 164 trauma surgeries.
The main disorders of cervical spine surgery weremyelopathy due to spondylosis or OPLL. We
successfully adopted double-door open laminoplasty
by splitting the spinal processes for most of 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.

245

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35. Kyomoto M, Shoyama Y, Saiga K, Moro T,
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40. Taketomi S, Inui H, Yamagami R, Shirakawa N,
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43. Fukushima M, Oshima Y, Oka H, Chang C,
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47. Makii Y, Asaka M, Setogawa S, Fujiki S, Hosaka
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51. Kaneko T, Oshima Y, Inoue H, Iwai H, Takano Y,
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52. Tonosu J, Oka H, Watanabe K, Abe H,
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53. Kondo M, Oshima Y, Inoue H, Takano Y, Inanami
H, Koga H: Significance and pitfalls of
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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:
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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
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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
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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:
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66. Inoue M, Okamoto K, Terashima A, Nitta T, Muro

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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,
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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)
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Fehlings MG: Impact of Cervical Spine
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Surgery for Degenerative Cervical Myelopathy:
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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,
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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
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84. Fehlings MG, Kato S, Lenke LG, Nakashima H,
Nagoshi N, Shaffrey CI, Cheung KMC, Carreon L,
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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
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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., Toshikatsu Kaburaki, M.D., Ph.D.

Lecturer
Megumi Honjo, M.D., Ph.D., Ryo Obata, M.D., Ph.D.,
Hiromasa Sawamura, M.D., Ph.D., Takashi Miyai, M.D., Ph.D.

Research Associate
Muneyuki Takao, M.D., Ryo Asaoka, M.D., Ph.D., Tomoyasu Shiraya, M.D., Ph.D.
Hiroshi Murata, M.D., Takashi Fujishiro, M.D.,
Tatsuya Inoue, M.D., Ph.D., Rei Sakata, M.D., Ph.D., Tetsuya Toyono, M.D., Ph.D.,
Fumiyuki Araki, M.D., Ph.D., Rie Tanaka, M.D., Taku Toyama, M.D.
Junko Yoshida, M.D., Ph.D.

Homepage

http://www.todaiganka.jp/

Introduction and Organization
The Department of Ophthalmology, University ofTokyo School of Medicine, was founded in 1989.
Since then, the department has contributed to Japanese
ophthalmology not only by educating a large numberof eminent ophthalmologists in Japan, but also byproducing 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 32
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-ophthal-mology, 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, uveitis and strabismus. Surgeries are
performed in the operating theater of the hospital
under operating microscopes. Approximately 2100
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 a great potential in training
and promoting discussion.

Education
As an undergraduate course, we give lectures on
corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged in252practical training for medical students on ophthalmological examinations at the outpatient clinic. As apostgraduate 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 humour dynamics, immunology andmolecular biology. Special laboratories for physiology,
pharmacology and genetic engineering have been
established. Specific fields of research in our
department are as follows.
1. Lipid mediators in ocular diseases
2. Clinical investigation of normal tension
glaucoma
3. Drug development in IOP reduction of glaucoma
4. Screening method of glaucoma
5. Pathophysiology and molecular mechanisms of
diabetic retinopathy
6. Relationship between visual function and qualityof life in patient with low vision
7. Investigation of molecular mechanisms of retinal
arteritis and phlebitis
8. Investigation of gene mutations in primary
vitreoretinal lymphoma and development of newtreatment
9. Study of mechanisms involving disease-specific
HLA in Behcet's disease
10. Analysis of structure-function relationships inmacular diseases
11. Molecular analysis of corneal neovascularization
12. Gene therapy for corneal dystrophies
13. Analysis of Meibomian gland with Mibography
14. Analysis of safety of topical eye drops using
human corneal epithelial cell sheets
15. Clinical trial of corneal crosslinking for
keratoconus and keratoectasia
16. Ophthalmic examination of patients withcongenital insensitivity to pain with anhydrosis
17. Assessment of higher visual functions by fMRI
18. Relevance between ophthalmic diseases andcortical functions

Publications
1. Adachi S, Yuki K, Awano-Tanabe S, Ono T, Shiba
D, Murata H, Asaoka R, Tsubota K. Factors
associated with developing a fear of falling insubjects with primary open-angle glaucoma. BMC
Ophthalmol. 2018;18:39.
2. Aihara
M.
Response
toNovackre:"Pharmacokinetic
analysisofintraocularpenetration of latanoprost solutions with different
preservatives in human eyes". J Ocul Pharmacol
Ther. 2018;34:431.
3. Aoyama-Araki Y, Araki F, Shiraya T, Kato S.
Thorough perioperative laser photocoagulation inprevention of neovascular glaucoma after
vitrectomy for diabetic macular edema. Int J
Ophthalmol Clin Res. 2018;5:1-3.
4. Arai T, Tanaka R, Kaburaki T. Ocular inflamemation associated with polymyalgia rheumatica
without concomitant giant-cell arteritis: A reportof three cases. Ocul Immunol Inflamm. 2018;26:
779-82.
5. Azuma K, Asaoka R, Matsuda A, Lee J, Shimizu
K, Inui H, Murata H, Ogawa A, Yamamoto M,
Inoue T, Obata R. Two-year outcome of treatand-extend aflibercept after ranibizumab in
age-related macular degeneration and polypoidal
choroidal vasculopathy patients. Clin Ophthalmol.
2018;12:1589-97.
6. Hashimoto Y, Yokoo S, Usui T, Tsubota Y,
Yamagami S. High permeability and intercellularspace widening with brimonidine tartrate eye
drops in cultured stratified human corneal
epithelial sheets. Cornea. 2018;37:242-7.
7. Honjo M, Igarashi N, Kurano M, Yatomi Y,
Igarashi K, Kano K, Aoki J, Weinreb RN, Aihara
M. Autotaxin-lysophosphatidic acid pathway inintraocular pressure regulation and glaucoma
subtypes. Invest Ophthalmol Vis Sci. 2018;59:693-701.
8. Honjo M, Igarashi N, Nishida J, Kurano M,
Yatomi Y, Igarashi K, Kano K, Aoki J, Aihara M.
Role of the autotaxin-LPA pathway indexamethasone-induced fibrotic responses andextracellular matrix production in humantrabecular meshwork cells. Invest Ophthalmol Vis
Sci. 2018;59:21-30.

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9. Honjo M, Tanihara H. Impact of the clinical use
of ROCK inhibitor on the pathogenesis andtreatment of glaucoma. Jpn J Ophthalmol. 2018;
62:109-26.
10. Igarashi N, Honjo M, Kurano M, Yatomi Y,
Igarashi K, Kano K, Aoki J, Aihara M. Increased
aqueous autotaxin and lysophosphatidic acidlevels are potential prognostic factors after
trabeculectomy in different types of glaucoma. Sci
Rep. 2018;8:11304.
11. Igarashi N, Sawamura H, Kaburaki T, Aihara M.
Cancer-associated retinopathy developing after 10
years of complete breast cancer remission. Neuroophthalmol. 2018;55:261-5.
12. Karakawa A, Taoka K, Kaburaki T, Tanaka R,
Shinozaki-Ushiku A, Hayashi H, MiyagiMaeshima A, Nishimura Y, Uekusa T, Kojima Y,
Fukayama M, Kurokawa M, Aihara M. Clinicalfeatures and outcomes of secondary intraocularlymphoma. Br J Haematol. 2018;183:668-71.
13. Matsuura M, Fujino Y, Kanamoto T, Murata H,
Yanagisawa M, Hirasawa K, Inoue T, Shoji N,
Inoue K, Yamagami J, Asaoka R. Improving thestructure-function relationship in glaucomatousand normative eyes by incorporating photoreceptor layer thickness. Sci Rep. 2018;8:10450.
14. Matsuura M, Murata H, Fujino Y, Hirasawa K,
Yanagisawa M, Asaoka R. Evaluating theusefulness of MP-3 microperimetry in glaucoma
patients. Am J Ophthalmol. 2018;187:1-9.
15. Matsuura M, Murata H, Fujino Y, Hirasawa K,
Yanagisawa M, Asaoka R. Reply. Am J
Ophthalmol. 2018;190:201-2.
16. Miyai T. Fuchs endothelial corneal dystrophy andmitochondria. Cornea. 2018;37 Suppl 1:S74-s7.
17. Murata H, Zangwill LM, Fujino Y, Matsuura M,
Miki A, Hirasawa K, Tanito M, Mizoue S, Mori K,
Suzuki K, Yamashita T, Kashiwagi K, Shoji N,
Asaoka R. Validating variational Bayes linear
regression method with multi-central datasets.
Invest Ophthalmol Vis Sci. 2018;59:1897-904.
18. Nakahara H, Kaburaki T, Tanaka R, Matsuda J,
Takamoto M, Ohtomo K, Okinaga K, Komae K,
Numaga J, Fujino Y, Aihara M. Monoclonal
immunoglobulin heavy chain gene rearrangementin Fuchs' uveitis. BMC Ophthalmol. 2018;18:74.
19. Obata R, Yanagi Y, Inoue T, Yasuda M, Oshima Y,

Sawaguchi S, Iwase A, Araie M. Prevalence andfactors associated with age-related maculardegeneration in a southwestern island populationof Japan: the Kumejima Study. Br J Ophthalmol.
2018;102:1047-53.
20. Omoto T, Sakisaka T, Toyono T, Yoshida J,
Shirakawa R, Miyai T, Yamagami S, Usui T.
Descemet stripping automated endothelial
keratoplasty for failed penetrating keratoplasty:
Influence of the graft-host junction on the graft
survival rate. Cornea. 2018;37:462-5.
21. Ono T, Iida M, Mori Y, Nejima R, Iwasaki T,
Amano S, Miyata K. Outcomes of bee sting
injury: comparison of hornet and paper wasp. Jpn
J Ophthalmol. 2018;62:221-5.
22. Ono T, Iida M, Sakisaka T, Minami K, Miyata K.
Effect of laser peripheral iridotomy using argon
and neodymium-YAG lasers on corneal
endothelial cell density: 7-year longitudinalevaluation. Jpn J Ophthalmol. 2018;62:216-20.
23. Ono T, Mori Y, Nejima R, Iwasaki T, Amano S,
Miyata K. Optical coherence tomography
examination of the anterior segment in a case of
corneal perforation and lens trauma by chestnut
burr. Case Rep Ophthalmol. 2018;9:154-9.
24. Ono T, Mori Y, Nejima R, Ogata M, Minami K,
Miyata K. Sustainability of pain relief after
corneal collagen cross-linking in eyes withbullous keratopathy. Asia Pac J Ophthalmol(Phila). 2018;7:291-5.
25. Sawamura H, Gillebert CR, Todd JT, Orban GA.
Binocular stereo acuity affects monocular threedimensional shape perception in patients withstrabismus. Br J Ophthalmol. 2018;102:1413-8.
26. Shirahama S, Kaburaki T, Nakahara H, Tanaka R,
Takamoto M, Fujino Y, Kawashima H, Aihara M.
Epidemiology of uveitis (2013-2015) and changes
in the patterns of uveitis (2004-2015) in thecentral Tokyo area: a retrospective study. BMC
Ophthalmol. 2018;18:189.
27. Shiraya T, Kato S, Araki F. Therapeutic efficacy
of subthreshold laser photocoagulation using a
conventional pattern scan laser for macular edemain a retrospective study. Int J Ophthalmol Clin Res.
2018;5:1-8.
28. Tanaka R, Kaburaki T, Ohtomo K, Takamoto M,
Komae K, Numaga J, Fujino Y, Aihara M.

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Clinical characteristics and ocular complicationsof patients with scleritis in Japanese. Jpn J
Ophthalmol. 2018;62:517-24.
29. Tanaka R, Sakurai K, Kaburaki T. Scleritis
associated with SAPHO syndrome: A case report.
Ocul Immunol Inflamm. 2018;26:767-9.
30. Terao R, Honjo M, Aihara M. Apolipoprotein M
inhibits angiogenic and inflammatory response by
Sphingosine 1-phosphate on retinal pigment
epithelium cells. Int J Mol Sci. 2018;19:112.
31. the aqueous-outflow pathway. Invest Ophthalmol
Vis Sci. 2018;59:1844-54.
32. Yanagisawa M, Kato S, Ochiai M. Comparison of
Esterman disability scores obtained using
Goldmann perimetry and the Humphrey field
analyzer in Japanese low-vision patients. PLoS
One. 2018;13:e0203258.
33. Yanagisawa M, Yamashita T, Matsuura M, Fujino
Y, Murata H, Asaoka R. Changes in axial lengthand progression of visual field damage inglaucoma. Invest Ophthalmol Vis Sci. 2018;59:
407-17.
34. Yoshida J, Murata H, Miyai T, Shirakawa R,
Toyono T, Yamagami S, Usui T. Characteristics
and risk factors of recurrent keratoconus over thelong term after penetrating keratoplasty. Graefes
Arch Clin Exp Ophthalmol. 2018;256:2377-83.

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Department ofOtorhinolaryngology and Head& Neck Surgery
Professor
Tatsuya Yamasoba, M.D., Ph.D.

Associate Professor
Shin-ichi Iwasaki, MD., Ph.D.

Kenji Kondo, M.D., Ph.D.

Lecturer
Takaharu Nito, M.D., Ph.D.

Mizuo Ando, M.D., Ph.D.

Masafumi Yoshida, M.D., Ph.D.

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

Research Associate
Yu Matsumoto, M.D., Ph.D.

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

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

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

Hironobu Nishijima, M.D., Ph.D.

Osamu Fukuoka, M.D.

Ryoji Kagoya, M.D., Ph.D.

Takao Goto, M.D.

Yuya Shimizu, M.D.

Yayoi Kikkawa, 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, out-

patient 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
are provided to approximately 150 out-patients on adaily basis in all areas of otorhinolaryngology andrelated specialties, and approximately 300 new patients
visit monthly.

256

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 nanotechnology
2) Clinical application of otoacoustic emissions andauditory brainstem responses.
3) Histochemistry of olfactory epithelium in development and aging.
4) Clinical neurophysiology of the facial nerves
focusing on degeneration and regeneration inpatients.
5) Histochemistry of head and neck cancer pathology.
6) The central auditory cortex research using MEG.
7) Auditory brainstem response and speech andhearing after the new born hearing screening.
8) Pathology and electrophysiology of the larynx.
9) Vestibular research on the oculomotor and balancesystems in the brain.
10) Vestibular myogenic evoked potentials in cochlear
implant and inner ear anomaly.
11) Hair cell physiology in the vestibular end organ.
12) Newborn hearing screening and language development in deaf children.
13) Physiology bone conduction innovation of bone
conduction hearing and bilateral hearing.
14) Embryology of middle, inner ear and central
auditory system.
15) Therapeutic effects of growth factors on facial
nerve regeneration after injury16) Metabolic conversion of odorant molecules bynasal mucus
Various clinical and basic researches are conducted257

by staffs, residents, and graduate students as well as
doctors at affiliated hospitals.

References
1. Arakawa K, Hata K, Yamamoto Y, Nishikawa T,
Tanaka T, Kiyomatsu T, Kawai K, Nozawa H,
Yoshida M, Fukuhara H, Fujishiro M, Morikawa T,
Yamasoba T, Koike K, Fukayama M, Watanabe T.
Nine primary malignant neoplasms-involving theesophagus, stomach, colon, rectum, prostate, andexternal ear canal-without microsatellite instability: a case report. BMC Cancer. 18: 24, 2018.
2. Baba S, Kondo K, Yamasoba T. Electrophysiological Evaluation of the Facial Muscles inCongenital Unilateral Lower Lip Palsy. Otol
Neurotol. 39: 106-110, 2018
3. Fujimoto C, Kawahara T, Kinoshita M, Kikkawa
YS, Sugasawa K, Yagi M, Yamasoba T, Iwasaki S,
Murofushi T. Aging Is a Risk Factor for Utricular
Dysfunction in Idiopathic Benign Paroxysmal
Positional Vertigo. Front Neurol. 9: 1049, 2018
4. Fujimoto C, Suzuki S, Kinoshita M, Egami N,
Sugasawa K, Iwasaki S. Clinical features of otolithorgan-specific vestibular dysfunction. Clin Neurophysiol. 129: 238-245, 2018
5. Fujimoto C, Egami N, Kawahara T, Uemura Y,
Yamamoto Y, Yamasoba T, Iwasaki S*. Noisy
galvanic vestibular stimulation sustainably improves posture in bilateral vestibulopathy. Front
Neurol. 9: 900, 2018
6. Fukusumi T, Guo TW, Sakai A, Ando M, Ren S,
Haft S, Liu C, Amornphimoltham P, Gutkind JS,
Califano JA. The NOTCH4-HEY1 Pathway
Induces Epithelial-Mesenchymal Transition in
Head and Neck Squamous Cell Carcinoma. Clin
Cancer Res. 24: 619-633, 2018
7. Goto T, Nito T, Ueha R, Yamauchi A, Sato T,
Yamasoba T. Unilateral vocal fold adductor
paralysis after tracheal intubation. Auris Nasus
Larynx. 45: 178-181, 2018
8. Hasegawa H, Shin M, Kondo K, Saito N.
Reconstruction of Dural Defects in Endoscopic
Transnasal Approaches for Intradural Lesions
Using Multilayered Fascia with a Pressure-Control
Spinal Drainage System. World Neurosurg. 114:
e1316-e1324, 2018

9. Hasegawa H, Shin M, Kondo K, Hanakita S,
Mukasa A, Kin T, Saito N. Role of endoscopictransnasal surgery for skull base chondrosarcoma:
a retrospective analysis of 19 cases at a single
institution. J Neurosurg. 128: 1438-1447, 2018
10. Hosoya M, Kobayashi R, Ishii T, Senarita M,
Kuroda H, Misawa H, Tanaka F, Takiguchi T,
Tashiro M, Masuda S, Hashimoto S, Goto F,
Minami S, Yamamoto N, Nagai R, Sayama A,
Wakabayashi T, Toshikuni K, Ueha R, Fujimaki Y,
Takazawa M, Sekimoto S, Itoh K, Nito T, Kada A,
Tsunoda K. Vocal Hygiene Education Program
Reduces Surgical Interventions for Benign Vocal
Fold Lesions: A Randomized Controlled Trial.
Laryngoscope. 128: 2593-2599, 2018
11. Iwasaki S, Fujimoto C, Egami N, Kinoshita M,
Togo F, Yamamoto Y, Yamasoba T. Noisy
vestibular stimulation increases gait speed innormals and in bilateral vestibulopathy. Brain
Stimul. 11: 709-715, 2018
12. Kaneoka A, Yang S, Inokuchi H, Ueha R,
Yamashita H, Nito T, Seto Y, Haga N. Presentationof oropharyngeal dysphagia and rehabilitativeintervention
followingesophagectomy:asystematic review. Dis Esophagus. 31: 8, 2018
13. Katano A, Takahashi W, Yamashita H, Yamamoto
K, Ando M, Yoshida M, Saito Y, Abe O,
Nakagawa K. Radiotherapy alone and withconcurrent chemotherapy for nasopharyngeal
carcinoma: A retrospective study. Medicine(Baltimore). 97: e0502, 2018
14. Katsushika M, Kashio A, Ogata E, Akamatsu Y,
Hoshi Y, Iwasaki S, Yamasoba T. Outcomes ofcochlear implantations for mumps deafness: A
report of four pediatric cases. Int J Pediatr
Otorhinolaryngol. 114: 76-79, 2018
15. Kiyama Y, Kikkawa YS, Kinoshita M, Matsumoto
Y, Kondo K, Fujimoto C, Iwasaki S, Yamasoba T,
Manabe T. The adhesion molecule cadherin 11 isessential for acquisition of normal hearing ability
through middle ear development in the mouse. Lab
Invest. 98: 1364-1374, 2018
16. Kobayashi K, Matsumoto F, Miyakita Y, Mori T,
Shimoi T, Murakami N, Yoshida A, Arakawa A,
Omura G, Fukawasa M, Matsumoto Y, Matsumura
S, Itami J, Narita Y, Yoshimoto S. Impact ofSurgical Margin in Skull Base Surgery for Head

258

and Neck Sarcomas. J Neurol Surg B Skull Base.
79: 437-444, 2018
17. Kondo K, Baba S, Suzuki S, Nishijima H, Kikuta
S, Yamasoba T. Infraorbital Nerve LocatedMedially to Postoperative Maxillary Cysts: A Risk
of Endonasal Surgery. ORL J Otorhinolaryngol
Relat Spec. 80: 28-35, 2018
18. Liu C, Guo T, Xu G, Sakai A, Ren S, Fukusumi T,
Ando M, Sadat SH, Saito Y, Khan Z, Fisch KM,
Califano J. Characterization of Alternative Splicing Events in HPV-Negative Head and Neck
Squamous Cell Carcinoma Identifies an Oncogenic
DOCK5 Variant. Clin Cancer Res. 24: 5123-5132,
2018
19. Mukai T, Hoshi Y, Sahara T, Ueha R. Tracheal
Stenosis by Brachiocephalic Artery Compression.
Clin Surg. 3: 2066, 2018
20. Nakada T, Kikuta S, Mori H, Shimizu Y, Nishijima
H, Kondo K, Yamasoba T. Low CT Attenuation
Values of Sinonasal Benign Tumours Relative tothe Brainstem Identify Schwannomas. ORL J
Otorhinolaryngol Relat Spec. 80: 41-50, 2018
21. Nakajima T, Koide S, Yasuda T, Hasegawa T,
Yamasoba T, Obi S, Toyoda S, Nakamura F, Inoue
T, Poole DC, Kano Y. Muscle hypertrophy following blood flow-restricted, low-force isometricelectrical stimulation in rat tibialis anterior: role formuscle hypoxia. J Appl Physiol. 125: 134-145,
2018
22. Narushima M, Yamasoba T, Iida T, Matsumoto Y,
Yamamoto T, Yoshimatsu H, Timothy S, Pafitanis
G, Yamashita S, Koshima I. Pure Skin Perforator
Flaps: The Anatomical Vascularity of theSuperthin Flap. Plast Reconstr Surg. 142: 351e360e, 201823. Nishijima H, Suzuki S, Kondo K, Yamasoba T,
Yanagimoto S. Environmental factors associatedwith allergic rhinitis symptoms in Japanese
university students: A cross-sectional study. Auris
Nasus Larynx. 45: 1006-1013, 2018
24. Nishijima H, Kondo K, Yamamoto T, Nomura T,
Kikuta S, Shimizu Y, Mizushima Y, Yamasoba T.
Influence of the location of nasal polyps on
olfactory airflow and olfaction. Int Forum Allergy
Rhinol. 8: 695-706, 2018
25. Nomura T, Ushio M, Kondo K, Kikuchi S. Effects
of nasal septum perforation repair on nasal airflow:

An analysis using computational fluid dynamics on
preoperative and postoperative three-dimensionalmodels. Auris Nasus Larynx. 45: 1020-1026, 2018
26. Ren S, Gaykalova D, Wang J, Guo T, Danilova L,
Favorov A, Fertig E, Bishop J, Khan Z, Flam E,
Wysocki PT, DeJong P, Ando M, Liu C, Sakai A,
Fukusumi T, Haft S, Sadat S, Califano JA.
Discovery and development of differentiallymethylated regions in human papillomavirusrelated oropharyngeal squamous cell carcinoma.
Int J Cancer. 143: 2425-2436, 201827. Shimizu Y, Yagi M. Pulsatile tinnitus and carotid
artery dissection. Auris Nasus Larynx. 45: 175-177,
2018
28. Shin M, Shojima M, Kondo K, Hasegawa H,
Hanakita S, Ito A, Kin T, Saito N. Endoscopic
Endonasal Craniofacial Surgery for Recurrent
Skull Base Meningiomas Involving the
Pterygopalatine Fossa, the Infratemporal Fossa, theOrbit, and the Paranasal Sinus. World Neurosurg.
112: e302-e312, 201829. Suzuki S, Yasunaga H, Matsui H, Fushimi K, Ando
M, Yamasoba T. Postoperative mechanical bowel
obstruction after pharyngolaryngectomy for hypopharyngeal cancer: Retrospective analysis using a
Japanese inpatient. Head Neck. 40: 1548-1554,
2018
30. Suzuki S, Yasunaga H, Matsui H, Fushimi K,
Yamasoba T. Trend in otolaryngological surgeries
in an era of super-aging: Descriptive statistics
using a Japanese inpatient database. Auris Nasus
Larynx. 45: 1239-1244, 201831. Tuerdi A, Kikuta S, Kinoshita M, Kamogashira T,
Kondo K, Iwasaki S, Yamasoba T. Dorsal-zonespecific reduction of sensory neuron density in theolfactory epithelium following long-term exercise
or caloric restriction. Sci Rep. 8: 17300, 2018
32. Ueha R, Nito T, Goto T, Sato T, Ushiku T,
Yamasoba T. Bilateral vocal cord immobility
resulting from cytomegalovirus pharyngitis: A
case report. J Infect Chemother. 24:142-146, 2018
33. Ueha R, Ueha S, Kondo K, Kikuta S, Yamasoba T.
Cigarette Smoke-Induced Cell Death Causes
Persistent Olfactory Dysfunction in Aged Mice.
Front Aging Neurosci. 10: 183, 2018
34. Ueha R, Kondo K, Ueha S, Yamasoba T. DoseDependent Effects of Insulin-Like Growth Factor

259

1 in the Aged Olfactory Epithelium. Front Aging
Neurosci. 10: 385, 201835. Ueha R, Goto T, Sato T, Nativ-Zeltzer N, Shen SC,
Nito T, Belafsky PC, Yamasoba T. High
Resolution Manofluorographic Study in Patients
With Multiple System Atrophy: Possible Early
Detection of Upper Esophageal Sphincter andProximal Esophageal Abnormality. Front Med(Lausanne). 5: 286, 2018
36. Ueha R, Goto T, Kaneoka A, Takano T, Sato T,
Hirata Y, Nito T, Yamasoba T. Management oflaryngeal cleft in mechanically ventilated children
with severe comorbidities. Auris Nasus Larynx.
45: 1121-1126, 2018
37. Ueha R, Shichino S, Ueha S, Kondo K, Kikuta S,
Nishijima H, Matsushima K, Yamasoba T.
Reduction of Proliferating Olfactory Cells and
Low Expression of Extracellular Matrix Genes Are
Hallmarks of the Aged Olfactory Mucosa. Front
Aging Neurosci. 10: 86, 2018

260

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261

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.

2.

3.

4.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with 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. Endo S, Takahashi T, Sato M, Noya Y, Obana M:
Effects of l-Carnitine Supplementation, Botulinum
Neurotoxin Injection, and Rehabilitation for a

5.

6.

7.

8.

9.

Chronic Stroke Patient. J Stroke Cerebrovasc Dis
27: 3342-3344, 2018
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
Up and Go test for measuring objective functional
impairment in patients with long-standing rheumatoid arthritis: a cross-sectional study. Int J Rheum
Dis 21: 1793-1800, 2018
Taya M, Amiya E, Hatano M, Maki H, Nitta D,
Saito A, Tsuji M, Hosoya Y, Minatsuki S, Nakayama A, Fujiwara T, Konishi Y, Yokota K, Watanabe
M, Morita H, Haga N, Komuro I: High-intensity
aerobic interval training can lead to improvementin skeletal muscle power among in-hospital patients with advanced heart failure. Heart Vessels
33: 752-759, 2018
Tanaka T, Ito H, Oshima H, Haga N, Tanaka S:
Total hip arthroplasty in a patient with
oto-spondylo-megaepiphyseal dysplasia, plannedby three-dimensional motion-analyses and fullscale three-dimensional plaster model of bones.
Case Reports in Orthopedics 2018 Jan 23; 2018:
8384079. eCollection 2018
Sawada Y, Sasabuchi Y, Nakahara Y, Matsui H,
Fushimi K, Haga N, Yasunaga H: Early rehabilitation and in-hospital mortality in community-acquired pneumonia patients admitted to an intensive care unit: propensity-matched analysis. Am
J Crit Care 27: 97-103, 2018
Mano H, Fujiwara S, Haga N: Adaptive behaviour
and motor skills in children with upper limb deficiency. Prosthet Orthot Int 42: 236-240, 2018
Mano H, Fujiwara S, Takamura K, Kitoh H, Takayama S, Ogata T, Hashimoto S, Haga N: Congenital limb deficiency in Japan: A cross-sectional nationwide survey on its epidemiology. BMC Musculoskelet Disord 19: 262, 2018
Mano H, Takiakwa K, Haga N: Intellectual characteristics using WISC-IV in children with myelomeningocele. Cogent Med 5: 1151827, 2018
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262with rheumatoid arthritis: A prospective cohort
study. Int J Rheum Dis 21: 1801-1808, 2018
10. Kaneoka A, Yang S, Inokuchi H, Ueha R, Yamashita H, Nito T, Seto Y, Haga N: Presentation oforopharyngeal dysphagia and rehabilitative intervention following esophagectomy: a systematic review. Dis Esophagus 31: 1-11, 2018
11. Ueha R, Takano T, Hirata Y, Sato T, Goto T, Kaneoka A, Nito T. Yamasoba T: Management of laryngeal cleft in mechanically ventilated children
with severe comorbidities. Auris Nasus Larynx 45:
1121-1126, 2018
12. 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) for musculoskeletal oncology patients. J Orthop Sci pii:
S0949-2658(18)30317-8, 2018.11
13. 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 of threeconservative treatments in patients with lumbar
spinal stenosis: lumbar spinal stenosis with acupuncture and physical therapy study (LAP study).
BMC Complementary and Alternative Medicine
18(1):19, 201814. Suga M, Kawakubo Y, Nishimura Y, Hashimoto K,
Yumoto M, Kasai K: Lack of correlation between
phonetic magnetic mismatch field and plasma
D-serine levels in humans. Clinical Neurophysiology 129(7):1444-1448, 2018

Surgical Sciences
3. Vital Care Medicine

264

Department of Anesthesiology
Professor
Yoshitsugu Yamada, M.D., Ph.D.

Associate Professor
Kanji Uchida, M.D., Ph.D.

Masahiko Sumitani, M.D., Ph.D.

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

Masahiko Bougaki, M.D., Ph.D. Mori Yoshiteru, M.D.

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

Gaku Kawamura, M.D.

Associate
Masaaki Asamoto, M.D.,

Miki Shinokawa, M.D.,

Yoshiomi Kusakabe, M.D., Ph.D.

Ayako Hirai, M.D., Michiko Ushio, M.D., Jun Hozumi, M.D., Ph.D., Yuko Araki, M.D.,
Atsuko Kato, M.D.,

Takuma Hiraiwa, M.D.,

Yasuko Okagami, M.D.,

Mizuho Sato, M.D.,

Ai Furuta, M.D., Emi Morinushi, M.D.,

Takuya Ohata, M.D.,
Seiichiro Kawashima, M.D.,

Hayato Narita, M.D.,

Masae Ando, M.D.,

Yuji Ueda, M.D., Satoshi Kasahara, 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
27 faculty staffs, 9 graduate students and 16 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 12,000. 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 2018 to March 2019, the number of
ambulatory patients was about ten thousands; twohundreds and seventy of those were newcomer patients.
Currently we have three beds in the ward. We take care
40 patients in our ward and approximately 100 in other265

wards 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) Kato A, Tamai H, Uchida K, Ikeda T, Yamada Y.
Intraoperative hemodynamics monitoring in apatient with pheochromocytoma multisystem
crisis: a case report. JA Clin Rep 2018;4:35(2) Kusakabe Y, Uchida K, Yamamura Y, Hiruma T,
Totsu T, Tamai Y, Tsuyuzaki H, Hasegawa K,
Chang K, Yamada Y. Early-phase Innate Immune

266

Suppression in Murine Severe Sepsis Is Restoredwith Systemic Interferon-β. Anesthesiology 2018;
129(1):131-142(3) Abe H, Sumitani M, Uchida K, Ikeda T, Matsui H,
Fushimi K, Yasunaga H, Yamada Y. Association
between mode of anaesthesia and severe maternal
morbidity during admission for scheduled
Caesarean delivery: a nationwide population-based
study in Japan, 2010-2013. British J Anaesth 2018;
120(4):779-789(4) Hiruma T, Tsuyuzaki H, Uchida K, Trapnell BC,
Yamamura Y, Kusakabe Y, Totsu T, Suzuki T,
Morita S, Doi K, Noiri E, Nakamura K, Nakajima
S, Yahagi N, Morimura N, Chang K, Yamada Y.
Interferon-β Improves Sepsis-related Alveolar
Macrophage Dysfunction and Post-septic ARDSrelated Mortality. Am J Respir Cell Mol Biol.
2018;59(1):45-55(5) Watanabe K, Ito N, Ohata T, Kariya T, Inui H,
Yamada Y Perioperativeballoon pulmonary
angioplasty enabled noncardiac surgery of a patientwith chronic thromboembolic pulmonary hypertension (CTEPH). Medicine 2018;98(10):e14807(6) Hozumi J, Sumitani M, Nishizawa D, Nagashima
M, Ikeda K, Abe H, Kato R, Kusakabe Y, Yamada
Y, Japanese TR-Cancer Pain Research Group.
Resistin Is a Novel Marker for Postoperative Pain
Intensity. Anesthesia and Analgesia 2019;128(3):563-568(7) Yokoshima Y, Sumitani M, Nishizawa D,
Nagashima M, Ikeda K, Kato R, Hozumi J, Abe H,
Azuma K, Tsuchida R, Yamada Y; Japanese TRCancer Pain Research Group. Gammaaminobutyricacid
transaminase
genetic
polymorphism is a candidate locus forresponsiveness to opioid analgesics in patientswith cancer pain: An exploratory study.
Neuropsychopharmacol Rep. 2018;38(4):175-181(8) Sumitani M, Sakai T, Matsuda Y, Abe H,
Yamaguchi S, Hosokawa T, Fukui S Executive
summary of the Clinical Guidelines of
Pharmacotherapy for Neuropathic Pain: second
edition by the Japanese Society of Pain Clinicians
Journal of Anesthesia 2018;32(3):463-478(9) Sumitani M, Nishizawa D, Nagashima M, Ikeda K,
Abe H, Kato R, Ueda H, Yamada Y Association
Between Polymorphisms in the Purinergic P2Y12

Receptor Gene and Severity of Both Cancer Pain
and Postoperative Pain. Pain Medicine 2018;19(2):348-354(10)Kuwajima K, Sumitani M, Kurano M, Kano K,
Nishikawa M, Uranbileg B, Tsuchida R, Ogata T,
Aoki J, Yatomi Y, Yamada Y. Lysophosphatidic
acid is associated with neuropathic pain intensity
in humans: An exploratory study. PLoS One 2018;13(11):e0207310

267

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

Lecturer
Masataka Gunshin, M.D.

Kent Doi, M.D.

Chiaki Toida, M.D.

Takahiro Hiruma, M.D.

Ryota Inokuchi, M.D.

Kohei Yoshimoto, M.D.

Ryohei Horie, M.D.

Naoki Hayase, M.D.

Akinori Maeda, M.D.

Shunsuke Tagami, M.D.

Mio Kurimoto, M.D.

Go Takeda, M.D.

Yasutaka Watanabe, M.D.

Project Lecturer
Yoshihiro Ueda, M.D.

Research Associate

Project Research Associate
Masaki Mochizuki, 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.

Clinical activities
Our clinical activities are divided into four
categories as follows:
1) Emergency medicine
Our department is responsible for not only tertiary

268

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 intestineand kidney has been conducted to clarify themechanisms of remote organ injury in multiple organ
dysfunction syndrome. Our clinical studies revealed
that organ network disruption could be observed by
network analysis with clinical parameters and new
biomarkers of ICU patients.

269

References
1. Wada T, Yasunaga H, Yamana H, Matsui H,
Fushimi K, Morimura N. Development andvalidation of an ICD-10-based disability predictive
index for patients admitted to hospitals with trauma.
Injury. 2018 Mar;49(3):556-563.
2. Furugori S, Kato M, Abe T, Iwashita M, Morimura
N. Treating patients in a trauma room equippedwith computed tomography and patients' mortality:
a non-controlled comparison study. World J Emerg
Surg. 2018 Mar 27;13:16.
3. Inokuchi R, Maehara H, Iwai S, Iwagami M, Sato
H, Yamaguchi Y, Asada T, Yamamoto M,
Nakamura K, Hiruma T, Doi K, Morimura N.
Interface design dividing physical findings into
medical and trauma findings facilitates clinicaldocument entry in the emergency department: A
prospective observational study. Int J Med Inform.
2018 Apr;112:143-148.
4. Toida C, Muguruma T, Abe T, Shinohara M,
Gakumazawa M, Yogo N, Shirasawa A, Morimura
N. Introduction of Pediatric Physiological andAnatomical Triage Score in Mass-Casualty
Incident. Prehosp Disaster Med. 2018 Apr;33(2):147-152.
5. Kitamura T, Iwami T, Atsumi T, Endo T, Kanna T,
Kuroda Y, Sakurai A, Tasaki O, Tahara Y, Tsuruta
R, Tomio J, Nakata K, Nachi S, Hase M,
Hayakawa M, Hiruma T, Hiasa K, Muguruma T,
Yano T, Shimazu T, Morimura N; special committee that aims to improve survival after out‐of‐hospital cardiac arrest (OHCA) by providing
evidence‐based
therapeuticstrategy
andemergency medical system from the Japanese
Association for Acute Medicine (JAAM). The
profile of Japanese Association for Acute Medicine- out-of-hospital cardiac arrest registry in 20142015. Acute Med Surg. 2018 Apr 25;5(3):249-258.
6. Aoki M, Hagiwara S, Oshima K, Suzuki M,
Sakurai A, Tahara Y, Nagao K, Yonemoto N,
Yaguchi A, Morimura N; SOS-KANTO 2012
Study Group. Obesity was associated with worse
neurological outcome among Japanese patientswith out-of-hospital cardiac arrest. Intensive CareMed. 2018 May;44(5):665-666.
7. Oi Y, Sato K, Nogaki A, Shinohara M, Matsumoto

J, Abe T, Morimura N. Association between
venous blood lactate levels and differences inquantitative capillary refill time. Acute Med Surg.
2018 Jun 5;5(4):321-328.
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Health Sciences and Nursing
1. Health Sciences

271

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.

272

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.

3.

4.

5.

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JM, Sims T, Markus HR, Kitayama S, Kawakami
N, Karasawa M, Coe CL, Love GD, Ryff CD.
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Kawada T. Associations of non-standard employment with cardiovascular risk factors: findings
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PERMA-Profiler: A validation study among
Japanese workers. J Occup Health. 2018; 60(5):383-393. DOI: 10.1539/joh.2018-0050-OA.
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among Japanese White-Collar Employees: a
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Arima H, Asai Y, Inoue A, Inoue R, Iwanaga M,
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Shimazu A, Kuribayashi K, Kasai K, Kawakami
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10;20(8):e10231. DOI: 10.2196/10231.
36. Watanabe K, Sakuraya A, Kawakami N, Imamura
K, Ando E, Asai Y, Eguchi H, Kobayashi Y,
Nishida N, Arima H, Shimazu A, Tsutsumi A.
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syndrome onset among workers: a systematic
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Twisk J, Burger S, Rozental A, Lange A, Williams
A D, Zarski A C, Geraedts A, van Straten A,
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D, Snoek F J, Andrews G, Andersson G, Choi I,
Ruwaard J, Klein J P, Newby J M, Schroder J,
Laferton J A C, van Bastelaar K, Imamura K,
Vernmark K, Bos L, Sheeber L B, Kivi M,
Berking M, Titov N, Carlbring P, Johansson R,
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Kaldo V, Forsell Y, Lindefors N, Kraepelien M,
Bjorkelund C, Kawakami N, & Cuijpers P. Do
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Associations among workplace environment, selfregulation, and domain-specific physical activities
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10.15226/2374-6874/5/1/00145.
40. Iwanaga M, Imamura K, Shimazu A, Kawakami
N (2018) The impact of being bullied at school on
psychological distress and work engagement in acommunity sample of adult workers in Japan.
PLoS ONE 13(5): e0197168. DOI: 10.1371/
journal.pone.0197168
41. Inoue A, Kawakami N, Eguchi H, Tsutsumi A.
Interaction effect of job insecurity and roleambiguity on psychological distress in Japaneseemployees: a cross-sectional study. Int Arch
Occup Environ Health. 2018; 91(4): 391-402.
DOI: 10.1007/s00420-018-1288-5
42. Imamura K, Asai Y, Watanabe K, Tsutsumi A,
Shimazu A, Inoue A, Hiro H, Odagiri Y,
Yoshikawa T, Yoshikawa E, Kawakami N Effectof the National Stress Check Program on mental
health among workers in Japan: A 1-year
retrospective cohort study J Occup Health (inpress).
43. Erika Obikane, Tomohiro Shinozaki, Daisuke
Takagi, Norito Kawakami. Impact of Childhood
Abuse on Suicide-Related Behavior: Analysis
Using Marginal Structural Models. Journal of
Affective Disorders. 2018; 234: 224-230. DOI:
10.1016/j.jad.2018.02.034.
44. Xu QY, Fukasawa M, Kawakami N, Baba T,
Sakata K, Suzuki R, Tomita H, Nemoto H,
Yasumura S, Yabe H, Horikoshi N, Umeda M,
Suzuki Y, Shimoda H, Tachimori H, Takeshima T,
Bromet EJ. Cumulative incidence of suicidal
ideation and associated factors among adults
living in temporary housing during the three years
after the Great East Japan Earthquake. Journal ofaffective disorders. 2018;232:1-8. DOI: 10.1016/j.
jad.2018.01.021.

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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
Tomohiro Shinozaki, Ph.D., M.P.H., Kosuke Kashiwabara, Ph.D.

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

Homepage

http://www.epistat.m.u-tokyo.ac.jp/en/

Introduction and Organization
The Department of Epidemiology and Biostatistics
evolved from the Department of Epidemiology in
1992. Since then, we have been responsible forproviding educational courses on methodology of
epidemiologic research and biostatistics to undergraduate students. We belong to Graduate School of
Medicine as Departments of Biostatistics/ Epidemiology and Preventive Health Sciences, providing
education for undergraduate as well as graduateschool students and consultation to clinical researchers.
Unfortunately, education programs for biostatistics
and epidemiological methodology are not sufficient inJapanese universities and graduate schools comparedto the situation in the US and European countries.
Nevertheless, the necessity for collaboration among
biostatisticiansandclinicalresearchers/
epidemiologists has been claimed in recent years.
Hence, the central missions of our educational courses
are devoted to provide students expert knowledge andextensive experience in biostatistics and epidemiology
to take part in clinical/epidemiological research as

biostatisticians or methodologists. We do not only
focus on practical aspects on statistical analysis in
medical research but also place emphasis on themethodologicalprinciplesofbiostatistics/
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.

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Teaching activities
 Undergraduate Courses
1) Epidemiology (2 credits)
2) Biostatistics (2 credits; named “Statistics” inmedical doctor course)3) 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)4) Informatics technology for clinical medicine,
nursing and health science (2 credit; 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 Support 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. Obikane E, Shinozaki T, Takagi D, Kawakami N.
Impact of childhood abuse on suicide-related
behavior: analysis using marginal structural

279

2.

3.

4.

5.

6.

7.

8.

models. J Affect Disord. 2018;234:224–230.
Kawahara T, Fukuda M, Oba K, Sakamoto J,
Buyse M. Meta-analysis of randomized clinical
trials in the era of individual patient data sharing.
Int J Clin Oncol. 2018;23:403–409.
Yamazaki Y, Oba K, Matsui Y, Morimoto Y.
Vasoactive-inotropic score as a predictor of
morbidity and mortality in adults after cardiac
surgery with cardiopulmonary bypass. J Anesth.
2018;32:167–173.
Hagiwara Y, Ohashi Y, Uesaka K, Boku N,
Fukutomi A, Okamura Y, Konishi M, Matsumoto I,
Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H,
Morinaga S, Kainuma O, Imai K, Sata N,
Hishinuma S, Ojima H, Yamaguchi R, Hirano S,
Sudo T. Health-related quality of life of adjuvant
chemotherapy with S-1 versus gemcitabine forresected pancreatic cancer: results from arandomized phase III trial (JASPAC 01). Eur J
Cancer. 2018;93:79–88.
Takeuchi Y, Shinozaki T, Matsuyama Y. A
comparison of estimators from self-controlledcase series, case-crossover design, and sequence
symmetry analysis for pharmacoepidemiologicalstudies. BMC Med Res Methodol. 2018;18:4.
Hagiwara Y, Shiroiwa T, Shimozuma K,
Kawahara T, Uemura Y, Watanabe T, Taira N,
Fukuda T, Ohashi Y, Mukai H. Impact of adverse
events on health utility and health-related qualityof life in patients receiving first-line chemotherapy for metastatic breast cancer: results fromthe SELECT BC study. Pharmacoeconomics.
2018;36:215–223.
Takeuchi Y, Shinozaki T, Kumamaru H,
Hiramatsu T, Matsuyama Y. Analyzing intent-totreat and per-protocol effects on safety outcomesusing a medical information database: An
application to the risk assessment of antibioticinduced liver injury. Expert Opin Drug Saf. 2018;
17:1071–1079.
Tabuchi T, Shinozaki T, Kunugita N, Nakamura M,
Tsuji I. Study Profile: The Japan “Society and
New Tobacco” Internet Survey (JASTIS): alongitudinal internet cohort study of heat-not-burntobacco products, electronic cigarettes andconventional tobacco products in Japan. J
Epidemiol. 2018, online.

9. Shimada H, Fukagawa T, Haga Y, Oba K. Does
postoperative morbidity worsen the oncologicaloutcome after radical surgery for gastrointestinal
cancers? A systematic review of the literature.
Ann Gastroenterol Surg. 2017;1:11–23.
10. Kashiwabara K, Matsuyama Y. Reasonable
two-stage adaptive designs for single-arm phase II
clinical trials. Pharm Stat 2018;17:770–780.
11. Hagiwara Y, Fukuda M, Matsuyama Y. The
number of events per confounder for valid
estimation of risk difference using modified leastsquares regression. Am J Epidemiol. 2018;187:
2481–2490.
12. Taniguchi Y, Kitamura A, Shinozaki T, Seino S,
Yokoyama Y, Narita M, Amano H, Matsuyama Y,
Fujiwara Y, Shinkai S. Trajectories of arterial
stiffness and all-cause mortality amongcommunity-dwelling older Japanese. Geriatr
Gerontol Int. 2018;18(7):1108–1113.
(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.
Staff members of the two departments include a
professor, an associate professor, a lecturer, anassociate, and a technical specialist. All five members,
a project research associate, six project researchers,281

nine lecturers from other organizations, and fivevisiting 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. Seventeen bachelor theses, twenty-two
master theses, and eleven doctoral dissertations werecompleted between April 2004 and March 2019. Our
departments’ 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
Department of Biomedical Ethics
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
region8) Historical analyses for the term “bioethics” in the282Japanese context

References
1. Akabayashi A, Nakazawa E, Caplan AL. Geneediting: who should decide? Nature. 2018 Dec;
564(7735):190.
doi: 10.1038/d41586-018-07720-3.
2. Akabayashi A, Nakazawa E, Ino H, OzekiHayashi R, Jecker NS. Sacrificing the Fukushima
50 again? J Public Health. 2018 Aug 28. doi:
10.1093/pubmed/fdy143.
3. Akabayashi A, Nakazawa E, Jecker NS. Japan
must tighten up clinical trial of stem cells forheart failure. Nature. 2018 Aug; 560(7719):431.
doi: 10.1038/d41586-018-06015-x.
4. Akabayashi A, Nakazawa E, Jecker NS.
Endangerment of the iPSC stock project in Japan:
on the ethics of public funding policies. J Med
Ethics. 2018;44(10):700-702.
doi: 10.1136/medethics-2018-105024.
5. Akabayashi A, Nakazawa E, Jecker NS. What areconsidered 'good facts'? J Med Ethics. Published
Online First: 18 February 2019.
doi: 10.1136/medethics-2018-105333.
6. Akabayashi A, Nakazawa E, Jecker NS. The
world's first clinical trial for an aplastic anemia
patient with thrombocytopenia administering
platelets generated from autologous iPS cells. Int
J Hematol. 2019 Feb;109(2):239-240.
doi: 10.1007/s12185-018-02565-y.
7. Akabayashi A, Nakazawa E, Ozeki-Hayashi R,
Tomiyama K, Mori K, Demme RA, Akabayashi A.
Twenty years after enactment of the organtransplant law in Japan: Why are there still so few
deceased donors? Transplant Proc. 2018 Jun;50(5):1209-1219.
doi: 10.1016/j.transproceed.2018.02.078.
8. Akabayashi A, Nakazawa E, Uetake Y. Two major
concerns surrounding governmental approval oftumourectomized kidney transplants in Japan.
Nephrology and Renal Diseases. 2018;3(2):1-2.
9. Arai N, Takimoto Y, Nakazawa E, Akabayashi A.
Considerations on the factors influencing living
kidney donors' autonomous decision-making: A
systematic literature review. Transplant Proc.
2018 Dec;50(10): 3036-3044.

doi: 10.1016/j.transproceed.2018.06.015.
10. Nakazawa E, Maeda S, Yamamoto K, Akabayashi
A, Uetake Y, Shaw MH, Demme RA, Akabayashi
A. Reuse of cardiac organs in transplantation: an
ethical analysis. BMC Med Ethics. 2018 Aug
17;19(1):77. doi: 10.1186/s12910-018-0316-z.
11. Nakazawa E, Shimanouchi A, Akabayashi A,
Akabayashi A. Should the Japanese government
support travels for transplantation as a policy
under the National Health Insurance system?
Transpl Int. 2018 Jun;31(6):670-671.
doi: 10.1111/tri.13156.
12. Nakazawa E, Tsuchiya A. 2018. Polarity of Public
Perception over General Consent: Survey on
Consciousness of Healthy Japanese Participants in
Brain Database Projects. Annals of Bioethics andClinical Applications. 2018;1(1):000102.
13. Nakazawa E, Yamamoto K, Akabayashi A.
Fairness and Desert: A Critique of the Random
Selection Criterion in Clinical Trials. Am J Bioeth.
2018 Apr;18(4):81-82.
doi: 10.1080/15265161.2018.1444818.
14. Nakazawa E, Yamamoto K, Akabayashi A,
Akabayashi A. Regulations on Genome Editing of
Human Embryos in Japan: Our Moral Moratorium.
Camb Q Healthc Ethics. 2018 Jul;27(3):360-365.
doi: 10.1017/S0963180117000743.
15. 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.
16. 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(3):385-389.
doi: 10.1016/j.neuron.2019.01.006.
17. Takahashi S, Johnston J, Patrizio P. Lessons fromthe premature adoption of preimplantation embryo
testing. Genet Med. 2018 Sep 28. doi:
10.1038/s41436-018-0314-z.
18. Toda S, Nakazawa E, Yamamoto K, Akabayashi A.
From “cannot” function to “might” function:
Assessment of actual levels of consciousness andpotential consciousness in patient care: Japaneseexperiences. AJOB Neurosci. 2018 Mar;9(1):2022.
doi: 10.1080/21507740.2018.1425762.

283

19. Toda S, Yamamoto K, Nakazawa E, Akabayashi A.
Bridging matters of uncertainty: The importanceof focusing on the “state in between” for disordersof consciousness. AJOB Neurosci. 2018 Jun;9(2):83-84.
doi: 10.1080/21507740.2018.1466836.
20. Yoshida S, Tamate S. CQ Review; The Future of
Bioethics: International Dialogues (Akabayashi A,
ed. Oxford University Press. 2014). Camb Q
Healthc Ethics. 2019 Jan;28(1):186-188.

Health Sciences and Nursing
2. Preventive and Administrative Nursing

285

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

286

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287

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, nursing professionals and medical
institutions were surveyed about working conditionsin the nursing profession. This was a Ministry of
Health, Labor, and Welfare Special Research Project.

References
1. Takemura Y, Kunie K, Takahashi Y.
Acknowledging and re-acknowledging theboundary between groups of nurses in theworkplace after the nuclear accident in Fukushima[Conference Proceeding]. Advanced Practices in
Nursing 2018; 3:45. DOI: 10.4172/2573-0347C10-045
2. Kunie K, Takahashi Y, Takemura Y. Separation at
workplace after the nuclear accident due to The
Great East Japan Earthquake: Is the classification
for dividing hospital nurses accurate? [Conference
Proceeding]. Advanced Practices in Nursing 2018;
3:46. DOI: 10.4172/2573-0347-C10-045
3. Takahashi Y, Kunie K, Takemura Y. How nurses
recognized their workplace situations when

considering whether or not to be at work after the
Fukushima nuclear accident: experiences of nurses
at hospitals outside the evacuation zone.
[Conference Proceeding]. Advanced Practices in
Nursing 2018;3:47. DOI: 10.4172/2573-0347C10-045

288

Department of Family Nursing
Professor
Kiyoko Kamibeppu, Ph.D., R.N., P.H.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 10 doctoral students, 4
master’s students, 28 visiting researchers, and 3
administrative staff.

In our department, research topics span a variety of
topics, focusing on both healthy families and thoseaffected by health problems and including diverse
developmental stages such as perinatal and later-life
periods. Our on-going research projects include thefollowing:
1. Mitigation of postpartum depression andprevention of child abuse and neglect;
2. Development of a Pediatric Quality of Life (QOL)
Inventory for children with chronic illness andtheir parents;
3. Support for survivors of childhood cancer
including caring of their late effects, special needs
education, school reentry and working;
4. Caregiving burden and utilization of respite careservices in families of children with medical
complexity;
5. Support for dying patients and their families(QOL and family functioning);
6. Livelihood supports for families of elderly people
with dementia.
7. Transitional care for children, adolescent andyoung adult with childhood-onset chronic
diseases and their families.
Studies on “Late effects in pediatric cancer
survivors” and “Supporting pediatric cancer survivors’
reentry to school” have been ongoing, in collaboration

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

289with pediatric cancer researchers and a variety offamily support organizations across the country.
Funding for these 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) anda 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
research that explore the various experiences ofchildren with cancer and their families who wereextensively affected by the Tohoku Earthquake of
2011.
Studies focusing on transition such as “transferring
into adult health care” and “promoting self-care andautonomy” in patients with child chronic diseases has
been conducted since 2016. We established atransition outpatient clinic in the University of Tokyo
Hospital in June 2016 and have been providing
transitional cares for patients with congenital heartdisease, epilepsy, chromosomal abnormality, hematologic disease, and endocrine disease in the clinic. We
also developed the tool “My Health Passport” in orderfor patients to summarize the information about theirdisease and share their experiences with others (e.g.,friends and coworkers) and established an evidence of
its effectiveness. Furthermore, we have beendeveloping newly check lists to evaluate long-term
follow ups in patients after hematopoietic stem celltransplantation and supports for school reentry inpediatric cancer survivors. Those studies and activities
have been ongoing in interdisciplinary collaboration
with health professionals in the University of Tokyo
Hospital.
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. Shimada H, Kada A, Shima H, Tono C, Yuza Y,
Kurosawa H, Watanabe A, Ito M, Uryu H,
Kamibeppu K, Kiyokawa N, Adachi S, Saito AM
and Tanizawa A. Rationale and design of a
Prospective, Multicentre, Stop Tyrosine Kinase
Inhibitor Trial of Paediatric Patients with Chronic
Myeloid Leukaemia with Sustained Complete
Molecular Response (STKI-14). Hiroshima Journal of Medical Sciences, 2018 Mar; 67(1): 7-13.
2. Niiyama H, Kontkanen I, Paarvilainen E,
Kamibeppu K. A comparison of personality
maturity among Japanese youth and finnish young
adult students: A cross-sectional study using
Erikson Psychosocial Stage Inventory and Sense
of Coherence Scale. International Journal of Adolescence and Youth, 2018 Feb; 23(4): 482-495.
3. Sato I, Higuchi A, Yanagisawa T, Murayama S,
Kumabe K, Sugiyama K, Mukasa A, Saito N,
Sawamura Y, Terasaki M, Shibui S, Takahashi J,
Nishikawa R, Ishida Y, Kamibeppu K. Employment status and termination among survivors ofpediatric brain tumors: a cross-sectional survey.
International Journal of Clinical Oncology. 2018
Oct; 23(5): 801-811.
4. Nakamura M, Kita S, Kikuchi R, Hirata Y, Shindo
T, Shimizu N, Inuzuka R, Oka A, Kamibeppu K.
A qualitative assessment of adolescent girls’
perception of living with congenital heart disease:
Focusing on future pregnancies and childbirth.
Journal of Pediatric Nursing. 2018 Jan-Feb; 38:e12-e18.
5. Fukui C, Sakka M, Amiya RM, Sato I,
Kamibeppu K. Validation of family conflict scales
for family caregivers of persons with dementia inlong-term care facilities and exploration of family
conflicts and support. International Psychogeriatrics. 2018 May; 30(5): 749-759.
6. Kikuchi R, Mizuta K, Urahashi T, Sanada Y,
Yamada N, Onuma E, Sato I, Kamibeppu K.
Quality of life after living donor liver transplant
for biliary atresia in Japan. Pediatrics International. 2018 Feb; 60(2): 183-190.

290

7. Kasahara-Kiritani M, Matoba T, Kikuzawa S,
Sakano J, Sugiyama K, Yamaki C, Mochizuki M,
Yamazaki Y. Public perceptions toward mental
illness in Japan. Asian Journal of Psychiatry. 2018
Jun; 35: 55-60.
8. Komachi M, Kamibeppu K. Association between
resilience and acute stress symptoms at early
admission to the intensive care unit. Mental
Health & Prevention. 2018 Mar; 9: 34-41.
9. Sanjo M, Morita T, Miyashita M, Sato K,
Kamibeppu K, Tsuneto S, Shima Y. Are bereaved
family members satisfied with information
provision about palliative care units in Japan?
American Journal of Hospice and Palliative
Medicine. 2018 Feb; 35(2): 275-283.
10. Kamibeppu K, Fukuzawa R. Trajectory
Equifinality Approach: TEA. Japanese Journal of
Research in Family Nursing. 2018 Sep; 24(1):123-125.
11. Maruyama A, Fukuzawa R, Otomo E, Kamibeppu
K. Temporal perspectivenes of mothers regarding
their babies prenatally diagnosed with congenital
heart defects: Evolution and turning points onmeanings of “normalcy”. Japanese Journal of
Research in Family Nursing. 2018 Sep; 24(1): 6273.
12. Ikeda K, Sato I, Kamibeppu K. Intervention for
siblings of hospitalized children with cancer:
Contents and impacts of shared information. 2018
Sep; 13(1): 61-73.

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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 Professors
Chie Teramoto, Ph.D., R.N., P.H.N.
Riho Iwasaki, Ph.D., R.N., P.H.N.

Project Assistant Professor
Mahiro Fujisaki-Sakai, Ph.D., R.N., P.H.N.

Homepage

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

Introduction and Organization
Department of Community Health Nursing wasestablished in June 1992. Department of Public HealthNursing was established related to opening of mastercourse for public health nurses in 2006. In addition,
program for public health nurse license was started in2014, and our department is in charge of it. At present,
there are four faculty members introduced above and 9
graduate course students (4 in master course, 5 indoctoral course) in the department. Also, we accept
many visiting researchers from other colleges andinstitutions.

Education
1. Undergraduate program, in the School of Integrated Health Sciences
1) Home Health Nursing (2 credits, lectures)
The aim of this class is to have a deep understanding of the social context around the home carepatients and the medical, health and welfare system.
Students learn the basics of care management,

home health care service, and health care system.
2) Community Health Nursing (2 credits, lectures)
In this class, students learn the methodology andbasic theory of health promotion, disease
prevention and resilience toward society for
individuals, families, and groups in community.
3) Home Health Nursing Practice (2 credits, practice)This program offers opportunities to learn the basisof home nursing and understand the life of homecare patients and their family at home-visit nursing
station and hospital’s department of dischargeplanning. Basic techniques and the role of nursing
through collaboration with other profession are
mastered.
2. Graduate program, in the Graduate School of
Health Sciences and Nursing (* program for publichealth nurse curriculum)1) Advanced Community Health Nursing I(2 credits, lectures)This program is to study the health at thecommunity-level and theory and application of the292

community organization.
2) Advanced Community Health Nursing II(2 credits, lectures)This program involves studying issues in home careresearch and qualitative research methodology forcommunity health nursing.
3) Advanced Community Health Nursing Seminar I,
II and Practice I, II (2 credits, practice)This seminar and practice include a weekly
research meeting and monthly lecture (3rd Friday
of each month). At the research meeting, students
and faculty members will hold journal readings or
research consultation. At the lecture, one or two
guest lecturers will introduce their research or
clinical topics.
4) Skills for Public Health Nursing I (2 credits,
lectures)*This program aims to provide knowledge and skills
that support the techniques required to promote thehealth of people living in the community. Students
will learn basic theory regarding public healthnursing.
5) Skills for Public Health Nursing II (2 credits,
lectures)*This program aims to provide knowledge and skills
to support the techniques required to promote thehealth of people living in the community. Students
will learn the legal bases and social systems
involved in public health nursing.
6) Public Health Nursing I (2 credits, lectures)*This program involves learning the history,
international tendency, and basic theory regarding
public health nursing.
7) Public Health Nursing II (2 credits, lectures)*This program involves learning the ethics and basic
theory of public health nursing, and provides anunderstanding of occupational health nursing.
8) Public Health Nursing III (2 credits, lectures)*In this program, students will prepare for Public
Health Nursing Practice I & II.
9) Public Administration for Nurses (2 credits,
lectures)*This program aims to empower students to discuss
health policy from an ethical perspective, development of public health program or policy, andleadership. Students will learn public philosophy,
policy-making, and leadership.

10) Public Health Nursing Practice I (1 credit,
practice)*This program intends to generate understanding of
the process of public health nurses’ continuous careprovision or activity, focusing on support for theindividual/family and a specific public health issue.
11) Public Health Nursing Practice II (4 credits,
practice)*This program is intended to help further
understanding of community assessment and thedevelopment of a community program for publichealth nurses. Students will participate in programs,
meetings, and other daily activities held by publichealth nurses. Throughout their assessment,
students are expected to foster their ability to
manage and research public health nursing practice.

Research
Our research focuses on the development andevaluation of health care programs, establishment ofcommunity health care systems, and standardization ofskills among public health nurses in response to thehealth care needs of individuals, families, aggregatesand communities. Our research is supported by a Grantin-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology,
Health Science research, and other foundations.
Ongoing research projects in our department arelisted 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 thisstatus.
2. Discharge planning
Discharge planning is an interdisciplinary processthat is ideally available to aid patients and their families
in developing a feasible plan for the next step of care.
Demand for discharge planning is increasing. We are293attempting to standardize discharge planning activities
and develop outcome indicators and an educational
program on discharge planning for ward nurses. We arealso 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 andsocial 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 in particularon skills regarding new community diagnostic method
and group dynamics.

Publications
1. Morita K, Ono S, Ishimaru M, Matsui H, Naruse T,
Yasunaga H. Factors affecting discharge to homeamong geriatric intermediate care facility residents
in Japan. Journal of the American Geriatrics
Society, 2018; 66(4), 728-734. DOI: 10.1111/jgs.
15295.
2. Iwasaki R, Kageyama M, Nagata S. The structureof the perceived professional identity of Japanesepublic health nurses. Public Health Nursing, 2018;35(3), 220-227. doi: 10.1111/phn.12395.
3. Nakamura Y, Matsumoto H, Yamamoto-Mitani N,

Suzuki M, Igarashi A. Impact of support agreement
between municipalities and convenience store
chain companies on store staff's support activities
for older adults. Health Policy, 2018; 122(12),1377-1383. doi: 10.1016/j.healthpol.2018.09.015.
4. Tanaka T, Matsumoto H, Son B, Imaeda S,
Uchiyama E, Taniguchi S, et al. Environmental andphysical factors predisposing middle-aged andolder Japanese adults to falls and fall-related
fractures in the home. Geriatrics & Gerontology
International, 2018; 18(9), 1372–1377.
5. 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 & Social Carein the Community, 2018; Epub. DOI: 10.1111/hsc.
12707.
6. Takahashi K, Tanaka T, Suthutvoravut U,
Yoshizawa Y, Fujisaki M, Iijima K. Effect of afrailty check-up program on older adults' behavior
change : a qualitative study. The journal of Japan
Mibyo System Association, 2018; 24(2), 84-87.
7. Teramoto C, Nagata S, Naruse T, Yokota S,
Yamamoto-Mitani N．Pattern of Revisit 30 days
after Discharge from the Emergency Department:
A Comparative Case Study ． Journal of Japan
Academy of Nursing Science, 2018; 38, 336-345．
8. Yokobori H, Okochi A, Tadaka E, Ito E, Arimoto A,
Shiratani K. Child Day Care Center Nurses’
Support for Children with Potential Developmental
Problems and Their Parents. Journal of Japan
Academy of Community Health Nursing, 2018;21(1), 56-62.
9. Igarashi A, Matsumoto H, Suzuki M, Hamada T, ，Aoki S, Aburayama K, Murata S, Suzuki M, Yasui
H, Yamamoto-Mitani N．Use of convenience storesin community-dwelling older adults who utilize
home help services offered under the long-termcare insurance : A cross-sectional questionnaire
survey of older adults on the support for daily life
provided by convenience stores．Japanese journalof gerontology, 2018; 40(3), 283–291.
10. Ishizaki T, Mitsutake S, Teramoto C，Shimizu S,
Ito H. Visit medical treatment by home medical
institution to home medical care patient with homeinsurance card address place in Tokyo. Journal of294

Health and Welfare Statistics, 2018; 65(13), 1-7.
11. Mitsutake S, Ishizaki T, Teramoto C, Tsuchiya R,
Shimizu S, Ito H. The associations between
readmission within 30 days and the medical
institute factors among older patients receiving
home medical care. Japanese journal of geriatrics,
2018; 55(4), 612-623.
12. Imaeda S, Son B, Uchiyama E, Tanaka T,
Taniguchi S，Miyoshi Y，Suthutvoravut U，Baba
A，Sumikawa Y, Matsubara T, Otsuki T, Tanaka T,
Iijima K, Okata J. Combined Bedside and HomeVisit lnterview Clarifies Exact Fall Situations
Causing Femoral Fracture. Japanese journal of fall
prevention, 2018; 5(2), 132.

Health Sciences and Nursing
3. Clinical Nursing

296

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

297

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

298

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. Yamamoto-Mitani N, Saito Y, Futami A, Takaoka
M, Igarashi A. Nurses’ and care workers’
perception of care quality in Japanese long-termcare wards: A qualitative descriptive study.
Global Qualitative Nursing Research. 2018;5:2333393618812189.
2. Nakamura Y, Matusmoto H, Yamamoto-Mitani N,
Suzuki M, Igarashi A. Impact of support agreement between municipalities and convenience
store chain companies on store staff's support
activities for older adults. Health Policy. 2018;
122(12):1377-1383.
3. Igarashi A, Yamamoto-Mitani N, Morita K,
Matsui H, Lai CKY, Yasunaga H. Classificationof long-term care wards and their functional
characteristics: analysis of national hospital data
in Japan. BMC health services research. 2018;18:655.
4. Noguchi-Watanabe M, Yamamoto-Mitani N,
Takai Y. A Cyclic model describing the processof sustaining meaningfulness in practice: hownurses continue working at one home care agency.
Global Qualitative Nursing Research. 2018;5:2333393618788265.
5. Lai CKY, Igarashi A, Yu CTK, Chin KCW. Does
life story work improve psychosocial well-being
for older adults in the community? A quasiexperimental study. BMC Geriatr. 2018;18(1):119.
6. Rakotonandrasana DH, Tsukahara T, YamamotoMitani N. Antimalarial drug prescribing byhealthcare workers when malaria testing is

negative: a qualitative study in Madagascar.
Tropical Medicine and Health. 2018;46:13.
7. Eltaybani S, Noguchi-Watanabe M, Igarashi A,
Saito Y, Yamamoto-Mitani N. Factors related tointention to stay in the current workplace among
long-term care nurses: A nationwide survey.
International Journal of Nursing Studies. 2018;80:
118-127.
8. Yamanaka T, Hirota Y, Noguchi-Watanabe M,
Tamai A, Eto M, Iijima K, Akishita M. Changes
in attitude of medical students toward home careduring a required two-week home care clinicalclerkship program. Geriatrics and Gelontology
International. 2018;18(4):655-656.
9. Saito S, Igarashi A, Noguchi-Watanabe M, Takai
Y, Yamamoto-Mitani N. Work values and theirassociation with burnout/work engagement amongnurses in long-term care hospitals. Journal of
Nursing Management. 2018;26(4):393-402.
10. Eltaybani S, Mohamed N, and Abdelwareth M.
Nature of nursing errors and their contributing
factors in intensive care units. Nursing in Critical
Care. doi: 10.1111/nicc.12350. Epub 2018 Apr
27.
11. Horinuki F, Noguchi-Watanabe M, Takai Y,
Yamahana R, Ohno N, Okada S, Mori S,
Yamamoto-Mitani. The experience of persons
with hematological malignancy when communicating with healthcare professionals. Qualitative
Health Research. 2018;28(3):479-490.
12. Takano J, Yamahana R, Yamamoto-Mitani N.
Factors associated with nurses' terminal care
attitudes in palliative care units in Japan.
Palliative Care Research. 2018;13(4):357-366.
13. Ishii A, Igarashi A, Takemura Y, Suzuki M,
Yamamoto-Mitani N. Relationship between theemployment status of nursing assistants working
in the neurosurgery and adverse events forpatients / overtime hours worked by nurses: A
nationwide cross-sectional survey. Nursing
research collection. 2018;25:23-33.
14. Yamamoto-Mitani N. Process of idea and outlineof "category-oriented case study". The process
and outline of “category-oriented case study”.
Nursing Research. 2018;51(5):404-413.
15. Ikeda M, Noguchi-Watanabe M, Karasawa K. 2
Writing down nursing practice and making a catch299

copy. Nursing Research. 2018;51(5):414-422.
16. Noguchi-Watanabe M, Yamamoto-Mitani N.
Organizing "Headings" and "Subheadings" andpresenting “category-oriented case study” at aconference. Nursing Research. 2018;51(5):423430.
17. Noguchi-Watanabe M, Yoshida S, YamamotoMitani N. Process of making thesis and creating aplace for research. Nursing Research. 2018;51(5):431-437.
18. Yoshida S, Noguchi-Watanabe M, YamamotoMitani N. Peer-review experience of “categorybased case study” papers. Nursing Research.
2018;51(5):438-446.
19. Yamahana R, Saito N, Yoshida S. Ethicalconsiderations to consider in “category-orientedcase study”. Nursing Research. 2018;51(5):447455．
20. Saito N, Yamamoto-Mitani N, Ietaka H, Yoshida S.
Academic of “category-oriented case study”
Nursing Research. 2018;51(5):456-465．
21. Yamamoto-Mitani N, Ietaka H, Yoshida S. Quality
evaluation of “category-oriented case study”.
Nursing Research. 2018;51(5):466-471.
22. Igarashi A, Oe M, Yamamoto-Mitani N. Feature
Knowing Asian Universities Improve Japan's
nursing research skills Inspection report fromeach university. 3. Hong Kong University ofTechnology. Nursing Research. 2018;51(7):641649.
23. Sakka M, Yamamoto-Mitani N. Rapid increase of"older people" and change of geriatric nursing Diversity of perceptions of the elderly-. Nursing
Education. 2018;59(11):970-974.

300

Department ofMidwifery and Women's Health
Associate Professor
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.

Assistant Professor
Naoko Hikita, Ph.D., R.N.M.

Homepage

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

Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
It has 4 faculty members introduced above, 15
graduate students (8 in master’s courses, 7 in doctoral
courses), 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)

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
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)

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

3011) Adequate maternal nutrition and weight management
This study examines the maternal body composition, lipid metabolic biomarkers, and nutritional
intake to optimize weight management and ahealthy lifestyle during pregnancy to prevent low
birth weight. Based on our investigations on the
optimal maternal nutritional status and gestational
weight gain, we propose a health guidance that canhelp lower the risk of pregnancy complications andadverse 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 andits related factors in Mongolia
This study uses biomarkers to investigate theprevalence of secondhand smoke (SHS) exposure
during pregnancy and the effects of SHS on birthoutcomes in Mongolia. Data were collected
through investigations to create an effective healtheducation.
2. Development of a support system for reliablechildbirth1) Development of assessment methods of birth canalusing 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 to maternalsafety and comfort during childbirth is developed.

3. Development of a support system for women’s
health1) Life and sleep among working mothers of infants
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 tothe 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 women and factors
associated with their surgical treatment.
6)

Factors related to postpartum parenting
self-efficacy
This study investigates factors related to maternal
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 pelvic
floor disorders (e.g., urinary incontinence).
Furthermore, this study aims to develop the pelvic
floor muscle training program.

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4. Creating evidence of health guidance for neonatalskin care1) Development of an effective skin care intervention
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 askin condition.

Publications
1. Yonezawa K, Haruna M, Matsuzaki M, Shiraishi
M, Kojima R. Effects of moisturizing skincare on
skin barrier function and the prevention of skinproblems in 3-month-old infants: A randomized
controlled trial The Journal of Dermatology.
2018;45;24–30.
2. Hikita N, Haruna M, Matsuzaki M, Shiraishi M,
Takehara K, Dagvadorj A. Sumya N, Bavuusuren
B, Baljinnyam P, Ota E, Mori R. Utilisation ofmaternal and child health handbook in Mongolia:
A cross-sectional study. Health Education Journal.
2018; 77(4) 458–469
3. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Pre-pregnancy BMI, gestational
weight gain and body image are associated withdietary under-reporting in pregnant Japanesewomen. Journal of Nutritional Science. 2018;2;7:e12.
4. Matsuzaki M, Kusaka M, Sugimoto T, Shiraishi
M, Kobayashi R, Watanabe S, Haruna M. The
Effects of a Yoga Exercise and Nutritional
Guidance Program on Pregnancy Outcomes
Among Healthy Pregnant Japanese Women: A
Study Protocol for a Randomized Controlled Trial.
Journal of Alternative and Complementary
Medicine. 2018;24(6):603–610.
5. Lyberg A, Dahl B, Haruna M, Takegata M,

Severinsson E. Links between patient safety andfear of childbirth-A meta-study of qualitative
research. Nursing Open. 2018;16;6(1):18–29.
6. Takegata M, Haruna M, Morikawa M, Yonezawa
K, Komada M, Severinsson E. Qualitative
exploration of fear of childbirth and preferences
for mode of birth among Japanese primiparas.
Nursing & Health Sciences. 2018;20(3):338–345.
7. Rönnerhag M, Severinsson E, Haruna M,
Berggren I. Qualitative study of women's
experiences of safe childbirth in maternity care.
Nursing & Health Sciences. 2018;20(3):331–337.
8. Yonezawa K, Haruna M, Matsuzaki M. How
mothers deal with when they experienced any
anxiety about their newborns’ skin, and handlingthe related anxiety. Japanese Journal of Maternal
Health. 2018;58(4):648-654. (In Japanese)
9. Shima S, Haruna M, Matsuzaki M, Sasagawa E,
Yonezawa K. Factors related to breastfeeding
continuation after returning to work among
working women. Tokyo Journal of Maternal
Health. 2018;34(1):54-61. (In Japanese)
10. Matsumoto H, Matsuzaki M, Shiraishi M, Haruna
M. Relationship between body image and dietaryintake among women at one month postpartum.
Japanese Journal of Maternal Health. 2018;59(2):406–415. (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,
4 doctoral course students, 8 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. Evans-Lacko S, Aguilar-Gaxiola S, Al-Hamzawi
A, Alonso J, Benjet C, Bruffaerts R, Chiu WT,
Florescu S, de Girolamo G, Gureje O, Haro JM,
He Y, Hu C, Karam EG, Kawakami N, Lee S,
Lund C, Kovess-Masfety V, Levinson D, NavarroMateu F, Pennell BE, Sampson NA, Scott KM,
Tachimori H, Ten Have M, Viana MC, Williams
DR, Wojtyniak BJ, Zarkov Z, Kessler RC,
Chatterji S, Thornicroft G. Socio-economic variations in the mental health treatment gap for people
with anxiety, mood, and substance use disorders:
results from the WHO World Mental Health(WMH) surveys. Psychol Med. 2018 Jul; 48(9):1560-1571. DOI: 10.1017/S0033291717003336.
2. Kessler RC, Aguilar-Gaxiola S, Alonso J, Bromet
EJ, Gureje O, Karam EG, Koenen KC, Lee S, Liu
H, Pennell BE, Petukhova MV, Sampson NA,
Shahly V, Stein DJ, Atwoli L, Borges G, Bunting
B, de Girolamo G, Gluzman SF, Haro JM, Hinkov
H, Kawakami N, Kovess-Masfety V, NavarroMateu F, Posada-Villa J, Scott KM, Shalev AY,
Ten Have M, Torres Y, Viana MC, Zaslavsky AM.
The associations of earlier trauma exposures andhistory of mental disorders with PTSD after
subsequent traumas. Mol Psychiatry. 2018 Sep;
23(9):1892-1899. DOI: 10.1038/mp.2017.194.
3. Shimazu A, Schaufeli WB, Kubota K, Watanabe
K, Kawakami N. Is too much work engagement
detrimental? Linear or curvilinear effects on
mental health and job performance. PLoS One.

2018 Dec 26; 13(12):e0208684. DOI: 10.1371/
journal.pone.0208684.
4. Takagaki K, Okamoto Y, Jinnin R, Mori A,
Nishiyama Y, Yamamura T, Yokoyama S, Shiota S,
Okamoto Y, Miyake Y, Ogata A, Kunisato Y,
Shimoda H, Kawakami N, Furukawa TA,
Yamawaki S. Enduring effects of a 5-week
behavioral activation program for subthresholddepression among late adolescents: an exploratory
randomized controlled trial. Neuropsychiatr Dis
Treat. 2018 Oct 9;14:2633-2641. DOI: 10.2147/
NDT.S172385.
5. Sasaki N, Sato S, Yamaguchi S, Shimodaira M,
Kawakami N. Development of a scale to assess
motivation for competitive employment among
persons with severe mental illness. PLoS One.
2018 Oct 2;13(10):e0204809. DOI: 10.1371/
journal.pone.0204809.
6. Ishikawa H, Tachimori H, Takeshima T, Umeda M,
Miyamoto K, Shimoda H, Baba T, Kawakami N.
Prevalence, treatment, and the correlates ofcommon mental disorders in the mid 2010's inJapan: The results of the world mental healthJapan 2nd survey. J Affect Disord. 2018 Dec 1;
241:554-562. DOI: 10.1016/j.jad.2018.08.050.
7. Tsuno K, Kawachi I, Kawakami N, Miyashita K.
Workplace Bullying and Psychological Distress: A
Longitudinal
Multilevel
AnalysisAmongJapanese Employees. J Occup Environ Med. 2018
Dec;60(12):1067-1072. doi: 10.1097/JOM.000000
0000001433.
8. Kido Y, Kawakami N, Kayama M. Comparison of
hospital admission rates for psychiatric patientscared for by multidisciplinary outreach teams withand without peer specialist: a retrospective cohort
study of Japanese Outreach Model Project 20112014. BMJ Open. 2018 Aug 17;8(8):e019090.
DOI: 10.1136/bmjopen-2017-019090.
9. Chiba R, Umeda M, Goto K, Miyamoto Y,
Yamaguchi S, Kawakami N. Correction to: The
property of the Japanese version of the Recovery
Knowledge Inventory (RKI) among mental healthservice providers: a cross sectional study. Int J
Ment Health Syst. 2018 Jun 19;12:34. DOI: 10.
1186/s13033-018-0214-2.
10. Miyamoto Y, Yoo J, Levine CS, Park J, Boylan
JM, Sims T, Markus HR, Kitayama S, Kawakami

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N, Karasawa M, Coe CL, Love GD, Ryff CD.
Culture and social hierarchy: Self- and otheroriented correlates of socioeconomic status acrosscultures. J Pers Soc Psychol. 2018 Sep;115(3):427-445. DOI: 10.1037/pspi0000133.
11. Ando E, Kachi Y, Kawakami N, Fukuda Y,
Kawada T. Associations of non-standard
employment with cardiovascular risk factors:
findings from nationwide cross-sectional studies
in Japan. Ind Health. 2018 Jul 27;56(4):336-345.
DOI: 10.2486/indhealth.2017-0079.
12. Miki T, Eguchi M, Akter S, Kochi T, Kuwahara K,
Kashino I, Hu H, Kabe I, Kawakami N, Nanri A,
Mizoue T. Longitudinal adherence to a dietary
pattern and risk of depressive symptoms: the
Furukawa Nutrition and Health Study. Nutrition.
2018 Apr;48:48-54. DOI: 10.1016/j.nut.2017.10.
023.
13. Kitayama S, Park J, Miyamoto Y, Date H, Boylan
JM, Markus HR, Karasawa M, Kawakami N, Coe
CL, Love GD, Ryff CD. Behavioral Adjustment
Moderates the Link Between Neuroticism andBiological Health Risk: A U.S.-Japan Comparison
Study. Pers Soc Psychol Bull. 2018 Jun;44(6):809-822. DOI: 10.1177/0146167217748603.
14. Alonso J, Liu Z, Evans-Lacko S, Sadikova E,
Sampson N, Chatterji S, Abdulmalik J,
Aguilar-Gaxiola S, Al-Hamzawi A, Andrade LH,
Bruffaerts R, Cardoso G, Cia A, Florescu S, deGirolamo G, Gureje O, Haro JM, He Y, de Jonge P,
Karam EG, Kawakami N, Kovess-Masfety V, Lee
S, Levinson D, Medina-Mora ME, Navarro-Mateu
F, Pennell BE, Piazza M, Posada-Villa J, Ten
Have M, Zarkov Z, Kessler RC, Thornicroft G;
WHO World Mental Health Survey Collaborators.
Treatment gap for anxiety disorders is global:
Results of the World Mental Health Surveys in 21
countries. Depress Anxiety. 2018 Mar;35(3):195208. DOI: 10.1002/da.22711.
15. Inoue A, Kawakami N, Eguchi H, Tsutsumi A.
Interaction effect of job insecurity and roleambiguity on psychological distress in Japaneseemployees: a cross-sectional study. Int Arch
Occup Environ Health. 2018 May;91(4):391-402.
DOI: 10.1007/s00420-018-1288-5.
16. Tsutsumi A, Shimazu A, Eguchi H, Inoue A,
Kawakami N. A Japanese Stress Check Program

screening tool predicts employee long-term
sickness absence: a prospective study. J Occup
Health. 2018 Jan 25;60(1):55-63. DOI: 10.1539/
joh.17-0161-OA.
17. Watanabe K, Kawakami N, Shiotani T, Adachi H,
Matsumoto K, Imamura K, et al. The JapaneseWorkplace PERMA-Profiler: A validation study
among Japanese workers. J Occup Health. 2018
Sep 26;60(5):383-393. doi: 10.1539/joh.20180050-OA.
18. Watanabe K, Kawakami N. Effects of a MultiComponent Workplace Intervention Program withEnvironmental Changes on Physical Activity
among Japanese White-Collar Employees: a
Cluster-Randomized Controlled Trial. Int J Behav
Med. 2018 Dec;25(6):637-648. DOI: 10.1007/
s12529-018-9747-7.
19. Eguchi H, Watanabe K, Kawakami N, Ando E,
Arima H, Asai Y, Inoue A, Inoue R, Iwanaga M,
Imamura K, Kobayashi Y, Nishida N, Otsuka Y,
Sakuraya A, Tsuno K, Shimazu A, Tsutsumi A.
Psychosocial factors at work and inflammatory
markers: protocol for a systematic review andmeta-analysis. BMJ Open. 2018 Aug 29;8(8):e022612. DOI: 10.1136/bmjopen-2018-022612.
20. Imamura K, Furukawa TA, Matsuyama Y,
Shimazu A, Kuribayashi K, Kasai K, Kawakami
N. Differences in the Effect of Internet-Based
Cognitive Behavioral Therapy for Improving
Nonclinical Depressive Symptoms Among
Workers by Time Preference: Randomized
Controlled Trial. J Med Internet Res. 2018 Aug
10;20(8):e10231. DOI: 10.2196/10231.
21. Watanabe K, Sakuraya A, Kawakami N, Imamura
K, Ando E, Asai Y, Eguchi H, Kobayashi Y,
Nishida N, Arima H, Shimazu A, Tsutsumi A.
Work-related psychosocial factors and metabolic
syndrome onset among workers: a systematic
review and meta-analysis. Obes Rev. 2018 Nov;
19(11):1557-1568. DOI: 10.1111/obr.12725.
22. Nakanishi M, Hirooka K, Imai Y, Inoue S, Yukari
Y, Katayama C, Miyamoto Y, Shindo Y, Ueno H,
Toya J, Takano Y, Nishida A. Dementia carecompetence among care professionals andreduced challenging behavior of home-dwellingpersons with dementia: a pre- and postintervention data analysis. Journal of Alzheimer’s

306

Disease. J Alzheimers Dis. 2018;64(2):515-523.
DOI: 10.3233/JAD-171077.
23. Watanabe K, Kawakami N, Otsuka Y, Inoue S.
Associations among workplace environment,
self-regulation, and domain-specific physicalactivities among white-collar workers: a
multilevel longitudinal study. Int J Behav Nutr
Phys Act. 2018 May 31;15(1):47. DOI: 10.1186/
s12966-018-0681-5.
24. Iwanaga M, Miyamoto Y, Kawakami N. Use ofnatural products for complementary healthapproaches among psychiatric outpatients inJapan. SOJ psychology. 2018;5(1):1-8. DOI: 10.
15226/2374-6874/5/1/00145.
25. Iwanaga M, Imamura K, Shimazu A, Kawakami
N. The impact of being bullied at school on
psychological distress and work engagement in acommunity sample of adult workers in Japan.
PLoS One. 2018 May 10;13(5):e0197168. DOI:
10.1371/journal.pone.0197168.
26. Inoue A, Kawakami N, Eguchi H, Tsutsumi A.
Interaction effect of job insecurity and roleambiguity on psychological distress in Japaneseemployees: a cross-sectional study. Int Arch
Occup Environ Health. 2018;91(4):391-402. DOI:
10.1007/s00420-018-1288-5.
27. Imamura K, Asai Y, Watanabe K, Tsutsumi A,
Shimazu A, Inoue A, Hiro H, Odagiri Y,
Yoshikawa T, Yoshikawa E, Kawakami N. Effectof the National Stress Check Program on mental
health among workers in Japan: A 1-year
retrospective cohort study. J Occup Health. 2018
Jul 25;60(4):298-306. DOI: 10.1539/joh.20170314-OA.
28. Obikane E, Shinozaki T, Takagi D, Kawakami N.
Impact of Childhood Abuse on Suicide-Related
Behavior: Analysis Using Marginal Structural
Models. J Affect Disord. 2018 Jul;234:224-230.
DOI: 10.1016/j.jad.2018.02.034.
29. Xu QY, Fukasawa M, Kawakami N, Baba T,
Sakata K, Suzuki R, et al. Cumulative incidenceof suicidal ideation and associated factors among
adults living in temporary housing during thethree years after the Great East Japan Earthquake.
J Affect Disord. 2018 May;232:1-8. DOI: 10.
1016/j.jad.2018.01.021.

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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 departments are currently headed by one
professor and assisted by an associate professor, two
research associates, a project research associate, aproject academic support staff member, two part-time
lecturers for undergraduate courses, and six part-time308

lecturers for graduate courses. The student bodyconsists of four doctoral course students, nine mastercourse students, and three 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 2018, ourprogram included themes related to:a) Policy creation for solving the problems confronted
in nursingb) Health support servicesc) Hospital management based on nursingd) Creation of a nursing body of knowledge based on
nursing research.
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 2018 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 2018 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 2018 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, malnutrition,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

309

and other departments at The University of Tokyo
Hospital.
5) Nursing Science and Engineering (S2 in 4th yr; 2credits)
Gaining a thorough understanding of a given medical
situation, as well as determining the appropriate
medical intervention for a patient require theknowledge and skills from Nursing Science andEngineering. These include the processes involved intranslational research: 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 2018 program included the following:a) Necessity and importance of Nursing Science andEngineeringb) Methods and application of the research of Nursing
Science and Engineering6) 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 2018 was supported by the long-term carefacility owned by Medical Corporation Tatsuoka.
7) Bachelor’s thesis
The following research themes were submitted in 2018:
 “Development of software for the management ofskin tears using machine learning”, which received
the award for excellence thesis from the School ofIntegrated Health Sciences
 “Exploring the utilization of communication robots
for patients with dementia in the long-term carefacility” (in Japanese) “Cross-sectional study of the deep tissue injuries inwheelchair basketball athletes” (in Japanese)
2. Graduate course
1) Gerontological Nursing I (S1; 2 credits)
The main theme of Gerontological Nursing I in 2018
was 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 threefields and critically evaluated.
2) Gerontological Nursing II (A1; 2 credits)
Gerontological Nursing II provided lectures regarding
recent topics around gerontological medicine andnursing from broad viewpoints, including biological,
individual, and social aspects, by part-time lecturers
and specialists from each research field. The aim of thiscourse was to understand and learn scientific ways ofthinking about gerontological considerations of the
future Japanese community. The main themes in 2018
were as follows:a) Systematic review for randomized controlled trial
and observational studyb) Community nurse specialist’ consideration of the
problems in home-care nursing for elderly patientsc) Basics of nutritiond) Dysphagia in gerontological nursing; teamapproach for dysphagia rehabilitatione) Safety of patients in healthcaref) Technology of human support robotsg) Making an enriched end of life3) Wound Care Management I (S2; 2 credits)
The main topic of Wound Care Management I in 2018
was 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 pressure ulcer and efforts of nursingc) Principles of measurement and data organization;
application of measurement devices to medical, care,and welfare researchd) Creation of global standards of foot ulcer care—developing a needs-oriented caree) Basics and application of biological nursingf) Nursing translational research in the creation of new
nursing techniquesg) Basics of ultrasound technology and application for
the assessment of pressure ulcers

3104) Wound Care Management II (A2; 2 credits)
The main theme of Wound Care Management II in 2018
was to obtain deeper insight in our own researchknowledge through lectures and discussion by
specialists from various basic and advanced research
fields. The topics were as follows:a) Morphological analysis of genes and proteins;
control of cytokines and prevention of scarformation in wound healingb) The roles of theory and experience in theadvancement of dermatological nursingc) Simulation-based education in interprofessional
collaboration; point-of-care ultrasonography inanesthesia and critical cared) Activities of wound, ostomy and continence nursinge) Preventive care for pressure ulcers―evidence of thepressure distributionf) Keratinocyte biologist’s version of wound healing―focusing on cell growth factors and stem cellsg) Application of pharmacological nursing to skin5) Master’s theses
The following research themes were submitted in 2018:
 “Development of an algorithm using ultrasoundassisted peripheral intravenous catheter placement
for reducing catheter failure: a pretest-posttest study”
 “Can bacterial dissemination within bed
environment be associated with biofilm on pressure
ulcers?” “Relationship between pressure ulcers and dynamic
buttock pressure distributions during performancein wheelchair basketball athletes”
 “Effectiveness of biofilm-based wound care system
on wound healing in chronic wounds”
6) Doctoral theses
The following research themes were submitted in 2018:
 “Interventional study by care bundle to reducemechanical irritation for prevention of peripheral
intravenous catheter”

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 2018, 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 organized theInternational Summer Program for Skin Integrity inJapan 2018 in August 2018. Participants, researchersand graduate students from five countries discussed
chronic wounds, skincare, and lymphoedema.
Additionally, our department has been promoting
collaborative research with researchers in universities
around the world. Our counterparts include: Universityof 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 theInternational Board of Directors for International
Lymphoedema Framework.

Research activities
1. Activity policy
Our gerontological nursing research focuses on those
suffering from geriatric syndromes, such as pressure

2. Research fields and themes in 2018
1) Basic experimental studies
・ Development of a novel method for controllingwound infection focusing on gene expression of

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bacteria 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
・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 basketball athletes・Survey on the relationship between the microbiota
in the 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
Several awards were given for our research, as follows:・Congress award in the category of oral presentationfrom the 25th Annual Meeting of the JapaneseContinence Society.
Yoshida M, Matsunaga A, Igawa Y, Fujimura T,
Shinoda Y, Sato Y, Kamei J, Niimi A, Watanabe D,
Aizawa N, Honma N, Haga N, Kume H, Sanada H.
Effectiveness of perioperative ultrasound-guided
pelvic floor muscle training on the promotion ofearly recovery of urinary continence after robotassisted radical prostatectomy. Program of the 25th
Annual Meeting of the Japanese Continence Society.
2018:198.
・Award from the 27th Annual Congress of JapaneseSociety of Wound, Ostomy, and ContinenceManagement.
Mori T, Araki D, Noguchi H, Ohno M, Sanada H.
Developing an estimation algorithm of depth andsize of pressure ulcer via machine learning of imagesof pressure ulcers taken by digital camera. Journal ofJapanese Society of Wound, Ostomy and ContinenceManagement. 2018;22(2):176.
・President award from the 27th Annual Congress ofJapanese Society of Wound, Ostomy, and Continence Management.
Nakagami G, Koyanagi H, Sasaki S, Sanada H.
Risk factors of pressure ulcer development based on
severity in patients at high risk of developingpressure ulcers under incentive system at auniversity hospital. Journal of Japanese Society ofWound, Ostomy and Continence Management.
2018;22(2):164.
・Incentive award from the 6th Annual Congress of
Nursing Science and Engineering.
Arai R, Murayama R, Oe M, Tanabe H, Iizuka Y,
Komiyama C, Kadowaki T, Sanada H. Bloodcollection assistance device for self-monitoring
blood glucose in elderly patients with diabetes.
Journal of Nursing Science and Engineering.

312

2016;3(2):86-92.
・Congress award from the 6th Annual Congress of
Nursing Science and Engineering.
Komagata K, Yabunaka K, Nakagami G, Ikeda M,
Takehara K, Takemura Y, Sanada H. Confirming theplacement of nasogastric tubes by hand-carriedultrasonography device. Journal of Nursing Scienceand Engineering. 2018;5(1):52-7.
・Article award from the Japanese Society of Wound,
Ostomy, and Continence Management 2018.
Nozawa K, Tamai N, Minemtsu T, Kitamura A,
Saegusa M, Amaike K, Sanada H. Situation of
occurrence and morphological characteristics ofpressure ulcers among inpatients with mental illness.
Journal of Japanese Society of Wound, Ostomy, andContinence. 2017;21(1):10-24.
・ Award from the president of Japanese Nursing
Association.
Sanada H.

References
Shikama M, Nakagami G, Noguchi H, Mori T,
Sanada H. Development of personalized fitting
device with three-dimensional solution forprevention of NIV oral-nasal mask-related pressure
ulcers. Respiratory Care. 2018;63(8):1024-32.
2. Mugita Y, Minematsu T, Nakagami G, Sanada H.
Influence of digestive enzymes on development ofincontinence-associated dermatitis: inner tissue
damage and skin barrier impairment caused bylipidolytic enzymes and proteases in rat macerated
skin. International Wound Journal. 2018;15(4):623-32.
3. Ogai K, Matsumoto M, Aoki M, Dai M, Maeba H,
Uchide K, Junko S. Comparative study on highfrequency ultrasonography and histologicalstructure of the skin: Relationship between
collagen/elastin content and echogenicity. Journalof Nursing Science and Engineering. 2018;5(1):6573.
4. Minematsu T, Nakagami G, Mugita Y, Tamai N,
Sanada H. Development of a distribution analysis
method for metalloproteinase activity by
combining wound blotting and zymography
techniques: A pilot study in mice. Journal of
Nursing Science and Engineering. 2018;5(1):58-64.
1.

5. Matsumoto M, Ogai K, Ohashi R, Tanaka K, Aoki
M, Kobayashi M, Sugama J. Influences of different
wiping methods cleaning agent removal on theeffectiveness of skin dirt removal: A quasiexperimental study. Journal of Nursing Science andEngineering. 2018;5(1):22-30.
6. Matsui Y, Murayama R, Tanabe H, Oe M, Motoo Y,
Wagatsuma T, Michibuchi M, Kinoshita S, Sakai K,
Konya C, Sugama J, Sanada H. Factors associatedwith severe skin disorder after extravasation of
intravenously infused antineoplastic agents.
Journal of Nursing Science and Engineering. 2018;
5(1):31-40.
7. Komagata K, Yabunaka K, Nakagami G, Ikeda M,
Takehara K, Takemura Y, Sanada H. Confirming
the placement of nasogastric tubes by hand-carriedultrasonography device. Journal of Nursing
Science and Engineering. 2018;5(1):52-7.
8. Miura Y, Nakagami G, Yabunaka K, Tohara H,
Noguchi H, Mori T, Sanada H. A Randomized
Controlled Trial to Investigate the Effectiveness of
the Prevention of Aspiration Pneumonia Using
Recommendations for Swallowing Care Guided by
Ultrasound Examination. Healthcare (Basel).
2018;6(1):E15.
9. Matsumoto M, Ogai K, Aoki M, Urai T, Yokogawa
M, Tawara M, Kobayashi M, Minematsu T, Sanada
H, Sugama J. Changes in dermal structure and skinoxidative stress in overweight and obese Japanesemales after weight loss: a longitudinal observation
study. Skin Research and Technology. 2018;24(3):407-41.
10. Yabunaka K, Matsumoto M, Yoshida M, Tanaka S,
Miura Y, Tsutaoka T, Handa M, Nakagami G,
Sugama J, Okada, Sanada H. Assessment of rectal
feces storage condition by a point-of-care pocketsize ultrasound device for healthy adult subjects: apreliminary study. Drug Discoveries andTherapeutics. 2018;12(1):42-6.
11. Koyano Y, Nakagami G, Minematsu T, Sanada H.
Reliability of the skin blotting method when usedon the elderly. International Wound Journal. 2018;
15:807-13.
12. Oe M, Takehara K, Noguchi H, Ohashi Y, Fukuda
M, Kadowaki T, Sanada H. Skin hydration of theheel with fissure in patients with diabetes: a cross-313

sectional observational study. Chronic Wound CareManagement and Research. 2018;5:11-6.
13. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Pre-pregnancy body mass index,
gestational weight gain, and body image areassociated with dietary under-reporting in pregnant
Japanese women. Journal of Nutritional Science.
2018;7(e12):1-10.
14. Sakurai S, Hanafusa N, Kato H, Iizaka S,
Murayama R, Nangaku M. Questionnaire survey
on nutritional supplement therapy and exercise
training at hemodialysis facilities in Japan. Renal
Replacement Therapy. 2018;3(60).
15. Tanaka S, Yabunaka K, Matsumoto M, Tamai N,
Noguchi H, Yoshida M, Nakagami G, Sugama J,
Sanada H. Fecal Distribution Changes Using
Colorectal Ultrasonography in Older People with
Physical and Cognitive Impairment Living inLong-Term Care Facilities: A LongitudinalObservational Study. Healthcare. 2018;6(2):55.
16. Murayama R, Takahashi T, Tanabe H, Yabunaka K,
Oe M, Komiyama C, Sanada H. Exploring thecauses of peripheral intravenous catheter failure
based on shape of catheters removed from various
insertion sites. Drug Discoveries and Therapeutics.
2018;12(3):170-7.
17. Imran, Defa A, Haryanto J, Oe M, Okuwa M,
Nakatani T, Sanada H, Sugama J. Effects ofunderstanding wellbeing on psychological aspects
and wound healing in patients with diabetic footulcer recurrence: a pilot randomized controlled
trial. The Diabetic Foot Journal. 2018;21(2):11925.
18. Ibuki A, Minematsu T, Yoshida M, Iizaka S,
Matsumoto M, Sugama J, Sanada H. Microsatellite
polymorphism in the Heme oxygenase-1 genepromoter is associated with dermal collagendensity in Japanese obese male subjects. PLoS One.
2018;13(7):e0199994.
19. 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
radicalprostatectomy? Neurourology
andUrodynamics. 2018;38(1):158-64.

20. Yoshida M, Igawa Y, Higashimura S, Suzuki M,
Sanada H. Effectiveness of a hydrophilic-coatedcompact catheter in preventing urinary tract
infections and improving quality of life in female
patients managed with clean intermittent selfcatheterization: A prospective multicenter
randomized parallel comparative trial. Japanese
Journal of Wound, Ostomy and ContinenceManagement. 2018; 22(4):335-44.
21. Kimori K, Konya C, Matsumoto M. VenipunctureInduced Hematomas Alter Skin Barrier Function in
the Elderly Patients. SAGE Open Nursing. 2018;4:
1-8.
22. Saegusa M, Noguchi H, Nakagami G, Mori T,
Sanada H. Evaluation of comfort associated withthe use of a robotic mattress with an interfacepressure mapping system and automatic inner aircell pressure adjustment function in healthy
volunteers. Journal of Tissue Viability. 2018;27(3):146-52.
23. Kase R, Amemiya A, Okonogi R, Yamakawa H,
Sugawara H, Tanaka YL, Komiyama M, Mori T.
Examination of the effect of suitable size and widthof shoes for the prevention of diabetic foot ulcer
under the second and fifth metatarsal head. Sensors.
2018;18(10):1-10.
24. Dai M, Shogenji M, Matsui K, Kimori K, Sato A,
Maeda H, Okuwa M, Koyano C, Sugama J, Sanada
H. Validity of pocket ultrasound device to measure
thickness of subcutaneous tissue for improving
upper
limb
lymphoedema
assessment.
Lymphoedema Resaerch and Practice. 2018;6(1):10-20.
25. Yabunaka K, Nakagami G, Tabata K, Sugama J,
Matsumoto M, Iuchi T, Kido Y, Sanada H.
Constipation in the elderly in a Japanese long-term
medical facility: An ultrasonographic investigation.
Drug Discoveries and Therapeutics. 2018;12(4):233-8.
26. Kitamura A, Minematsu T, Nakagami G, Sanada H.
Assessment of histopathology of wounds based onprotein distribution detected by wound blotting.
SAGE Open Medicine. 2018;6:1-6.
27. Aoki M, Ogai K, Kobayashi M, Minematsu T,
Nakatani T, Okuwa M, Sanada H, Sugama J.
Comparison of ceramide kinetics in the stratum
corneum between dry skin and normal skin using

314

animal models with fluorescent imaging method.
Skin Research and Technology. 2018;25(2):158-64.
28. Abe-Doi M, Oe M, Murayama R, Zushi Y, Tanabe
H, Sanada H. Impact of squeezing condition to
obtain sufficient blood volume for self-monitoringof blood glucose using an automatic puncturing
and sampling system. Journal of Diabetes Scienceand Technology. 2018;12(5):1041-4.
29. Matsumoto M, Tanaka S, Yabunaka K, Yoshida M,
Miura Y, Tsutaoka T, Handa M, Nakagami G,
Sugama J, Okada S, Sanada H. Ultrasonographic
evaluation of functional constipation in healthy
adults: A report of two cases. Drug Discoveries andTherapeutics. 2018;12(5):304-8.
30. Oe M, Takehara K, Suriadi, Sanada H. Introductionof care to prevent diabetic foot ulcer in Indonesia.
Japanese Journal of Foot Care. 2018;16(2):80-4.

International Health
1. International Social Medicine

316

Department of
Global Health Policy
Professor
Kenji Shibuya, MD, DrPH

Assistant Professor
Sarah Abe, MSc, PhD
Shuhei Nomura, MSc

Project Assistant Professor
Md. Mizanur Rahman, MSc, PhD

Homepage

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

Introduction and Organization
Our mission is to improve population health byenhancing accountability and improving the evidencebase for global health programs, through the provisionof the best possible information and rigorous
monitoring and evaluation. The department's members
generate knowledge and ideas through their research,strengthen technical and leadership skills througheducational programs, and enhance national capacities
through collaborative projects, especially in thedeveloping world. As of March 2019 the department,
headed by Professor Kenji Shibuya, included thefollowing staff complement; one assistant professors(Shuhei Nomura); one project assistant professors (Md.
Mizanur Rahman); three post-doctoral fellows; 12
adjunct lecturers; 15 doctoral students; and eightmaster’s students.
The priority areas of research are:
- 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. Furthermore,through the Global Health Entrepreneurship Program(GHE) students are able to develop skills andexperience to become future leaders in global health.
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,

317

students are encouraged to consult with faculty
advisers to choose elective courses best suited to theirneeds.

A guest speaker or a master or doctoral student presents
his/her research. There is a 15-minute presentationfollowed by a 30-minute discussion.

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
degree should take the lectures to acquire fundamental
public health skills such as health policy, biostatistics
and epidemiology.

Research

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 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 Kenji Shibuya
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. Co: Shuhei Nomura
Development of health system performance evaluation
methods by prefecture in Japan. Research on Region
Medical (Ministry of Health, Labour and Welfare). PI
Kenji Shibuya
Research to establish resource allocation for thedevelopment of pharmaceuticals, medical devices, andmedical technology based on the burden of disease inJapan. Special Research (Ministry of Health, Labourand 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
Pursuit of health and medical systems to enhance wellbeing in Fukushima Prefecture—toward real recovery
from the Fukushima Nuclear Accident. Research Grant
Program (The Toyota Foundation). Co: 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
NomuraA comprehensive study of the burden of disease in318Japan. Grant-in-Aid for Scientific Research (Ministryof Education, Culture, Sports, Science and Technology).
PI: Kenji Shibuya
7.

Publications
1.

2.

3.

4.

5.

6.

Sakamoto H, Ezoe S, Hara K, Hinoshita E,
Sekitani Y, Abe K, Inada H, Kato T, Komada K,
Miyakawa M, Yamaya H, Yamamoto N, Abe SK,
Shibuya K. Japan's contribution to making global
health architecture a top political agenda byleveraging the G7 presidency. Journal of Global
Health. 2018;8(2).
GBD 2017 SDG Collaborators. Measuring
progress from 1990 to 2017 and projecting
attainment to 2030 of the health-related
Sustainable Development Goals for 195
countries and territories: a systematic analysis for
the Global Burden of Disease Study 2017. The
Lancet. 2018; 392(10159), P2091-2138.
GBD 2017 Population and Fertility Collaborators.
Population and fertility by age and sex for 195
countries and territories, 1950–2017: asystematic analysis for the Global Burden of
Disease Study 2017. The Lancet. 2018;
392(10159), P1995-2051.
GBD 2017 Risk Factor Collaborators.Global,
regional, and national comparative risk
assessment of 84 behavioural, environmental andoccupational, and metabolic risks or clusters ofrisks for 195 countries and territories, 1990–
2017: a systematic analysis for the Global
Burden of Disease Study 2017. The Lancet. 2018;
392(10159), P1923-1994.
GBD 2017 DALYs and HALE Collaborators.
Global, regional, and national disability-adjusted
life-years (DALYs) for 359 diseases and injuries
and healthy life expectancy (HALE) for 195
countries and territories, 1990–2017: asystematic analysis for the Global Burden of
Disease Study 2017.The Lancet. 2018;
392(10159), P1859-1922.
GBD 2017 Disease and Injury Incidence andPrevalence Collaborators. Global, regional, andnational incidence, prevalence, and years lived
with disability for 354 diseases and injuries for
195 countries and territories, 1990–2017: a

8.

9.

10.

11.

12.

13.

14.

systematic analysis for the Global Burden of
Disease Study 2017. The Lancet. 2018;
392(10159), P1789-1858.
GBD 2017 Causes of Death Collaborators.
Global, regional, and national age-sex-specificmortality for 282 causes of death in 195 countries
and territories, 1980–2017: a systematic analysis
for the Global Burden of Disease Study 2017.
The Lancet. 2018; 392(10159), P1736-1788.
GBD 2017 Mortality Collaborators. Global,
regional, and national age-sex-specific mortality
and life expectancy, 1950–2017: a systematic
analysis for the Global Burden of Disease Study
2017. The Lancet. 2018; 392(10159), P16841735.
Nomura S, Murakami M. Public HealthPreparedness for and Response to Nuclear
Disasters: An Editorial. International Journal ofEnvironmental Research and Public Health.
2018; 15(11), 2489.
Takiyama H, Ozawa T, Ishihara S, Fujishiro M,
Shichijo S, Nomura S, Miura M, Tada T.
Automatic
anatomicalclassificationofesophagogastroduodenoscopy images using deep
convolutional neural networks. Scientific Reports.
2018; 14;8(1):7497.
Yamamoto K, Ozaki A, Nomura S, Senoo Y,
Yoshida I, Maeda Y, Ohnishi M, Tanimoto T,
Kami M. Bibliometric Study of Obstetrics
Articles Published in the Journal of the American
Medical Association, 1997-2016. Cureus. 2018;10(10): e3448.
Otsuki S , Saito E, Sawada N, Abe SK Hidaka A,
Yamaji T, Shimazu T, Goto A, Iwasaki M, Iso H,
Mizoue T, Shibuya K , Inoue M, Tsugane S.
Female reproductive factors and risk of all-cause
and cause-specific mortality among women: The
Japan Public Health Center-based Prospective
Study (JPHC study). Annals of Epidemiology.
2018. Online first.
Nishi A, Singkham P, Takasaki Y, Ichikawa M,
Chadbunchachai W, Shibuya K, Tanasugarn C.
Motorcycle helmet use to reduce road traffic
deaths in Thailand. Bulletin of the World HealthOrganization. 2018; 96: 514-514A.
Leppold C, Ochi S, Nomura S, Murray V. The
Great East Japan Earthquake, tsunamis and

319

15.

16.

17.

18.

19.

20.

21.

Fukushima Daiichi nuclear power plant disaster:Lessons for evidence integration from a WADEM
2017 presentation and panel discussion.
Prehospital and Disaster Medicine. 2018;1-4.
Nomura S#, Shimada Y#, Ozaki A, Higuchi A,
Hori A, Sonoda Y, Yamamoto Y, Yoshida I,
Tsubokura M. Balancing the risk of theevacuation and sheltering-in-place options: asurvival study following Japan’s 2011
Fukushima nuclear incident. BMJ Open. 2018; 8:e021482. #Authors contributed equally to thiswork and share co-first authorship.
Han SM, Rahman MM, Rahman MS, Swe KT,
Palmer M, Sakamoto H, Nomura S, Shibuya K.
Progress towards universal health coverage in
Myanmar: a national and subnational assessment.
The Lancet Global Health. 2018; 9: e989-e997.
Sakamoto H , Ezoe S, Hara K, Hinoshita E,
Sekitani Y, Abe K, Inada H, Kato T, Komada K,
Miyakawa M, Yamaya H, Yamamoto N, Abe SK,
Shibuya K. The G7 presidency and universal
health coverage, Japan’s contribution. Bulletin of
the World Health Organization. 2018; 96:355–
359.
Swe KT, Rahman MM, Rahman MS, Saito E,
Abe SK, Gilmour S, Shibuya K. Cost andeconomic burden of illness over 15 years in
Nepal: A comparative analysis. PLoS One. 2018;
13(4): e0194564.
Liu Y, Shu XO, Wen W, Saito E, Rahman MS,
Tsugane S et al. Association of leisure-time
physical activity with total and cause-specificmortality: a pooled analysis of nearly a half
million adults in the Asia Cohort Consortium.
International Journal of Epidemiology. 2018;
dyy024.
Haruyama R, Gilmour S, Ota E, Abe SK, Rahman
MM, Nomura S, Miyasaka N, Shibuya K. Causes
and risk factors for singleton stillbirth in Japan:
Analysis of a nationwide perinatal database,2013–2014. Scientific Reports. 2018; 8(1):4117.
Morita T, Nomura S, Furutani T, Leppold C,
Tsubokura M, Ozaki A, Ochi S, Kami M, Kato S,
Oikawa T. Demographic transition and factors
associated with remaining in place after the 2011
Fukushima nuclear disaster and related
evacuation orders. PloS One. 2018; 13(3):e0194134.
22. Narita S, Saito E, Sawada N, Shimazu T, Yamaji
T, Iwasaki M, Ishihara J, Takachi R, Shibuya K,
Inoue M, Tsugane S. Dietary Consumption of
Antioxidant Vitamins and Subsequent Lung
Cancer Risk: The Japan Public Health Center‐based Prospective Study. International Journalof Cancer. 2018. Online first.
23. Sakamoto H, Rahman MM, Nomura S, Okamoto
E, Koike S, Yasunaga H et al.Japan Health
System Review . Vol. 8 No. 1. New Delhi: World
Health Organization, Regional Office for SouthEast Asia, 2018.
24. Rahman MS, Rahman MM, Gilmour S, Swe KT,
Abe SK, Shibuya K. Trends in, and projectionsof, indicators of universal health coverage in
Bangladesh, 1995–2030: a Bayesian analysis of
population-based household data. The Lancet
Global Health. 2018; 6: e84-94.

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Department of Community andGlobal HealthProfessor, Academic Leader
Masamine Jimba, MD, PhD, MPH

Assistant Professors
Akira Shibanuma, MID
Junko Kiriya, PhD
Ken I.C. Ong, MSc

Website: http://www.ich.m.u-tokyo.ac.jp/en/index.html
Introduction and Organization
The Department of Community and Global Health(formerly Department of International Community
Health) has been headed by four professors since
1993: Professors Gen Ohi (1993-1996), Som-Arch
Wongkhomthong (1996-1999), Susumu Wakai (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

the students in this department are international
students.

International Cooperation
Activities
As part of our international cooperation activities,
we provided technical assistance of developing thematernal and child health handbook in 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
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 2018, the members of the department include
department chair and professor, 3 assistant professors,
3 secretaries, 13 visiting lecturers, 13 doctoral
students, 20 master's degree students, 3 research
students, and 39 visiting scientists. More than half of

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.

321

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,
Bangladesh, Viet Nam, Lao PDR, Cambodia,
Indonesia, Ghana, Tanzania, Kenya, Zambia, and Peru.

Publications
1. Saw TN, Yasuoko J, Saw YM, Than TM, Win EM,
Aung ZZ, Cho SM, Shibanuma A, Poudel KC,
Win HH, Iriyama S, Jimba M. Factors associatedwith concurrent sexual partnerships among men
who have sex with men in Yangon, Myanmar.
Nagoya J Med Sci. 2018 Nov;80(4):505-518.
2. Kitamura A, Jimba M, MaCahey J, Paolucci G,
Shah S, Hababeh M, Shahin Y, Seita A. Healthand dignity of Palestine refugees at stake: a needfor international response to sustain crucial life
services at UNRWA. Lancet.2018 Dec 22 -Jan 4
2019; 392:2736–44.
3. Jimba M, Fujimura SM. Shrink the universal
health coverage cube. Lancet. 2018 Dec 13;
392:2551.
4. Kunii N, Fujimura MS, Komasa Y, Kitamura A,
Sato H, Takatsuji T, Jimba M, Kimura S. The
Knowledge and Awareness for Radiocesium Food
Monitoring after the Fukushima Daiichi Nuclear
Accident in Nihonmatsu City, Fukushima
Prefecture. Int J Environ Res Public Health. 2018
Oct 18;15(10).
5. Shibanuma A, Yeji F, Okawa S, Mahama E,
Kikuchi K, Narh K, Enuameh Y, Nanishi K,
Oduro A, Owusu-Agyei S, Gyapong M, Asare GQ,
Yasuoka J, Ansah EK, Hodgson A, Jimba M, The
Ghana EMBRACE Implementation Research
Project Team. The coverage of continuum of carein maternal, newborn and child health: a crosssectional study of woman-child pairs in Ghana.
BMJ Global Health 2018;3:e000786.
6. Shakya P, Tanaka M, Shibanuma A, Jimba
M.Nepalese migrants in Japan: What is holding
them back in getting access to healthcare? PLoS
One. 2018 Sep 7;13(9):e0203645.
7. Iwagami M, Tangpukdee N, Wilairatana P,
Krudsood S, Dao LD, Nakazawa S, Sinuon M,
Socheat D, Yasuoka J, Jimba M, Watanabe H,
Kobayashi J, Toma H, Vanisaveth V,
Hongvanthong B, Brey PT, Kano S. Different

322

Pfcrt genotypes and related microsatellite DNApolymorphisms on Plasmodium falciparum
differed among populations in the Greater
Mekong Subregion. Parasitol Int. 2018 Aug 27.
pii: S1383-5769(17)30395-1.
8. Poudel KC, Jimba M. [Comment]HIV care
continuum for key populations in Indonesia.
Lancet HIV. 2018 Aug 21. pii: S2352-3018(18)30169-3.
9. Araki H, Ong KIC, Lorphachan L, Soundala P,
Iwagami M, Shibanuma A, Hongvanthong B,
Brey PT, Kano S, Jimba M. Mothers' Opisthorchis
viverrini infection status and raw fish dishconsumption in Lao People's Democratic
Republic: determinants of child infection status.
Trop Med Health. 2018 Aug 7;46:29.
10. Yoshikawa K, Shakya TM, Poudel KC, Jimba M.
Agreement on Reporting Intimate Partner
Violence Among Nepalese Couples: A CrossSectional Study. J Interpers Violence. 2018 Jul 1:
886260518788371.
11. Matsumoto-Takahashi ELA, Tongol-Rivera P,
Villacorte EA, Angluben RU, Jimba M, Kano S.
Bottom-up approach to strengthen communitybased malaria control strategy from community
health workers' perceptions of their past, present,
and future: a qualitative study in Palawan,
Philippines. Trop Med Health. 2018 Jul 4;46:24.
12. Pokhrel KN, Sharma VD, Pokhrel KG, Neupane
SR, Mlunde LB, Poudel KC, Jimba M.
Investigating the impact of a community homebased care on mental health and anti-retroviraltherapy adherence in people living with HIV in
Nepal: a community intervention study. BMC
Infect Dis. 2018 Jun 7;18(1):263.
13. Nishikawa M, Yamanaka M, Kiriya J, Jimba M.
Providing Japanese health care information forinternational visitors: digital animation intervention. BMC Health Serv Res. 2018 May 21;
18(1):373.
14. Shah R, Kiriya J, Shibanuma A, Jimba M. Use ofmodern contraceptive methods and its association
with QOL among Nepalese female migrants
living in Japan. PLoS One. 2018 May 16;13(5):e0197243.
15. Kikuchi K, Ayer R, Okawa S, Nishikitani M,
Yokota F, Jimba M, Nakashima N. Interventions

integrating non-communicable disease prevention
and reproductive, maternal, newborn, and childhealth: A systematic review. Biosci Trends. 2018;12(2):116-125.
16. Okawa S, Mwanza Kabaghe S, Mwiya M,
Kikuchi K, Jimba M, Kankasa C, Ishikawa N.
Psychological well-being and adherence toantiretroviral therapy among adolescents livingwith HIV in Zambia. AIDS Care. 2018 May;30(5):634-642.

International Health
2. International Biomedical Sciences

324

Department of Human Genetics
Professor
Katsushi Tokunaga, Ph.D.

Associate Professor
Akihiko Mabuchi, M.D., Ph.D.

Assistant professor
Yuki Hitomi, Ph.D.,

Hiromi Sawai, Ph.D.

Project Assistant professor
Yosuke Kawai, Ph.D.,

Homepage

Yosuke Omae, Ph.D.,

Seik-Soon Khor, Ph.D.

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

Introduction and Organization
The Department of Human Genetics wasestablished in 1992. Currently, the department has 1
professor, 1 associate professor, 5 assistant professors,
1 research associate, 5 graduate students, and 6
research assistants/technicians. We also accept a few
graduate students from clinical departments 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
The Department of Human Genetics is broadlyinterested in the human genome diversity, especiallyin the Asian populations. Specifically, we are using
genomic research tools including SNP and micro-

satellite analyses, as well as gene expression profiling,
to better understand the genetic background of avariety of complex diseases, especially sleep disorders
and infectious diseases,
Major research projects:
1) Theoretical and experimental analyses on thegenetics of complex diseases, including thedevelopment of statistical approaches for susceptibility gene mapping in complex diseases,
genomic studies for the understanding of genetic
background and pathogenesis of autoimmune
diseases, sleep disorders, hypertension, diabetes,
as well as for host susceptibility factors to
infectious diseases.
2) Development of new methodologies for genome
polymorphism and gene expression analyses.
3) Analysis on the genome diversity of Asia-Pacificpopulations.
4) Analyses on the molecular mechanisms of HLAassociated autoimmune and infectious disorders,by protein functional studies.
5) Genetic analyses combined with epidemiologicalstudies for bone and joint diseases. This study
focuses on the elucidation of genetic susceptibility
to those, based on four cohorts established inJapan.

325

References
1. Shimada M, Otowa T, Miyagawa T, Umekage T,
Kawamura Y, Bundo M, Iwamoto K, Ikegame T,
Tochigi M, Kasai K, Kaiya H, Tanii H, Okazaki Y,
Tokunaga K, and Sasaki T: An epigenome-wide
methylation study of healthy individuals with orwithout depressive symptoms. J. Hum. Genet.
63(3): 319-326, 2018.
2. Khor SS, Morino R, Nakazono K, Kamitsuji S,
Akita M, Kawajiri M, Yamasaki T, Kami A, Hoshi
Y, Tada A, Ishikawa K, Hime M, Kobayashi M,
Kurume N, Kamatani N, Tokunaga K, andJohnson TA: Genome-wide association study ofself-reported food reactions in Japanese identifies
shrimp and peach specific loci in the
HLA-DR/DQ gene region. Sci. Rep. 8(1): e1069,
2018.
3. Ueta M, Hamuro J, Nishigaki H, Nakamura N,
Shinomiya K, Mizushima K, Hitomi Y,
Tamagawa-Mineoka R, Yokoi N, Naito Y,
Tokunaga K, Katoh N, Sotozono C, and Kinoshita
S: Mucocutaneous inflammation in the Ikaros
Family Zinc Finger 1-keratin 5-specific transgenic
mice. Allergy 73(2): 395-404, 2018.
4. Ikeda M, Takahashi A, Kamatani Y, Okahisa Y,
Kunugi H, Mori N, Sasaki T, Ohmori T, Okamoto
Y, Kawasaki H, Shimodera S, Kato T, Yoneda H,
Yoshimura R, Iyo M, Matsuda K, Akiyama M,
Ashikawa K, Kashiwase K, Tokunaga K, Kondo
K, Saito T, Shimasaki A, Kawase K, Kitajima T,
Matsuo K, Itokawa M, Someya T, Inada T,
Hashimoto R, Inoue T, Akiyama K, Tanii H, Arai
H, Kanba S, Ozaki N, Kusumi I, Yoshikawa T,
Kubo M and Iwata N: A genome-wide association
study identifies two novel susceptibility loci andtrans population polygenicity associated withbipolar disorder. Mol. Psychiatry 23(3): 639-647,
2018.
5. Suzuki A, Kawano S, Mituyama T, Suyama M,
Kanai Y, Shirahige K, Sasaki H, Tokunaga K,
Tsuchihara K, Sugano S, Nakai K, and Suzuki Y:
DBTSS/DBKERO for integrated analysis oftranscriptional regulation. Nucleic Acids Research46(D1): D229-D238, 2018.
6. Morimoto Y, Shimada-Sugimoto M, Otowa T,
Yoshida S, Kinoshita A, Mishima H, Yamaguchi

N, Mori T, Imamura A, Ozawa H, Kurotaki N,
Ziegler C, Domschke K, Deckert J, Umekage T,
Tochigi M, Kaiya H, Okazaki Y, Tokunaga K,
Sasaki T, Yoshiura KI, and Ono S: Whole-exome
sequencing and gene-based rare variant
association tests suggest that PLA2G4E might bea risk gene for panic disorder. Transl. Psychiatry8(1): e41, 2018.
7. Shimada M, Miyagawa T, Toyoda H, Tokunaga K,
and Honda M: Epigenome-wide association studyof DNA methylation in narcolepsy: an integrated
genetic and epigenetic approach. Sleep 41(4):2018.
8. Nishida N*, Sugiyama M*, Sawai H*(equal
contribution), Nishina S, Sakai A, Ohashi J, Khor
SS, Kakisak K, Tsuchiura T, Hino K, Sumazaki R,
Takikawa Y, Murata K, Kanda T, Yokosuka O,
Tokunaga K, and Mizokami M: Key
HLA-DRB1-DQB1 haplotypes and role of the
BTNL2 gene for response to a hepatitis B vaccine.
Hepatology 68(3): 848-858, 2018
9. Im C, Sapkota Y, Moon W, Kawashima M,
Nakamura M, Tokunaga K, and Yasui Y:
Genome-wide haplotype association analysis ofprimary biliary cholangitis risk in Japanese. Sci.
Rep. 8(1): e7806, 2018.
10. Suvichapanich S, Fukunaga K, Zahroh H,
Mushiroda T, Mahasirimongkol S, Toyo-Oka L,
Chaikledkaew U, Jittikoon J, Yuliwulandari R,
Yanai H, Wattanapokayakit S, and Tokunaga K:
NAT2 ultra-slow acetylator and risk ofanti-tuberculosis drug-induced liver injury: agenotype-based meta-analysis. Pharmacogenet.
Genomics 28(7): 167-176, 2018.
11. Sawai H, Nishida N, Khor SS, Honda M,
Sugiyama M, Baba N, Yamada K, Sawada N,
Tsugane S, Koike K, Kondo Y, Yatsuhashi H,
Nagaoka S, Taketomi A, Fukai M, Kurosaki M,
Izumi N, Kang JH, Murata K, Hino K, Nishina S,
Matsumoto A, Tanaka E, Sakamoto N, Ogawa K,
Yamamoto K, Tamori A, Yokosuka O, Kanda T,
Sakaida I, Itoh Y, Eguchi Y, Oeda S, Mochida S,
Yuen MF, Seto WK, Poovorawan Y, Posuwan N,
Mizokami M and Tokunaga K: Genome-wide
association study identified new susceptible
genetic variants in HLA class I region for hepatitis
B virus-related hepatocellular carcinoma. Sci. Rep.

326

8(1): e7958, 2018.
12. Nishida N*, Aiba Y*, Hitomi Y*, Kawashima
M*(equal contribution), Kjima K, Kawai Y, Ueno
K, Nakamura H, Yamashiki N, Tanaka T, Tamura
S, Mori A, Yagi S, Soejima Y, Yoshizumi T,
Takatsuki M, Tanaka A, Harada K, Shimoda S,
Komori A, Eguchi S, Maehar Y, Uemoto S,
Kokudo N, Nagasaki M, Tokunaga K, andNakamura M: NELFCD and CTSZ loci areassociated with jaundice-stage progression inprimary biliary cholangitis in the Japanese
population. Sci. Rep. 8(1): e8071, 2018.
13. Jia X, Horinouchi T, Hitomi Y, Shono A, Khor SS,
Omae Y, Kojima K, Kawai Y, Nagasaki M, Kaku
Y, Okamoto T, Ohwada Y, Ohta K, Okuda Y,
Fujimaru R, Hatae K, Kumagai N, Sawanobori E,
Nakazato H, Ohtsuka Y, Nakanishi K, Shima Y,
Tanaka R, Ashida A, Kamei K, Ishikura K, Nozu
K, Tokunaga K, and Iijima K, for the ResearchConsortium on Genetics of Childhood Idiopathic
Nephrotic Syndrome in Japan: Strong associationof
HLA-DR/DQ
locus
with
childhoodsteroid-sensitive nephrotic syndrome in theJapanese population. J. Am. Soc. Nephrol. 29(8):2189-2199, 2018.
14. Palittapongarnpim
P,
Ajawatanawong
P,
Viratyosin W, Smittipat N, Disratthakit A,
Mahasirimongkol S, Yanai H, Yamada N,
Nedsuwan S, Imasanguan W, Kantipong P,
Chaiyasirinroje B, Wongyai J, Toyo-oka L, Phelan
J, Parkhill J, Clark TG, Hibberd ML, Ruengchai
W, Palittapongarnpim P, Juthayothin T, Tongsima
S, and Tokunaga K: Evidence for host-bacterial
co-evolution via genome sequence analysis of 480
Thai Mycobacterium tuberculosis lineage 1
isolates. Sci. Rep. 8(1): e11597, 2018.
15. Han B, Akiyama M, Kim KK, Oh H, Choi H, Lee
CH, Jung S, Lee HS, Kim EE, Cook S,
Haritunians T, Yamazaki K, Park SH, Ye BD,
McGovern DPB, Esaki M, Kawaguchi T, Khor SS,
Taylor KD, Rotter JI, Suzuki Y, Matsui T, Motoya
S, Bang SY, Kim T-H, Momozawa Y, Kamatani Y,
Tokunaga K, Kubo M, Okada Y, Yang SK, andSong K: Amino acid position 37 of HLA-DRβ1
affects susceptibility to Crohn’s disease in Asians.
Hum. Mol. Genet. 27(22): 3901-3910, 2018.

16. Aiba Y, Harada K, Ito M, Suematsu T, Aishima S,
Hitomi Y, Nishida N, Kawashima M, Takatsuki M,
Eguchi S, Shimoda S, Nakamura H, Komori A,
Abiru S, Nagaoka S, Migita K, Yatsuhashi H,
Tokunaga K, and Nakamura M: Increased
expression and altered localization of cathepsin Z
are associated with progression to jaundice stage
in primary biliary cholangitis. Sci. Rep. 8(1):e11808, 2018.
17. Miyagawa T, Khor SS, Toyoda H, Kanbayashi T,
Imanishi A, Sagawa Y, Kotorii N, Kotorii T,
Ariyoshi Y, Hashizume Y, Ogi K, Hiejima H,
Kamei Y, Hida A, Miyamoto M, Ikegami A, Wada
Y, Takami M, Higashiyama Y, Fukai R, Kondo H,
Fujimura Y, Tamura Y, Taniyama Y, Omata N,
Tanaka Y, Moriya S, Furuya H, Kato M,
Kawamura Y, Honda Y, Miyashita A, Kojima H,
Saji H, Shimada M, Yamasaki M, Kobayashi T,
Misawa R, Shigematsu Y, Kuwano R, Sasaki T,
Ishigooka J, Wada Y, Tsuruta K, Chiba S, Tanaka
F, Yamada N, Okawa M, Kuroda K, Kume K,
Hirata K, Uchimura N, Shimizu T, Inoue Y,
Mishima K, Honda M, and Tokunaga K: A variant
at 9q34.11 is associated with HLA-DQB1*06:02
negative essential hypersomnia. J. Hum. Genet.
63(12): 1259-1267, 2018.
18. Latt KZ, Honda K, Thiri M, Hitomi Y, Omae Y,
Sawai H, Kawai Y, Teraguchi S, Ueno K,
Nagasaki M, Mabuchi A, Kaga H, Komatsuda A,
Tokunaga K, and Noiri E: Identification of a
two-SNP PLA2R1 haplotype and HLA-DRB1
alleles as primary risk associations in idiopathic
membranous nephropathy. Sci. Rep. 8(1): e15576,
2018.

327

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
postdoctoral researcher, one assistant clerk, one
technical assistant, seventeen visiting lecturers,
fourteen visiting researchers, and seven graduate
students, including one overseas 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

32810) 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, andmild
encephalitis/encephalopathy
withareversible 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 studies on childhood
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. Hoque SA, Kobayashi M, Takanashi S, Anwar KS,
Watanabe T, Khamrin P, Okitsu S, Hayakawa S,
Ushijima H. Role of rotavirus vaccination on an
emerging G8P[8] rotavirus strain causing an
outbreak in central Japan. Vaccine 2018; 36(1):43-49.
2. Kakiuchi S, Tsuji M, Nishimura H, Wang L,
Takayama-Ito M, Kinoshita H, Lim CK,
Taniguchi S, Oka A, Mizuguchi M, Saijo M.
Human parainfluenza virus type 3 infections inhematopoietic stem cell transplantation patients:
The mode of nosocomial infections and theprognosis. Japanese Journal of Infectious Diseases
2018; 71(2): 109-115.
3. Khamrin P, Kumthip K, Thongprachum A,
Takanashi S, Okitsu S, Maneekarn N, Hayakawa
S, Ushijima H. Evaluation of immunochromatographic test for dual detection of noroviruses andgroup A rotaviruses in stool samples. ClinicalLaboratory 2018; 64(5): 793-796.
4. Kurahashi H, Azuma Y, Masuda A, Okuno T,
Nakahara E, Imamura T, Saitoh M, Mizuguchi M,
Shimizu T, Ohno K, Okumura A. MYRF is
associated with encephalopathy with reversible
myelin vacuolization. Annals of Neurology 2018;
83(1): 98-106.
5. Khandoker N, Thongprachum A, Takanashi S,
Okitsu S, Nishimura S, Kikuta H, Yamamoto A,
Sugita K, Baba T, Kobayashi M, Hayakawa S,
Mizuguchi
M,
Ushijima
H.
Molecular
epidemiology of rotavirus gastroenteritis in Japan
during2014-2015:
Characterizationofre-emerging G2P[4] after rotavirus vaccine
introduction. Journal of Medical Virology 2018;
90(6): 1040-1046.
6. Mizuguchi M, Hoshino A, Saitoh M.
Classification and epidemiology of acuteencephalopathy. In: Yamanouchi H, Moshe SL,
Okumura A(Eds) Acute encephalopathy andencephalitis in infancy and its related disorders.
Elsevier, St. Louis, 2018, pp. 5-10.
7. Mizuguchi M, Hoshino A, Saitoh M. Acutenecrotizing encephalopathy. In: Yamanouchi H,
Moshe SL, Okumura A(Eds) Acute encephalopathy and encephalitis in infancy and its related

329

disorders. Elsevier, St. Louis, 2018, pp. 87-92.
8. Okitsu S, Hikita T, Thongprachum A, Khamrin P,
Takanashi S, Hayakawa S, Maneekarn N,
Ushijima H. Detection and molecular characterization of two rare G8P[14] and G3P[3] rotavirus
strains collected from children with acutegastroenteritis in Japan. Infection, Genetics andEvolution 2018; 62: 95-108.
9. Okuda K, Takao K, Watanabe A, Miyakawa T,
Mizuguchi M, Tanaka T. Comprehensive
behavioral analysis of the Cdkl5 knockout mice
revealed significant enhancement in anxiety- andfear-related behaviors and impairment in bothacquisition and long-term retention of spatialreference memory. PLoS One. 2018;13(4):e0196587.
10. Tanaka M, Sato A, Kasai S, Hagino Y,
Kotajima-Murakami H, Kashii H, Takamatsu Y,
Nishito Y, Inagaki M, Mizuguchi M, Hall FS, Uhl
GR, Murphy D, Sora I, Ikeda K. Brain
hyperserotonemia causes autism-relevant social
deficits in mice. Molecular Autism 2018; 9: 60.
11. Thongprachum A, Fujimoto T, Takanashi S, Saito
H, Okitsu S, Shimizu H, Khamrin P, Maneekarn N,
Hayakawa S, Ushijima H. Detection of nineteen
enteric viruses in raw sewage in Japan. Infection,
Genetics and Evolution 2018; 63: 17-23.

330

Department of Human Ecology
Professor
Masahiro UMEZAKI, Ph.D.

Associate Professor
Shoko KONISHI, Ph.D. (From June 1, 2018)

Research Associate
Satoko KOSAKA, Ph.D.
Lena TAKAYASU, Ph.D. (From July 1, 2018)

Homepage

http://www.humeco.m.u-tokyo.ac.jp/en/

Introduction and Organization
Department of Human Ecology was founded when
Kenji Uraguchi was appointed to the professorship of
Human Ecology course on April 1, 1965. Following
retirement of professor Uraguchi as of March 31, 1966,
professor Haruo Katsunuma (appointed also as
professor of Public Health course, School of
Medicine) became a joint professor of the Human
Ecology course. Tsuguyoshi Suzuki was appointed as
an associate professor and worked in the department
until August 31, 1971 when he was transferred toFaculty of Medicine, Tohoku University as a professor.
After professor Katsunuma left the department on
March 31, 1972, professor Akira Koizumi became thehead of the Human Ecology course on April 1, 1972.
Professor Koizumi was transferred to Public Healthcourse, School of Medicine on March 31, 1976, andassociate professor Shosuke Suzuki served as adepartment head from April 1 1976 to March 1979.
Tsuguyoshi Suzuki was appointed as a professor of
the Human Ecology course as of April 16, 1979. He
founded theoretical framework of the current humanecology which is based on studying adaptation
mechanisms of humans to environment. Afterassociate professor Shosuke Suzuki was transferred toFaculty of Medicine, Gunma University, as professor
on July 31, 1981, Ryutaro Ohtsuka was appointed as
an associate professor on September 1. Associate

professor Ohtsuka established the methodology ofcollecting quantitative information on demography,
nutrition, and subsistence targeting small-scale
populations based on extensive fieldwork, which
methodology is still utilized by the current department
members. Following the retirement of professor
Tsuguyoshi Suzuki on March 31, 1992, Ryutaro
Ohtsuka was appointed as a professor as of April 1 inthe same year.
Chiho Watanabe was appointed as an associate
professor on December 1997. He expanded
methodologies that examine relationships between
environment and health by utilizing various tools suchas measuring biomarkers in biological specimens
collected in the field, and animal experiments.
Professor Ohtsuka retired on March 31, 2005 andChiho Watanabe was appointed as a professor as ofApril 1, 2005. Masahiro Umezaki was appointed as an
associate professor in August 2005. While relying thequantitative research based on fieldwork, he has also
been exploring new research topics including
relationship between gut microflora (internal
environment) and health. Professor Chiho Watanabe
was transferred from the University of Tokyo to the
National Institute of Environmental Studies as of April
1, 2017. Masahiro Umezaki was appointed as aprofessor as of January 1, 2018. Shoko Konishi was
appointed as an associate professor as of June 1, 2018.

331

In fiscal year 2018 the department had four
faculties; Dr. Umezaki, Dr. Konishi, Dr. Kosaka, andDr. Takayasu. There were 11 extra-university lecturersdelivering lectures in either graduate or undergraduate
course. Professor Umezaki held additional roles in the
Integrated Research System for Sustainability Science(IR3S) as well as in the Earth Observation Data Integration & Fusion Research Initiative (EDITORIA).

Teaching activities
The department is one of the six departments of the
School of International Health. Human Ecology
Special Lecture I focused on the basic components of
Human Ecology such as demography, nutrition, andenvironment and introducing the notion of humanecosystem. In “Human Ecology Special Lecture II”,emphases were on recent topics and ongoing
researches in the field of Human Ecology and relatedareas. With these classes for the Graduate Students,
we tried to describe Human Ecology as a basic
component of International Health, and gave examplesof the recent issues that have been dealt with andapproaches used in this field. The lectures for the
Graduate Course were given in English.
In the undergraduate course, the department is incharge of a part of the School of Integrated Health
Sciences, providing the lectures on “Human Ecology”,“Environment and Health”, “Demography”, “International Health”, and “Medical Anthropology”. We
were also responsible for organizing “Pharmacology
and Toxicology”, “Physiology”, as well as“Environmental Engineering/ Human Engineering”.
At the undergraduate level, our emphases are in
introducing global-scale issues such as population
explosion, food security, and environmental issues inrelation to the problems that Asia-Pacific region(including Japan) has been facing. Another emphasis
was on the relation between human activities andchemical contamination of the environment.

Research activities
Human ecology is literally the understanding of
human population in the context of their respective
ecology as well as in the global context. Most of ourresearch tackles the tasks that have been dealt in thefield of “Environmental Health” and/or “Population

Ecology [of human]”, but with more comprehensive
and broader context. Therefore, we need to adopt
different approaches including fieldwork, experiment,
as well as GIS/GPS analyses. Our study fields include
Asian-Oceanian (including Japan) rural as well urban
communities, focusing on population, nutrition,
growth, environment, and sustainability. Experimental
studies focusing on the effects of perinatal exposures
to heavy metals have been conducted, emphasizing thefactors that modify the effects. Almost all the studies
require “transdisciplinary” approach, hence, we arecollaborating with various domestic and overseas
research institutes. The following is a list of major
activities conducted in the past year.
1. Environmental contamination by metals and its
health impacts in South Asia
In the As-contaminated area in Myanmar, we
recruited and followed pregnant mothers at clinics
and collected biological specimens. We reported
association between in utero exposure to heavy
metals and infants’ telomere length after birth.
2. Adaptation to low-protein dietPrevious studies reported that Papua New Guinea
Highlanders show masculine body and do not show
clinical symptoms of protein deficiency, although
their main diet is sweet potatoes and their protein
intake levels is low. To elucidate the biologicalmechanisms underlying this, we conducted fieldand experimental studies.
3. Adaptive strategy to aging and depopulation
The population issues (low fertility, aging,
population decrease) that Japanese people are now
facing are the first problem that humans face at a
global scale. Targeting Japanese rural communities,
the front-runners of this global issue, we conducted
population projection and studies on their food
habit, nutritional intake, and subjective perceptionof health. At the mean time, we also conducted astudy to categorize original strategies against aging
and depopulation that were used in each local
community.
4. Nutrition and eating behaviors in Indonesia
We have been conducting field surveys every

332

year in the same villages in West Java, Indonesia. In
2018, we made a list of edible plants that people
collect from their field and natural environment inand around the village. In addition, interviews on
perception on food items in terms of healthinesswere conducted.
5. Study on time to pregnancy
Time to pregnancy is defined as the duration
between discontinuation of contraception andconception. We found that mothers with longer timeto pregnancy were more likely to experience
spontaneous preterm birth. We also reported thathigher age of both women and men were associatedwith longer time to pregnancy.
6. Study on menstrual cycle
We conducted studies on the correlates of
menstrual cycle variability. We reported that urinary
concentration of oxidative stress biomarker was not
associated with menstrual cycle length or regularity.
7. Study using Komo-Ise dataset
The Komo-Ise cohort was established in 1993
targeting more than 10,000 inhabitants in Isesaki
city and Komochi village in Gunma prefecture,
Japan. We published two article using this dataset.
One was about the association between parity andmortality, and the other was about the association
between thoughts of death and mortality.
8. Health transition in Lao PDR
The objective of the project is to investigate thehypothesis that consumption of wild plants among
the people in mountainous regions in Laos has
effect to reduce the risk of non-communicablediseases. By targeting villages with different extent
of industrialization, we did interview survey
together with collection of biological specimens.
Individual
variationin
consumptionofphytochemicals, the extent of oxidative stress,
inflammation and the risk of non-communicablediseases were investigated.
9. Fetal microbiome
Recent progress of DNA-based technologies has
been casted doubt on sterile womb hypothesis. We

conducted culture-based and 16S rRNA sequence
analysis on mice fetal samples, and suggested thepossibility that some of the bacterial species
establish on fetus during pregnancy.
10. Child undernutrition in Cebu, Philippine
Focusing on child undernutrition, data on childfood intake and physical activity, as well ashousehold environment such as sanitation, foodinsecurity, and parents’ status, were collected.
Analysis suggested that parents’ BMI, householdincome and household size were associated withchild undernutrition.

References
1. Konishi S, Ng CFS, Watanabe C. (2018). U-shaped
association between fertility and mortality in acommunity-based sample of Japanese women. J
Epidemiol Community Health, 72:337-341.
2. Konishi S, Sakata S, Ng CFS, Watanabe C. (2018).
Conception delay and spontaneous and indicatedpreterm birth among primiparous women in Japan.
Jpn J Health Hum Ecol, 84:117-128.
3. Konishi S, Sakata S, Oba SM, O’Connor KA.
(2018). Age and time to pregnancy for the first childamong couples in Japan. J Pop Stud
(Jinkogakukenkyu) 54:1-18.
4. Konishi S, Yoshinaga J, Nishihama Y, Onoda Y,
Chisaki Y, Imai H. (2018). Urinary 8-Hydroxy-2’deoxyguanosine (8-OHdG) concentrations andmenstrual cycle characteristics in female university
students. Int J Environ Res Public Health, 15:2616
https://doi.org/10.3390/ijerph15122616.
5. Kosaka S, Suda K, Gunawan B, Raksanagara A,
Watanabe C, Umezaki M. (2018). Urban-ruraldifference in the determinants of dietary and energy
intake patterns: A case study in West Java, Indonesia.
PLOS ONE, 13(5): e0197626.
6. Nishihama Y, Ameda R, Yoshinaga J, Konishi S,
Yoneyama M, Nakajima D, Shiraishi H, Imai H.
(2018). Inter- and intra-individual variation in
urinary concentratiosn of parabens in male andfemale Japanese subjects. J Environ Sci Health A,
53:73-78.
7. Sakata S, Konishi S, Ng CFS, Watanabe C. (2018)
Preterm birth rates in Japan from 1979 to 2014:

333

Analysis of national vital statistics. J Obstet Gynecol
Res, 44:390-396.
8. Stickley A, Ng CFS, Watanabe C, Inoue Y,
Koyamagi A, Konishi S. (2018). General thoughts ofdeath and mortality: findings from the Komo-Isecohort, Japan. doi: 10.1017/S2045796018000434
Epidemiol Psychiatr Sci, 1-8.
9. Suda K, Gunawan B, Kosaka S, Dede HA, Umezaki
M. (2018). Changing cropping systems in
Sundanese villages in West Java, Indonesia. People
and Culture in Oceania, 34:79-88.
10. Wai KM, Umezaki M, Kosaka S, Mar O, Umemura
M, Fillman T, Watanabe C. (2018). Impact ofprenatal heavy metal exposure on newborn
leucocyte telomere length: A birth-cohort study.
Environ Pollut, 243:1414-1421.

334

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

335

 Drug discovery and development against protozoan
infections such as malaria and amebiasis
 Elucidation of divergence of RNA maturation andtranslation

References
1. Andrabi SBA, Tahara M, Matsubara R, Toyama T,
Aonuma H, Sakakibara H, Suematsu M, Tanabe K,
Nozaki T, Nagamune K. Plant hormone cytokinins
control cell cycle progression and plastid replicationin apicomplexan parasites. Parasitol Int. 2018
Feb;67(1):47-58. doi: 10.1016/j.parint.2017.03.003.
2. Hartuti, E. D., Inaoka, D. K., Komatsuya, K.,
Miyazaki, Y., Miller, R. J., Xinying, W., Sadikin,
M., Prabandari, E. E., Waluyo, D., Kuroda, M.,
Amalia, E., Matsuo, Y., Nugroho, N. B., Saimoto,H., Pramisandi, A., Watanabe, Y. I., Mori, M.,
Shiomi, K., Balogun, E. O., Shiba, T., Harada, S.,
Nozaki, T., Kita, K.Biochemical studies ofmembrane bound Plasmodium falciparum mitochondrial L-malate:quinone oxidoreductase, apotential drug target. Biochim Biophys Acta. 2017
Dec 18; 1859(3):191-200. doi: 10.1016/j.bbabio.
2017.12.004.
3. Nakada-Tsukui, K., Sekizuka, T., Sato-Ebine, S.,
Escueta-de Cadiz, A., Ji, D., Tomii, K., Kuroda, M.,
Nozaki, T. AIG1 affects in vitro and in vivo
virulence in clinical isolates of Entamoeba
histolytica. PLoS Pathog, 14(3):e1006882, 2018.
doi: 10.1371/journal.ppat.1006882.
4. Nurkanto, A., Jeelani, G., Yamamoto, T., Naito, Y.,
Hishiki, T., Mori, M., Suematsu, M., Shiomi, K.,
Hashimoto, T. Nozaki, T. Characterization andvalidation of Entamoeba histolytica pantothenate
kinase as a novel anti-amebic drug target. International Journal for Parasitology: Drugs and Drug
Resistance, 8:125-136, 2018. doi: 10.1016/j.ijpddr.
2018.02.004.
5. Santos, H. J., Makiuchi, T., and Nozaki, T.
Reinventing an organelle: The reduced mitochondrion in parasitic protists. Trends Parasitol. 34:10381055, 2018. (Review) doi: 10.1016/j.pt.2018.08.008.
6. Das, K. and Nozaki, T. Non-vesicular lipid transportmachinery in Entamoeba histolytica. Frontiers Cell.
Inf. Microbiol., 8:315, 2018. (Review) doi: 10.3389/
fcimb.2018.00315.

7. Raj, D., Chowdhury, P., Sarkar, R., Saito-Nakano,Y., Okamoto, K., Dutta, S., Nozaki, T., Ganguly, S.
Pyruvate protects Giardia trophozoites fromcysteine-ascorbate deprived medium induced
cytotoxicity. Korean J Parasitol. 56(1):1-9, 2018.
doi: 10.3347/kjp.2018.56.1.1.
8. Iwasaki A, Tadenuma T, Sumimoto S, Shiota I,
Matsubara T, Saito-Nakano Y, Nozaki T, Sato T,
Suenaga K. Hoshinoamides A and B, Acyclic
Lipopeptides from the Marine Cyanobacterium
Caldora penicillata. J Nat Prod. 81:2545-2552,
2018. doi: 10.1021/acs.jnatprod.8b00643.
9. Nurkanto, A., Jeelani, G., Yamamoto, T., Hishiki, T.,
Naito, Y., Suematsu, M., Hashimoto, T. and Nozaki,
T. Biochemical, metabolomic, and genetic analysesof dephospho coenzyme A kinase Involved incoenzyme A biosynthesis in the human entericparasite Entamoeba histolytica. Front. Microbiol.
9:2902, 2018. doi: 10.3389/fmicb.2018.02902.
10. Mori, M., Tsuge, S., Fukasawa, W., Jeelani, G.,
Nakada-Tsukui, K., Nonaka, N., Matsumoto, A.,
Omura, S., Nozaki, T.*, and Shiomi, K.* Discoveryof antiamebic compounds that inhibit cysteinesynthase from the enteric parasitic protist
Entamoeba histolytica by screening of microbial
secondary metabolites. Front Cell Inf Microbiol 8:409, 2018. (*double correspondence) doi: 10.3389/
fcimb.2018.00409
11. Hanadate, Y.†, Saito-Nakano, Y. †, Nakada-Tsukui,K., and Nozaki, T. Identification and characterization of the Entamoeba histolytica Rab8a binding
protein: a Cdc50 homolog. Int J Mol Sci, 19(12). pii:
E3831, 2018. († equal contribution). doi: 10.3390/
ijms19123831.

School of Public Health
1. Epidemiology and Health Sciences

337

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

338with 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 MBE, Okubo H, Sasaki S.
Prevalence and characteristics of misreporting ofenergy intake in Japanese adults: the 2012 National
Health and Nutrition Survey. Asia Pac J Clin Nutr
2018; 27(2): 441-50.
2. Murakami K, Sasaki S. Glycemic index andglycemic load of the diets of Japanese adults: the2012 National Health and Nutrition Survey, Japan.
Nutrition 2018; 46: 53-61.
3. Miyake Y, Tanaka K, Okubo H, Sasaki S, Furukawa
S, Arakawa M. Soy isoflavone intake andprevalence of depressive symptoms during pregnancy in Japan: baseline data from the Kyushu
Okinawa Maternal and Child Health Study. Eur J
Nutr 2018; 57: 441-50.
4. Miyake Y, Tanaka K, Okubo H, Sasaki S,
Furukawa S, Arakawa M. Dietary patterns anddepressive symptoms during pregnancy in Japan:
Baseline data from the Kyushu Okinawa Maternaland Child Health Study. J Affect Disord 2018;
225: 552-8.
5. Murakami K, Sasaki S. A low-glycemic index and-glycemic load diet is associated with not only
higher intakes of micronutrients but also higher
intakes of saturated fat and sodium in Japanesechildren and adolescents: the National Health andNutrition Survey. Nutr Res 2018; 49: 37-47.
6. Suga H, Asakura K, Kobayashi S, Nojima M,
Sasaki S, the Three-generation Study of Womenon Diets and Health Study Group. Association
between habitual tryptophan intake and depressive
symptoms in young and middle-aged women. J
Affect Disord 2018; 231: 44-50.
7. Shinozaki N, Murakami K, Asakura K, Uechi K,
Kobayashi S, Masayasu S, Sasaki S. Dietaryphosphorus intake estimated by 4-day dietary
records and two 24-hour urine collections andtheir associated factors in Japanese adults. Eur J

Clin Nutr 2018; 72(4): 517-25.
8. Suga H, Asakura K, Sasaki S, Nojima M, Okubo
H, Hirota N, Notsu A, Fukui M, Date C.
Validation study of a self-administered diethistory questionnaire for estimating amino acidintake among Japanese adults. Asia Pac J Clin
Nutr 2018; 27(3): 638-45.
9. Murakami K, Livingstone MB, Sasaki S. Diet
quality scores in relation to metabolic risk factors
in Japanese adults: a cross-sectional analysis fromthe 2012 National Health and Nutrition Survey,
Japan. Eur J Nutr 2018; : [Epub ahead of print].
10. Murakami K, Livingstone MB, Sasaki S.
Meal-specific dietary patterns and their contribution
to overall dietary patterns in the Japanese context:
findings from the 2012 National Health andNutrition Survey, Japan. Nutrition 2018; 59: 108115.
11. Murakami K, Livingstone MB, Sasaki S.
Thirteen-Year Trends in Dietary Patterns among
Japanese Adults in the National Health andNutrition Survey 2003?2015: Continuous Westernization of the Japanese Diet. Nutrients 2018;
10(8): 994.
12. Murakami K, Okubo H, Livingstone MBE,
Fujiwara A, Asakura K, Uechi K, Sugimoto M,
Wang HC, Masayasu S, Sasaki S. Adequacy ofusual intake of Japanese children aged 3-5 years:
A nationwide study. Nutrients 2018; 10(9): 1150.
13. Tsujiguchi H, Hori D, Kambayashi Y, Hamagishi
T, Asakura H, Mitoma J, Kitaoka M, Anyenda EO,
Nguyen TTT, Yamada Y, Hayashi K, Konoshita T,
Sagara T, Shibata A, Sasaki S, Nakamura H.
Relationship between screen time and nutrient
intake in Japanese children and adolescents: across-sectional observational study. Environ
Health Prev Med 2018; 23(1): 34.
14. 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 2018; : [Epub ahead of print].
15. Fujiwara A, Murakami K, Asakura K, Uechi K,
Sugimoto M, Wang H, Masayasu S, Sasaki S.
Estimation of starch and sugar intake in a

339Japanese population based on a newly developed
food composition database. Nutrients 2018;10(10): 1474.
16. Murakami K, Livingstone MBE, Sasaki S, Hirota
N, Notsu A, Miura A, Todoriki H, Fukui M, Date
C. Applying a meal coding system to 16-dweighed dietary record data in the Japanesecontext: towards the development of simple mealbased dietary assessment tools. J Nutr Sci 2018;
7: e29.
17. Murakami K, Livingstone MBE, Fujiwara A,
Sasaki S. Breakfast in Japan: findings from the2012 National Health and Nutrition Survey.
Nutrients 2018; 10(10): 1551.
18. Sugawa M, Okubo H, Sasaki S, Nakagawa Y,
Kobayashi T, Kato K. Lack of a meaningful
association between dietary patterns and in vitro
fertilization outcome among Japanese women.
Reprod Med Biol 2018; 17(4): 466-73.

340

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/※The following information is the same as that of the previous year for certain reasons.

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 applied course of clinical epidemiology supports
the students to build a research hypothesis, design a
study, and prepare a study protocol for fund proposal.
The course on health care organization management
provides basics of financial accounting, and management frameworks on human resource, strategy, information, and risk, helping the students deepen theknowledge through in-class discussion over real-casescenarios.
The Department accepted 10 master students for the
fiscal years of 2017.

Research activities
Current activities in this Department cover a broad
range of health services research, including clinical341

epidemiological studies, economic evaluation ofhealth technology and health policy, quality of life
research, and hospital administration and quality
assurance.
The Department also contributes to clinical and healthservice research using a large claim database based on
the Japanese original patient classification system,
Diagnosis Procedure Combination (DPC). DPC database allows a unique and detailed analysis on theprocess of care in acute care hospitals in this country.
DPC database also provides resource diagnosis in
hospital levels as well as regional levels, whencombined with other public data sources such as thePatient Survey, and Hospital Census.

7.

8.

References
1.

2.

3.

4.

5.

6.

Aso S, Matsui H, Fushimi K, Yasunaga H.
Resuscitative endovascular balloon occlusion of
the aorta or resuscitative thoracotomy with aortic
clamping for non-compressible torso hemorrhage: a retrospective nationwide study. Journalof Trauma and Acute Care Surgery 2017;
82(5) :910–914
Hasegawa W, Yamauchi Y, Yasunaga H,
Takeshima H, Sakamoto Y, Jo T, Sasabuchi Y,
Matsui H, Fushimi K, Nagase T. Prognostic
nomogram for inpatients with asthma exacerbation. BMC Pulmonary Medicine 2017;17:108
Ishimaru M, Ono S, Suzuki S, Matsui H, Fushimi
K, Yasunaga H. Artificial nutrition dependence
after cetuximab vs. cisplatin combined withradiotherapy for advanced head and neck cancer:
A propensity score matched analysis. Head &Neck 2017;39(2):320-325
Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. Factors affecting in-hospitalmortality and likelihood of undergoing surgicalresection in patients with primary cardiac tumors.
Journal of Cardiology 2017;69(1):287-292.
Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. Treatments and in-hospital mortality in acute myocardial infarction patients withrheumatoid arthritis: a nationwide retrospective
cohort study in Japan. Clinical Rheumatology
2017;36(5):995-1004
Isogai T, Matsui H, Tanaka H, Fushimi K,

9.

10.

11.

12.

13.

Yasunaga H. In-hospital management andoutcomes in patients with peripartum cardiomyopathy: a descriptive study using a national
inpatient database in Japan. Heart and Vessels
2017;32(8):944-951
Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. Seasonal variation in patientcharacteristics and in-hospital outcomes of
Takotsubo syndrome: a nationwide retrospective
cohort study in Japan. Heart and Vessels 2017;32:1271–1276
Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. Clinical characteristics of patientswith Takotsubo syndrome diagnosed withoutcoronary artery evaluation: A retrospective
nationwide study. Journal of Cardiology 2017;
71(3):268-276.
Iwagami M, Yasunaga H, Matsui H, Horiguchi
H, Fushimi K, Noiri E, Nangaku M, Doi K.
Impact of end-stage renal disease on hospitaloutcomes among patients admitted to intensive
care units: A retrospective matched-pair cohort
study. Nephrology 2017;22(8):617-623.
Jo T, Yasunaga H, Sasabuchi Y, Michihata N,
Morita K, Yamauchi Y, Hasegawa W, Takeshima
H, Sakamoto Y, Matsui H, Fushimi K, Nagase T.
Association between dementia and discharge
status in patients hospitalized with pneumonia.
BMC Pulmonary Medicine 2017;17(1):128
Kawata M, Sasabuchi Y, Inui H, Taketomi S,
Matsui H, Fushimi K, Chikuda H, Yasunaga H,
Tanaka T. Annual trends in knee arthroplasty andtibial osteotomy: Analysis of a national databasein Japan. Knee 2017;24(5):1198-1205
Kikuchi H, Hamanaga C, Yasunaga H, Matsui H,
Hashimoto H. Privacy-preserving multiple linear
regression of vertically partitioned real medical
datasets. Advanced Information Networking andApplications (AINA), 2017 IEEE 31st International Conference
Kishimoto M,Yamana H, Inoue H, Noda
T,Myojin T, Matsui H, Yasunaga H, Kawaguchi
M, Imamura T. Sivelestat sodium and mortality inpneumonia patients requiring mechanical ventilation: propensity score analysis of a Japanesenationwide database. Journal of Anesthesia 2017;31(3):405-412

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14. Koike S, Matsumoto M, Ide H, Kawaguchi H,
Shimpo M, Yasunaga H. Internal medicine board
certification and career pathways in Japan. BMC
Med Educ. 2017;17(1):83.
15. Maeda T, Sasabuchi Y, Matsui H, Ohnishi Y,
Miyata S, Yasunaga H. Safety of tranexamic use
during pediatric cardiac surgery: a nationwide
database study. Journal of Cardiothoracic and
Vascular Anesthesia 2017;31(2):549-553
16. Matsui H, Jo T, Fushimi K, Yasunaga H.
Outcomes after early and delayed rehabilitationfor exacerbation of chronic obstructive
pulmonary disease: a nationwide retrospective
cohort study in Japan. Respiratory Research
2017;21;18(1):68.
17. Morita K, Matsui H, Fushimi K, Yasunaga H.
Association between nurse staffing andin-hospital bone fractures: A retrospective cohort
study. Health Services Research 2017;52(3):1005-1023
18. Morita K, Matsui H, Fushimi K, Yasunaga H.
Association between advanced practice nursing
and 30-day mortality in mechanically ventilated
critically ill patients: a retrospective cohort study.
Journal of Critical Care 2017;41:209-215
19. Nagano M, Ichinose J, Sasabuchi Y, Nakajima J,
Yasunaga H. Surgery versus percutaneoustranscatheter embolization for pulmonary
arteriovenous malformation: Analysis of anational inpatient database in Japan. J Thorac
Cardiovasc Surg. 2017;154(3):1137-43.
20. Odagiri H, Yasunaga H, Matsui H, Matsui S,
Fushimi K, Kaise M. Hospital volume andadverse events following esophageal endoscopic
submucosal dissection: analysis of a national
inpatient database in Japan. Endoscopy 2017;
49(4):321-326
21. Odagiri H, Yasunaga H. Complications
following endoscopic submucosal dissection for
gastric, esophageal, and colorectal cancer: areview of studies based on nationwide large-scale
databases. Ann Transl Med. 2017;5(8):189.
22. Ohya J, Oshima Y, Chikuda H, Oichi T, Matsui H,
Fushimi K, Tanaka S, Yasunaga H. Seasonal
Variations in the Risk of Reoperation for SurgicalSite Infection Following Elective Spinal Fusion
Surgery: A Retrospective Study Using the

23.

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25.

26.

27.

28.

29.

30.

Japanese Diagnosis Procedure Combination
Database. Spine 2017;42(14):1068-1079
Oichi T, Chikuda H, PhD, Ohya J, Ohtomo R,
Morita K, Matsui H, Fushimi K, Tanaka S,
Yasunaga H. Mortality and morbidity after
spinal surgery in patients with Parkinson’s
disease: a retrospective matched-pair cohort study.
Spine Journal 2017;17(4):531-537
Okubo Y, Michihata N, Yoshida K, Morisaki N,
Matsui H, Fushimi K, Yasunaga H. Impact ofpediatric obesity on acute asthma exacerbation in
Japan. Pediatr Allergy Immunol. 2017;28(8):763767.
Okubo Y, Michihata N, Morisaki N, Kinoshita N,
Miyairi I, Urayama KY, Yasunaga H. Recent
patterns in antibiotic use for children with group
A streptococcal infections. Journal of Global
Antimicrobial Resistance 2017;13;13:55-59.
Ono S, Ono Y, Matsui H, Yasunaga H. Impact ofclinic follow-up visits on body weight control inpeople with prediabetes or diabetes mellitus:
Japanese nonelderly cohort study. Family
Practice 2017;34(5):552-557
Ono S, Ono Y, Matsui H, Yasunaga H. Enhanced
Oral Care and Health Outcomes among Nursing
Facility Residents: Analysis Using the National
Long-term Care Database in Japan. Journal of theAmerican Medical Directors Association 2017;18(3):277.e1-277.e5
Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi
K, Tanaka Y. Clinical characteristics andoutcomes of myxedema coma: analysis of anational inpatient database in Japan. J Epidemiol
2017;27:117-122
Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi
K, Tanaka Y. Clinical Features and PracticePatterns of Treatment for Adrenal Crisis: A
Nationwide Cross-Sectional Study in Japan.
European Journal of Endocrinology 2017:176,
329–337
Sakamoto Y ， Yamauchi Y ， Yasunaga H ，
Takeshima H, Hasegawa W，Jo T，Matsui H，Fushimi K, Nagase T. Guidelines-concordant
empiric antimicrobial therapy and mortality inpatients with severe community-acquired
pneumonia requiring mechanical ventilation.
Respiratory Investigation 2017;55(1):39-44

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31. Sakamoto Y ， Yamauchi Y ， Yasunaga H ，
Takeshima H, Hasegawa W，Jo T，Matsui H，Fushimi K, Nagase T. Development of anomogram for predicting in-hospital mortality ofpatients with exacerbation of chronic obstructive
pulmonary disease. International Journal of
Chronic Obstructive Pulmonary Disease 2017;12:
1605-1611.
32. Sako A, Yasunaga H, Matsui M, Fushimi K,
Hamasaki H, Katsuyama H, Tsujimoto T, Goto A,
Yanai H. Hospitalization with hypoglycemia inpatients without diabetes mellitus: a retrospective
study using a national inpatient database in Japan,
2008-2012. Medicine 2017;96(25):e7271
33. Sasabuchi Y, Matsui H, Yasunaga H, Fushimi K.
Increase in Avoidable Hospital Admissions after
the Great East Japan Earthquake. Journal of
Epidemiology & Community Health 2017;71(3):248-252.
34. Sasabuchi Y, Matsui H, Yasunaga H, Fushimi K.
Epidural analgesia is infrequently used in patientswith acute pancreatitis: a descriptive study. Acta
Gastro-enterologica Belgica 2017;80(3)35. Sato M, Tateishi R, Yasunaga H, Matsui H,
Fushimi K, Ikeda H, Yatomi Y, Koike K.
Association between hospital volume andin-hospital mortality following radiofrequency
ablation for hepatocellular carcinoma: A national
survey of 36,675 patients. BJS Open 2017;1:
50–54
36. Sato M, Tateishi R, Yasunaga H, Horiguchi H,
Matsui H, Yoshida H, Fushimi K, Koike K. The
ADOPT-LC Score: A Novel Predictive Index of
In-hospital Mortality of Cirrhotic Patients
Following Surgical Procedures. Hepatology
Research 2017;47(3):E35-E43.
37. Sato M, Tateishi R, Yasunaga H, Matsui H,
Horiguchi H, Fushimi K, Koike K. Mortality andhemorrhagic complications associated with radiofrequency ablation for treatment of hepatocellular
carcinoma in patients on hemodialysis forend-stage renal disease: A nationwide survey. J
Gastroenterol Hepatol. 2017;32(11):1873-1878.
38. Shakya S, Matsui H, Fushimi K, Yasunaga H.
In-hospital complications after implantation ofcardiac implantable electronic devices: analysis
of a national inpatient database in Japan. Journal

39.

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46.

of Cardiology 2017;70(5):405-410.
Sugihara T, Yasunaga H, Matsui H, Nagao G,
Ishikawa A, Fujimura T, Fukuhara H, Fushimi K,
Ohori M, Homma Y. Accessibility to surgicalrobot technology and prostate-cancer patient
behavior for prostatectomy. Jpn J Clin Oncol.
2017;47(7):647-651
Tagami T, Matsui H, Moroe Y, Fukuda R, Shibata
A, Tanaka C, Unemoto K, Fushimi K, Yasunaga
H. Antithrombin use and 28-day in-hospitalmortality among severe burns patients: anobservational nationwide study. Annals of
Intensive Care 2017;7(1):18.
Tagami T, Yasunaga H, Yokota H. Antiarrhythmic drugs for out-of-hospital cardiac arrestwith refractory ventricular fibrillation. Critical
Care 2017;21:59.
Takeuchi T, Yasunaga H, Matsui H, Fushimi K.
Pediatric urolithiasis associated with acutegastroenteritis: an inpatient database study inJapan. European Journal of Pediatrics 2017;
176(4):501-507
Tomio J, Yamana H, Matsui H, Yamashita H,
Yoshiyama T, Yasunaga H. Tuberculosis
screening prior to anti-tumor necrosis factor
therapy among patients with immune-mediatedinflammatory diseases in Japan: a study using alarge-scale health insurance claims database.
International Journal of Rheumatic Diseases 2017
Nov;20(11):1674-1683
Urushiyama H, Jo T, Yasunaga H, Yamauchi Y,
Matsui H, Hasegawa W, Takeshima H, Hiraishi Y,
Mitani A, Fushimi K, Nagase T. Adjuvant
chemotherapy versus chemoradiotherapy forsmall cell lung cancer with lymph nodemetastasis: a retrospective observational study
with use of a national database in Japan. BMC
Cancer 2017;17(1):613
Wada T, Yasunaga H, MD, Yamana H, Matsui H,
Matsubara T, Fushimi K, Nakajima S.
Relationship between Hospital Volume andOutcomes in Patients with Traumatic Brain
Injury: A Retrospective Observational Study
using a National Inpatient Database in Japan.
Injury 2017;48(7):1423-1431
Wada T, Yasunaga H, MD, Yamana H, Matsui H,
Matsubara T, Fushimi K, Nakajima S.

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Development and validation of a new ICD-10–
based trauma mortality prediction scoring systemusing a Japanese national inpatient database.
Injury Prevention 2017;23(4):263-267.
47. Yagi M, Yasunaga H, Matsui H, Fushimi K,
Fujimoto M, Koyama T, Fujitani J. Impact ofRehabilitation on Outcomes in Patients with
Ischemic Stroke: A Nationwide Retrospective
Cohort Study in Japan. Stroke 2017;48(3):740746
48. Yamana H, Moriwaki M, Horiguchi H, Kodan M,
Fushimi K, Yasunaga H. Validity of diagnoses,
procedures, and laboratory data in Japaneseadministrative data. J Epidemiology 2017;27(10):476-482

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Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., 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. Patient-provider communication (1): Patient pers-

pective
3. Patient-provider communication (2): Healthcare
professional education
4. Communication in group and organization
5. Interpersonal communication skills for behavioral
changes
6. Public health communication skills for behavioral
changes
7. Evaluation and research in health communication
8. How to write persuasive health materials
9. Media and communication (1): Television
10. Media and communication (2): News paper
11. Media and communication (3): Internet
12. Entertainment education
13. Communicating for policy and advocacy
14. Group discussion[Health Communication Practice]
1. How to write persuasive health materials
2. Coaching
3. Manners in interpersonal relationship4. MBTI (Myers-Briggs Type Indicator) (1)(2)(3)5. Mass communication: Media doctor
6. Internet communication (1)(2)[Medical research and CDISC standards]
1. Introduction to CDISC standards
2. Introduction to data management in clinicalresearch
3. Data and metadata – Define.xml
4. Standardization of case report form – CDASH
5. Standardization of data format – SDTM
6. Standardization of dataset for analysis – AdaM

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7.

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.
Based on the analysis of the communication in actual
as well as simulated medical encounters, weinvestigate 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 have developed a measure of health literacy
considering the social and cultural context of Japan,
and investigated its relationship with patient andprovider communication, and patient health behaviors
and outcomes.
(4) Research on MediaWe have analyzed contents and suitability of healthinformation delivered by mass media and social media.
We also have conducted researches to increaseinfluence of small media such as leaflets, and held
seminars for health 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
attained by the medical research data center at the
UMIN.

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(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. Goto E, Ishikawa H,Nakayama K, Kiuchi T.
Comprehensive Health Literacy and HealthRelated Behaviors Within a General Japanese
Population: Differences by Health Domains. Asia
Pacific Journal of Public Health, 30(8) 717-726,
2018.
2. Ueno H, Yamazaki Y, Yonekura Y, Park MJ,
Ishikawa H, Kiuchi T. Reliability and validity of a
12-item medication adherence scale for patientswith chronic disease in Japan. BMC HealthServices Research 2018;18:592.
3. Okuhara T, Ishikawa H, Urakubo A, Hayakawa M,
Yamaki C, Takayama T, Kiuchi T. Cancer
information needs according to cancer type: A
content analysis of data from Japan's largest
cancer information website. Preventive Medicine
Reports 12: 245-252, 2018
4. Okuhara T., Ishikawa H., Goto E., Okada M.,
Kato M., Kiuchi T. Processing fluency effect of aleaflet for breast and cervical cancer screening: arandomized controlled study in Japan. Psychology,
Health & Medicine 23(10):1250-1260, 2018.
5. Okuhara T., Ishikawa H., Okada M., Kato M.,
Kiuchi T. Persuasiveness of Statistics andPatients’ and Mothers’ Narratives in Human
Papillomavirus
VaccineRecommendation
Messages: A Randomized Controlled Study inJapan. Frontiers in Public Health.6:105, 2018.
6. Okuhara T., Ishikawa H., Okada M., Kato M.,
Kiuchi T. Japanese anti- versus pro-influenza
vaccination websites: a text mining analysis.
Health Promotion International. day015, 2018

School of Public Health
2. Behavioral Health Sciences

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Departments ofHealth and Social Behavior &Health Education and HealthSociology
Professor in health and social behavior
Hideki Hashimoto, M.D., D.PH.

Associate Professor in health education and health sociology
Naoki Kondo, M.D., Ph.D.

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 by
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, each ofwhich focusing 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

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the data-control committee, to share analytic schemeand to enhance inter-disciplinary studies so as tobetter identify common factors as well as uniquefactors affecting health inequality in Japanese context.
Following third follow-up for children conducted in
2015-2016, and third follow-up of respondent adults
in 2017.
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.

2.

3.

4.

5.

6.

7.

Miyata H, Mori M, Kokudo N, Gotoh M, Konno
H, Wakabayashi G, Matsubara H,Watanabe T,
Ono M, Hashimoto H, Yamamoto H, Kumamaru
H, Kohsaka S, Iwanaka T. Association between
institutional procedural preference and inhospital outcomes in laparoscopic surgeries;
Insights from a retrospective cohort analysis of anationwide surgical database in Japan. PLoS One.
2018 Mar 5; 13(3): e0193186. doi: 10.1371/
journal.pone.0193186.
Takahashi A, Kumamaru H, Tomotaki A,
Matsumura G, Fukuchi E, Hirata Y,Murakami A,
Hashimoto H, Ono M, Miyata H. Verification of
Data
AccuracyinJapan
Congenital
Cardiovascular Surgery Database Including Its
Postprocedural Complication Reports. World J
Pediatr Congenit Heart Surg. 2018 Mar;9(2):150156. doi: 10.1177/2150135117745871.
Anezaki H, Hashimoto H. Time cost of childrearing and its effect on women’s uptake of freehealth checkups in Japan. Soc Sci Med. 2018 Mar
17;205:1-7. doi:10.1016/j.socscimed.2018.03.
025.
Murakami K, Ohkubo T, Hashimoto H.
Socioeconomic Inequalities in Oral HealthAmong Unmarried and Married Women:
Evidence From a Population-Based Study inJapan. J Epidemiol. 2018 Mar 24. doi: 10.2188/
jea.JE20170088.
Nakamura S, Hashimoto H. Couple Reports on
Intimate Partner Violence and their HealthImpact: Evidence From a Population-Based
Survey in Japan. J Interpers Violence. 2018 May
1:886260518777008. doi: 10.1177/08862605187
77008.
Sakamoto S, Rahman MM, Nomura S, et al.
Japan Health System Review. February
2018?ISBN 978-92-9022-626-3. World HealthOrganization, Regional Office for South-East
Asia (Chapter contribution by H Hashimoto N
Kondo, Chapter 6 and 7)
Hashimoto H, Kawakami N. Chapter 13. Health
Equity IN; Bhugra D, Bhui K, Yeung Shan WongS, and Gilman SE eds. Oxford Textbook of

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8.

9.

10.

11.

12.

13.

14.

15.

Public Mental Health, Oxford University Press,
forthcoming
Suga H, Hashimoto H. Age threshold forrecommending higher protein intake to prevent
age-related muscle weakness: A crosssectional
study in Japan.PLoS ONE 2018; 13(12):e0208169.
Baum F, Popay J, Delany-Crowe T, Freeman T,
Musolino C, Alvarez-Dardet C,Ariyaratne V,
Baral K, Basinga P, Bassett M, Bishai DM,
Chopra M, Friel S,Giugliani E, Hashimoto H,
Macinko J, McKee M, Nguyen HT, Schaay N,
Solar O,Thiagarajan S, Sanders D. Punching
above their weight: a network to understandbroader determinants of increasing life
expectancy. Int J Equity Health. 2018 Aug13;
17(1):117. doi: 10.1186/s12939-018-0832-y.
Masuda, R., Lanier, P. & Hashimoto, H. The
association between paternal job stress andmaternal child corporal punishment; Evidence
from population-based survey in metropolitan
Japan. J Fam Viol (2018).
Kachi Y, Hashimoto H, Eguchi H. Genderdifferences in the effects of job insecurity on
psychological distress in Japanese workers: a
population-based panel study. Int Arch Occup
Environ Health. 2018 Nov;91(8):991-999. doi:10.
1007/s00420-018-1338-z.
Heo J*, Lin S-F, Kondo N, Hwang J, Lee J-K, Oh
J. Values and happiness among Asianadolescents: a cross-national study. Journal ofYouth Studies 2018:1-16.
Shrestha S*, Aihara Y, Bhattarai AP, Bista N,
Kondo N, Futaba K, Nishida K, Shindo J.
Development of an objective water security
index and assessment of its association withquality of life in urban areas of developing
countries. SSM Popul Health 2018;6:276-85.
Barauskaite D*, Gineikiene J, Fennis BM,
Auruskeviciene V, Yamaguchi M, Kondo N.
Eating healthy to impress: How conspicuous
consumption, perceived self-control motivation,and descriptive normative influence determinefunctional food choices. Appetite 2018;131:5967.
Tani Y, * Suzuki N, Fujiwara T, Hanazato M,
Kondo N, Miyaguni Y, Kondo K. Neighborhood

16.

17.

18.

19.

20.

21.

22.

23.

food environment and mortality among older
Japanese adults: results from the JAGES cohort
study. Int J Behav Nutr Phys Act 2018;15:101.
Higuchi M*, Suzuki K, Ashida T, Kondo N,
Kondo K. Social Support and Access to HealthCare Among Older People in Japan: Japan
Gerontological Evaluation Study (JAGES). Asia
Pac J Public Health 2018;30:425-36.
Hiyoshi A, Kondo N*, Rostila M. Increasing
income-based inequality in suicide mortality
among working-age women and men, Sweden,
1990-2007: is there a point of trend change? J
Epidemiol Community Health 2018;72:1009-15.
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 2018. Epub ahead of print
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 20102013 JAGES Longitudinal Study. J Epidemiol
2019;29:65-72.
Tsuji T*, Kondo K, Kondo N, Aida J, Takagi D.
Development of a risk assessment scalepredicting incident functional disability amongolder people: Japan Gerontological Evaluation
Study. Geriatr Gerontol Int 2018;18:1433-8.
Shrestha S*, Nakamura T, Magome J, Aihara Y,
Kondo N, Haramoto E, Malla B, Shindo J,
Nishida K. Groundwater use and diarrhoea inurban Nepal: novel application of a geostatisticalinterpolation technique linking environmental
and epidemiologic survey data. Int Health 2018;
10:324-32.
Moriyama H*, Fuchimukai T, Kondo N,
Takayama JI. Obesity in elementary school
children after the Great East Japan Earthquake.
Pediatr Int 2018;60:282-6.
Honjo K*, Tani Y, Saito M, Sasaki Y, Kondo K,
Kawachi I, Kondo N. Living Alone or With
Others and Depressive Symptoms, and Effect
Modification by Residential Social Cohesion
Among Older Adults in Japan: The JAGES

353

24.

25.

26.

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Longitudinal Study. J Epidemiol 2018;advpub.
Kondo N*. Increasing Research Opportunities in
Asia
AmidstDramatically
Changing
Epidemiologic Patterns. J Epidemiol 2018;28:
277-8.
Kondo N*, Ishikawa Y. Affective stimuli inbehavioural interventions soliciting for healthcheck-up services and the service users'socioeconomic statuses: a study at Japanesepachinko parlours. J Epidemiol Community
Health 2018;72:e1.
Saito J*, Shibanuma A, Yasuoka J, Kondo N,
Takagi D, Jimba M. Education and indoor
smoking among parents who smoke: themediating role of perceived social norms ofsmoking. BMC Public Health 2018;18:211.
Cable N*, Hiyoshi A, Kondo N, Aida J, Sjoqvist
H, Kondo K. Identifying Frail-Related
Biomarkers among Community-Dwelling Older
Adults in Japan: A Research Example from theJapanese Gerontological Evaluation Study.
Biomed Res Int 2018;2018:5362948.
Yamaguchi M*, Kondo N, Hashimoto H.
Universal school lunch programme closes asocioeconomic gap in fruit and vegetable intakes
among school children in Japan. Eur J Public
Health 2018;28:636-41.
Saito T*, Kondo N, Shiba K, Murata C, Kondo K.
Income-based inequalities in caregiving time anddepressive symptoms among older family
caregivers under the Japanese long-term careinsurance system: A cross-sectional analysis.
PLoS One 2018;13:e0194919.
Tani Y,* Kondo N, Noma H, Miyaguni Y, Saito
M, Kondo K. Eating Alone Yet Living With
Others Is Associated With Mortality in Older
Men: The JAGES Cohort Survey. J Gerontol B
Psychol Sci Soc Sci 2018;73:1330-4.
Lee H-Y, Kondo N, Oh J*. Medical expenditureand unmet need of the pre-elderly and the elderly
according to job status in Korea: Are the elderly
indeed most vulnerable? PLOS ONE 2018;13:e0193676.
Imai Y*, Nagai M, Ohira T, Shirai K, Kondo N,
Kondo K. Impact of social relationships onincome-laughter relationships among older
people: the JAGES cross-sectional study. BMJ

33.

34.

35.

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37.

38.

Open 2018;8:e019104.
Zaitsu M*, Kawachi I, Ashida T, Kondo K,
Kondo N. Participation in Community Group
Activities Among Older Adults: Is Diversity ofGroup Membership Associated With Better Selfrated Health? J Epidemiol 2018;28:452-7.
Haseda M, Kondo N*, Takagi D, Kondo K.
Community social capital and inequality indepressive symptoms among older Japanese
adults: A multilevel study. Health Place 2018;52:
8-17.
Sasaki I*, Kondo K, Kondo N, Aida J, Ichikawa
H, Kusumi T, Sueishi N, Imanaka Y. Are pension
types associated with happiness in Japanese older
people?: JAGES cross-sectional study. PLoS
One 2018;13:e0197423.
Obikane E, Shinozaki T, Takagi D, Kawakami N.
Inpact of childhood abuse on suicide-related
behavior: Analysis using marginal structuralmodels. Journal of Affective Disorders 2018;234:224-230.
Yamaguchi M, Inoue Y, Shinozaki T, Saito S,
Takagi D, Kondo K, Kondo N. Community social
capital and depressive symptoms among older
people in Japan. A multilevel longitudinal study.
Journal of Epidemiology 2018; JE20180078.
Haseda M, Kondo N, Ashida T, Tani Y, Takagi
D, Kondo K. Community social capital, built
environment, and income-based inequality indepressive symptoms among older people inJapan: An ecological study from the JAGES
Project. Journal of Epidemiology 2018; 28:108116.

School of Public Health
3. Health Services Sciences

355

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.
Research Associate

Toki Saito, Ph.D.
Ayako Kohyama-Koganeya, Ph.D.

Homepage:

http://park.itc.u-tokyo.ac.jp/CIEMedUTokyo/wp/

Introduction and Organization
Information engineering in Japan places a great dealof weight on computer hardware, software, and dataprocessing. It is a discipline that seeks objective dataand emphasizes the conception of new methods ofdata transfer, storage, processing, and input/output. It
also targets research on developing computer devices
and systems.
Reviewing the history of the application ofcomputers in medicine, calculating machines forsupporting scientists and technologists first appearedin the 1950s. In the 1960s, computers were used foraccounting and various statistics. The personal
computer appeared in the 1980s and was adopted for
personal use in many professions. The systematizationof large hospitals, such as university hospitals, pushedahead rapidly.
In the 1990s, the computer began to be used as atool to help human thinking, such as in presentations,design, and discovery. When computers became
connected to each other through the internet, thedistribution of information became very easy andrapid, not only within organizations, but alsointernationally.
In 2003, a high-quality, "finished" sequence of thehuman genome was completed. At the dawn of thetwenty-first century, bioinformatics appeared as a new
discipline, one that uses applied mathematics,
informatics, statistics, computer science, and bio-chemistry to solve biological problems. In medicine,advanced information technologies have been applied
to health information infrastructures, electrical clinicalguidelines, and knowledge navigation systems.
In response to the needs of the time, the Departmentof Clinical Information Engineering (CIE) wasestablished at the School of Public Health in April
2007. Its predecessor was the clinical informationengineering division of clinical bioinformatics, using
Special Coordination Funds for Promoting Scienceand Technology from the Ministry of Education,
Culture, Sports, Science, and Technology, of Japan.

Teaching activities
The purpose of the Department of Clinical
Information Engineering is to nurture talented people
who have special knowledge and skills at aninternational level in order to apply advanced
information technologies to practical projects inclinical medicine and the health sciences. It offers
courses on information system design, development
methodology, evaluation and project management inbiomedicine, health care and public health in the
School of Public Health, and data mining and virtual
reality for clinical decision-making in social medicine.
Famous visiting lecturers and researchers from the
National Cancer Center and other universities havegiven lectures here, furthering our hope of becoming aworld leader in this field.

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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. Shimoda, A., Ichikawa, D., & Oyama, H. (2018).
Using machine-learning approaches to predict
non-participation in a nationwide general healthcheck-up scheme. Computer Methods andPrograms in Biomedicine. https://doi.org/10.1016/
j.cmpb.2018.05.032
2. Endo, N., Ujita, W., Fujiwara, M., Miyauchi, H.,
Mishima, H., Makino, Y., Hashimoto, L., Oyama,
H., … Kakeyama, M. (2018). Multiple animal
positioning system shows that socially-reared
mice influence the social proximity of isolationreared cagemates. Communications Biology, 1(1).
https://doi.org/10.1038/s42003-018-0213-5
3. Shimoda, A., Ichikawa, D., & Oyama, H. (2018).
Prediction models to identify individuals at risk ofmetabolic syndrome who are unlikely toparticipate in a health intervention program. International Journal of Medical Informatics, 111, 90–
99. https://doi.org/10.1016/j.ijmedinf.2017.12.009
4. Ujita, W., Kohyama-Koganeya, A., Endo, N.,
Saito, T., & Oyama, H. (2018). Mice lacking afunctional NMDA receptor exhibit social subordination in a group-housed environment. FEBS
Journal, 285(1), 188–196. https://doi.org/10.1111/
febs.14334

357

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 an introductory course,
Environmental Health for graduate students under
SPH. This course is to transfer scientific knowledge
such as basic concepts and methods for healthrisk/impact assessment in environmental healthperspectives, focusing on how environmental stressors
are associated with health at individual and populationlevels.
Another course with an advanced level, Methods forEnvironmental Health Research, is scheduled toprovide next year. This course deals with statisticaland epidemiological methodologies in estimating theeffects of environmental risk factors on health.
GEH journal clubOn a weekly basis, GEH has participated in a
conference call to multiple schools/institutes* for twohours long to read andenvironmental epidemiology.
*

discuss

articlesin

Seoul National University, Korea Advanced Institute of Science &Technology (KAIST), National Institute for Environmental Studies,
University of Tsukuba, Kyoto University, 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.
Research collaborations currently involved include:
1. Global perspectives of seasonal variability ofsuicide and the short-term association between
suicide and ambient temperature including daily
time-series database across 13 countries, as a partof the Multi-Country Multi-City (MCC)
Collaborative Research Network
2. Health risk assessment of climate change and air
pollution in northeast Asian countries
3. Establishment of an early warning system for
malaria incidence in southern Africa
In this year, we organized two special lectures toexchange research ideas and experiences with thefollowing topics:
1. Climate change and health: challenges of global
and environmental health, by Professor Ho Kim

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from Seoul National University, South Korea
2. Modelling desert dust exposure events for
epidemiological short-term health effects studies,by Associate Professor Aurelio Tobias from theInstitute of Environmental Assessment and Water
Research (IDAEA) and Spanish Council for
Scientific Research (CSIC), Spain

References
1. Lee W, Kim Y, Honda Y, Kim H. Association
between diurnal temperature range and mortality
modified by temperature in Japan, 1972-2015:
investigation of spatial and temporal patterns for
12 cause-specific deaths. Environment International 2018:119:379-387.
2. Chung Y, Yang D-W, Gasparrini A, VicedoCabrera A, Ng CFS, Kim Y, Honda Y, Hashizume
M. Changing susceptibility to non-optimum
temperatures in Japan, 1972-2012: the role ofclimate, demographic and socio-economic factors.
Environ Health Perspect 2018:126(5):057002.
3. Matsushita N, Ng CFS, Kim Y, Suzuki M, Saito N,
Ariyoshi K, Villarama JB, Go WS, Hashizume M.
The non-linear and lagged relationship between
rainfall and leptospirosis and the intermediate roleof floods in the Philippines. PLoS Negl Trop Dis
2018:12(4):e0006331.

Endowed Department

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Department of Health Care Safety
Management (Tokio Marine &Nichido)Project Adjunct Assoc. Professor
Masaki Anraku, M.D., Ph.D.

Project Assistant Professor
Maiko Mizuki, MPH.

Project Researcher
Yuri Asano, MPH. Shintaro Hara, Ph.D.

Project Academic Support Specialist
Yuriko Kobashi

Visiting Researcher
Tomoko Matsuura, M.S., Shinji Nagakawa, M.D., Ph.D.,
Reiko Segawa, R.N., M.S. Keiko Katsui,Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/iryou_anzen.html
http://hcsm.m.u-tokyo.ac.jp/※The following information is the same as that of the previous year for certain reasons.

Introduction and Organization
The Department of Health Care Safety Management
was established in December, 2005 within the “22ndCentury Medical and Research Center” at the
University of Tokyo Hospital based upon contributions by the Tokio Marine & Nichido Fire InsuranceCo., Ltd.
Public concern regarding malpractice and the medical
related disputes has risen in developed countries
accompany several publicized cases such as the public
inquiry into children’s heart surgery at the Bristol
Royal Infirmary and the accidental chemotherapy
overdoses occurring at the Dana-Farber Cancer
Institute at the end of the 20th century. Reports of themedia in our country concerning malpractice and the

medical related disputes increased suddenly from1999. Fears also rose regarding possible criminal
prosecutions through the mandatory reporting to thepolice provided in the Medical Practitioners Law
Article 21. Some incidents become targets ofinvestigations although several verdicts resulted inacquittals. Nonetheless, there exist various discussions
and some confusion over the intervention of the police
authority and criminal procedures into the process of
medical treatment.
On another front, in medical related disputes
involving civil claims for compensation for damages,
many cases have been dealt with and resolved throughvarious measures such as explanation and reconciliation settlement before becoming a lawsuit. In spite ofsuch efforts, the number of civil health care lawsuits

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has kept increasing from the 1970s (about 100 new
cases received per year) to 2004 (1110 new cases peryear), with the pace that has doubled every ten years.
Though the number of civil health care lawsuits showsa trend for decrease after 2004, many medical
treatment disputes resulted in lawsuits in 2017, with
857 new cases received and 782 cases resolved.
In our department, while looking straight at therealities of malpractice and the medical related
disputes, we aim, from each aspect of the patient, thehealth care provider, and society, for a healthy
rebuilding of the health care system and the recoveryof confidence in medical treatment via thinking about
the ideal ways to build a better legal system. Together
therewith, we are establishing an approach that
promotes mutual understanding by conversations
between the patient and the health care provider,improves the quality and safety of medical care inorder to facilitate future medical care.

Research activities
Basic researches concerning both the prevention of
malpractice and the honest resolution of medical
accidents (including the preventing of disputes andlawsuits) are urgent issues. In addition, we conducted
research for the Patient Safety Support Cente as
Health & Labour Sciences Research since 2012. In
addition, we started Development of long-term
oxygenator for chronic lung disease patient (AMED
under grant) since 2017.
Such research activities are vigorously carried out inour department to return the results widely in societyby the development of educational activities.

Teaching activities
We promote education based on the research results
described above for the purpose of training
researchers and graduate students in the university.

Clinical activities
Based on the research results described above,
department is creating a system to identify issues incare settings, to examine those issues, to inform
personnel in care settings of those issues, and tocontinually assist personnel in those settings. Lectures

and talks to legal professionals, the medical
establishment, welfare providers, and personnel in
related fields regarding topics such as patient
education, education to improve counseling, andinformation about advanced medical care.
*Patient Safety Support Center Comprehensive
Support Project
Training and related activities are carried our targetingthe personnel of the “Patient Safety Support Centers”
established in each prefecture of Japan pursuant to theprovisions of the Medical Care Law (a Ministry of
Health, Labor and Welfare commissioned project).

References
Conference Presentations
1. Shintaro Hara, Takashi Isoyama, Terumi Yurimoto,
Xin-Yang Li, Itsuro Saito, Masaki Anraku, Yusuke
Abe, Development of the Sequential flow pump:Principle of the sequential pressurization andhemolysis results in secondary model. ASAIO,
2017. Chicago

362

Department of Artificial
Intelligence in Healthcare
Project Associate Professor
Yoshimasa Kawazoe, M.D., Ph.D.

Project Research Associate
Emiko Shinohara, Ph.D.

Project Researcher
Kiminori Shimamoto, M.E.

Project Academic Support Staff
Mari Hashimoto, R.N., P.H.N.

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 a363

patient is receiving treatment for by computer
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

364

make it difficult to be handled as chronological dataand 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.
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

2.

3.

in health care by giving presentations at various
conferences.
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
1. Kawazoe Y, Shimamoto K, Yamaguchi R,
Shintani-Domoto Y, Uozaki H, Fukayama M, Ohe
K. Faster R-CNN-Based Glomerular Detection in
Multistained Human Whole Slide Images. Journalof Imaging. 2018; 4(7):91.
2. Shinichiroh Yokota, Emiko Shinohara, KazuhikoOhe. Can Staff Distinguish Falls: Experimental
Hypothesis Verification Using Japanese Incident
Reports and Natural Language Processing.
Studies in health technology and informatics. 250,
pp.159-163.
3. R. A. Ghani, K. Nishanth, Ai Nakajima, N.
Kimura, P. Radkohl, S. Iwai, Y. Kawazoe, Y.
Iwasawa, K. Nakayama, Y. Matsuo: An analysis
of human gaze data for autonomous medical
image diagnostics, The 28th Annual Conferenceof the Japanese Neural Network Society (JNNS),
Workshop, 2018.
4. Satoshi Iwai, Emiko Shinohara, Takeshi Imai,
Yoshimasa Kawazoe, Kazuhiko Ohe, Listing
differential diagnoses from symptoms of patientswith vertigo using knowledge graph, APAMI2018,
Colombo, Sri Lanka, October 2018.
5. Ryohei Yamaguchi, Yukako Shintani-Domoto,
Hiroshi Uozaki, Akira Shimizu, Michio Nagata,
Kiminori Shimamoto, Yoshimasa Kawazoe,
Kazuhiko Ohe. Evaluation of concordance of365

descriptors of glomerular images in renal biopsy
for medical imaging system by artificial
intelligence. Japan Journal of Medical Informatics.
2018; 38(suppl.): 760-765. (In Japanese)
6. Hidetoshi
Yamashita,
Hisahi
Kurasawa,
Yoshimasa
Kawazoe,Kazuhiko
Ohe.
Investigation of the Explanatory Variables from
Health Insurance Claim Databases of inpatients toExtrapolate Main Diseases in Japan. Japan Journalof Medical Informatics. 2018; 38(suppl.): 404-409.
(In Japanese)

366

Health Economy and Society
PolicyProject Professor
Tomoyuki Takura, Ph.D, MEng.

Assistant Professor
Yoshiaki Shintani, 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 anddevelopment 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 meta-

367

2.

3.

4.

5.

6.

analysis. Cardiol Res Pract. 2019; 1840894. Inpress.
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). Costeffectiveness analysis of the pharmacologicalmanagement of chronic low back pain with four
leading drugs. J Orthop Sci. 2019 In press.
Tomoyuki Takura, Takashi Takei, Kosaku Nitta.
"Socioeconomics of Administering Rituximab for
Nephrotic
Syndrome".
Contributions
toNephrology. 2018;195:110-119.
Tomoyuki Takura. Background and Current Trends
in Medical Economics Research in the Circulatory
Field. Circ Rep. 2018;0:11-14.
Tomoyuki Takura. An Evaluation of Clinicaleconomics and Cases of Cost-effectiveness. Intern
Med. 2018;57(9):1191-1200.
Satoshi Kodera, Hiroyuki Morita, Arihiro Kiyosue,
Jiro Ando, Tomoyuki Takura, Issei Komuro. CostEffectiveness of PCSK9 Inhibitor Plus Statin in
Patients With Triple-Vessel Coronary Artery
Disease in Japan. Circ J. 2018;82(10):2602-2608

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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 Ono Pharmaceutical Co. Ltd.,Showa Yakuhin Kako Co., Ltd., Nippon Zoki
Pharmaceutical Co., Ltd., MTG Co., Ltd., Sompo
Holdings, Inc, NUVASIVE Japan, and Shionogi & Co.,
Ltd..The department is a collaboration among the
Department of Orthopaedics, the Department of
Rehabilitation Medicine, and the Department ofAnaesthesiology and Pain Medicine. Currently, ouraims are to design an algorithm for diagnosing andtreating most types of musculoskeletal pain that do nothave established treatment 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.
In April 2014, the course on medical research andthe 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, andAnaesthesiology and Pain Relief Centre (University ofTokyo Hospital). On the basis of an extensive
epidemiological survey, we will identify risk factorsthat contribute to determining the therapeutic strategy
for treating musculoskeletal pain as well as the
prognosis. In addition, on the basis of these
determined risk factors, we will develop and propose
diagnostic tools/algorithms as well as prevention andtreatment programmes. Then we will collect andanalyse clinical data and systematise the diagnosis,
prevention, and treatment of chronic pain – mainly
musculoskeletal pain.

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Research activities
In 2014 the first year after the course’s inauguration– we will explore the risk factors that contribute todetermining the therapeutic strategy for treatingmusculoskeletal pain and the prognosis through thefollowing methods:
1) Identify risk factors associated with the onset andexacerbation of musculoskeletal pain through anapproach that integrates physical and psychosocial
factors as well as biomechanics;
2) Verify the validity of the standard values ofscreening tools recommended worldwide for their use
in Japan; and3) Evaluate the brain function of people who are on
administrative leave due to low back pain, since thisphenomenon is a major social problem.
Specifically, we will conduct the following research:
1) Explore the risk factors associated with the onset of
low back pain that interferes with work and its
conversion to chronicity by using a cohort of about
2,000 persons from four types of occupations (i.e.
clerical staff, nurses, sales and marketing associates,and personnel in the transportation industry) andcollecting multi-faceted information at baseline;
2) Calculate (on the basis of the prevalence and datafrom approximately 50,000 people in Japan) the
standard values for a screening tool by using aworldwide stratification system that considers
psychosocial factors, namely the subgrouping fortargeted treatment (STarT) back scoring system, inJapanese subjects. Follow-up surveys at 6 months will
be conducted on approximately 2,000 randomly
extracted people who have complaints of low backpain, and a weighted psychological validation of thetool will be performed
3) Elucidate the properties of brain functions inpatients with LSS compared with a control groupcomposed of healthy subjects. In addition, we will
clarify the changes due to interventions by using 18

fluoro-2-deoxyglucose positron emission tomography
images of the brain taken before and after therapeuticinterventions (e.g. exercise and cognitive behaviouraltherapy, which are highly recommended worldwide)
on approximately 15 cases of refractory low back painthat led to a leave of absence from work.
Prospects for future research
We plan to train clinicians with skills in musculoskeletal pain rehabilitation, including specialised
exercise therapy and cognitive behavioural therapy fornonspecific low back pain, which is the most frequent
type of musculoskeletal pain. By collaborating with
the Department of Nursing, we plan to develop simple
tools to prevent low back pain, which will be useful inthe clinical settings and for industrial hygiene.
Moreover, we plan to verify and diagnose the tools’
utility and conduct further research on preventive
tools and therapeutic programmes.

References
1. 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, in press.
2. 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,
Yoshimura N. Serum levels of matrix
metalloproteinase-3 and autoantibodies related torheumatoid arthritis in the general Japanese
population and their association with osteoporosis
and osteoarthritis: the ROAD study. J Bone
Miner Metab 36:246-253,2018.
3. 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, in press.
4. Ogihara S, Yamazaki T, Inanami H, Oka H,

370

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 13:e0205539,
2018.
5. 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 13:e0200208,
2018.
6. 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. Osteoporos Int, 2018.
7. 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) 43:E1469-E1473, 2018.
8. 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 analysis.
Spine J 18(12):2205-2212,2018.
9. 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 13:e0193208, 2018.
10. Fujii T, Oka H, Katsuhira J, Tonosu J, Kasahara S,
Tanaka S, Matsudaira, K. Disability due to knee
pain and somatising tendency in Japanese adults.
BMC Musculoskelet Disord 19:23, 2018.
11. Fujimoto Y, Fujii T, Oshima Y, Oka H, Tanaka S,

Matsudaira K. The association between neck andshoulder discomfort-Katakori-and high somatizing tendency. Mod Rheumatol:1-14, 2018.
12. 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, in press.
13. Hasegawa T, Katsuhira J, Oka H, Fujii T,
Matsudaira K. Association of low back load withlow back pain during static standing. PloS one 13:
e0208877, 2018.
14. Hashimoto Y, Matsudaira K, Sawada SS, Gando Y,
Kawakami R, Kinugawa C, Okamoto T,
Tsukamoto K, Miyachi M, Naito H, Blair SN.
Objectively Measured Physical Activity and Low
Back Pain in Japanese Men. J Phys Act Health
15:417-422, 2018.
15. ○Hashimoto Y, Matsudaira K, Sawada SS, Gando
Y, Kawakami R, Sloan RA, Kinugawa C,
Okamoto T, Tsukamoto K, Miyachi M, Naito H.
Association between objectively measured
physical activity and body mass index with low
back pain: a large-scale cross-sectional study ofJapanese men. BMC public health 18:341, 2018.
16. Igawa T, Katsuhira J, Hosaka A, Uchikoshi K,
Ishihara S, Matsudaira K. Kinetic and kinematic
variables affecting trunk flexion during level
walking in patients with lumbar spinal stenosis.
PloS one 13:e0197228, 2018.
17. Katsuhira J, Yamamoto S, Machida N, Ohmura Y,
Fuchi M, Ohta M, Ibayashi S, Yozu A, Matsudaira
K. Immediate synergistic effect of a trunk orthosis
with joints providing resistive force and anankle-foot orthosis on hemiplegic gait. Clin
Interv Aging 13:211-20, 2018.
18. Matsudaira K, Oka H, Oshima Y, Chikuda H,
Taniguchi Y, Matsubayashi Y, Kawaguchi M, SatoE, Murano H, Laurent T, Tanaka S, Mannion AF.
Development of the Japanese Core Outcome
Measures
Index(COMI):
cross-cultural
adaptation and psychometric validation. BMC
Musculoskelet Disord 19:71, 2018.
19. ○Matsudaira K, Takahashi M, Kawaguchi M,
Hamaguchi A, Haga Y, Koga T. Assessment ofrisk factors for non-specific chronic disabling low

371back pain in Japanese workers-findings from the
CUPID (Cultural and Psychosocial Influences on
Disability) study. Ind Health ,in press.
20. 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 28:235-241, 2018.
21. 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 18:
19, 2018.
22. 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 :1-17, 2018.
23. Takahashi M, Uetake C, Nakayama N, Eura A,
Yamaguchi N, Kameda Y, Muto G, Endo M,
Kawamata K, Fujii T, Oka H, Matsudaira K. A
cooperative support model for cancer therapy andemploymentbalance:fromfocus-groupinterviews of health and business professionals.
Ind Health, in press.
24. Tonosu J, Inanami H, Oka H, Takano Y, Koga H,
Yuzawa Y, Shiboi R, Oshima Y, Baba S, Tanaka S,
Matsudaira K. Factors related to subjective
satisfaction
following
microendoscopic
foraminotomy for cervical radiculopathy. BMC
Musculoskelet Disord 19:30, 2018.
25. Tonosu J, Oka H, Watanabe K, Abe H,
Higashikawa A, Yamada K, Kuniya T, Nakajima
K, Tanaka S, Matsudaira K. Validation study of adiagnostic scoring system for sacroiliac jointrelated pain. J Pain Res 11:1659-1663, 2018.
26. Tsuji T, Matsudaira K, Sato H, Vietri J, Jaffe DH.

Association between presenteeism and healthrelated quality of life among Japanese adults withchronic lower back pain: a retrospective
observational study. BMJ open 8:e021160, 2018.
27. Yamada K, Kubota Y, Iso H, Oka H, Katsuhira J,
Matsudaira K. Association of body mass index
with chronic pain prevalence: a large populationbased cross-sectional study in Japan. J Anesth 32:
360-7, 2018.

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Department of Medical Genomics
Project Associate Professor
Shogo Ehata, M.D., Ph.D. (~August, 2018),
Noriko Hosoya, M.D., Ph.D. (November, 2018~).

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. Since September 2018,
this department has been co-supported by Laboratoryof Molecular Radiology (Professor Kiyoshi
Miyagawa), and Dr. Noriko Hosoya has served as
Project Associate Professor of this department sinceNovember 2018.
Department of Medical Genomics enjoys a wide
range of research collaboration with many academic
institutes within Japan and also from abroad.
Especially, this department is under an intimate
collaboration with Department of MolecularPathology and Laboratory of Molecular Radiology.
We also support cancer genomic medicine using a
multiplex genome sequencing, named "Todai
OncoPanel”, which recently started at the Universityof Tokyo Hospital.

Teaching activities
We take 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 accept undergraduate students taking “Free
Quarter” and “Early-Exposure-to-Medicine” courses.
We also take 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 deliver training
on basic medical research for both undergraduate
students and graduate students.

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Research activities
Department of Medical Genomics tries 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.
(4) Role of proto-oncogene c-Ski in renal cell cancer
progression
Transforming growth factor beta (TGF-β) is involved

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in the pathogenesis and progression of various cancers,
but its roles in renal cancer have not been fully
elucidated. We investigated the role of TGF-β inprogression of clear cell renal carcinoma (ccRCC). We
first studied the expression levels of components of
the TGF-β signaling pathway, and found that theexpression of c-Ski, a transcriptional corepressor of
Smad-dependent TGF-β signaling, was increased in
ccRCC tissues compared to normal renal tissues. We
then conducted functional analyses of c-Ski.
Overexpression of c-Ski in human ccRCC cells
promoted tumor formation in vivo using a mousemodel. Enhancement of tumor formation was also
observed by a dominant-negative mutant of the TGF-β
type II receptor into ccRCC cells. TGF-β signaling
failed to affect tumor angiogenesis; however,apoptosis of ccRCC cells was stimulated by TGF-β.
These findings suggested that c-Ski inhibits TGF-βsignaling in ccRCC cells, which results in attenuationof the tumor-suppressive effects of TGF-β (Taguchi etal, Cancer Sci 2019).
(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.

References
1. Tanaka Y, Kawazu M, Yasuda T, Tamura M,
Hayakawa F, Kojima S, Ueno T, Kiyoi H, Naoe T,
Mano H. Transcriptional activities of DUX4
fusions in B-cell acute lymphoblastic leukemia.
Haematologica 103, e522-e526, 2018.
2. Ishii M, Suehara Y, Sano K, Kohsaka S, Hayashi
T, Kazuno S, Akaike K, Mukaihara K, Kim Y,
Okubo T, Takamochi K, Takahashi F, Kaneko K,
Saito T. Proteomic signatures corresponding to
the SS18/SSX fusion gene in synovial sarcoma.
Oncotarget 9, 37509-37519, 2018.
3. Yachi K, Tsuda M, Kohsaka S, Wang L, Oda Y,
Tanikawa S, Ohba Y, Tanaka S. miR-23a
promotes invasion of glioblastoma via HOXD10regulated glial-mesenchymal transition. Signal
Transduct Target Ther 3, 33.doi:10.1038/s41392018-0033-6. eCollection 2018.
4. Nagano M, Kohsaka S, Ueno T, Kojima S, Saka K,
Iwase H, Kawazu M, Mano H. High-throughput
functional evaluation of variants of unknown
significance in ERBB2. Clin Cancer Res 24,
5112-5122, 2018.
5. Asada S, Goyama S, Inoue D, Shikata S, Takeda
R, Fukushima T, Yonezawa T, Fujino T, Hayashi
Y, Kawabata KC, Fukuyama T, Tanaka Y,
Yokoyama A, Yamazaki S, Kozuka-Hata H,
Oyama M, Kojima S, Kawazu M, Mano H,
Kitamura T. Mutant ASXL1 cooperates with
BAP1 to promote myeloid leukaemogenesis. Nat
Commun 9, 2733, 2018.
6. Kang C, Saso K, Ota K, Kawazu M, Ueda T,
Okada H. JMJD2B/KDM4B inactivation in
adipose tissues accelerates obesity and systemic
metabolic abnormalities. Genes Cells 23, 767-777,
2018.
7. 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, Mano H.

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Fusion kinases identified by genomic analyses ofsporadic microsatellite instability-high colorectal
cancers. Clin Cancer Res 25, 378-389, 2018.
8. Kage H, Kohsaka S, Shinozaki-Ushiku A, Ushiku
T, Takai D, Nakajima J, Miyagawa K, Aburatani
H, Mano H, Nagase T. Spontaneous Transformation from EGFR and ALK Wild-Type Lung
Adenocarcinoma to Neuroendocrine Carcinoma. J
Thorac Oncol 13, e126-e128, 2018.
9. Konishi Y, Kawamata F, Nishihara H, Homma S,
Kato Y, Tsuda M, Kohsaka S, Einama T, Liu C,
Yoshida T, Nagatsu A, Tanino M, Tanaka S,
Kawamura H, Kamiyama T, Taketomi A. Tumor
budding and human chorionic gonadotropin-β
expression correlate with unfavorable patient
outcome in colorectal carcinoma. Med Oncol 35,
104, 2018.
10. Akaike K, Suehara Y, Kohsaka S, Hayashi T,
Tanabe Y, Kazuno S, Mukaihara K, Toda-Ishii M,
Kurihara T, Kim Y, Okubo T, Hayashi Y,
Takamochi K, Takahashi F, Kaneko K, Ladanyi
M, Saito T. PPP2R1A regulated by PAX3/FOXO1
fusion contributes to the acquisition of aggressive
behavior in PAX3/FOXO1-positive alveolar
rhabdomyosarcoma. Oncotarget 9, 25206-25215,
2018.
11. Tanabe Y, Suehara Y, Kohsaka S, Hayashi T,
Akaike K, Mukaihara K, Kurihara T, Kim Y,
Okubo T, Ishii M, Kazuno S, Kaneko K, Saito T.
IRE1α-XBP1 inhibitors exerted anti-tumor
activities in Ewing’s sarcoma. Oncotarget 9,14428-14443, 2018.
12. Kawamata F, Nishihara H, Homma S, Kato Y,
Tsuda M, Konishi Y, Wang L, Kohsaka S, Liu C,
Yoshida T, Tanino M, Tanaka S, Kawamura H,
Kamiyama
T,
TaketomiA.
Chorionic
Gonadotropin-β
Modulates
EpithelialMesenchymal Transition in Colorectal Carcinoma
Metastasis. Am J Pathol 188, 204-215, 2018.
13. Kohsaka S, Saito T, Akaike K, Suehara Y,
Hayashi T, Takagi T, Kaneko K, Ueno T, Kojima
S, Kohashi KI, Mano H, Oda Y, Yao T. Pediatricsoft tissue tumor of the upper arm with LMNANTRK1 fusion. Hum Pathol 72, 167-173, 2018.
14. Kohsaka S, Petronczki M, Solca F, Maemondo M.
Tumor clonality and resistance mechanisms in
EGFR mutation-positive non-small-cell lungcancer: implications for therapeutic sequencing.
Future Oncol 15, 637-652, 2018.
15. Miyazono K, Katsuno Y, Koinuma D, Ehata S,
Morikawa M. Intracellular and extracellular
TGF-signaling in cancer: Some recent topics.
Front Med 12, 387-411, 2018.

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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
Osteoclast differentiation and RANKL signaling
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
demonstrate that RANK/RANKL signaling is essential
for osteoclastogenesis in vivo. We aim to elucidate
the molecular mechanism underlying RANKLinduced osteoclast differentiation, in order to develop
the novel therapeutic strategies for the treatment ofvarious bone diseases such as RA and osteoporosis(Tsukasaki et al, J Bone Miner Res, 2016; Okamoto etal, Physiol Rev, 2017).
Recently, a fully human anti-RANKL neutralizing
antibody has been introduced for the treatment of
osteoporosis and skeletal-related events by bonetumors, and has been approved in Japan for thetreatment of bone erosion associated with RA. 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 haverecently demonstrated that oral administration of thesmall-molecule RANKL inhibitor against RANKL
suppressed the metastasis of human breast cancer cellline and murine melanoma cell line to bone (Nakai etal, Bone Res, 2019).
Roles of T cells in bone destruction associated with
inflammation
The bone destruction in RA is the result of theenhanced osteoclast activity due to the inflammatory
responses triggered by the activation of pathogenic
helper T cells. We previously reported using amouse model of autoimmune arthritis that a subset of
Foxp3+ T cells loses Foxp3 expression under arthritic
conditions and converts into IL-17-prodcing T cells(called exFoxp3Th17 cells).
exFoxp3Th17 cells
display a greater capacity for inducing both synovitis
and osteoclastic bone resorption (Komatsu et al, Nat
Med, 2014). The conversion of Foxp3+ T cells into
effector T cells has also been observed in various
diseases such as diabetes and multiple sclerosis. We
have recently demonstrated that exFoxp3Th17 cells
also act as osteoclastogenic T cells in alveolar bone
destruction in periodontitis.
exFoxp3Th17 cells
accumulate in periodontitis tissues in response to oral
bacteria, and stimulate mesenchymal cells including
osteoblastic cells and periodontal ligament cells to
induce RANKL. We found that exFoxp3Th17 cells
protect against bacteria by evoking mucosal immune
responses as well as removing the tooth (Tsukasaki etal, Nat Commun, 2018). Our findings introduce a
new concept that bone destruction contributes to thehost defense against oral bacteria in periodontitis.
In recent years, Jak inhibitors have attracted
attention as potential agents for the autoimmune
diseases such as rheumatoid arthritis. We haverecently found that protein arginine methylation, a
post-translational modification, is critically involvedin the regulation of the Jak signaling pathway. T
cell-specific deficiency of the arginine methyltransferase PRMT5 led to a decrease in the number of
peripheral CD4, CD8 and regulatory T cells, and analmost complete loss of iNKT cells.
PRMT5mediated arginine methylation was essential for the
expressionofthecytokine-signal-transducing
components, the common cytokine receptor γ-chain(γc) and JAK3, which are required for thedevelopment of iNKT cells and the proliferation andsurvival of peripheral T cells. PRMT5 induced thearginine methylation of the spliceosomal component
SmD3 that promoted the splicing of pre-mRNA
encoding γc and JAK3 (Inoue et al, Nature Immunol,2018). This study presented a novel regulatory
mechanism governing γc family cytokine-Jak3
signaling in T cells.

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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. Hayashi M, Nakashima T, Yoshimura N, Okamoto
K, Tanaka S, Takayanagi H. Autoregulation of
Osteocyte Sema3A Orchestrates Estrogen Action
and Prevents Bone Ageing. Cell Metabolism, 29:
1-11, 2019
2. 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
3. Inoue M, Okamoto K, Terashima A, Nitta T, Muro
R, Negishi-Koga T, Kitamura T, Nakashima T,
Takayanagi H. Arginine methylation controls thestrength of γc family cytokine signaling in T cellmaintenance. Nature Immunology, 19: 1265-1276,
2018
4. Okamoto K, Takayanagi H. Osteoimmunology.
Cold Spring Harbor Perspectives in Medicine, 9:

1, 2019

379

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

380

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 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
Yukihiro Nomura, Ph.D., R.T., Tomomi Takenaga, Ph.D., R.T., Masaki Murata, 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)to create a large database of health screening clinicaldata including medical images, (2) to develop methods
to analyze large volumes of medical images and to
search for algorithms to detect subtle abnormal
findings in these images, and (3) to evaluate theclinical usefulness of such image processing methods
and to apply the system in clinical settings.
The department comprises three project associate
professors, five project research associates and two
project researchers, along with a medical staff ofapproximately 50 employees in the health-screening
center.

Clinical Activities
CDRPM is responsible for the clinical activities in

the CDRPM Health Screening Center. The following
diagnostic imaging modalities are installed tofacilitate high level of diagnostic accuracy: positronemission computed tomography (PET), 3-teslamagnetic resonance imaging (3T-MRI) system, multidetector CT (MDCT), ultrasound imaging system, anddigital mammography.

Teaching Activities
At present, CDRPM does not accept students.
However, CDRPM participates in the education of
students and residents in the Department of Radiology.
CDRPM endeavors to help students whose research
themes include image analysis such as computerassisted detection, or epidemiologic studies employing
health-screening data.

Research Activities
1) Health screening database
We have developed a unique health screening information system to facilitate daily management of the382

health screening activities and to input healthscreening data. This information system is still underconstant revision. The medical images acquired in thehealth screenings are stored in the hospital picturearchiving and communication system (PACS) for
clinical use. Medical images used solely for research
purposes are stored in an independent PACS installedinside the CDRPM department.
2) Image processing software development
We have structured an integrated software developing
system to facilitate the production of image processing
software. The system is divided into the clinical partand the research part, with the data in the latter being
anonymized. The clinical part consists of case entry
for software development, and clinical application of
the developed software. The research part consists ofan interface to obtain images of the representative
cases to develop the software, and an interface to test
the developed software with the accumulated cases.
3) Clinical evaluation, application of software, andepidemiological studies
Researches based on the health-screening database arecarried out in collaboration with other researchers ofvarious specialties. Images are analyzed using thedeveloped software.

References(1) Nakao T, Hanaoka S, Nomura Y, Sato I, Nemoto
M, Miki S,Maeda E, Yoshikawa T,Hayashi N,et al.
Deep neural network-based computer-assisted
detection of cerebral aneurysms in MR
angiography. J Magn Reson Imaging 2018 Apr;
47(4):948-953.
(2) Naganawa S, Maeda E, Hagiwara A, Amemiya S,
Gonoi W, Hanaoka S,Yoshikawa T, et al. Vaginal
delivery-related changes in the pelvic organ
position and vaginal cross-sectional area in thegeneral population. Clin Imaging 2018;50:86-90.
(3) Oshina M, Horii C, Hirai S, Matsubayashi Y,
Taniguchi Y, Hayashi N, et al. Comparison ofFreehand Sagittal Trajectories for Inserting
Pedicle Screws Between C7 and T5. Clin Spine
Surg 2018 Aug;31(7):E357-E362.
(4) Anno M, Oshima Y, Taniguchi Y, Matsubayashi Y,

Kato S, Soma K, Oka H, Hayashi N, et al.
Prevalence and Natural Course of Transverse
Ligament of the Atlas Calcification in
Asymptomatic Healthy Individuals. Spine (Phila
Pa 1976) 2018 Dec 15;43(24):E1469-E1473.

383

Department of Home Care
Medicine
Project Associate Professor
Takashi Yamanaka, M.D., Ph.D.

Project Assistant Professor
Kiwami Kidana, M.D., Ph.D.

Project Researcher
Shigemasa Katayama, M.D., Ph.D., Tatsuya Kurokawa, M.D., Ph.D.,
Kiyotaka Kase, M.D., Ph.D., Maiko Mizuki, MPH.

Project Academic Support Staff
Satomi Kudo

Homepage

http://chcm.umin.jp/

Introduction and Organization
Department of Home Care Medicine was establishedin 2018 at the 22nd Century Medical and ResearchCenter in the University of Tokyo Hospital based upon
contributions by Mr. Kazuteru Noguchi, JSH Co., Ltd.,
Japan Home Medical Care Inc., Towa Pharmaceutical
Co. Ltd., Sawai Pharmaceutical Co. Ltd. and AKTIO
Corporation. Our department collaborates with
Department of Geriatric Medicine. We have takenover educational activities and research activities fromCenter for Home Care Medicine, Faculty of Medicine.
With the increase in the elderly population, home care
medicine is more needed compared with the past. We
teach home care medicine to medical students andtrainee doctors along with studying the topics of homecare medicine to systematize it.

Education
Clinical education of home care medicine is provided
for fifth and sixth year medical students. We create apersonalized mandatory program of home care
medicine and give an orientation of the program. Then
medical students learn about home care medicine withphysicians, nurses, medical social workers or caremanagers in the community. We 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 caregivers4) Drug treatment in home medical care5) Skills of medical therapeutics and care in homecare medicine
6) Research about home medical care of thepsychiatric patients

384

Publications
English Article
1. Yamanaka T, Hirota Y, Noguchi-Watanabe M,
Tamai A, Eto M, Iijima K, Akishita M. Changes in
attitude of medical students toward home careduring a required 2-week home care clinicalclerkship program. Geriatr Gerontol Int.
2018;18(4):655-656.
Conference Presentations
1. Yamanaka T, Hirota Y, Furuta T, Iijima K,
Akishita M: Trajectories of Quality of Life andWell-being in Elderly Home Care Patients.
American Geriatrics Society 2018 Annual
Scientific Meeting. J Am Geriatr Soc 2018:66(Suppl2);S54. 2018. Orlando, FL, USA.
2. Osawa I, Yoneda A, Ishii S, Yamaguchi K,
Yamaguchi Y, Tsuji K, Yamanaka T, Akishita M:
Medication prescription in home visits byphysicians. American Geriatrics Society 2018
Annual Scientific Meeting. J Am Geriatr Soc
2018:66(Suppl2);S276. 2018. Orlando, FL, USA.
3. Yamanaka T: International symposium of
home-based care: Delivery and payment models(Panelist). International Training Workshop ofHome Care. 2018. Shandong University, Jinan,
P.R. China.
4. Yamanaka T: Home care medicine education.
International Training Workshop of Home Care.
2018. Shandong University, Jinan, P.R. China.
5. Yamanaka T: Home-based medical care in Japan.
International Training Workshop of Home Care.
2018. Shandong University, Jinan, P.R. China.

385

Department of
Therapeutic Strategy forHeart Failure
Research Associate Professor
Masaru Hatano, M.D., Ph.D

Research Lecturer
Amiya Eisuke, M.D., Ph.D

Research Assistant Professor
Seitaro Nomura, M.D., Ph.D

Project Researcher
Toshiyuki Ko，M.D., Ph.D
Takayuki Fujiwara, M.D., Ph.D
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 of386

them were rescued with heart transplantation or bridge
to recovery. We implant centrifugal VAD (EVAHEART,
HVAD and HeartMate3) or axial VAD (HeartMate II
and Jarvik 2000) considering patients’ physics andclinical status).
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.

2.

3.

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 ;4(6):670-680.
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 ;35(11):1604.e9-1604.e12.
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, 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,

387

4.

5.

6.

7.

8.

9.

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; 83(10):2084-2184.
Minatsuki S, Hatano M, Maki H, Takimoto E,
Morita H, Komuro I. Analysis of Oxygenation in
Chronic
Thromboembolic
PulmonaryHypertension Using Dead Space Ratio andIntrapulmonary Shunt Ratio. Int Heart J. 2019;60(5):1137-1141.
Ikeda N, Hatano M, Nagamatsu T, Nakamura M.
Successful right heart remodelling and subsequentpregnancyinapatient
withchronic
thromboembolic
pulmonary
hypertension
undergoing balloon pulmonary angioplasty: a casereport. Eur Heart J Case Rep. 2019; 3(2). pii:
ytz063.
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. 2019. pii: S0914-5087(19)30221-7.
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 ofCardiology for the Creation of Future Medicine.
Circ J. 2019;83(9):1829-1835.
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. 2019. (In Press)
Sawada N, Kawata T, Daimon M, Nakao T, Hatano

M, Maki H, Kimura K, Hirokawa M, Ishiwata J,
Xu B, Yatomi Y, Komuro I. Detection of
Pulmonary Hypertension with Systolic Pressure
Estimated by Doppler Echocardiography. Int HeartJ. 2019; 60(4):836-844.
10. 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; 19(1):151.
11. 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
12. 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. 2019. (InPress)
13. 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.
14. Fukuda K, Date H, Doi S, Fukumoto Y, Fukushima
N, Hatano M, Ito H, Kuwana M, Matsubara H,
Momomura SI, Nishimura M, Ogino H, Satoh T,
Shimokawa H, Yamauchi-Takihara K, Tatsumi K,
Ishibashi-Ueda H, Yamada N, Yoshida S, Abe K,
Ogawa A, Ogo T, Kasai T, Kataoka M, Kawakami
T, Kogaki S, Nakamura M, Nakayama T, Nishizaki
M, Sugimura K, Tanabe N, Tsujino I, Yao A,
Akasaka T, Ando M, Kimura T, Kuriyama T,
Nakanishi N, Nakanishi T, Tsutsui H; Japanese
Circulation Society and the Japanese Pulmonary

388

Circulation and Pulmonary Hypertension Society
Joint Working Group. Guidelines for the Treatmentof Pulmonary Hypertension (JCS 2017/JPCPHS
2017). Circ J. 2019; 83(4):842-945.
15. Minatsuki S, Takeda N, Soma K, Katoh M, Maki
H, Hatano M, Takimoto E, Manabe I, Komuro I.
Murine Model of Pulmonary Artery Overflow
Vasculopathy
Revealed
Macrophage
Accumulation in the Lung. Int Heart J. 2019; 60(2):451-456.
16. 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.
17. 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 humaninducedpluripotent
stem
cell-derived
cardiomyocytes. J Mol Cell Cardiol. 2019; 128:9095.
18. 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.
19. Nomura S. Genetic and non-genetic determinantsof clinical phenotypes in cardiomyopathy. J
Cardiol. 2019;73(3): 187-190.

389

Department of Biostatistics andBioinformatics
Project Professor
Daisuke Koide, R.Ph., HIM, Ph.D.

Project Associate Professor
Akihiro Hirakawa, Ph.D.

Project Lecturer
Kentaro Sakamaki, 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 govern-

ment 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390

38 credits, we issue a certificate along with the Master
degree.
Biostatistics
Statistical inference, categorical data analysis,
survival analysis, longitudinal data analysis, Bayesianstatistics, multiple comparison procedure, multivariate
analysis, causal inference, missing data analysis,
stochastic process and time series analysis,
pharmacometrics, statistical programming, genomic
data analysis
Clinical research and epidemiology
Clinical trial methodology, design and analysis of
epidemiological research, research ethics andguidelines, medical research and CDISC standards,
general clinical medicine, regulatory science, medical
writing, medical technology evaluation exercises
In addition, the students receive the OJT at
University of Tokyo Hospital and the National Cancer
Center. The OJT programs are developed by thebiostatisticians of each institution. In the first year of
master's program, the students learn the basic practiceof biostatistician through the training at the Universityof Tokyo Hospital. In the second year, at the National
Cancer Research Center, students receive advanced
training in how to plan the design and analysis ofclinical researches.
2) Seminars and symposiums for the healthcare
professionals and biostatisticians
We give seminars about clinical trial methodologies
and biostatistics for physician, nurse, clinical researchcoordinator, monitor, and other healthcare professionals. We also hold symposia for biostatisticians inacademia and pharmaceutical companies in order toshare and discuss the “state-of-the-arts” of statisticalmethodologies.

Research activities
In the department of biostatistics and bioinformatics,
the main research areas are as follows:
1) Statistical methodology and design of clinical trials
and epidemiology

We study on the statistical methodologies and design
for streamlining clinical trial and estimating treatment
effect precisely. The research area includes Bayesian
design in oncology, clinical trial design using
biomarkers, adaptive design, study on the use ofBayesian statistics in clinical trials, causal inference,and multiple comparison method.
2) Epidemiological methodology
Epidemiology deals with health or disease related
incidence quantitatively in large populations,evaluates cause and effective factors, and ultimately
finds the measures of prevention. It starts fromepidemics (such as infectious diseases) and now its
focus is on lifestyle related diseases, such as cardiovascular disorders. Also, several kinds of medical
databases are developed rapidly in Japan. It is
important to conduct epidemiological, pharmacoepidemiological and clinical epidemiological studies
using such databases.
3) Pharmacoepidemiology
Pharmacoepidemiology is a study to investigate drug
use and its effects in a population. We are engaged inresearch on effectiveness, risk, and cost using dataobtained from hospital information system andelectronic medical record.
4) Clinical Epidemiology
Clinical epidemiology is the application of theprinciples and methods of epidemiology to conductclinical research studies focusing on prevention,
diagnosis, prognosis, and treatment of disease. As thebasic science of Evidence-based Medicine, the importance of clinical epidemiology has been increasing.
5) Medical informatics
Medical informatics is a science of studying how to
use data, information and knowledge in the all
medical fields, such as clinical, medical studies,
education and government. Recently, the area of
medical informatics is much expanding because of the
progress of genomic studies or bioinformatics, andintroduction of new technologies, such as virtual
reality and artificial intelligence (AI).
6) Algebraic statistics

391

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
statistics are useful. I currently work on the topics
related to Groebner basis theory and the holonomic
gradient method.

References
1. Ando T, Ooba N, Mochizuki M, Koide D, Kimura
K, Lee SL, Setoguchi S, Kubota K. Positive
predictive value of ICD-10 codes for acute
myocardial infarction in Japan: a validation study
at a single center. BMC Health Serv Res. 2018
Nov 26; 18(1): 895. doi: 10.1186/s12913-0183727-0.
2. Kubota K, Ooba N, Kamijima Y, Sato K, Koide D.
The use of anticoagulants in patients with
non-valvular atrial fibrillation between 2005 and2014: A drug utilization study using claims data inJapan. PLoS One. 2018 Sep 5;13(9):e0203380.
doi: 10.1371/journal.pone.0203380. eCollection
2018
3. Ono S, Ono Y, Koide D, Yasunaga H:
Relationshipbetweensevererespiratory
depresssion and codeine-containing antitussives inchildren: a nested case-control study. J Epidemiol.
2019 Mar 2. doi: 10.2188/jea.JE20180224.
4. Hirakawa A, Hatakeyama T, Kobayashi D,
Nishiyama C, Kada A, Kiguchi T, Kawamura T,
Iwami T. Real-time feedback, debriefing, andretraining system of cardiopulmonary resuscitation for out-of-hospital cardiac arrests: study
protocol for a randomized controlled trial. Trials.
2018; 19:510
5. Hirakawa A, Asano J, Sato H, Teramukai S.
Master protocol trials in oncology: Review andnew trial designs. Contemporary Clinical Trial
Communications, 2018;12:1-8
6. Kakurai Y, Kaneko S, Hamada C, Hirakawa A(corresponding author). Dose individualizationand variable selection using Bayesian Lasso inearly phase dose-finding trials. Applied Statistics.
2019; 68:445-460.

7. Kada A, Hirakawa A, Kinoshita F, Kobayashi Y,
Hatakeyama T, Kobayashi D, Nishiyama C,
Iwami T. Sample size estimation and reestimation of cluster randomized controlled trials
for real-time feedback, debriefing, and retraining
system of cardiopulmonary resuscitation for outof-hospital cardiac arrests. Contemporary Clinical
Trials Communications. 2019; 14: 100316.
8. 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. 2019 Mar
30. doi: 10.1002/cpt.1442

392

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 a endowed chair established on April 1,
2018, under the donations of Medtronic Japan Co.,
Ltd., Abbott Japan Co., Ltd., Boston Scientific Japan
Co., Ltd., and Fukuda Denshi Tokyo Central Sales Co.,Ltd.
In conjunction with the department ofcardiovascular medicine, this course develops leadingedge medical care and elucidates the pathogenesis ofunresolved heart failure and cardiovascular disease
and analysis of the pathological condition using
cultured cells, experimental animals, and patient
specimens. By clarifying the new disease pathogenesis
mechanism and pathogenesis mechanism, it aims at
elucidating the fundamental pathophysiology ofcardiovascular disease and developing development
prevention methods, new diagnostic methods, and newtherapeutic methods.
In Japan, cardiovascular death is the leading
cause of death in the elderly and is the leading causeof shortening healthy lifespan. Despite the emergenceof various new drugs, new devices, and new treatments, we have not succeeded in reducing cardiovascular death for the last 20 years. We have foundthat it is important not to study cardiomyocytes alone,
but to examine noncardiomyocytes in consideration ofheart 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 senseand has been considered since ancient times, 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 create an understanding of new
cardiac control mechanisms and novel therapeutictargets. In addition, as a therapeutic development, weare promoting research that will be the basis for thedevelopment of clinical new approaches such as drugintervention approaches to non-cardiomyocytes, brain
imaging diagnosis, and brain stimulation therapy.

Clinical activities
In this course, in order to achieve the researchmentioned above purpose, medical treatment using thelatest equipment and devices in the circulatory region
will be practiced at the University of Tokyo Hospital.

Teaching activities
The results of the above research are presented at theuniversity and academic conferences, the importanceof this field is well known, and widely presented bydissertation. In addition, we are actively engaged inoutreach activities for society.

393

Research activities
The heart and blood vessels maintain homeostasis incooperation with organs throughout the body, and thefailure of this cooperation is considered to cause theonset of heart failure and sudden death. The therapy
that improved the prognosis of cardiovascular death isa drug that acts on the whole body, not on the heartalone, except for cardiac resynchronization therapy
and implantable defibrillator. From this point of view,as a research to improve the prognosis of cardiovascular death, we will proceed with the research,
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, while the other half are
non-cardiomyocytes, and 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 clarifying the pathogenesis of heart failurethat is its failure.
Furthermore, as a study of inter-organ
cooperation, the relationship between the heart and thebrain is examined in detail, and as diagnosis andtreatment of heart failure and arrhythmia, the possibility of imaging diagnosis of the cranial nerve andintervention to the brain and nerve is examined.

References
1. Nakayama Y, Fujiu K., Can Anti-inflammatory
Therapy Prevent Atrial Fibrillation in Myocardial
Infarction Patients?, Int Heart J. 2018;59(1):3-5.
2.. Matsubara T, Fujiu K, Correlation between
nutritional state and prognosis of heart failure,with a focus on the immune system, Int Heart J.
2018;59(2):245-247
3.. Kojima T; Fujiu K, Fukuma N, Matsunaga H,
Oshima T; Matsuda J; Matsubara T; Shimizu Y;
Oguri G; Hasumi E; Morita H; Komuro I,
Periprocedural Complications in Patients Undergoing Catheter Ablation of Atrial Fibrillation
without Discontinuation of a Vitamin K
Antagonist and DOACs, Circ J, 2018, 82(6):15521557
4. Makimoto H, Shimizu K, Fujiu K, Lin T, Oshima

T, Amiya E, Yamagata K, Kojima T, Daimon M,
Nagatomo R, Waki K, Meyer C, Komuro I, Effectof Sympatholytic Therapy on Circadian Cardiac
Autonomic Activity in Non-diabetic Chronic
Kidney Disease, Int Heart J, 2018 Nov 28;59(6):1352-1358. doi: 10.1536/ihj.17-561.
5. Iwazaki K, Kojima T, Murasawa T, Yokota J,
Tanimoto H, Hasumi E, Cho K, Fujiu K, Komuro
I, A case of a cardiac resynchronization therapydefibrillator exhibiting a lower and alternately
variable basic rate, Int Heart J, 2018 May 30;
59(3):626-629
6. Yonenaga A, Hasumi E, Fujiu K, Ushiku A,
Hosoya Y, Hatano M, Ando J, Morita H,
Watanabe M, Komuro I, Prognostic improvementof acute necrotizing eosinophilic myocarditis(ANEM) through a rapid pathological diagnosis
and appropriate therapy, Int Heart J, 2018 May
30;59(3):641-646.
7. Sugita J, Fujiu K, Systemic Inflammatory StressResponse during Cardiac Surgery, Int Heart J.
2018, 2018;59(3):457-459.
8. Oshima T, Fujiu K, The Impact of Non-Cardiac
Drugs on the Cardiac Repolarization Phase, Int
Heart J. 2018;59(4):677-679.
9. Ota S, Horisaki R, Kawamura Y, Ugawa M, Sato I,
Hashimoto K, Kamesawa R, Setoyama K,
Yamaguchi S, Fujiu K, Waki K, Noji H, Ghost
Cytometry, Science, 2018; 360 (6394): 1246 DOI:
10.1126/science.aan0096
10. Hasumi E, Fujiu K, Kawada T, Komuro I, The
influence of His-bundle pacing on tricuspid valvefunctioningusing three-dimensional echocardiography, Heart Rhythm Case Reports, 2018, DOI:
https://doi.org/10.1016/j.hrcr.2018.06.003
11. Matsuda J, Fujiu K, Directional Coronary
Atherectomy as Coronary Pathohistology, Int
Heart J. 2018, 2018;59(5):903-905
12. Kaneko H, Kitamura M, Neuss M, Okamoto M,
Schmidt T, Alessandrini H, Kuck KK, Komuro I,
Frerker C, Butter C. MitraClip in Patients withMitral Regurgitation and Left Ventricular
Ejection Fraction< 30%- Potential Implications
for the Treatment of Patients in Japan. Circ J.
2018 Sep 25;82(10):2672-2675.

394

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 the Laboratoryoffers, therefore, the research currently being
promoted is expected to lead to the elucidation of thepathophysiology of diabetes and related metabolic
diseases, where rare disease-derived tissue- and iPS
cell-based investigations are expected to provide
invaluable insights into the pathophysiology ofdiabetes as a common disease. Thus, the Laboratory is
devoted to promoting relevant research leading to thedevelopment of innovative diagnostic, preventive andtherapeutic modalities, thereby contributing to theeffective prevention and treatment of diabetes.

Teaching activities
Working in collaboration with its closely related
Laboratory, Departments of Diabetes and Metabolic
Disease, Division of Nephrology and Endocrinology,
the Laboratory aims to foster internationally-oriented
young talents in both an academic and social 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 role in theclinical researcher development program by the395

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 analysis of
the physiological functions of organs and systems thatplay a key role in the onset of diabetes, i.e., pancreatic
endocrine cells, liver, adipose tissue, skeletal muscle,
nervous system, immune system and intestinal tract,
as well as diseases resulting from disruption of theirfunctions by drawing fully on state-of-the-art omic
(genomic, epigenomic, metabolomic, and metagenomic) and iPS-cell technologies and genetic celland 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. Structure and function analysis ofadiponectin receptors toward development ofnovel antidiabetic agents promoting healthy
longevity.
Endocrine J. 65, 871-977, 2018
2. Iwabu M, Okada-Iwabu M, Yamauchi T and
Kadowaki T. Effects of aerobic exercise on
adiponectin and glucose metabolism.
Diabetes Frontier Online 5, e1-009, 2018
3. Odawara S, Nemoto K, Nakagawa T, Takahashi O,
Kobayashi D, Iwabu M, Okada-Iwabu M,
Yamauchi T, Kadowaki T and Izumo H.
Usefulness of post-delivery oral glucose tolerance
test in women with gestational diabetes mellitus.
Diabetes Frontier Online 5, e1-010, 2018

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Department of Advanced Clinical
Science and Therapeutics
Project Associate Professor
Mutsuo Harada, M.D., Ph.D.

Project Assistant Professor
Kouji Wakayama, M.D., Ph.D.

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.
This department hopes to develop not only basic
research, but also applications to devise new clinicalstrategies.

Research activities
Followings are our recent basic and clinical research
activities.
Basic Research• New strategies to regulate acute rejection and graftarterial diseases in cardiac transplantation.
• New strategies to regulate acute/chronic myocarditis.
• New strategies to regulate acute myocardial infarction and ischemia/reperfusion injury.
• New strategies to regulate restenosis after coronary
angioplasty.
• New strategies to regulate atherosclerosis andaneurism.
• New strategies to regulate systolic/diastolic heart
failure.
• New strategies to regulate sleep apnea syndromeand circadian rhythm abnormality.
• New strategies to regulate cardio-kidney syndrome.
• New strategies to regulate oral-pathogen induced
cardiovascular diseases.

• Development of gene therapies (anti-inflammationetc.).
• 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.).
• Expanding the use of foods and natural extracts.
• Expanding the application of existing drugs anddevices.
• Analysis of angiogenesis using in situ hybridization.
Clinical Research• Gene therapies to prevent restenosis and thrombosis
after coronary intervention.
• Pathophysiology of oral disorder and cardiovasculardiseases.
• Pathophysiology of sleep apnea syndrome andcardiovascular diseases.
• Pathophysiology of renal dysfunction and cardiovascular diseases.

References
1. Akimoto S, Suzuki JI, Aoyama N, Ikeuchi R,
Watanabe H, Tsujimoto H, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Komuro I. A
Novel Bioabsorbable Sheet That Delivers NF-κB
Decoy Oligonucleotide Restrains Abdominal

397

2.

3.

4.

5.

6.

7.

Aortic Aneurysm Development in Rats. Int HeartJ. 2018 Sep 26;59(5):1134-1141.
Takeda N, Inuzuka R, Maemura S, Morita H,
Nawata K, Fujita D, Taniguchi Y, Yamauchi H,
Yagi H, Kato M, Nishimura H, Hirata Y, Ikeda Y,
Kumagai H, Amiya E, Hara H, Fujiwara T,
Akazawa H, Suzuki JI, Imai Y, Nagai R,
Takamoto S, Hirata Y, Ono M, Komuro I. Impact
of Pathogenic FBN1 Variant Types on the
Progression of Aortic Disease in Patients With
Marfan Syndrome. Circ Genom Precis Med. 2018
Jun;11(6)Aoyama N, Suzuki JI, Kobayashi N, Hanatani T,
Ashigaki N, Yoshida A, Shiheido Y, Sato H,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Minabe M, Izumi Y, Isobe M. JapaneseCardiovascular Disease Patients with Diabetes
Mellitus Suffer Increased Tooth Loss in Comparison to Those without Diabetes Mellitus -A
Cross-sectional Study. Intern Med. 2018 Mar 15;
57(6):777-782.
Aoyama N, Suzuki JI, Kobayashi N, Hanatani T,
Ashigaki N, Yoshida A, Shiheido Y, Sato H, Izumi
Y, Isobe M. Increased Oral Porphyromonas
gingivalis Prevalence in Cardiovascular Patientswith Uncontrolled Diabetes Mellitus. Int Heart J.
2018 Jul 31;59(4):802-807.
Shimamura M, Nakagami H, Shimizu H,
Wakayama K, Kawano T, Ikeda Y, Hayashi H,
Yoshida S, Mochizuki H, Morishita R.
Therapeutic Effects of Systemic Administration of
the Novel RANKL-Modified Peptide, MHP1, forIschemic Stroke in Mice. Biomed Res Int. 2018
Jul 30;2018:4637084.
Hara H, Takeda N, Kondo M, Kubota M, Saito T,
Maruyama J, Fujiwara T, Maemura S, Ito M,
Naito AT, Harada M, Toko H, Nomura S,
Kumagai H, Ikeda Y, Ueno H, Takimoto E,
Akazawa H, Morita H, Aburatani H, Hata Y,
Uchiyama M, Komuro I. Discovery of a Small
Molecule to Increase Cardiomyocytes and Protect
the Heart After Ischemic Injury. JACC BasicTransl Sci. 2018 Nov 12;3(5):639-653.
Takeda N, Inuzuka R, Maemura S, Morita H,
Nawata K, Fujita D, Taniguchi Y, Yamauchi H,
Yagi H, Kato M, Nishimura H, Hirata Y, Ikeda Y,
Kumagai H, Amiya E, Hara H, Fujiwara T,

Akazawa H, Suzuki JI, Imai Y, Nagai R,
Takamoto S, Hirata Y, Ono M, Komuro I. Impact
of Pathogenic FBN1 Variant Types on the
Progression of Aortic Disease in Patients With
Marfan Syndrome. Circ Genom Precis Med. 2018
Jun;11(6)8. Fujiwara T, Takeda N, Hara H, Morita H,
Kishihara J, Inuzuka R, Yagi H, Maemura S, Toko
H, Harada M, Ikeda Y, Kumagai H, Nomura S,
Takimoto E, Akazawa H, Ako J, Komuro I.
Distinct variants affecting differential splicing of
TGFBR1 exon 5 cause either Loeys-Dietz
syndrome or multiple self-healing squamous
epithelioma. Eur J Hum Genet. 2018 Aug;26(8):1151-1158.
9. Nomura S, Satoh M, Fujita T, Higo T, Sumida T,
Ko T, Yamaguchi T, Tobita T, Naito AT, Ito M,
Fujita K, Harada M, Toko H, Kobayashi Y, Ito K,
Takimoto E, Akazawa H, Morita H, Aburatani H,
Komuro I. Cardiomyocyte gene programs
encoding morphological and functional signaturesin cardiac hypertrophy and failure. Nat Commun.
2018 Oct 30;9(1):4435.
10. Harada M, Ishizuka M, Murakami H, Toko H.
Targeting
Vascular
Inflammaging
with
Amlodipine for Atherosclerosis Prevention. Int
Heart J. 2018;59(3):465-466.
11. Tobita T, Nomura S, Fujita T, Morita H, Asano Y,
Onoue K, Ito M, Imai Y, Suzuki A, Ko T, Satoh M,
Fujita K, Naito AT, Furutani Y, Toko H, Harada M,
Amiya E, Hatano M, Takimoto E, Shiga T,
Nakanishi T, Sakata Y, Ono M, Saito Y,
Takashima S, Hagiwara N, Aburatani H, Komuro
I. Genetic basis of cardiomyopathy and the
genotypes involved in prognosis and left
ventricular reverse remodeling. Sci Rep. 2018 Jan
31;8(1).

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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,since the start of this year we have entered the dawn ofa new age in which drugs are utilized more efficiently
and delivered more reliably in regional health care,leading to improved patient outcomes. Regional
formularies are being established, combatting polypharmacy has become the biggest issue confronting
clinicians (as revealed by the results of a questionnaire
survey), methodologies for implementing refillable
prescriptions in Japan are being put in place, and theLaw for Ensuring the Quality, Efficacy, and Safety ofDrugs and Medical Devices has come fully into effect.
A major rearrangement of the medical device landscapeis underway, 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. Specifically, doctors andpharmacists need to have a common understanding of
the disease being treated in order to be able to provide
appropriate drug therapy and follow the patient andaccurately evaluate their treatment. The delivery of
optimal drug therapy involves multiple interconnected
processes, from investigating what drugs should be
used to planning the treatment regimen, assessing
treatment compliance and effectiveness, and managing
adverse reactions, and only a multidisciplinary, teamoriented approach to health care will make it possible

to provide patients with efficient, effective drug therapy.
Unfortunately, there are currently few examples of such
“multidisciplinary approaches to delivering optimal
drug therapy.” Japan is becoming a super-aging society
in which the number of elderly patients receiving
multiple drug products is increasing sharply, and theappropriate delivery of drug treatments has therefore
become an extremely important issue. Because optimal
drug therapy delivery cannot be accomplished throughthe traditional health care system or through regional
health care systems, the construction of a new healthcare system for the delivery of drug therapy is required.
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 becauseof a lack of evidence.
For example, although dispensing limits for patientswith long-term prescriptions have been discussed incancer therapy and primary care settings, no theoreticalor empirical research has been conducted to study thisissue. Nor have any systems been put in place tomanage drug therapies based on predetermined
protocols for patients with chronic diseases who are instable condition. In addition, not enough empiricalresearch has been conducted on the development of
optimal treatment methods (e.g., optimal patient
selection, efficient treatment procedures) based on
postmarketing surveillance of expensive drug products.

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Against the aforementioned background, theobjective of this program is to conduct theoretical andempirical research on the development of new regional
health care and collaborative systems for doctors(hospitals/clinics) and pharmacists (both hospital andnon-hospital pharmacists) in order to try to construct a
new collaborative system for doctors and pharmacists
to optimize 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 Dr. Hirohisa
Imai, a lecturer in social medicine who is a specialist in
public health and welfare and epidemiology, and thelatter was until just recently Setsuko Kinoshita, apharmacist whose specialty is epidemiology (and who
has resigned her post for family reasons, and for whom
a replacement is being sought). The program also has 2
full-time administrative staff. In addition, graduate
students in the professional degree course of the Schoolof Public Health have been involved in this program’s
research activities and providing teaching support.

Education
The objective of this program is to develop healthcare specialists who can implement medical
collaborations that are suited to a super-aging society.
The era when a single doctor is capable of handling allof the care for a single patient is over. The coming age
will see physicians, pharmacists, nurses, public healthand welfare workers, etc. use a multidisciplinary

approach, and collaborate with the government as well,to implement 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
onpharmacoepidemiologicalandpharmacoeconomic issues, and provide instruction on
how to apply epidemiological approaches to identify
problems and formulate responses in regional healthcare. We will attempt to convey the significance andfundamentals of epidemiology to students with no field
experience by exposing them to common scenarios inregional 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 will teach graduate
students in the School of Public Health, and perform
interventional research on polypharmacy patients.
Graduate students in the latter stages of obtaining theirdoctorate degrees, who will be expected to performtheir own, independent research in the future, will
receive instruction in creating themes for research
papers, analyzing data, the handling of literaturereferences, and other basic and critical skills, and will
also receive guidance when writing their dissertations
on how to develop a consistently logical argument
throughout their dissertation as well as on how toproperly cite literature references.

Research
This program will utilize primarily prescription drug
data (including prescribing histories) and medical
record data to conduct theoretical and empiricalresearch focusing on the biostatistical andepidemiological methodologies involved in “thedevelopment of new methods of multidisciplinary
collaboration for optimizing physician-directed drug
therapies.”

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1. Research on prescription drug dispensing limits forpatients with long-term prescriptions
1) “Dispensing limits for patients with long-termprescriptions” refers to the practice of having
patients who have, for example, received a 90day 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 program plans to conduct a larger-scale
research study with the help of the Ministry of
Health, Labour and Welfare.
2. Research on multidisciplinary interventions in drug
therapy in regional health care1) This program will cooperate with regional
metropolitan
doctors’ andpharmacists’associations, national health insurance regional
branch offices, Japan Health Association branch
offices, prefectural health and welfare agency
pharmaceutical affairs bureaus, and the like toconduct research on optimal drug therapy
interventions for elderly patients. The patients
who should receive interventions will beidentified by a patient selection board comprisedof doctors and pharmacists, and saidinterventions 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 bysendingprescribing
physicians
andcompounding 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 is being required within the framework of regional comprehensive health caresystems. Although formularies may be one
effective method of accomplishing this,“Hospital Formularies” and “Regional
Formularies” are very different, although they
may appear alike, because the latter have many
stakeholders, and the implementation of suchformularies is therefore extremely difficult.
Although regional formularies have not yet
been implemented in Japan, this program isconducting research into how they can be
developed. This program will investigate, in aquantitative scientific manner, incentives andinducements for promoting data collection andanalysis and the screening and use of listed drug
products.
2) This program has started to conduct research toassess the effects of introducing regional
formularies using certain government-approved“Regional
HealthCare
Collaboration
Promotion Foundations.” This program willcollect data provided by prefectural healthinsurance and Japan Health Association offices
on patient characteristics, disease names,
medical institutions, drugs, etc. and perform an
impact assessment on the introduction ofregional formularies.
4. The development of systems for optimizing drug
therapies that utilize artificial intelligence
1) This research is being conducted with funds
provided by AMED and NEDO. A collaborative

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research project is underway with the Social
ICT Research Center of the University ofTokyo’s Graduate School of Information
Science and Technology that is aimed at
utilizing artificial intelligence to optimize thedelivery of drug therapies.
2) Adverse reactions have many causes, includinginteractions between different drugs andinteractions with the metabolites of certain
drugs, and the identification and prevention ofadverse reactions requires tremendous effort.
Because a tremendous amount of work is
required to investigate the causes of adverse
reactions and prevent them from occurring,systems are being developed that utilize
artificial intelligence to identify 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.

Publications
1. Nakagawa S, Nakaishi M, Hashimoto M, Ito H,
Yamamoto W, Nakashima R, Tanaka M, Fujii T,
Omura T, Imai S, Nakagawa T, Yonezawa A, Imai
H, Mimori T, Matsubara K. Effect of Medication
Adherence on Disease Activity among JapanesePatients with Rheumatoid Arthritis. PLOS ONE
13(11): e0206943, 2018
2. 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 temporal changes inchemotherapy-induced hair loss in breast cancer
patients. PLOS ONE 14(1): e0208118, 2019.
3. Fukatsu S, Ikemi Y, Yonezawa A, Ozaki J, Asano
M, Sakurai K, Uesugi M, Yoshida Y, Denda M,
Otani Y, Omura T, Imai S, Nakagawa S, Nakagawa
T, Imai H, Matsubara K．Health Care Economic
Effects of Prescriptions with “Management of
Unused Medicines” Pre-Printed as an Instruction
from the Prescribing Physician. Journal ofJapanese Society of Hospital Pharmacists: 54(3):

4.

5.
6.
7.

30307-312，2018．
Imai H. New Functions of Pharmacists Illustratedby Pharmacy KPIs The Journal of Community
Pharmacy and Pharmaceutical Sciences. 2018; Vol.
10 (No.1): 96-101
Imai H. Examples of Interventions That Can
Reduce Polypharmacy. Credentials. 2018; No. 116:
34-37
Imai H, Kumazawa R. Precautions for Treating
Elderly Patients – Prescribing Cautions. Rinsho
Derma. 2018; Vol. 60 (No. 6)
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.

402

Department of Integrated
Molecular Sciences on Metabolic
Diseases
Project Associate Professor
Masato Iwabu, M.D., Ph.D.

Project Lecturer
Miki Okada-Iwabu, Ph.D. (〜2017. Aug.)※The following information is the same as that of the previous year for certain reasons.

Introduction and Organization
The Department of Integrated Molecular Sciences on
Metabolic Diseases (DIMSMD) is devoted toclarifying the mechanisms of onset of lifestyle-relateddiseases resulting from interactions between genetic
and environmental factors in the Japanese population
as well as to contributing to the prophylaxis, diagnosis
and treatment of these diseases, in response to thedrastic increase in the number of diabetic patients
which is becoming a major social issue of current
interest. In this regard, the DIMSMD strives toestablish an accurate method through which to predictrisk for the onset of lifestyle-related diseases bytapping into a comprehensive database for genetic andenvironmental factors for these diseases which is
being developed to integrate “Informatics on Genetic
Predisposition to Lifestyle-related Diseases” asgenerated by cutting-edge advances such as single
nucleotide polymorphism analyses with “Informatics
on Environmental Factors for Lifestyle-relatedDiseases” that draw on surveys including detailed
questionnaires on diet intake. The DIMSMD istherefore expected to make significant scientific andsocial contributions by providing effective modalities
for primary prevention of diabetes, moleculardiagnosis of onset of diabetes and its pathology, andoptimal treatment of diabetes, and to play a major role
in reducing the number of newly onset diabetes aswell as in raising the treatment standard for diabetes.
The DIMSMD also aims to develop a system thatallows formulas to be developed to predict therapeutic
response to drugs as well as their safety to be
developed based on information available onenvironmental and genetic factors including gene
expression from patients being treated at University ofTokyo Hospital, and which allows safe and effective
use of drugs being developed in patients withlifestyle-related diseases.
The DIMSSMD has set as its final goal the
installment of a human metabolic disease tissue bankat University of Tokyo Hospital, which draws on an“integrated database” that offers comprehensive
information on gene expression in human hepatic andadipose tissue samples, electronic charts, SNP andlifestyle habits, which will allow validation ofmolecular targets in actual human diseases, design ofa clinical trial system based on SNP and gene
expression profiles, development of models forprediction of therapeutic response based on
environmental and genetic interactions, identificationof molecular targets, discovery of novel therapeutic
agents and safe and effective use of drugs thus
developed in time.
The DIMSMD is thus engaged in daily research
activities and clinical care aimed at contributing to theadvancement of health and medical care in the future.

403

Research activities
The DIMSMD Research Laboratory aims to elucidate
the molecular mechanisms of lifestyle-related diseases
such as the metabolic syndrome, diabetes andcardiovascular disease associated with obesity and to
put relevant molecular targets identified in the process
to effective use in the treatment of these diseases. Of
note, the DIMSMD Research Laboratory has animpressive track record in research in this area,
including identification of multiple “key molecules”
implicated in lifestyle-related diseases, such as
adiponectin receptors, which led to an elucidation ofsome of the processes through which lifestyle-relateddiseases develop and progress, based on functional
analyses that tap into developmental engineering and
RNA engineering. The DIMSMD ResearchLaboratory has also been credited with discoveringthat adiponectin is highly active in its high molecularweight form as a ligand to the adiponectin receptors
and that its quantitative measurement is useful in the
diagnosis of insulin resistance and the metabolic
syndrome. Not only that, the DIMSMD ResearchLaboratory has found that, via the adiponectin
receptors, the plant-derived peptide osmotin activates
the AMPK pathway which has a critical role inprotecting against lifestyle-related diseases. Currently,
the DIMSMD Research Laboratory is proactively
engaged in the development of definitive treatments
for lifestyle-related diseases that draw on ligands
specific for the adiponectin receptors.

References
1. Okada-Iwabu M, Yamauchi T, Iwabu M,
Kadowaki T. Aging and homeostasis. Development of novel AdipoR-targeted drugs with
exercise-mimicking and anti-aging properties.
Clin Calcium. 27(7): 975-981, 2017
2. Iwabu M, Yamauchi T, Okada-Iwabu M,
Kadowaki T. Developing Exercise-mimicking
Drugs toward Realization of Preemptive Medicine
for Lifestyle-related Diseases. Clin Calcium.
28(1): 73-80, 2018

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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. Homma, N. R., Zhou, M. I. Naseer, A. G.
Chaudhary, M. H. Al-Qahtani, and N. Hirokawa.
KIF2A regulates the development of dentate
granule cells and postnatal hippocampal wiring.
eLife 7: e30935. DOI: https://doi.org/10.7554/
eLife. 30935, 2018
2. Morikawa, Mo., Y. Tanaka, H. –S. Cho, M.
Yoshihara, and N. Hirokawa. The molecularmotor KIF21B mediates synaptic plasticity andfear extinction by terminating Rac1 activation.
Cell Rep. 23: 3864-3877, 2018.
3. Xu, F., H. Takahashi, Y. Tanaka, S. Ichinose, S.
Niwa, M. P. Wicklund, and N. Hirokawa. KIF1B
beta mutations detected in hereditary neuropathy
impair IGF1R transport and axon growth. J. Cell
Biol. 217:3480-3496. 2018
4. Wang, L., Y. Tanaka, D. Wang, R. Zhou, N.
Homma, Y. Miyamoto and N. Hirokawa. The
atypical kinesin KIF26A facilitates termination ofnoticeptive responses by sequestering focal adhesion
kinase. Cell Rep. 24:2894-2907, 2018
5. Shima, T., M. Morikawa, J. Kaneshiro, T. Kambara,
S. Kamimura, T. Yagi, H. Iwamoto, S. Uemura, H.
Shigematsu, M. Shiromizu, T. Ichimura, T.

405

Watanabe, R. Nitta, Y. Okada, N. Hirokawa.
Kinesin-binding triggered conformation switchingof microtubules contributes to polarized transport.
J. Cell Biol. 217:4164-4183, 2018

406

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 wasestablished 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 ofresearch experience on molecular genetics of neuro-

logical disorders during the period of the “free–quarter
program”. In the post-graduate education, we offer
programs for graduate students including molecular
genetics, neurobiology and translational 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
mutations (Mitsui J, et al. JAMA Neurol. 2016;73:

407

977-80, Kasai T, et al. PLoS One. 2016;11:e0147574,
Schottlaender LV, et al. PLoS One. 2016;11:e0149557,
Barca E, et al. J Neuropathol Exp Neurol. 2016;75:
663-72, Compta Y, Parkinsonism Relat Disord. 2018;46:16-23, Du J, et al. Parkinsonism Relat Disord.
2018 Dec;57:58-62.). Based on these studies, we havestarted a multicenter-based (13 institutions) phase II
clinical trial to evaluate the clinical efficacy of ahigh-dose ubiquinol (reduced form of coenzyme Q10)
supplementation for suppressing progression ofsymptoms of patients with MSA. To facilitate
recruitment of MSA patients into the clinical trial, and,to establish a detailed natural history of MSA, westarted 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
Japanese with generous help by Dr. Gregor Wenning,
the original author of UMSARS. We also prepared a
training video focusing on items of UMSARS, where
rating tends to vary among raters to reduce thevariance of rating among raters.

References
1. Enomoto Y, Tsurusaki Y, Yokoi T, Abe-Hatano C,
Ida K, Naruto T, Mitsui J, Tsuji S, Morishita S,
Kurosawa K. CNV analysis using whole exome
sequencing identified biallelic CNVs of VPS13B
in siblings with intellectual disability. Eur J Med
Genet. 2018 Dec 30. pii: S1769-7212(18)30157-5.
doi: 10.1016/j.ejmg.2018.12.015.
2. Yoshikawa K, Kuwahara M, Saigoh K, Ishiura H,
Yamagishi Y, Hamano Y, Samukawa M, Suzuki H,
Hirano M, Mitsui Y, Tsuji S, Kusunoki S. The
novel de novo mutation of KIF1A gene as thecause for Spastic paraplegia 30 in a Japanese case.
eNeurologicalSci. 2018 Nov 22;14:34-37. doi:
10.1016/j.ensci.2018.11.026.
3. 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, andenzymatic study in a Japanese family with a GBA
gross deletion. Parkinsonism Relat Disord. 2018

Dec 2. pii: S1353-8020(18)30525-X. doi: 10.
1016/j.parkreldis.2018.11.028.
4. Nagase M, Yamamoto Y, Mitsui J, Tsuji S.
Simultaneous detection of reduced and oxidized
forms of coenzyme Q10 in human cerebral spinal
fluid as a potential marker of oxidative stress. J
Clin Biochem Nutr. 2018 Nov;63(3):205-210.
doi: 10.3164/jcbn.17-131.
5. 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):171176. doi: 10.1038/s10038-018-0538-4.
6. 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. 2018 Oct
24. pii: jnnp-2018-318568. doi: 10.1136/jnnp2018-318568.
7. Tokushige SI, Matsuda SI, Oyama G, Shimo Y,
Umemura A, Sasaki T, Inomata-Terada S, Yugeta
A, Hamada M, Ugawa Y, Tsuji S, Hattori N, Terao
Y. Effect of subthalamic nucleus deep brain
stimulation on visual scanning. Clin Neurophysiol. 2018 Nov;129(11):2421-2432. doi: 10.
1016/j.clinph.2018.08.003.
8. Nakamoto FK, Okamoto S, Mitsui J, Sone T,
Ishikawa M, Yamamoto Y, Kanegae Y, Nakatake Y,
Imaizumi K, Ishiura H, Tsuji S, Okano H. The
pathogenesis
linkedtocoenzyme
Q10
insufficiency in iPSC-derived neurons frompatients with multiple-system atrophy. Sci Rep.
2018 Sep 21;8(1):14215. doi: 10.1038/s41598018-32573-1.
9. Kurihara M, Bannai T, Otsuka J, Kawabe
Matsukawa M, Terao Y, Shimizu J, Tsuji S. Optic
neuropathy and decorticate-like posture aspresenting symptoms of Bickerstaff's brainstem
encephalitis: A case report and literature review.
Clin Neurol Neurosurg. 2018 Oct;173:159-162.
doi: 10.1016/j.clineuro.2018.08.019.
10. Koh K, Ishiura H, Tsuji S, Takiyama Y. JASPAC:

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Japan Spastic Paraplegia Research Consortium.
Brain Sci. 2018 Aug 13;8(8). pii: E153. doi: 10.
3390/brainsci8080153.
11. Yamaguchi N, Mano T, Ohtomo R, Ishiura H,
Almansour MA, Mori H, Kanda J, Shirota Y, Taira
K, Morikawa T, Ikemura M, Yanagi Y, Murayama
S, Shimizu J, Sakurai Y, Tsuji S, Iwata A. An
Autopsy Case of Familial Neuronal Intranuclear
Inclusion Disease with Dementia and Neuropathy.
Intern Med. 2018 Dec 1;57(23):3459-3462. doi:
10.2169/internalmedicine.1141-18.
12. Tokushige SI, Terao Y, Matsuda S, Furubayashi T,
Sasaki T, Inomata-Terada S, Yugeta A, Hamada M,
Tsuji S, Ugawa Y. Does the Clock Tick Slower or
Faster in Parkinson's Disease? - Insights Gained
From the Synchronized Tapping Task. Front
Psychol. 2018 Jul 11;9:1178. doi: 10.3389/fpsyg.
2018.01178.
13. Nishioka Y, Shindoh J, Inagaki Y, Gonoi W,
Mitsui J, Abe H, Yoshioka R, Yoshida S,
Fukayama M, Tsuji S, Hashimoto M, Hasegawa K,
Kokudo N. Host MICA Polymorphism as a
Potential Predictive Marker in Response to
Chemotherapy for Colorectal Liver Metastases.
Dig Dis. 2018; 36(6): 437-445. doi: 10.1159/
000490411.
14. Cen Z, Jiang Z, Chen Y, Zheng X, Xie F, Yang X,
Lu X, Ouyang Z, Wu H, Chen S, Yin H, Qiu X,
Wang S, Ding M, Tang Y, Yu F, Li C, Wang T,
Ishiura H, Tsuji S, Jiao C, Liu C, Xiao J, Luo W.
Intronic pentanucleotide TTTCA repeat insertionin the SAMD12 gene causes familial cortical
myoclonic tremor with epilepsy type 1. Brain.
2018 Aug 1; 141(8): 2280-2288. doi: 10.1093/
brain/awy160.
15. Koh K, Ishiura H, Beppu M, Shimazaki H,
Ichinose Y, Mitsui J, Kuwabara S, Tsuji S,
Takiyama Y; Japan Spastic Paraplegia ResearchConsortium. Novel mutations in the ALDH18A1
gene in complicated hereditary spastic paraplegiawith cerebellar ataxia and cognitive impairment. J
Hum Genet. 2018 Sep; 63(9): 1009-1013. doi:
10.1038/s10038-018-0477-0.
16. Horita S, Simsek E, Simsek T, Yildirim N, Ishiura
H, Nakamura M, Satoh N, Suzuki A, Tsukada H,
Mizuno T, Seki G, Tsuji S, Nangaku M. SLC4A4
compound heterozygous mutations in exon-intron

boundary regions presenting with severe proximal
renal tubular acidosis and extrarenal symptoms
coexisting with Turner's syndrome: a case report.
BMC Med Genet. 2018 Jun 18;19(1):103. doi:
10.1186/s12881-018-0612-y.
17. Tsuchida T, Mano T, Koshi-Mano K, Bannai T,
Matsubara T, Yamashita S, Ushijima T, Nagata K,
Murayama S, Toda T, Tsuji S, Iwata A.
Methylation changes and aberrant expression of
FGFR3 in Lewy body disease neurons. Brain Res.
2018 Oct 15;1697:59-66. doi: 10.1016/j.brainres.
2018.06.017.
18. Kodama S, Mano T, Kakumoto T, Ishiura H,
Hagiwara A, Kamiya K, Hayashi T, Tsuji S.
Ketotic hyperglycemia-related seizure withreversible white matter lesion: Metabolic implication of its reversibility based on magnetic
resonance spectroscopy study. J Neurol Sci. 2018
Jul 15;390:20-21. doi: 10.1016/j.jns.2018.04.006.
19. Kurihara M, Sasaki T, Ishiura H, Tsuji S. HIV
Dementia with a Decreased Cardiac 123Imetaiodobenzylguanidine Uptake Masquerading
as Dementia with Lewy Bodies. Intern Med. 2018
Oct 15; 57(20): 3007-3010. doi: 10.2169/internal
medicine.0876-18.
20. Higuchi Y, Okunushi R, Hara T, Hashiguchi A,
Yuan J, Yoshimura A, Murayama K, Ohtake A,
Ando M, Hiramatsu Y, Ishihara S, Tanabe H,
Okamoto Y, Matsuura E, Ueda T, Toda T,
Yamashita S, Yamada K, Koide T, Yaguchi H,
Mitsui J, Ishiura H, Yoshimura J, Doi K,
Morishita S, Sato K, Nakagawa M, Yamaguchi M,
Tsuji S, Takashima H. Mutations in COA7 cause
spinocerebellar ataxia with axonal neuropathy.
Brain. 2018 Jun 1;141(6):1622-1636. doi: 10.
1093/brain/awy104.
21. Misawa S, Kuwabara S, Sato Y, Yamaguchi N,
Nagashima K, Katayama K, Sekiguchi Y, Iwai Y,
Amino H, Suichi T, Yokota T, Nishida Y,
Kanouchi T, Kohara N, Kawamoto M, Ishii J,
Kuwahara M, Suzuki H, Hirata K, Kokubun N,
Masuda R, Kaneko J, Yabe I, Sasaki H, Kaida KI,
Takazaki H, Suzuki N, Suzuki S, Nodera H,
Matsui N, Tsuji S, Koike H, Yamasaki R,
Kusunoki S; Japanese Eculizumab Trial for GBS(JET-GBS) Study Group. Safety and efficacy ofeculizumab in Guillain-Barré syndrome: a multi-

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centre, double-blind, randomised phase 2 trial.
Lancet Neurol. 2018 Jun;17(6):519-529. doi: 10.
1016/S1474-4422(18)30114-5.
22. Horikawa Y, Hosomichi K, Enya M, Ishiura H,
Suzuki Y, Tsuji S, Sugano S, Inoue I, Takeda J. No
novel, high penetrant gene might remain to befound in Japanese patients with unknown MODY.
J Hum Genet. 2018 Jul;63(7):821-829. doi: 10.
1038/s10038-018-0449-4.
23. Ishiura H, Doi K, Mitsui J, Yoshimura J,
Matsukawa MK, Fujiyama A, Toyoshima Y,
Kakita A, Takahashi H, Suzuki Y, Sugano S, Qu
W, Ichikawa K, Yurino H, Higasa K, Shibata S,
Mitsue A, Tanaka M, Ichikawa Y, Takahashi Y,
Date H, Matsukawa T, Kanda J, Nakamoto FK,
Higashihara M, Abe K, Koike R, Sasagawa M,
Kuroha Y, Hasegawa N, Kanesawa N, Kondo T,
Hitomi T, Tada M, Takano H, Saito Y, Sanpei K,
Onodera O, Nishizawa M, Nakamura M, Yasuda T,
Sakiyama Y, Otsuka M, Ueki A, Kaida KI,
Shimizu J, Hanajima R, Hayashi T, Terao Y,
Inomata-Terada S, Hamada M, Shirota Y, Kubota
A, Ugawa Y, Koh K, Takiyama Y, OhsawaYoshida N, Ishiura S, Yamasaki R, Tamaoka A,
Akiyama H, Otsuki T, Sano A, Ikeda A, Goto J,
Morishita S, Tsuji S. Expansions of intronic
TTTCA and TTTTA repeats in benign adultfamilial myoclonic epilepsy. Nat Genet. 2018
Apr; 50(4): 581-590. doi: 10.1038/s41588-0180067-2.
24. Tohnai G, Nakamura R, Sone J, Nakatochi M,
Yokoi D, Katsuno M, Watanabe H, Watanabe H,
Ito M, Li Y, Izumi Y, Morita M, Taniguchi A,
Kano O, Oda M, Kuwabara S, Abe K, Aiba I,
Okamoto K, Mizoguchi K, Hasegawa K, Aoki M,
Hattori N, Onodera O, Naruse H, Mitsui J,
Takahashi Y, Goto J, Ishiura H, Morishita S,
Yoshimura J, Doi K, Tsuji S, Nakashima K, Kaji
R, Atsuta N, Sobue G; Japanese Consortium for
Amyotrophic
LateralSclerosis
Research(JaCALS). Frequency and characteristics of the
TBK1 gene variants in Japanese patients withsporadic amyotrophic lateral sclerosis. Neurobiol
Aging. 2018 Apr; 64:158.e15-158.e19. doi: 10.
1016/j.neurobiolaging.2017.12.005.
25. Tanabe H, Higuchi Y, Yuan JH, Hashiguchi A,
Yoshimura A, Ishihara S, Nozuma S, Okamoto Y,

Matsuura E, Ishiura H, Mitsui J, Takashima R,
Kokubun N, Maeda K, Asano Y, Sunami Y, Kono
Y, Ishigaki Y, Yanamoto S, Fukae J, Kida H,
Morita M, Tsuji S, Takashima H. Clinical andgenetic features of Charcot-Marie-Tooth disease
2F and hereditary motor neuropathy 2B in Japan.
J Peripher Nerv Syst. 2018 Mar;23(1):40-48. doi:
10.1111/jns.12252.
26. Amano-Takeshige H, Oyama G, Kanai K,
Miyagawa T, Mitsui J, Ugawa Y, Tsuji S, Hattori
N. A Japanese family with mutation in theproteinase inhibitor 12 L47P gene: A case report.
J Neurol Sci. 2018 Jan 15;384:126-128. doi: 10.
1016/j.jns.2017.11.029.
27. Walsh RR, Krismer F, Galpern WR, Wenning GK,
Low PA, Halliday G, Koroshetz WJ, Holton J,
Quinn NP, Rascol O, Shaw LM, Eidelberg D,
Bower P, Cummings JL, Abler V, Biedenharn J,
Bitan G, Brooks DJ, Brundin P, Fernandez H,
Fortier P, Freeman R, Gasser T, Hewitt A,
Höglinger GU, Huentelman MJ, Jensen PH,
Jeromin A, Kang UJ, Kaufmann H, Kellerman L,
Khurana V, Klockgether T, Kim WS, Langer C,
LeWitt P, Masliah E, Meissner W, Melki R,
Ostrowitzki S, Piantadosi S, Poewe W, Robertson
D, Roemer C, Schenk D, Schlossmacher M,
Schmahmann JD, Seppi K, Shih L, Siderowf A,
Stebbins GT, Stefanova N, Tsuji S, Sutton S,
Zhang J. Recommendations of the Global
Multiple System Atrophy Research Roadmap
Meeting. Neurology. 2018 Jan 9;90(2):74-82. doi:
10.1212/WNL.0000000000004798.
28. Kubota A, Ishiura H, Mitsui J, Sakuishi K, Iwata
A, Yamamoto T, Nishino I, Tsuji S, Shimizu J. A
Homozygous LAMA2 Mutation of c.818G>A
Caused Partial Merosin Deficiency in a JapanesePatient. Intern Med. 2018 Mar 15;57(6):877-882.
doi: 10.2169/internalmedicine.9588-17.
29. Ohtomo G, Mano T, Seto A, Tsuji S. Degenerationof the Substantia Nigra Following Ipsilateral
Striatal Infarction. Intern Med. 2018 Mar 1;
57(5):767-768. doi: 10.2169/internalmedicine.
9442-17.
30. Ohtomo R, Bannai T, Ohtomo G, Shindo A,
Tomimoto H, Tsuji S, Iwata A. Cilostazol
alleviates white matter degeneration caused bychronic cerebral hypoperfusion in mice:

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Implication of its mechanism from gene
expression analysis. Neurosci Lett. 2018 Jan 1;
662:247-252. doi: 10.1016/j.neulet.2017.10.045.
31. Naruse H, Ishiura H, Mitsui J, Date H, Takahashi
Y, Matsukawa T, Tanaka M, Ishii A, Tamaoka A,
Hokkoku K, Sonoo M, Segawa M, Ugawa Y, Doi
K, Yoshimura J, Morishita S, Goto J, Tsuji S.
Molecular epidemiological study of familial
amyotrophic lateral sclerosis in Japanese
population by whole-exome sequencing andidentification of novel HNRNPA1 mutation.
Neurobiol Aging. 2018 Jan;61:255.e9-255.e16.
doi: 10.1016/j.neurobiolaging.2017.08.030.
32. Morimoto S, Hatsuta H, Motoyama R, Kokubo Y,
Ishiura H, Tsuji S, Kuzuhara S, Murayama S.
Optineurin pathology in the spinal cord ofamyotrophic
lateralsclerosis/parkinsonismdementia complex patients in Kii Peninsula, Japan.
Brain Pathol. 2018 May; 28(3):422-426. doi: 10.
1111/bpa.12558.
33. Kurihara M, Ishiura H, Sasaki T, Otsuka J,
Hayashi T, Terao Y, Matsukawa T, Mitsui J,
Kaneko J, Nishiyama K, Doi K, Yoshimura J,
Morishita S, Shimizu J, Tsuji S. Novel De Novo
KCND3 Mutation in a Japanese Patient withIntellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia. Cerebellum. 2018 Apr;
17(2):237-242. doi: 10.1007/s12311-017-0883-4.
34. Matsumoto L, Suzuki K, Mizuno Y, Ohike Y,
Ozeki A, Ono S, Takanashi M, Sawaki D, Suzuki
T, Yamazaki T, Tsuji S, Iwata A. Association of
subclinical carotid atherosclerosis with immediate
memory and other cognitive functions. Geriatr
Gerontol Int. 2018 Jan;18(1):65-71. doi: 10.1111/
ggi.13142.

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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

412

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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Division of Chronic Kidney Disease(CKD) Pathophysiology
Division Chief (Professor)
Reiko Inagi, Ph.D.

Assistant Professor
Tsuyoshi Inoue, M.D., Ph.D.

Postdoctoral fellow
Yu Ishimoto, M.D., Ph.D. (Division of Nephrology and Endocrinology)

PhD Students
Hiroshi Maekawa, M.D. (Division of Nephrology and Endocrinology)
Sho Hasegawa, M.D. (Division of Nephrology and Endocrinology)
JSPS Research Fellowship for Young Scientists (DC2)
Rie Fujii, M.D. (Division of Nephrology and Endocrinology)
Rie Uni, M.D. (Division of Nephrology and Endocrinology)

Visiting Researcher
Bongkod Surattichaiyakul, M.D.
(Bhumirajanakarindra Kidney Institute Hospital, Bangkok, Thailand)
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

414

replacement therapy. A second risk is the development
and progression of lifestyle-related diseases, such asheart attack and arteriosclerosis. The kidneys work
closely with the heart and other organs, and a decrease
in renal function causes dysfunction of the heart andblood vessels. This adverse impact of the progressionof CKD on other organs underlines the importance of
the kidneys in maintaining general health. Further,many researchers have also focused on the vicious
spiral of aging and CKD: aging worsens the
progression of CKD, while CKD accelerates aging.
With our modern lifestyles and the super-aging society,
CKD cannot be separated from lifestyle-relateddiseases, and senility cannot be separated from CKD.
Creating a healthy, long-lived society full of energy
and vigor requires that the quality of life (QOL) of theelderly be improved. In turn, total medical
expenditures will also be decreased. These are important issues requiring urgent solutions. Against thisbackground, the Division of CKD Pathophysiology
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)
 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)AwardsDr. Tsuyoshi Inoue received the Medical Research
Encouragement Prize of The Tokyo Medical
Association.
Dr. Yu Ishimoto received the YIA (Young
Investigator Award) at the 61st annual meeting of415Japanese Society of Nephrology.
Dr. Hiroshi Maekawa received the Best Presentation
Award Runner Up at the 2nd Conference of Uremic
Toxin research.
Dr. Sho Hasegawa received the Best Presentation
Award at the Japan Kidney Council 2018.
Dr. Sho Hasegawa received the CKD Award at the 8thChronic Kidney Disease Frontier.

References
1. Inoue T, Maekawa H, Inagi R. Organelle crosstalkin the kidney. Kidney Int. 2019 Mar 4. doi:10.
1016/j.kint.2018.11.035. [Epub ahead of print]
2. 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 ischemia/
reperfusion injury in the kidney. Kidney Int.
2019 Mar;95(3):563- 576. doi:10.1016/j.kint.
2018.09.020.
3. 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. ATF6α
downregulation of PPARα promotes lipotoxicityinduced tubulointerstitial fibrosis. Kidney Int.
2019 Mar;95(3):577-589. doi: 10.1016/j.kint.
2018.09.023.
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. Ishimoto Y, Tanaka T, Yoshida Y, Inagi R.
Physiological and pathophysiological role ofreactive oxygen species and reactive nitrogenspecies in the kidney. Clin Exp Pharmacol
Physiol. 2018 Nov;45(11):1097-1105. doi: 10.
1111/1440-1681.13018.
6. Tanaka S, Sugiura Y, Saito H, Sugahara M,
Higashijima Y, Yamaguchi J, Inagi R, Suematsu

M, Nangaku M, Tanaka T. Sodium-glucose
cotransporter 2 inhibition normalizes glucose
metabolism and suppresses oxidative stress in thekidneys of diabetic mice. Kidney Int. 2018 Nov;
94(5):912-925. doi: 10.1016/j.kint.2018.04.025.
7. Anusornvongchai T, Nangaku M, Jao TM, Wu CH,
Ishimoto Y, Maekawa H, Tanaka T, Shimizu A,
Yamamoto M, Suzuki N, Sassa R, Inagi R. Palmitate
deranges erythropoietin production via transcription
factor ATF4 activation of unfolded protein response.
Kidney Int. 2018 Sep;94(3):536-550. doi: 10.1016/j.
kint.2018.03.011.

416

Department of
Immunotherapeutics
Project Professor
Kazuhiro Kakimi, M.D., Ph.D.

Project Lecturer
Hirokazu Matsushita, M.D., Ph.D.

Homepage

http://immunoth.umin.jp/

Introduction and Organization
The aim of our Department is to execute basic andclinical research on cancer immunology and immunotherapy and to establish its role in the treatment ofcancer. Cancer immunotherapy requires the expansionof functional T cells and/or dendritic cells (DC) thatare responsible for the anti-tumor immune response invivo. The GMP-level Cell Processing Center (CPC)
was installed in the Department. Peripheral bloodmononuclear cells (PBMC) are isolated from thepatients and processed in the CPC to ensure that they
maintain optimal functionality, or for triggering new
functions in vitro prior to clinical application.
Autologous cells derived from cancer patients are processed for therapeutic use in our CPC in accordancewith all current regulations and ethical obligations.
To perform reliable high quality translational
research, we designed our Department’s facilities
literally from the bench to the bedside. The Department consists of three divisions, (1) laboratory forbasic and pre-clinical research (2); Cell Processing
Center and (3) outpatient clinic. Because these threedivisions are situated side-by-side on the same floor,
close cooperation between the members of each groupcan be more easily and better organized. As soon as
blood is drawn from the patient at the outpatient clinic,
it is directly transferred to the CPC through the
pass-box between the two. The cells processed andcultured in the CPC are scrutinized in the laboratorynext door to the clinic and CPC regarding their quality

and function. Those cultured cells which are approved
following this examination are transferred back to theclinic and administered to the patient. The patients arefollowed-up at regular intervals by the research staff
at the laboratory to monitor their immune responses toevaluate the impact of the immunotherapy.
All protocols for cancer immunotherapy performed in our Department are submitted to theinstitutional review board (IRB). Once approved, theprotocols are registered in the UMIN clinical researchregistration system to provide open access to any
interested parties. Because the cells used for treatment
are derived from each individual patient; it is difficult
to guarantee consistent quality. However, we doeverything possible to provide the cultured cells withthe best conditions, by means of well-trained specialist staff following standard operating procedures. All
these efforts allow us to reliably perform cancer
immunotherapy clinical trials in cooperation withmany clinical departments of the University of Tokyo
Hospital.
Since “The Act on the Safety of Regenerative
Medicine” and the “Pharmaceuticals, Medical Devices
and Other Therapeutic Products Act” came into effective on November 25, 2014, we registered our cellprocessing facility and got approved (DC3140011).
All the protocols for cell therapy was also reviewed
and approved by institutional committee for theregenerative medicine.

417

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 are underway 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.
2. UMIN registration number ： UMIN000001419
active, recruiting. The efficacy and safety ofautologous γδ T cell transfer therapy foresophageal cancer
3. UMIN registration number ： UMIN000008097
active, recruiting. Combination of chemotherapy
with docetaxel / cisplatin / fluorouracil (DCF) andautologous γδ T cell transfer therapy foresophageal cancer.
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 by means of experiments using animalmodels and by the immunological monitoring of thepatients themselves in clinical research.

Research activities
All our research activities are directed atunderstanding the dynamics of the immune response
in vivo at the molecular, cellular and organismal levels
and to develop more effective immunotherapy against
cancer. To this end, we perform both clinical immunology in humans and basic preclinical immunology
using animal models. We especially focus on thespatiotemporal analysis of anti-tumor immunity inboth humans and experimental animals. During thecourse of each trial, many samples from the clinic aredelivered to the research laboratory to monitor
immune responses in patients. Tumor-specific immunity is evaluated using standardized immunologicalassays, such as ELISA, ELISPOT and flow cytometry.
To develop novel immunological interventions,tumor-bearing mice are used to confirm principles
believed to be the basis for the new immunotherapy.
Using many different TCR-transgenic and human
MHC class I-bearing mice we can provide clear
answers regarding the antigen-specific immune
response. As described above, we pursue a researchstrategy of going back and forth from the bench to thebedside and from basic to clinical immunology inorder to maximize benefit to patients via the rapid
application of new knowledge to clinical practice.

List of Publications
1. Hoshikawa M, Aoki T, Matsushita H, Karasaki T,
Hosoi A, Odaira K, Fujieda N, Kobayashi Y,
Kambara K, Ohara O, Arita J, Hasegawa K, Kakimi
K, Kokudo N. NK cell and IFN signatures are
positive prognostic biomarkers for resectablepancreatic cancer. Biochem Biophys Res Commun.
2018 Jan 8;495(2):2058-2065.
2. Hosoi A, Takeda K, Nagaoka K, Iino T, Matsushita
H, Ueha S, Aoki S, Matsushima K, Kubo M,
Morikawa T, Kitaura K, Suzuki R, Kakimi K.
Increased diversity with reduced “diversity
evenness” of tumor infiltrating T-cells for the
successful cancer immunotherapy. SCIENITIFICREPORTS. 2018 Jan 18;8(1):1058.
3. Yamamoto M, Nomura S, Hosoi A, Nagaoka K, Iino
T, Yasuda T, Saito T, Matsushita H, Uchida E, Seto Y,
Goldenring JR, Kakimi K, Tatematsu M, Tsukamoto.
Established gastric cancer cell lines transplantable
into C57BL/6 mice show fibroblast growth factor
receptor 4 promotion of tumor growth. Cancer Sci.

418

2018 May;109(5):1480-1492.
4. Imai Y, Hasegawa K, Matsushita H, Fujieda N, SatoS, Miyagi E, Kakimi K, Fujiwara K. Expression ofmultiple immune checkpoint molecules on T cells inmalignant ascites from epithelial ovarian carcinoma.
Oncol Lett. 2018, May;15(5):6457-6468.
5. Karasaki T, Qiang G, Anraku M, Sun Y,
Shinozaki-Ushiku A, Sato E, Kashiwabara K,
Nagayama K, Nitadori JI, Sato M, Murakawa T,
Kakimi K, Fukayama M, Nakajima J. High CCR4
expression in the tumor microenvironment is a poor
prognostic indicator in lung adenocarcinoma. J
Thorac Dis. 2018 Aug;10(8):4741-4750.
6. Kawashima M, Sato M, Murakawa T, Anraku M,
Konoeda C, Hosoi A, Kakimi K, Nakajima J. Roleof Toll-like Receptor 4 Expressed by Fibroblasts in
Allograft Fibrosis in Mouse Orthotopic Tracheal
Transplantation.
Transplant
Proc.
2018
Dec;50(10):3863-3872.

4.

5.

6.

Presentation at International
conference
1. 2018/4/16, AACR(American Association for Cancer
Research) Annual Meeting 2018、McCormick Place
North/South Chicago, Illinois, Akihiro Hosoi,
Hirokazu Matsushita, Kazuyoshi Takeda, Ryuji
Suzuki, Kazuhiro Kakimi, Diversity evenness of
TCR repertoire in the tumor and periphery reflects
antitumor activity and immune-related adverse
events, respectively
2. 2018/4/18, AACR(American Association for Cancer
Research) Annual Meeting 2018、McCormick Place
North/South Chicago, IllinoisHirokazu Matsushita,
Kosei Hasegawa, Katsutoshi oda, Shogo Yamamoto,
Kayo Asada, Akira Yabuno, Akira Nishijima,
Takahiro krasaki, Yuji Ikeda, Keiichi Fujiwara,
Hiroyuki Aburatani, Kazuhito Kakimi, Neoantigen
load and HLA-class I expression characterize asubset of HR-proficient high-grade serous ovariancarcinomas with favorable prognosis and T cellinflamed phenotype.
3. 2018/6/27, THE 45th NAITO CONFERENCE ON
Immunological and Molecular Bases for Cancer
Immunotherapy, SAPPORO, Japan, Akihiro HOSOI,
Hirokazu MATSUSHITA, Kazuhiro KAKIMI, Shoji
IKEDA, Diversity evenness of TCR repertoire is

7.

8.

9.

associated with anti-tumor immunity and immunerelated adverse events
2018/6/27, THE 45th NAITO CONFERENCE ON
Immunological and Molecular Bases for Cancer
Immunotherapy, SAPPORO, Japan, Yukari
KOBAYASHI,
KosukeODAIRA,
Kaori
KAMBARA, Nao FUJIEDA, AKihiro HOSOI, Koji
NAGAOKA, Hirokazu MATSUSHITA, Kazuhiro
KAKIMI, Detection of neoantigen-reactive T cell
response in mice and human
2018/6/28, THE 45th NAITO CONFERENCE ON
Immunological and Molecular Bases for Cancer
Immunotherapy, SAPPORO, Japan Kazuhiro
KAKIMI, An Immunogram for the cancer-immunity
cycle
2018/6/28, THE 45th NAITO CONFERENCE ON
Immunological and Molecular Bases for Cancer
Immunotherapy, SAPPORO, Japan, Hirokazu
MATSUSHITA, Kosei HASEGAWA, Kazuhito
KAKIMI, Neoantigen burden and HLA -class I
experession difine a subgroup of HR-proficent
high-grade serous ovarian carcinomas with
T-cell-inflamed phenotype and better prognosis
2018/6/28, THE 45th NAITO CONFERENCE ON
Immunological and Molecular Bases for Cancer
Immunotherapy, SAPPORO, Japan, Yasuyoshi
SATO, Hirokazu MATSUSHITA, Kazuhito
KAKIMI, Yasuyuki SETO, Phase I trial of
autologous tumor lysate-pulsed dendritic cell
vaccination therapy after resection of stage IIA(T2N0,T3N0)esophageal cancer
2018/6/28, THE 45th NAITO CONFERENCE ON
Immunological and Molecular Bases for Cancer
Immunotherapy,
SAPPORO,
Japan,Koji
NAGAOKA, Akihiro Hosoi, Tamaki IINO,
Hirokazu MATSUSHITA, Kazuhiro KAKIMI,
Dendritic cell vaccines induce phenopically,
metabolically and functionally distinct antigen
specific memory CD8⁺ T cells from those by peptide
vaccines
2018/6/28, THE 45th NAITO CONFERENCE ON
Immunological and Molecular Bases for Cancer
Immunotherapy, SAPPORO, Japan, Kosuke
ODAIRA, Ikuo WADA, Hitokazu MATSUSHITA,
Kazuhiro KAKIMI, Daisuke NOGUCHI, Integrated
analysis of tumor-microenvironment (TIME) andtumor infilrating cells in gastric cancer

419

10. 2018/9/25, IASLC 19th World Conference on Lung
Cancer, Tronto, Canada T. Karasaki, K. Kitano, K.
Nagayama, J. Nitadori, M. Sato, M. Anraku, K.
Kakimi, J. Nakajima, Difference of tumor
mutational burden is associated with distinct
immune microenvironment in the T-cell-inflamedlung adenocarcinoma.

420

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421

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.

2.

Sumitomo S, Nagafuchi Y, Tsuchida Y, Tsuchiya
H, Ota M, Ishigaki K, Nakachi S, Kato R,
Sakurai K, Hanata N, Tateishi S, Kanda H,
Suzuki A, Kochi Y, Fujio K, Yamamoto K. A
gene module associated with dysregulated TCR
signaling pathways in CD4+ T cell subsets inrheumatoid arthritis. J Autoimmun. 89:21-9, 2018
Sakurai K, Ishigaki K, Shoda H, Nagafuchi Y,
Tsuchida Y, Sumitomo S, Kanda H, Suzuki A,
Kochi Y, Yamamoto K, Fujio K. HLA-DRB1
Shared Epitope Alleles and Disease Activity Are
Correlated with Reduced T Cell Receptor
Repertoire Diversity in CD4+ T Cells in
Rheumatoid Arthritis. J Rhematol. 45(7): 905-14,
2018

422

Department of Ubiquitous
Preventive Medicine
Associate Professor

Yuichi Ikeda, M.D., Ph.D.

Assistant Professor

Kazutaka Ueda, M.D., Ph.D.

Introduction and Organization

Research Activities

As an official department in the Graduate School of
Medicine of the University of Tokyo, the Departmentof Ubiquitous Preventive Medicine was established inAugust 1st, 2007, with a donation from threepharmaceutical 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 wasestablished in 2007 within the University of Tokyo
Hospital. In collaboration with our department,
the Department of Clinical Epidemiology and
Systems also support the management of the
Department of Epidemiology and Preventive
Medicine.

Our goal is to create diagnostic and therapeutic basis
for prevention and early detection of cardiovasculardiseases by utilizing advanced techniques ofbiochemistry and molecular pharmacology.
Weespecially focus on the discovery of bioactive
molecules and diagnostic biomarkers in order topromote translational research, which connects basic
scientific findings to tangible clinical application.
One of our achievements is the establishment of anovel technique for detecting post-translational
modification and degradation of B-type natriuretic
peptide, one of the most important biomarkers in
cardiovascular pathologies such as ischemic heartdisease and heart failure. This unique technique wasdeveloped in collaboration with Shimadzu Corporation. We have already confirmed and published its
utility in clinical practice (Clin Chem, in press),further, issued press-release from the University ofTokyo 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.

423

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.

6.

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. Aoyama N, Suzuki JI, Kumagai H, Ikeda Y,
Akazawa H, Komuro I, Minabe M, Izumi Y, Isobe
M. Specific periodontopathic bacterial infection
affects hypertension in male cardiovasculardisease patients. Heart Vessels. 33(2):198-204,2018
2. Aoyama N, Suzuki JI, Kobayashi N, Hanatani T,
Ashigaki N, Yoshida A, Shiheido Y, Sato H,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Minabe M, Izumi Y, Isobe M. Japanesecardiovascular disease patients with diabetes
mellitus suffer inccreased tooth loss in comparison to those without diabetes mellitus -A
Cross-sectional Study. Intern Med. 57:777-782,
2018
3. Fujiwara T, Takeda N, Hara H, Morita H,
Kishihara J, Inuzuka R, Yagi H, Maemura S, Toko
H, Harada M, Ikeda Y, Kumagai H, Nomura S,
Takimoto E, Akazawa H, Ako J, Komuro I. Eur J
Hum Genet. 26:1151-1158, 2018
4. Takeda N, Inuzuka R, Maemura S, Morita H,
Nawata K, Fujita D, Taniguchi H, Yagi H, Kato M,
Nishimura H, Hirata Y, Ikeda Y, Kumagai H,
Amiya E, Hara H, Fujiwara T, Akazawa H, Suzuki
JI, Imai Y, Nagai R, Takamoto S, Hirata Y, Ono M,
Komuro I. Impact of pathogenic FBN1 variant
types on the progression of aortic disease inpatients with marfan syndrome. Circ Genom
Precis Med. 11:e002058, 2018
5. Akimoto S, Suzuki JI, Aoyama N, Ikeuchi R,
Watanabe H, Tsujimoto H, Wakayama K,

7.

8.

9.

Kumagai H, Ikeda Y, Akazawa H, Komuro I. A
novel bioabsorbable sheet that delivers NF-ĸB
decoy oligonucleotide restrains abdominal aortic
aneurysm development in rats. Int Heart J. 59:
1134-1141, 2018
Hara H, Takeda N, Kondo M, Kubota M, Saito T,
Maruyama J, Fujiwara T, Maemura S, Ito M,
Naito AT, Harada M, Toko H, Nomura S,
Kumagai H, Ikeda Y, Ueno H, Takimoto E,
Akazawa H, Morita H, Aburatani H, Hata Y,
Uchiyama M, Komuro I. Discovery of a small
molecule to increase cardiomyocytes and protect
the heart after ischimic injury. JACC BasicTransl Sci. 3:639-653, 2018
Komuro J, Ueda K, Kaneko M, Nitta S, Kasao M,
Yokoyama M. Various cardiac abnormalities
caused by bacterial myocarditis. Int Heart J. 59:
229-232, 2018
Ueda K, Takimoto E, Lu Q, Liu P, Fukuma N,
Adachi Y, Suzuki R, Chou S, Baur W, Aronovitz
MJ, Greenberg AS, Komuro I, Karas RH.
Membane-Initiated estrogen receptor signaling
mediates metabolic homeostasis via central
activation of protein phosphatase 2A. Diabetes.
67:1524-1537, 2018
Kaneko M, Ueda K, Nishimae I, Nitta S, Suzuki
M, Kasao M, Shirai T. Subendocardial ischemia
because of coronary artery spasm causes transient
severe mitral regurgitation. Circ Heart Fail. 11:
e005496, 2018

424

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,425

we accepted a research student from Korea. From thisyear, the student from Korea was accepted as a mastercourse student.

Teaching activities
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 Prof. Hiroyasu
Iwata, Waseda University for Gerontological Nursing
II for graduate course. In a part of GerontologicalNursing I for graduate course, the members in thedepartment lectured the features and reading methodof journal papers of engineering research based on
typical publications.
As for the other education activity, our department
supported management of the sixth seminar for
nursing science and engineering, which was organizedby global nursing research center. The staffs in our
department had engineering-related lectures. In
addition, our departments hold advanced lecture
course about 3D scanner and printer.
From establishment of global nursing research center,the laboratory have accepted training or visitation in
our laboratory 21 times (11 from foreigners, and 10
from domestic 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
naturally, 2) understanding the typical behaviors, and
3) predicting diseases, injuries, and accidents using
various sensing technology.
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 and algorithm for typical behavior pattern extraction andtransition 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 the clinical field, we started the research at the
University hospital using communication robots from2017. In this year, we extended the robot research
field to another facility with Department ofGerontological Nursing/Wound Care Management.
We started a new research theme collaborating with
Department of Gerontological Nursing/Wound CareManagement. The research aim is to investigate
relationship between pressure ulcer occurrence andpressure distribution during motion among wheel
chair athletes. A master course student, who was
belonging to Department of Gerontological Nursing/
Wound Care Management conducted qualitative
research on pressure distributions during motion andinvestigated the difference of pressure distribution
patterns and pressure parameters such as peekpressure between athletes with and without pressure
ulcers. He wrote master course thesis “Relationshipbetween pressure ulcers and dynamic buttock pressure
distributions during performance in wheelchairbasketball athletes” and graduated.

426

We achieved the following award in this year.
1. Taketoshi Mori, presentation award of JapaneseSociety of Wound, Ostomy, and ContinenceManagement (domestic conference)．Taketoshi Mori,
Koki Ono, Hiroshi Noguchi, Hiromi Sanada.
“Automatic estimation of depth and size of Design-Rfrom digital camera image using machine learning”.
Proceedings of the 27th annual conference of JapaneseSociety of Wound, Ostomy, and ContinenceManagement. O-13, 2018. (Sapporo, 2018/5/19)

References
1. H. Tanaka S, Yabunaka K, Matsumoto M, Tamai
N, Noguchi H, Yoshida M, Nakagami G, Sugama
J, Sanada H. Fecal distribution changes using
colorectal ultrasonography in older people withphysical and cognitive impairment at long-termcare facilities: A longitudinal observational study.
Healthcare, 2018; 6(2): 55. https://doi.org/10.
3390/healthcare6020055
2. Shikama M, Nakagami G, Noguchi H, Mori T,
Sanada H. Development of personalized fitting
device with three-dimensional solution for prevention of NIV oral–nasal mask-related pressure
ulcers. Respir Care.August 2018, 63 (8) 10241032; DOI: https://doi.org/10.4187/respcare.
05691
3. Manaka Saegusa, Hiroshi Noguchi, Gojiro
Nakagami, Taketoshi Mori, Hiromi Sanada.
Evaluation of comfort associated with the use of arobotic mattress with an interface pressure
mapping system and automatic inner air-cellpressure adjustment function in healthy volunteers.
Journal of Tissue Viability. 27(3):146-152, 8 2018.
https://www.journaloftissueviability.com/article/S
0965-206X(17)30131-6/fulltext DOI ： doi: 10.
1016/j.jtv.2018.06.002
4. Kase, R.; Amemiya, A.; Okonogi, R.; Yamakawa,
H.; Sugawara, H.; Tanaka, Y.L.; Komiyama, M.;
Mori, T. Examination of the Effect of Suitable
Size of Shoes under the Second Metatarsal Headand Width of Shoes under the Fifth Metatarsal
Head for the Prevention of Callus Formation in
Healthy Young Women. Sensors 2018, 18, 3269.
https://doi.org/10.3390/s18103269
5. Murayama R, Takahashi T, Tanabe H, Yabunaka K,

Oe M, Komiyama C, Sanada H. Exploring thecauses of peripheral intravenous catheter failure
based on shape of catheters removed from various
insertion sites. Drug Discoveries and Therapeutics.
2018;12(3):170-7.

427

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
Kimiyo Terada
Miyuki Kurosaki

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 Protocol development
 Regulatory science Ethics

428

 IT
 Safety information and PMS
 Translational research methodology
2. Acceptance of clinical trial staffs from other sites,that is, conducting an on-the-job training (OJT)
3. Support to clinical researchers, especially those in
the University of Tokyo Hospital, in collaboration
with the Clinical Research Support Center and theDepartment of Clinical Epidemiology and Systems;
 Consultation works on medical statistics andresearch methodology
 Functioning as a data center and stuffs
participate in projects as biostatisticians or
clinical data managers.

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.

4.

5.

6.

References
1. Yoshida Y, Nidatori J, Shinozaki-Ushiku Y, Sato J,
Miyaji T, Yamaguchi T, Fukayama M, Nakajima J.
Comparison between two-dimensional and threedimensional approaches to solid component
measurement as radiological criteria for sublobar
resection in lung adenocarcinoma of ≤2 cm. Surgery
Today (In press)
2. Akechi T, Yamaguchi T, Uchida M, Imai F, Momino
K, Katsuki F, Sakurai N, Miyaji T, Horikoshi M,
Furukawa T, Iwata H, Uchitomi Y. Smartphone
problem-solving and behavioural activation therapy
to reduce fear of recurrence among patients withbreast cancer (Smartphone Intervention to Lessen
fear of cancer recurrence: SMILE project): protocol
for a randomized controlled trial. BMJ Open 2018;8:e024794.
3. Matsuda Y, Morita T, Miyaji T, Ogawa T, Kato K,

7.

8.

Kawaguchi T, Tokoro A, Iwase S, Yamaguchi T,
Inoue Y. Morphine for Refractory Dyspnea inInterstitial Lung Disease: A Phase I Study (JORTCPAL 05). Journal of Palliative Medicine. J Palliat
Med. 2018 Aug 21. doi: 10.1089/jpm.2018.0272.
Zenda S, Yamaguchi T, Yokota T, Miyaji T, Mashiko
T, Tanaka M, Yonemura M, Takeno M, Okano T,
Kawasaki T, Nakamori Y, Ishii S, Shimada S,
Uchitomi Y. Topical Steroid versus Placebo for thePrevention of Radiation Dermatitis in Head andNeck Cancer Patients receiving Chemoradiotherapy:
The Study Protocol of J-SUPPORT 1602 (TOPICS
Study), a Randomized Double-blinded Phase 3 Trial.
BMC Cancer. 2018 Sep 6;18(1):873. doi: 10.1186/
s12885-018-4763-1
Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A,
Yabusaki H, Imano M, Imamoto H, Kodera Y,
Uenosono Y, Amagai K, Kadowaki S, Miwa H,
Yamaguchi H, Yamaguchi T, Miyaji T, andKitayama J, for the Japan Intraperitoneal Chemotherapy Study Group. Phase III Trial Comparing
Intraperitoneal and Intravenous Paclitaxel Plus S-1
Versus Cisplatin Plus S-1 in Gastric Cancer Patientswith Peritoneal Metastasis: PHOENIX-GC Trial. J
Clin Oncol May 10 2018
Yasaka M, Koretsune Y, Yamashita T, Oda E,
Matsubayashi D, Ota K, Kobayashi M, Matsushita Y,
Kaburagi J, Ibusuki K, Takita A, Iwashita M,
Yamaguchi T: Recurrent Stroke and Bleeding
Events after Acute Cardioembolic Stroke-Analysis
Using Japanese Healthcare Database fromAcute-Care Institutions. J Stroke Cerebrovasc Dis.
2018 Apr, 27(4):1012-1024. doi: 10.1016/j.
jstrokecerebrovasdis.2017.11.002. Epub 2017 Dec
12.
Fuji S, Utsunomiya A, Inoue Y, Miyagi T, Owatari S,
Sawayama Y, Moriuchi Y, Choi I, Shindo T, Yoshida
SI, Yamasaki S, Yamaguchi T, Fukuda T: Outcomesof patients with relapsed aggressive adult T-cellleukemia-lymphoma: clinical effectiveness of antiCCR4 antibody and allogeneic hematopoietic stem
cell transplantation. Haematologica. 2018 May;
103(5):e211-e214. doi: 10.3324/haematol.2017.
184564. Epub 2018 Jan 25. No abstract available.
Ishiki H, Yamaguchi T, Matsumoto Y, Kiuchi D,
Satomi E: Effect of early palliative care: complex
intervention and complex results. Lancet Oncol.

4292018 May; 19(5):e221. doi: 10.1016/S1470-2045(18)30238-9. No abstract available.
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: Role of up-front allogeneic
hematopoietic stem cell transplantation for patientswith aggressive adult T-cell leukemia-lymphoma: adecision analysis. Bone Marrow Transplant. 2018
Jul; 53(7):905-908. doi: 10.1038/s41409-017-00824. Epub 2018 Jan 25. No abstract available.
10. Harada K, Doki N, Miyazaki Y, Wakita A, Ohtake S,
Takada S, Komatsu H, Kubo K, Takeshita A, Adachi
Y, Kiyoi H, Yamaguchi T, Yoshida M, Naoe T,
Ohashi K: Clinical impact of underweight status at
diagnosis on elderly patients with acute myeloid
leukemia: a retrospective study of JALSG GML200.
Ann Hematol. 2018 Aug; 97(8):1481-1483. doi:
10.1007/s00277-018-3281-1. Epub 2018 Mar 1. No
abstract available.
11. Hashimoto H, Abe M, Yanai T, Yamaguchi T, Zenda
S, Uchitomi Y, Fukuda H, Mori M, Iwasa S,
Yamamoto N, Ohe Y: Study protocol for
J-SUPPORT 1604 (J-FORCE): a randomized,
double blind, placebo-controlled Phase III study
evaluating olanzapine (5 mg) plus standard triple
antiemetic therapy for prevention of chemotherapy
induced nausea and vomiting in patients receiving
cisplatin-based highly emetogenic chemotherapy.
Jpn J Clin Oncol. 2018 Oct 1; 48(10):950-952. doi:
10.1093/jjco/hyy114.
12. Yamaguchi T, Kitajima Y, Miyauchi Y, Izawa K,
Tanaka M, Hirata M, Sadatsuki Y, Ogawa Y:
Assessment of bleeding in patients with
disseminated intravascular coagulation after
receiving surgery and recombinant human soluble
thrombomodulin: A cohort study using a database.
PLoS One. 2018 Oct 8; 13(10):e0205146. doi:
10.1371/journal.pone.0205146. eCollection 2018.
13. Kako J, Morita T, Yamaguchi T, Kobayashi M,
Sekimoto A, Kinoshita H, Ogawa A, Zenda S,
Uchitomi Y, Inoguchi H, Matsushima E: Fan
Therapy Is Effective in Relieving Dyspnea inPatients With Terminally Ill Cancer: A Parallel-Arm,
Randomized Controlled Trial. J Pain Symptom
Manage. 2018 Oct; 56(4):493-500. doi: 10.1016/j.
jpainsymman.2018.07.001. Epub 2018 Aug 6.

14. Ishii T, Tanaka Y, Kawakami A, Saito K, Ichinose K,
Fujii H, Shirota Y, Shirai T, Fujita Y, Watanabe R,
Chiu SW, Yamaguchi T, Harigae H: Multicenter
double-blind randomized controlled trial to evaluate
the effectiveness and safety of bortezomib as atreatmentforrefractory
systemic
lupus
erythematosus. Mod Rheumatol. 2018 Nov; 28(6):986-992. doi: 10.1080/14397595.2018.1432331.
Epub 2018 Feb 15.
15. Okuyama J, Funakoshi S, Tomita H, Yamaguchi T,
Matsuoka H: Longitudinal characteristics ofresilience among adolescents: A high school student
cohort study to assess the psychological impact of
the Great East Japan Earthquake. Psychiatry Clin
Neurosci. 2018 Nov; 72(11):821-835. doi: 10.1111/
pcn.12772. Epub 2018 Sep 4.
16. Hirota S, Yamaguchi T: Factors distinguishingimportant identified risks from important potential
risks in orphan and nonorphan drugs: An analysis ofsafety specifications of Japan and European Unionrisk management plans. Pharmacoepidemiol Drug
Saf. 2018 Nov; 27(11):1231-1238. doi: 10.1002/pds.
4646. Epub 2018 Sep 5.
17. Hamano J, Takeuchi A, Yamaguchi T, Baba M, ImaiK, Ikenaga M, Matsumoto Y, Sekine R, Yamaguchi
T, Hirohashi T, Tajima T, Tatara R, Watanabe H,
Otani H, Nagaoka H, Mori M, Tei Y, Hiramoto S,
Morita T: A combination of routine laboratory
findings and vital signs can predict survival ofadvanced cancer patients without physician
evaluation: a fractional polynomial model. Eur J
Cancer. 2018 Dec;105:50-60. doi: 10.1016/j.ejca.
2018.09.037. Epub 2018 Nov 2.
18. Tanioka H, Miyamoto Y, Tsuji A, Asayama M,
Shiraishi T, Yuki S, Kotaka M, Makiyama A,
Shimokawa M, Shimose T, Masuda S, Yamaguchi T,
Komatsu Y, Saeki H, Emi Y, Baba H, Oki E,
Maehara Y; Kyushu Study Group of Clinical Cancer(KSCC): Prophylactic Effect of Dexamethasone on
Regorafenib-Related Fatigue and/or Malaise: A
Randomized, Placebo-Controlled, Double-Blind
Clinical Study in Patients with Unresectable
Metastatic
Colorectal
Cancer(KSCC1402/
HGCSG1402). Oncology. 2018; 94(5):289-296. doi:
10.1159/000486624. Epub 2018 Mar 7.
19. Akizawa T, Nangaku M, Yamaguchi T, Arai M,
Koretomo R, Matsui A, Hirakata H. A Placebo-

430

Controlled, Randomized Trial of Enarodustat inPatients with Chronic Kidney Disease Followed byLong-Term Trial. Am J Nephrol. 2019; 49(2):165174. doi: 10.1159/000496929. Epub 2019 Jan 30.
20. 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
temporal changes in chemotherapy-induced hair loss
in breast cancer patients. PLoS One. 2019 Jan 9;14(1):e0208118. doi: 10.1371/journal.pone.0208118.
eCollection 2019.
21. Fuji S, Yamaguchi T, Inoue Y, Utsunomiya A,
Moriuchi Y, Owatari S, Miyagi T, Sawayama Y,
Otsuka E, Yoshida SI, Fukuda T: VCAPAMP-VECP as a preferable induction chemotherapy
in transplant-eligible patients with aggressive adult
T-cell leukemia-lymphoma: a propensity scoreanalysis. Bone Marrow Transplant. 2019 Jan 21. doi:
10.1038/s41409-019-0446-z. [Epub ahead of print].
22. Miura T, Matsumoto Y, Kawaguchi T, Masuda Y,
Okizaki A, Koga H, Tagami K, Watanabe YS,
Uehara Y, Yamaguchi T, Morita T: Low Phase Angle
Is Correlated With Worse General Condition in
Patients with Advanced Cancer. Nutr Cancer. 2019
Jan 26: 1-6. doi: 10.1080/01635581.2018.1557216.
[Epub ahead of print].
23. Iwata H, Masuda N, Yamamoto Y, Fujisawa T,
Toyama T, Kashiwaba M, Ohtani S, Taira N, Sakai T,
Hasegawa Y, Nakamura R, Akabane H, Shibahara Y,
Sasano H, Yamaguchi T, Sakamaki K, Bailey H,
Cherbavaz DB, Jakubowski DM, Sugiyama N, Chao
C, Ohashi Y: Validation of the 21-gene test as apredictor of clinical response to neoadjuvant
hormonal therapy for ER+, HER2-negative breast
cancer: the TransNEOS study. Breast Cancer Res
Treat. 2019 Jan; 173(1):123-133. doi: 10.1007/
s10549-018-4964-y. Epub 2018 Sep 21.
24. Inoue A, Yamaguchi T, Tanaka K, Sakashita A, Aoe
K, Seki N, Hagiwara K.: Benefits of a Nationwide
Palliative Care Education Program on Lung Cancer
Physicians. Intern Med. 2019 Feb 1, doi: 10.2169/
internalmedicine.0872-18. [Epub ahead of print].
25. Wada S, Sadahiro R, Matsuoka YJ, Uchitomi Y,
Yamaguchi T, Shimizu K: Yokukansan for perioperative psychiatric symptoms in cancer patients
undergoing high invasive surgery. J-SUPPORT 1605

(ProD Study): study protocol for a randomized
controlled trial. Trials. 2019 Feb 8; 20(1):110. doi:
10.1186/s13063-019-3202-1.
26. Imai F, Momino K, Katsuki F, Horikoshi M,
Furukawa TA, Kondo N, Toyama T, Yamaguchi T,
Akechi T: Smartphone problem-solving therapy to
reduce fear of cancer recurrence among breast
cancer survivors: an open single-arm pilot study. Jpn
J Clin Oncol. 2019 Feb 22. pii: hyz005. doi:
10.1093/jjco/hyz005. [Epub ahead of print].

431

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.

Research activities
Although locomotive organ disorders are major causesof disability and require support, little information isavailable regarding their epidemiology. The Research
on Osteoarthritis/Osteoporosis Against Disability(ROAD) study, which started in 2005-7, is a
prospective cohort study that aims to elucidate theenvironmental and genetic background for bone andjoint diseases. It was designed to examine the extent
to which risk factors for these diseases are related toclinical features, laboratory and radiographic findings,
bone mass and geometry, lifestyle, nutritional factors,
anthropometric and neuromuscular measures, and fall
propensity. In addition, the study’s aim was also to
determine how these diseases affect activities of dailyliving and quality of life in Japanese men and women.
We have completed the baseline study in 2005-2007,
then, 2nd, 3rd and 4th follow-ups were completed in
2008-2010, 2012-2013, and 2015-2016, respectively.
We have been conducting further follow-up surveys.

References
1.

2.

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. Osteoporos Int 29, 2181-2190, 2018
Kodama R, Muraki S, Iidaka T, Oka H, Teraguchi
M, Kagotani S, Asai Y, Hashizume H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Tanaka S,
Yoshimura N: Serum levels of inflammatory
indices,matrix
metalloproteinase-3,
andautoantibodies related to rheumatoid arthritis in
general Japanese population and their association
with osteoporosis and osteoarthritis: The ROAD
study. J Bone Miner Metab 36, 246-253, 2018

432

3.

4.

5.

6.

7.

8.

9.

Wang K, Kim HA, Felson DT, Xu L, Kim DH,
Nevitt MC, Yoshimura N, Kawaguchi H, Lin J,
Kang X, Zhang Y: Radiographic Knee
Osteoarthritis and Knee Pain: Cross-sectional
study from five different racial/ethnic populations.
Sci Rep 8:1 364, 2018
Leyland KM, Gates LS, Nevitt M, Felson D,
Bierma-Zeinstra SM, Conaghan PG, Engebretsen
L, Hochberg M, Hunter D, Jones G, Jordan JM,
Judge
A,
Lohmander
S,
Roos
EM,
Sanchez-Santos MT, Yoshimura N, van Meurs
JBJ, Batt ME, Newton J, Cooper C, Arden NK:
Harmonising measures of osteoarthritis in
population-based cohort studies: an international
study. Osteoarthritis Cartilage 26: 872-879, 2018
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 ina large-scale, population-based cohort: The
Wakayama Spine Study. PLoS One 13: e0200208,
2018
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: 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
Metabolism, in press
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, in press
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, in press
10. Nagata K, Yoshimura N, Hashizume H, Yamada
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, in pressSocial Cooperation Program434

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 Co.,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
Co.).
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-435

disciplinary research and educational environment that
fosters young leaders in nursing research.

Teaching activities
This program guided Master’s and PhD 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 PhD
students within the Department of GerontologicalNursing/Wound Care management.
The primary master thesis in 2018 was titled“Development of an algorithm using ultrasoundassisted peripheral intravenous catheter placement for
reducing catheter failure: a pretest-post-test 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 health care.” 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 2018
 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. Abe-Doi M, Oe M, Murayama R, Zushi Y, Tanabe
H, Sanada H. Impact of squeezing condition to
obtain sufficient blood volume for self-monitoringof blood glucose using an automatic puncturing
and sampling system. Journal of Diabetes Scienceand Technology. 2018;12(5):1041-1044. doi:10.
1177/1932296818771108.
2. Murayama R, Takahashi T, Tanabe H, Yabunaka K,
Oe M, Komiyama C, Sanada H. Exploring thecauses of peripheral intravenous catheter failure
based on shape of catheters removed from various
insertion sites. Drug discoveries & therapeutics.
2018; 12(3):170-177. doi: 10.5582/ddt.2018.
01024.
3. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Pre-pregnancy body mass index,
gestational weight gain, and body image areassociated with dietary under-reporting in
pregnant Japanese women. Journal of Nutritional
Science. 2018;7,e12:1-10, doi:10.1017/jns.2018.3.

436

Department of
Imaging Nursing Science
Project Associate Professor
Koichi Yabunaka, Ph,D

Project Lecturer
Mikako Yoshida, Ph.D

Project Assistant Professor
Masaru Matsumoto, Ph.D.

Collaborative Researcher
Mayumi Handa, Mikihiko Karube

Homepage

http://www.imagingnursing.m.u-tokyo.ac.jp/index.html

Organization history and overview
The Imaging Nursing Science department was
founded as part of the Corporate Sponsored Research
Programs offered by the Graduate School of Medicine,
The University of Tokyo in April 2017 aiming torealize “a safe, secure and comfortable life for patients
receiving care”. The department seeks to conducttranslational research through surveys on the actual
nursing care condition that are based on imaging
technology, proposing nursing techniques, and theevaluation, with the goal of developing care systems
and applying it to clinical settings.
Specific plans include developing (1)an ultrasoundtechnology support system for nursing care; (2)aremote support system using imaging technology toassist medical care, and (3)development of innovativetechnologies using new imaging techniques innursing.
This Corporate Sponsored Research Program
established with cooperation of FUJIFILM Corp. andwith the Department of Gerontological Nursing /Wound Care Management as partner departments
aiming to find solutions to these challenges and tofurther the progress in nursing technologies. It aspires
to establish imaging nursing technologies in clinicalnursing settings in Japan, a forerunner in shifting
towards a globally unprecedented super-aging society
and to be the first transmitters of new discoveries tothe world.
Department members are Project Associate
Professor Koichi Yabunaka, Project Lecturer Mikako
Yoshida, Project Assistant Professor Masaru
Matsumoto, and Visiting Researchers Mayumi Handa
and Mikihiko Karube (FUJIFILM Corp.). Project
Associate Professor concurrently served as avisualized nursing field of division of care innovationin Medical Graduate School of Global Nursing
Research Center and is striving to establish anddisseminate imaging nursing skills in nursing
research.

Education
In FY 2018, we provided the following lectures forundergraduate, master course students, or Ph.D.
course students.
a) Human Anatomy (A1 in 3rd yr)b) Bioengineering Nursing (S2 in 4th yr)c) Gerontological Nursing I (S1)d) Wound Care Management (S2)
We instructed and cooperated with graduate students

437

of the Department of Gerontological Nursing / Wound
Care Management about their research plans throughseminars and practical training.
As external lectures and workshops to increaseawareness, we have held lectures on skin andelimination care at levels equivalent to curricula for
Certified Nurses in Wound, Ostomy and Continence
Nursing at the Fukuoka Nursing Association, Nurse
Training Center of the Kyoto Tachibana University
and Shizuoka Cancer Center. We have also held
lectures of training for specific medical interventionsin the Nursing Training School of the JapaneseNursing Association.
At the seminar on nursing science and engineeringsponsored by the Global Nursing Research Center, we
lectured imaging nursing skills to many nursing
researchers and clinical nurses. In addition, we gavehands-on training on ultrasound technology useful for
nursing to those who want hands-on seminar among
participants in this introductory seminar.

Research
This course seeks to develop nursing assessment
skills using ultrasonography techniques and promoteresearch in imaging nursing that directly contributes toclinical settings. To this end, we are developing a
versatile portable ultrasound device that is ultralightweight, produces high image quality and operates onwide range of frequencies. Furthermore, a nursing
assessment coaching software is developed by imaging analysis to support assessment by nurses that does
not require special techniques.
Specifically, we have conducted research anddevelopment 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.”1) Development and assessment of home/long-termcare facility multidisciplinary system to support
eating and swallowing2) Development and assessment of home/long-termcare facility multidisciplinary system to support
bowel elimination
In addition, we have developed software to support

autonomy in urinary elimination using ultrasounddevices and also have assessed deep tissue injury(unstageable pressure ulcers) with ultrasound devices.
Of these research activities, we have received
awards on the following subjects.
・Best Research Award from 25th Annual Meeting of
The Japanese Continence Society (September2018); “May perioperative ultrasound-guided pelvic
floor muscle training promote early recovery ofurinary continence after robot-assisted radical
prostatectomy?”
・Best Research Award from 6th Annual Meeting of
Nursing Science and Engineering (October 2018);“Confirming the placement of nasogastric tubes byhand-carried ultrasonography device.”

References
1. Ogai K, Matsumoto M, Aoki M, Dai M, Maeba H,
Uchide K, Junko S. Comparative study on
high-frequency ultrasonography and histologicalstructure of the skin ： Relationship between
collagen/elastin content and echogenicity. Journalof Nursing Science and Engineering. 2018;5(1):65-73.
2. Matsumoto M, Ogai K, Ohashi R, Tanaka K, Aoki
M, Kobayashi M, Sugama J. Influences ofdifferent wiping methods cleaning agent removalon the effectiveness of skin dirt removal：A quasiexperimental study. Journal of Nursing Scienceand Engineering. 2018;5(1):22-30.
3. Komagata K, Yabunaka K, Nakagami G, Ikeda M,
Takehara K, Takemura Y, Sanada H. Confirming
the placement of nasogastric tubes by handcarried ultrasonography device. Journal of
Nursing Science and Engineering. 2018;5(1):52-7.
4. Miura Y, Nakagami G, Yabunaka K, Tohara H,
Noguchi H, Mori T, Sanada H. A Randomized
Controlled Trial to Investigate the Effectivenessof the Prevention of Aspiration Pneumonia Using
Recommendations for Swallowing Care Guided
by Ultrasound Examination. Healthcare (Basel).
2018;6(1):E15.
5. Matsumoto M, Ogai K, Aoki M, Urai T,
Yokogawa M, Tawara M, Kobayashi M,
Minematsu T, Sanada H, Sugama J. Changes in438

dermal structure and skin oxidative stress inoverweight and obese Japanese males after weight
loss: a longitudinal observation study. Skin
Research and Technology. 2018;24(3):407-16.
6. Yabunaka K, Matsumoto M, Yoshida M, Tanaka S,
Miura Y, Tsutaoka T, H, a M, Nakagami G,
Sugama J, Okada, Sanada H. Assessment of rectal
feces storage condition by a point-of-care pocketsize ultrasound device for healthy adult subjects: apreliminary study. Drug Discoveries andTherapeutics. 2018;12(1):42-6.
7. Tanaka S, Yabunaka K, Matsumoto M, Tamai N,
Noguchi H, Yoshida M, Nakagami G, Sugama J,
Sanada H. Fecal Distribution Changes Using
Colorectal Ultrasonography in Older People with
Physical and Cognitive Impairment Living inLong-Term Care Facilities: A LongitudinalObservational Study. Healthcare. 2018;6(2):E55.
8. Murayama R, Takahashi T, Tanabe H, Yabunaka K,
Oe M, Komiyama C, Sanada H. Exploring thecauses of peripheral intravenous catheter failure
based on shape of catheters removed from various
insertion sites. Drug Discoveries and Therapeutics.
2018;12(3):170-7.
9. Ibuki A, Minematsu T, Yoshida M, Iizaka S,
Matsumoto M, Sugama J, Sanada H. Microsatellite polymorphism in the Heme oxygenase-1
gene promoter is associated with dermal collagendensity in Japanese obese male subjects. PLoS
One. 2018;13(7):e0199994.
10. 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?. Neurourology and
Urodynamics. 2019;38(1):158-164.
11. Yoshida M, Igawa Y, Higashimura S, Suzuki M,
Sanada H. Effectiveness of a hydrophilic-coatedcompact catheter in preventing urinary tract
infections and improving quality of life in female
patients managed with clean intermittent selfcatheterization: A prospective multicenter
randomized parallel comparative trial. Japanese
Journal Of Wound, Ostomy and ContinenceManagement. 2018;22(4):335-44.
12. Kimori K, Konya C, Matsumoto M. Venipuncture-

Induced Hematomas Alter Skin Barrier Functionin the Elderly Patients. SAGE Open Nursing.
2018;4:1-8.
13. Yabunaka K, Nakagami G, Tabata K, Sugama J,
Matsumoto M, Iuchi T, Kido Y, Sanada H.
Constipation in the elderly in a Japanese longterm medical facility: An ultrasonographic
investigation. Drug Discoveries and Therapeutics.
2018;12(4):233-8.
14. Matsumoto M, Tanaka S, Yabunaka K, Yoshida M,
Miura Y, Tsutaoka T, H, a M, Nakagami G,
Sugama J, Okada S, Sanada H. Ultrasonographic
evaluation of functional constipation in healthy
adults: A report of two cases. Drug Discoveries
and Therapeutics. 2018;12(5):304-8.

439

Department of Healthcare Quality
Assessment
Project Professor
Hiroaki Miyata, Ph.D.

Project Associate Professor
Kan Nawata, M.D., Ph.D.

Project Lecturer
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.
Norimichi Hirahara, Ph.D.
Hiroyuki Yamamoto, M.D., Ph.D., M.P.H.
Arata Takahashi, HIM, M.S.
Eriko Fukuchi, M.S.
Hideki Endo, M.D.
Shiori Nishimura, M.S.

Clerical Staff
Urara Isozumi, M.S.
Chieko Fujimura

Clerical Staff (Secretary)
Nanayo Kyougoku
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440

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 5,240 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, practical analyses, and the developmentof useful feedback systems. Recently, non-surgicalfields such as clinical oncology are also joining NCD
and this trend becomes stronger. Our benchmarking
projects backed up by NCD’s big data will keep
driving the quality improvement activities in many
healthcare fields.
Increasing number of clinical research, conducted incollaboration with professional societies, has come out
based on detailed analyses of NCD. Also, several
research projects are being developed in collaboration
with pharmaceutical and medical device companies,
especially for medication / device post-marketingsurveillance studies. Working in collaboration with
NCD, the industry, Pharmaceuticals and Medical
Devices Agency (PMDA), and the related medical

441

societies, HQA is supporting the development and the
conduct of these projects. Furthermore, HQA has been
involved in international research collaborations withnation-level registries abroad, including American
College of Surgeon’s NSQIP and Asian Cardiac
Database, participating in quality improvement
activities in different regions of the world.

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Nemoto M, Kagami Y, Endo M, Kimura M,
Kinoshita O, Nawata K, Morita H, Ono M,
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Miura S, Yamashita T, Hanyu M, Kumamaru H,
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M, Hiki N. Surgical risk and benefits oflaparoscopic surgery for elderly patients withgastric cancer: a multicenter prospective cohort
study. Gastric Cancer. 2018 Dec 11.
Sadanaga T, Hirota S, Enomoto K, Kohsaka S,
Tsujita K, Ito M, Mitamura H, Fukuda
K.Evaluation of sodium intake for the predictionof cardiovascular events in Japanese high-riskpatients: the ESPRIT Study. Hypertens Res.
42(2):233-240. 2018 Dec 5.
Kadowaki H, Amiya E, Hoshino Y, Tamura M,
Uehara M, Nakayama A, Nawata K, Domoto Y,
Saeki T, Ono M, Komuro I.
Enormous
Aneurysm in Coronary Artery Fistula With
Immunoglobulin G4-Related Disease. Can J
Cardiol. 35(2):230. 2018 Dec 5.
Inohara T, Manandhar P, Kosinski AS, Matsouaka
RA, Kohsaka S, Mentz RJ, Thourani VH, Carroll
JD, Kirtane AJ, Bavaria JE, CohenDJ, Kiefer TL,
Gaca JG, Kapadia SR, Peterson ED, Vemulapalli
S. Association of Renin-AngiotensinInhibitor
Treatment With MortalityandHeart Failure
Readmission in Patients With Transcatheter
Aortic Valve Replacement. JAMA. 320(21):2231-2241. 2018 Dec 4 .

31. Sughimoto K, Hirata Y, Hirahara N, Miyata H,
Suzuki T, Murakami A, Miyaji K, Takamoto S.
Mid-term result of atrioventricular valve replacement in patients with a single ventricle. Interact
Cardiovasc Thorac Surg. 27(6):895-900. 2018
Dec 1.
32. Shoji S, Kohsaka S, Kumamaru H, Sawano M,
Shiraishi Y, Ueda I, Noma S, Suzuki M,
Numasawa Y, Hayashida K, Yuasa S, Miyata H,
Fukuda K. Stroke After Percutaneous Coronary
Intervention in the Era of Transradial Intervention. Circ Cardiovasc Interv. 11(12):e006761.
2018 Dec.
33. Yoshitake S, Kinoshita O, Nawata K, Hoshino Y,
Itoda Y, Kimura M, Yamauchi H, Ono M.
Single-center experience of the bridge-to-bridge
strategy using the Nipro paracorporeal ventricularassist device. J Artif Organs. 21(4):405-411. 2018
Jun 25.
34. Shiraishi Y, Nagai T, Kohsaka S, Goda A,
Nagatomo Y, Mizuno A, Kohno T, Rigby A,
Fukuda K, Yoshikawa T, Clark AL, Cleland JGF.
"Outcome of hospitalised heart failure in Japanand the United Kingdom stratified by plasma
N-terminal pro-B-type natriuretic peptide."
ClinRes Cardiol. 107(12):1103-1110. 2018Dec.
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verification of data froma clinical database ofgastroenterologicalsurgery in Japan. Surg Today.
2018 Nov 7.
36. Marubashi S, Ichihara N, Kakeji Y, Miyata
H,Taketomi A, Egawa H, Takada Y,Umeshita
K,Seto Y, Gotoh M. "Real-time" risk models
ofpostoperative morbidity and mortality forlivertransplants. Ann Gastroenterol Surg. 3(1):75-95. 2018 Nov 2.
37. Saito A, Kumamaru H, Ono M, Miyata H,
Motomura N. Propensity-matched analysis of aside-clamp versus an anastomosis assist device incases of isolated coronary artery bypass grafting.
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Nov 1.
38. Kumamaru H, Lee MP, Choudhry NK, Dong YH,
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fibrillation: A cross-sectional analysis ofa multicenter outpatient registry. J Cardiol. 73(1):14-21.
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Shimada Y, Sato M, Toyooka S, OkadaY, Sato Y,
Yoshino I, Okada M, Okumura M,Chida M,
Fukuchi E, Miyata H. Risk assessments forbroncho-pleuralfistulaandrespiratory
failureafter lung cancer surgery by National
Clinical Database Japan. Gen Thorac Cardiovasc
Surg. 2018 Oct 16.
Iwatsuki M, Yamamoto H, Miyata H, Kakeji Y,
Yoshida K, Konno H, Seto Y, Baba H. Effect of
hospital and surgeon volume on postoperative
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Takeuchi Y, Shinozaki T, Kumamaru H,
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Shoaib A, Shiraishi Y, Kohsaka S, Piper S,
McDonagh TA, Hardman SMC, Goda A, Mizuno
A, Kohno T, Rigby AS, Yoshikawa T, Clark AL,
Anzai T, Cleland JGF. Mortality after admission
for heart failure in the UK comparedwith Japan.
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Phenotypic Variability ofan SCN5A Mutation:
Brugada Syndromeand Sick Sinus Syndrome. J
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Shiraishi Y, Kohsaka S, Sato N, Takano T, Kitai T,
Yoshikawa T, Matsue Y. 9-Year Trend in theManagement of Acute Heart Failure in Japan: A
Report Fromthe National Consortium of AcuteHeart Failure Registries. J Am Heart Assoc.
7(18):e008687. 2018 Sep 18.
Kohsaka S, Katada J, Saito K, Terayama Y.
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from Japanese administrative claims data. Curr
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Hiraide T, Sawano M, Shiraishi Y, UedaI,
Numasawa Y, Noma S, Negishi K, Ohki T, Yuasa
S, Hayashida K, Miyata H,Fukuda K, Kohsaka S.
Impact of catheter-induced iatrogenic coronary
artery dissection with or without postprocedural
flow impairment: A report from a Japanesemulticenter percutaneous coronary intervention
registry. PLoS One. 2018 Sep 28.
Kimura M, Kohno T, Makino S, Okuda S,
Nawata K, Yanagisawa R, Kojima H, Nishiyama
T, Aizawa Y, Yuasa S, Murata M, Maekawa Y,
Okamoto K, Shimizu H, Fukuda K. A taleof twosisters with hypertrophic cardiomyopathy andrecurrent embolism: When is the optimal timingof the intervention for left atrial appendage?
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Sep 22.
Kuno T, Numasawa Y, Sawano M, Katsuki T,
Kodaira M, Ueda I, Suzuki M, Noma S, Negishi
K, Ishikawa S, Miyata H, Fukuda K, Kohsaka S.
Effects of body habitus on contrast-induced acutekidney injury after percutaneouscoronary intervention. PLoS One. 13(9):e0203352. 2018 Sep
13.
Ohira S, Miyata H, Yamazaki S, Numata S,
Motomura N, Takamoto S, Yaku H. Deep sternal
wound infection after bilateral internal thoracic
artery grafting: Insights from a Japanese national
database. J Thorac Cardiovasc Surg. S0022-

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Hasumi E, Fujiu K, Kojima T, Kinoshita O,
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Novel extraction technique ofretained pacemakerand defibrillator lead during heart transplantation.
PLoS One. 13(9):e0203172. 2018 Sep 6.
Nitta D, Kinugawa K, Imamura T, Amiya
E,Hatano M, Kinoshita O, Nawata K, Ono M,
Komuro I.
A Useful Scoring System For
Predicting Right Ventricular Assist Device
Requirement Among Patients with a Paracorporeal Left Ventricular Assist Device. Int
Heart J. 59(5):983-990. 2018 Aug 29.
Shiraishi Y, Kohsaka S, Nagai T, Goda A,
Mizuno A, Nagatomo Y, Sujino Y, Fukuoka
R,Sawano M, Kohno T, Fukuda K, Anzai T,
Shadman R, Dardas T, Levy WC, Yoshikawa T.
Validation and Recalibration of Seattle Heart
Failure Model in Japanese Acute Heart Failure
Patients J Card Fail. S1071-9164(18)30868-6.
2018 Aug 10.
Nagai T, Sundaram V, Shoaib A, Shiraishi Y,
Kohsaka S, Rothnie KJ, Piper S, McDonagh TA,
Hardman SMC, Goda A, Mizuno A, Sawano M,
Rigby AS, Quint JK, Yoshikawa T, Clark AL,
Anzai T, Cleland JGF. Validation of U.S.
mortalityprediction models for hospitalized heart
failure in the United Kingdom and Japan. Eur J
Heart Fail. 20(8):1179-1190. 2018May 30.
Sawano M, Shiraishi Y, Kohsaka S, Nagai
T,Goda A, Mizuno A, Sujino Y, Nagatomo Y,
Kohno T, Anzai T, Fukuda K, Yoshikawa T.
Performance of the MAGGIC heart failureriskscore and its modification with the additionof discharge natriuretic peptides. ESC Heart Fail.
5(4):610-619. 2018 Mar 9.
Imamura M, Hirata K, Unno M, Kamiya K,
Gotoh M, Konno H, Shibata A, Sugihara K,Takahashi A, Nishiyama M, Hakamada K, Fukui
T, Furukawa T, Mizushima T, Mizuma M, Miyata
H, Mori M, Takemasa I, Mizuguchi T, Fujiwara T.
Current status of projects for developing cancerrelated clinical practice guidelines in Japan andrecommendations for the future. Int J Clin
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Takahashi A, Ono M, Iwanaka T, Miyata H,.

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Evaluating the quality of data from the Japanese
National Clinical Database 2011 via acomparison with regional government report data
and medicalcharts. Surg Today. 2018 Aug 7.
Ohashi M, Kohno T, Kohsaka S, Fukuoka R,
Hayashida K, Yuasa S, Sano M, Takatsuki S,
Fukuda K. Excessive Daytime Sleepiness Is
Associated With Depression Scores, But Not
With Sleep-Disordered Breathing in Patients
With Cardiovascular Diseases. Circ J. 82(8):2175-2183. 2018 Jul 25.
Kodaira M, Kuno T, Numasawa Y, Ohki T,
Nakamura I, Ueda I, Fukuda K, Kohsaka S.
Differences of in-hospital outcomes withinpatients undergoing percutaneous coronary
intervention at institutions with high versus low
procedural volume: a report from the Japanesemulticentre percutaneous coronary intervention
registry. Open Heart. 5(2):e000781. 2018 Jul 11.
Minakawa M, Fukuda I, Miyata H, Motomura N,
Takamoto S, Taniguchi S, Daitoku K, Kondo N;
Japan Cardiovascular Surgery Database Organization. Outcomes of Pulmonary Embolectomy for
Acute Pulmonary Embolism. Circ J.82(8):21842190. 2018 Jun 27.
Ikemura N, Sawano M, Ueda I, FukudaK,
Kohsaka S. Consequence of reimbursement
policy alteration for urgent PCI in Japan. Lancet.
391(10136):2208-2209. 2018 Jun 1.
Kosiborod M, Lam CSP, Kohsaka S, Kim DJ,
Karasik A, Shaw J, Tangri N, Goh SY, Thuresson
M, Chen H, Surmont F, Hammar N, Fenici P;
CVD-REAL Investigators and Study Group.
Cardiovascular Events Associated With SGLT-2
Inhibitors Versus Other Glucose-Lowering
Drugs: The CVD-REAL 2 Study. J Am Coll
Cardiol. 71(23):2628-2639. 2018 Mar 11.
Yamazoe M, Mizuno A, Kohsaka S, ShiraishiY,
Kohno T, Goda A, Higuchi S, Yagawa M,
Nagatomo Y, Yoshikawa T; West Tokyo Heart
Failure Registry Investigators Tokyo, Japan.
Incidence of hospital-acquired hyponatremia by
the dose and type of diuretics among patientswith acute heart failure and its association withlong-term outcomes. J Cardiol. 71(6):550-556.
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Nawata K, Fujita D, Taniguchi Y, Yamauchi H,
Yagi H, Kato M, Nishimura H, Hirata Y, Ikeda Y,
Kumagai H, Amiya E, Hara H, Fujiwara T,
Akazawa H, Suzuki JI, Imai Y, Nagai R,
Takamoto S, Hirata Y, Ono M, Komuro I. Impact
of Pathogenic FBN1 Variant Types on the
Progression of Aortic Disease in Patients With
Marfan Syndrome. Circ Genom Precis Med.
11(6):e002058. 2018 Jun
Takeda N, Inuzuka R, Maemura S, Morita H,
Nawata K, Fujita D, Taniguchi Y, Yamauchi H,
Yagi H, Kato M, Nishimura H, Hirata Y, Ikeda Y,
Kumagai H, Amiya E, Hara H, Fujiwara T,
Akazawa H, Suzuki JI, Imai Y, Nagai R,
Takamoto S, Hirata Y, Ono M, Komuro I. Impact
of Pathogenic FBN1 Variant Types on the
Progression of Aortic Disease in Patients With
Marfan Syndrome. Circ Genom Precis Med.
11(6):e002058. 2018 Jun.
Handa N, Kumamaru H, Torikai K, Kohsaka S,
Takayama M, Kobayashi J, Ogawa H, Shirato H,
Ishii K, Koike K, Yokoyama Y, Miyata H,
Motomura N, Sawa Y; Japanese TAVR Registry
Participants. Learning Curve for Transcatheter
Aortic Valve Implantation Under a Controlled
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Miyairi T, Miyata H, Chiba K, Nishimaki H,
Ogawa Y, Motomura N, Takamoto S; Japan Adult
Cardiovascular Database Organization. Influenceof Timing After Thoracic Endovascular Aortic
Repair for Acute Type B Aortic Dissection. Ann
Thorac Surg. 105(5):1392-1396.2018 May.
Sawano M, Kohsaka S, Kimura T, Takatsuki S,
Fukuda K. The Case of Dynamic CHA2DS2VASc Score: Beyond Risk Prediction. J Am Coll
Cardiol. 71(17):1942. 2018 May 1.
Ozaki Y, Katagiri Y, Onuma Y, Amano T,
Muramatsu T, Kozuma K, Otsuji S, Ueno T,
Shiode N, Kawai K, Tanaka N, Ueda K, Akasaka
T, Hanaoka KI, Uemura S, Oda H, Katahira Y,
Kadota K, Kyo E, Sato K, Sato T, Shite J, Nakao
K, Nishino M, Hikichi Y, Honye J, Matsubara T,
Mizuno S, Muramatsu T, Inohara T, Kohsaka S,
Michishita I, Yokoi H, Serruys PW, Ikari Y,
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Mizushima T, Yamamoto H, Marubashi S,
Kamiya K, Wakabayashi G, Miyata H, Seto Y,
Doki Y, Mori M. Validity and significance of
30-day mortality rate as a quality indicator for
gastrointestinal
cancersurgeries.
Ann
Gastroenterol Surg. 2(3):231-240. 2018 Apr 16.
Yoshida T, Miyata H, Konno H, Kumamaru H,
Tangoku A, Furukita Y, Hirahara N, Wakabayashi
G, Gotoh M, Mori M. Risk assessment ofmorbidities after right hemicolectomy based on
the National Clinical Database in Japan.Ann
Gastroenterol Surg. 2(3):220-230. 2018 Apr 16.
Miyata H, Mori M, Kokudo N, Gotoh M, Konno
H, Wakabayashi G, Matsubara H, Watanabe T,
Ono M, Hashimoto H, Yamamoto H, Kumamaru
H, Kohsaka S, Iwanaka T,. Association between
institutional procedural preference and inhospital outcomes in laparoscopic surgeries;
Insights from a retrospective cohort analysis of anationwide surgical database in Japan. PLoS One.
13(3):e0193186. 2018 Mar 5.
Yoshitake S, Kinoshita O, Nawata K, Hoshino Y,
Itoda Y, Kimura M, Yamauchi H, Ono M. Noveldriveline route for prevention from driveline
infection: Triple tunnel method. J Cardiol. 72(4):363-366. 2018 May 3.
Ueki C, Miyata H, Motomura N, SakataR,
Sakaguchi G, Akimoto T, Takamoto S; Japan
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coronary artery bypass grafting in patients withpreoperative renal failure. J Thorac Cardiovasc
Surg. 156(3):976-983. 2018 Apr 12.
Hirota Y, Sawano M, Numasawa Y, Ueda I,
Noma S, Suzuki M, Hayashida K, Yuasa S,
Maekawa Y, Kohsaka S, Fukuda K.
Characteristics and in-hospital outcomes inyoung patients presenting with acute coronary
syndrome treated by percutaneous coronary
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R, Tanaka M, Arai T, Minakata Y, Itabashi Y,
Murata M, Kohsaka S, Maekawa Y, Takahashi T,
Yoshitake A, Shimizu H, Fukuda K. Incidence,
predictors, and midterm clinical outcomes of left
ventricular obstruction after transcatheter aortic
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92(4):E288-E298. 2018 Jan 23.

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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.

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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

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Department of Ubiquitous
Health Informatics
Associate Professor
Waki Kayo, M.D., M.P.H., Ph.D.

Assistant Professor
Eriko Hasumi, 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.

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
therapy in DKD patients with microalbuminuria. This
study is a prospective, randomized, open-label,multicenter clinical trial. The target population consists of
155 patients (age ≥ 20 years) diagnosed with DKD
accompanied with microalbuminuria. We will randomize
the patients between the two groups—the intervention

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group that uses DialBeticsPlus in addition to receiving astandard therapy and the control group that only receives
a standard therapy. DialBeticsPlus is a modified version
of DialBetics. The study period is 12 months, with afollow-up survey at 18 months. The primary outcome forthis study is change after 12 months in albuminuria levels
measured in a first-morning void. Secondary outcomes
include changes in physical parameters, blood tests,
including 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 bemade of all-cause death, composite cardiovascularoutcomes, composite renal endpoint, efficacy of“hospital-led” and “dispensing-pharmacy-led” methodsof deploying DialBeticsPlus, safety, and usage pattern of
DialBeticsPlus. The study was approved in April 2018.
We began recruiting patients in July 2018 and finishedrecruiting in August 2019. The final 72-week 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 significantly in the intervention group.
We also expect other physical parameters and blood tests
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 sparegroup
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.
● HearTily:
Self-management
andrecordingapplication for arrhythmia
To investigate the association between arrhythmia andlifestyle, we developed the smartphone application"Heartily" for arrhythmic self-management again using
Apple’s ResearchKit by Apple Inc. About 15,000
participants used Heartily after the application was

released, and a new arrhythmia people were detected in
1.9% of them. Because the preliminary analysis wascompleted, we terminated the provision of the application.
● 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
fibrillationcanbedetectedbylong-termelectrocardiogram monitoring. The results are publishedin the form 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 theusers 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
submitted for publication in the form of a refereed journal
article.

● DialBeticsLite for health guidance object persons
Health guidance is a support program for object personsof metabolic syndrome to improve their lifestyle. We
conducted a clinical trial to study the effect of452

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.

● 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 subjects 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(Original article)
1. Makimoto H, Shimizu K, Fujiu K, Lin T, Oshima T,
Amiya E, Yamagata K, Kojima T, Daimon M,
Nagatomo R, Waki K, Meyer C, Komuro I. Effect ofSympatholytic Therapy on Circadian Cardiac
Autonomic Activity in Non-Diabetic Chronic
Kidney Disease. Int Heart J. 2018 Nov 28;59(6):1352-1358. doi: 10.1536/ihj.17-561. Epub 2018 Oct
25.
2. Hasumi E, Fujiu K, Kojima T, Kinoshita O, Nawata
K, Yamauchi H, Ono M, Komuro I. Novel extraction
technique of retained pacemaker and defibrillator
lead during heart transplantation. PLoSOne. 2018
Sep 6;13(9):e0203172. doi: 10.1371/journal.pone.
0203172. eCollection 2018.
3. Ota S, Horisaki R, Kawamura Y, Ugawa M, Sato I,
Hashimoto K, Kamesawa R, Setoyama K,
Yamaguchi S, Fujiu K, Waki K, Noji H.（＃Theseauthors equally contributed to this work.）Ghost
cytometry. Science. 2018 Jun 15;360(6394):1246-

4.

5.

1251. doi: 10.1126/science.aan0096
Kojima T, Fujiu K, Fukuma N, Matsunaga H,
Oshima T, Matsuda J, Matsubara T, Shimizu Y,
Oguri G, Hasumi E, Morita H, Komuro I.
Periprocedural
Complications
inPatients
Undergoing Catheter Ablation of Atrial Fibrillation
Without Discontinuation of a Vitamin K Antagonist
and Direct Oral Anticoagulants. Circ J. 2018 May
25;82(6):1552-1557. doi: 10.1253/circj.CJ-17-1114.
Epub 2018 Apr 13.
Pinto S, Waki K, Chiovato L, De Cata P, Dagliati A,
Tibollo V, Ruvolo G, Bellazzi R. Smartphone-Based
Self-Managementof
Non-Insulin-Dependent
Diabetes: A Japanese System at Use by an Italian
Patients' Cohort. J Diabetes Sci Technol. 2018 Jul;
12(4):903-904.

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Department of Skincare Science
Project Associate Professor
Takeo Minematsu, Ph.D.

Project Lecturer
Nao Tamai, Ph.D., R.N.

Homepage

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

Introduction and Organization

Research activities

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.

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 clinicalnurses in the bioengineering nursing research seminarorganized by Global Nursing Research Center on July
2017. We furthermore organized an advanced
hands-on seminar of bioengineering nursing researchmethodologies on February 2018.

Teaching activities
In FY2018, we provided the following lectures forundergraduates, master course students, or Ph.D.
course students:a) Introduction of Nursing Science (A in 1st/2nd yr)b) Gerontological Nursing in Gerontological Nursing(A2 in 3rd yr/ S1 in 4th yr)c) Clinical Practice (S2 in 4th yr)d) Gerontological Nursing I (S1)e) Wound Care Management I (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 in2018:
Master: “Relationship between pressure ulcers anddynamic buttock pressure distributions duringperformance in wheelchair basketball athletes”
Bachelor: “Subcutaneous tissue damage on the
buttocks in wheelchair basketball players”

2. Research themes in 2018
Since February 2017, we have worked with Saraya
Co., Ltd., to develop new nursing technologies using
wound blotting, with a goal of incorporating woundblotting into practical use and finally launched on
January 2018. In furtherance of this effort, we havealso contributed to the 2020 Tokyo Paralympic Gamesthrough pressure ulcer care for wheelchair athletes.

454

 Development of non-invasive skin assessment
methods using skin blotting
Evaluation of skin barrier functions
Detection of tinea pedis
Detection of dehydration
 Development and practical realization of woundassessment methods using wound blotting
Prediction of pressure ulcer healing
Detection of wound biofilm
 Scalp care science
Early detection and prevention of male patternalopecia
Changes of physiology on the scalp duringchemotherapy
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
Regarding international activities, our department
has been promoting collaborative research about
improving the prediction and prevention of skin tears
with researchers in Curtin University (Australia).
In addition, our research was recognized in the formof several awards, as follows: Article award from Japanese Society of Wound,
Ostomy, and Continence Management in 2018.
Nozawa K, Tamai N, Minematsu T, Kitamura A,
Saegusa M, Amaike K, Sanada H. Situation of
occurrence and morphological characteristics ofpressure ulcers among inpatients with mental
illness. J Jpn Soc Wound Ostomy ContinenceManag. 21(1): 10-24, 2017 Apr.

3.

4.

5.

6.

7.

8.

References
1. Matsumoto M, Ogai K, Aoki M, Urai T, Yokogawa
M, Tawara M, Kobayashi M, Minematsu T, Sanada
H, Sugama J. Changes in dermal structure and skinoxidative stress in overweight and obese Japanesemales after weight loss: a longitudinal observation
study. Skin Res Technol. 2018 Aug;24(3):407-416.
doi: 10.1111/srt.12443.
2. Mugita Y, Minematsu T, Nakagami G, Sanada H.
Influence of digestive enzymes on development of

9.

incontinence-associated dermatitis: inner tissue
damage and skin barrier impairment caused bylipidolytic enzymes and proteases in rat macerated
skin. International Wound Journal. 2018 Aug;
15(4):623-632. doi: 10.1111/iwj.12906.
Koyano Y, Nakagami G, Minematsu T, Sanada H.
Reliability of the skin blotting method when usedon the elderly. International Wound Journal. 2018
Oct;15(5):807-813. doi: 10.1111/iwj.12931.
Ibuki A, Minematsu T, Yoshida M, Iizaka S,
Matsumoto M, Sugama J, Sanada H. Microsatellite
polymorphism in the Heme oxygenase-1 genepromoter is associated with dermal collagendensity in Japanese obese male subjects. PLoS One.
2018 Jul 19;13(7): e0199994. doi: 10.1371/journal.
pone.0199994. eCollection 2018.
Aoki M, Ogai K, Kobayashi M, Minematsu T,
Nakatani T, Okuwa M, Sanada H, Sugama J.
Comparison of ceramide kinetics in the stratum
corneum between dry skin and normal skin using
animal models with fluorescent imaging method.
Skin Research and Technology. 25(2):158-164,
2019. doi: 10.1111/srt.12625.
Kitamura A, Minematsu T, Nakagami G, Sanada H.
Assessment of histopathology of wounds based onprotein distribution detected by wound blotting.
SAGE Open Medicine. 2018; 6: 20503121188122
20. doi: 10.1177/2050312118812220.
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. 19: 135-140, 2019. doi:
10.1111/ggi.13570.
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. 6: 33-40, 2019. doi: 10.24462/jnse.
6.1_33
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 alpha interleukin-1 alpha,vascular endothelial growth factor C, and heatshock protein 90 alpha: A pilot study. Journal of
Tissue Viability. 2019 May;28(2):87-93.doi: 10.
1016/j.jtv.2019.02.002.

455

Department of Prevention of
Diabetes and Lifestyle-RelatedDiseases
Project Professor
Takashi Kadowaki, M.D.,Ph.D.

Project Associate Professor
Hideki Kato, M.D.,Ph.D.

Project Assistant Professor
Satoko Yamaguchi, 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

456

containing household situation and health-related
questions, from Ministry of Health, Labor andWelfare.
2) Research on childhood obesity
Obesity is associated with a number of lifestylerelated diseases. In recent years, it was elucidated thatchildhood obesity is strongly linked to adult obesity,and importance of preventing childhood obesity has
been emphasized. However, the actual situation ofchildhood obesity and its complications in Japanremains to be understood. In collaboration with the
Department of Clinical Epidemiology and Health
Economics (Professor Hideo Yasunaga), we are
analyzing the degree of obesity and obesity-related
complications in children using Diagnosis Procedure
Combination (DPC) database.
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).

3.

4.

5.

6.

7.

In addition to moving these projects forward, we plan
to take on new projects using databases in the future.

References
1. Buse JB, Carlson AL, Komatsu M, Mosenzon O,
Rose L, Liang B, Buchholtz K, Horio H,
Kadowaki T. Fast-acting insulin aspart versus
insulin aspart in the setting of insulin
degludec-treated type 1 diabetes: Efficacy andsafety from a randomized double-blind trial.
Diabetes Obes Metab 2018;20:2885-2893.
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,

8.

9.

Ueki K, Ikeda H, Yoshida H, Moriya K,
Yotsuyanagi H, Kadowaki T, Fukayama M, Koike
K. Hepatic IRS1 and ß-catenin expression isassociated with histological progression and overt
diabetes emergence in NAFLD patients. J
Gastroenterol 2018;53:1261-1275.
Haneda M, Kadowaki T, Ito H, Sasaki K, Hiraide
S, Ishii M, Matsukawa M, Ueno M. Safety andEfficacy of Teneligliptin in Patients with Type 2
Diabetes Mellitus and Impaired Renal Function:
Interim Report from Post-marketing Surveillance.
Diabetes Ther 2018;9:1083-1097.
Kadowaki T, Haneda M, Ito H, Sasaki K, Hiraide
S, Matsukawa M, Ueno M. Relationship of Eating
Patterns and Metabolic Parameters, andTeneligliptin Treatment: Interim Results from
Post-marketing Surveillance in Japanese Type 2
Diabetes Patients. Adv Ther 2018;35:817-831.
Kadowaki T, Sarai N, Hirakawa T, Taki K, Iwasaki
K, Urushihara H. Persistence of oral antidiabetic
treatment for type 2 diabetes characterized by drugclass, patient characteristics and severity of renal
impairment: A Japanese database analysis.
Diabetes Obes Metab 2018;20:2830-2839.
Kadowaki T, Sasaki K, Ishii M, Matsukawa M,
Ushirogawa Y. Efficacy and Safety ofTeneligliptin 40 mg in Type 2 Diabetes: A Pooled
Analysis of Two Phase III Clinical Studies.
Diabetes Ther 2018;9:623-636.
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 2018;38.
Kubota T, Inoue M, Kubota N, Takamoto I,
Mineyama T, Iwayama K, Tokuyama K, Moroi M,
Ueki K, Yamauchi T, Kadowaki T. Downregulation of macrophage Irs2 by hyperinsulinemia
impairs IL-4-indeuced M2a-subtype macrophageactivation in obesity. Nat Commun 2018;9:4863.
Okada-Iwabu M, Iwabu M, Yamauchi T,
Kadowaki T. Structure and function analysis ofadiponectin receptors toward development ofnovel antidiabetic agents promoting healthy

457

longevity. Endocr J 2018;65:971-977.
10. Suzuki R, Eiki JI, Moritoyo T, Furihata K,
Wakana A, Ohta Y, Tokita S, Kadowaki T. Effectof short-term treatment with sitagliptin orglibenclamide on daily glucose fluctuation in
drug-naïve Japanese patients with type 2 diabetes
mellitus. Diabetes Obes Metab 2018;20:22742281.
11. Taira M, Imamura M, Takahashi A, Kamatani Y,
Yamauchi T, Araki SI, Tanaka N, van Zuydam NR,
Ahlqvist E, Toyoda M, Umezono T, Kawai K,
Imanishi M, Watada H, Suzuki D, Maegawa H,
Babazono T, Kaku K, Kawamori R, Groop LC,
McCarthy MI, Kadowaki T, Maeda S,
Consortium S. A variant within the FTO confers
susceptibility to diabetic nephropathy in Japanesepatients with type 2 diabetes. PLoS One 2018;13:e0208654.
12. Yamada T, Kamata R, Ishinohachi K, Shojima N,
Ananiadou S, Nom H, Yamauchi T, Kadowaki T.
Biosimilar vs originator insulins: Systematic
review and meta-analysis. Diabetes Obes Metab
2018;20:1787-1792.
13. Yamada T, Shojima N, Noma H, Yamauchi T,
Kadowaki T. Sodium-glucose co-transporter-2
inhibitors as add-on therapy to insulin for type 1
diabetes mellitus: Systematic review and metaanalysis of randomized controlled trials. Diabetes
Obes Metab 2018;20:1755-1761.
14. Yamada T, Shojima N, Noma H, Yamauchi T,
Kadowaki T. Weekly Versus Daily Dipeptidyl
Peptidase 4 Inhibitor Therapy for Type 2
Diabetes: Systematic Review and Meta-analysis.
Diabetes Care 2018;41:e52-e55.
15. 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 2018;3.
16. Yamamura T, Nozu K, Ueda H, Fujimaru R,
Hisatomi R, Yoshida Y, Kato H, Nangaku M,
Miyata T, Sawai T, Minamikawa S, Kaito H,
Matsuo M, Iijima K. Functional splicing analysis
in an infantile case of atypical hemolytic uremic
syndrome caused by digenic mutations in C3 and

MCP genes. J Hum Genet 2018;63:755-759.
17. Fujisawa M, Kato H, Yoshida Y, Usui T, Takata M,
Fujimoto M, Wada H, Uchida Y, Kokame K,
Matsumoto M, Fujimura Y, Miyata T, Nangaku M.
Clinical characteristics and genetic backgroundsof Japanese patients with atypical hemolytic
uremic syndrome. Clin Exp Nephrol 2018;22:1088-1099.
18. Kato H, Nangaku M, Okada H, Kagami S.
Controversies of the classification of TMA andthe terminology of aHUS. Clin Exp Nephrol
2018;22:979-980.
19. Ota S, Horisaki R, Kawamura Y, Ugawa M, Sato I,
Hashimoto K, Kamesawa R, Setoyama K,
Yamaguchi S, Fujiu K, Waki K, Noji H. Ghost
cytometry. Science 2018;360:1246-1251.

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Department of Innovative
Dementia Prevention
Project Associate Professor
Tadafumi Hashimoto, Ph.D.

Project Assistant Professor
Ryoko Ihara, M.D., Ph.D., 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, and Dr. Yutaro
Ito of Kobayashi also joined in the research project in
the replacement of Dr. Izawa.
The aged society in Japan urges us to challenge thedementing disorders including Alzheimer’s disease(AD), although there has 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“production”,“secretion”,“aggregation”
and

459

“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 (Hashimoto T, Soc for
Neuroscience meeting 2017). We will further identify
A species that are involved in the A dynamics in thebrain, including those specifically involved indeposition 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.

460⑤ 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. Mann DMA, Davidson YS, Robinson AC, Allen N,
Hashimoto T, Richardson A, Jones M, Snowden
JS, Pendleton N, Potter MC, Laquerriere A,
Prasher V, Iwatsubo T, Strydom A: Patterns andseverity of vascular amyloid in Alzheimer's
disease associated with duplication and missense
mutations in APP gene, Down Syndrome andsporadic
Alzheimer's
disease.
Acta
Neuropathologica, 136(4): 569-587, 2018
2. 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. Scientific Reports, 9(1): 2827, 2019
3. Wakabayashi T, Yamaguchi K, Matsui K, Sano T,
Kubota T, Hashimoto T, Mano A, Yamada K,

4.

5.

6.

7.

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. Molecular Neurodegeneration, 14(1): 15,
2019
Iwata A, Iwatsubo T, Ihara R, Suzuki K,
Matsuyama Y, Tomita N, Arai H, Ishii K, Senda M,
Ito K, Ikeuchi T, Kuwano R, Matsuda H, heJapanese ADNI: Effects of sex, education,
background, and chronic kidney disease grading
on longitudinal cognitive and functional decline inpatients in the Japanese Alzheimer's Disease
Neuroimaging Initiative study. Alzheimer's and
Dementia 12:4: 65-774, 2018.
Ihara R, Vincent BD, Baxter MR, Franklin EE,
Hassenstab JJ, Xiong C, Morris JC, Cairns NJ:
Relative neuron loss in hippocampal sclerosis ofaging and Alzheimer disease. Annals of
Neurology, 84(5): 741-753, 201
Ihara R, Iwata A, Suzuki K, Ikeuchi T, Kuwano R,
Iwatsubo T, the Japanese Alzheimer's Disease
Neuroimaging Initiative: Clinical and cognitive
characteristics of preclinical Alzheimer's diseasein the Japanese Alzheimer's Disease Neuroimaging Initiative cohort. Alzheimer's and
Dementia, 4, 645-651, 2018
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, the Alzheimer's disease neuroimaging initiative,
the Japanese Alzheimer's disease neuroimaging
initiative: Lower serum calcium as a potentiallyassociated actor for conversion of mild cognitive
impairment to early Alzheimer's disease in theJapanese Alzheimer's disease neuroimaging
initiative. Journal of Alzheimer's Disease, 68(2):777-788. 2019

461

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

462

conducted in 2018.
1) Venous thromboembolic events in patients withlung cancer treated with cisplatin-based versus
carboplatin/nedaplatin-based chemotherapy.
An association between chemotherapy and venous
thromboembolic events (VTEs) in patients with cancer
is well established, with cisplatin (CDDP) being oneof the most well-studied risk factors. However,whether CDDP is more strongly associated withoccurrence of VTEs than carboplatin (CBDCA) or
nedaplatin (CDGP) is controversial. Our purposes
were to characterize patients with lung cancer andin-hospital VTEs, identify risk factors associated with
VTEs, and compare the risks associated with CDDPbased versus CBDCA/CDGP-based chemotherapy.
We retrospectively identified patients with lungcancer who underwent platinum-based chemotherapy
from April 2012 to March 2015 from a national
inpatient database in Japan. We used multivariablelogistic regression analysis to analyze associations
between various factors, including chemotherapy
regimens and VTE.
Of 235 104 eligible patients, 675 (0.29%) had VTEs
after receiving platinum-based chemotherapy while
hospitalized. Multivariable analysis showed that age,
activity of daily living index, and invasive medical
procedures were significant risk factors for the occurrence of VTE. Furthermore, CDDP-based chemotherapy was associated with a higher rate of VTE than
CBDCA/CDGP-based chemotherapy (adjusted odds
ratio: 1.35; 95% confidence interval: 1.08-1.68;
P<0.01).
In conclusion, CDDP-based chemotherapy is astronger risk factor for VTEs than CBDCA/CDGPbased chemotherapy in patients with lung cancer.
2) Influence of Parkinsonism on outcomes of elderly
pneumonia patients
Pneumonia is one of the most frequent reasons for
hospitalization in patients with Parkinson's disease.
The present study aimed to evaluate the impact ofParkinsonism on the clinical courses of elderly
patients hospitalized for pneumonia.
We conducted a retrospective cohort study ofpatients aged >/=60 years who were hospitalized forpneumonia, using data from a national inpatient
database in Japan. We performed one-to-four
matching for age and sex between patients with andwithout Parkinsonism. Multivariable regression
analyses were carried out for in-hospital mortality,
length of stay, and discharge to home.
Patients with Parkinsonism had significantly lower
in-hospital mortality than those without Parkinsonism(odds ratio, 0.81; 95% confidence interval, 0.74-0.89).
Length of stay was 8.1% longer in patients with
Parkinsonism. Patients with Parkinsonism were lesslikely to be discharged to home (odds ratio, 0.62; 95%
confidence interval, 0.58-0.67).
Parkinsonism was not an independent predictor of
in-hospital mortality, but was related to prolonged
length of stay and discharge other than to home inpatients with pneumonia.
3) Oral fluorouracil vs vinorelbine plus cisplatin as
adjuvant chemotherapy for stage II-IIIA non-small
cell lung cancer: Propensity score-matched andinstrumental variable analyses
Adjuvant chemotherapy with vinorelbine plus
cisplatin (VNR/CDDP) is a standard regimen fortreatment of postoperative stage II-IIIA non-small celllung cancer (NSCLC). However, oral fluorouracil
offers a feasible alternative adjuvant chemotherapeutic
regimen. We compared the prognoses of patients with
NSCLC treated with adjuvant chemotherapy witheither VNR/CDDP or oral fluorouracil.
We identified patients with stage II-IIIA NSCLC who
underwent lung surgery followed by adjuvant
chemotherapy with VNR/CDDP (n = 384) or oral
fluorouracil (n = 268) between July 2010 and March
2015, using the national Japanese inpatient andoutpatient Diagnosis Procedure Combination database.
We compared recurrence-free survival between thegroups by multivariable Cox regression analysis for
one-to-one propensity score-matched patients and by
instrumental variable analysis.
Younger patients and patients with positive N2 nodes
were more likely to receive VNR/CDDP, while older
patients and those with T3N0 classification were more
likely to receive oral fluorouracil. Among 172 pairs ofpropensity-matched patients, time to adjuvant
chemotherapy was shorter for oral fluorouracilcompared with VNR/CDDP. Oral fluorouracil was
also significantly associated with improved
recurrence-free survival compared with VNR/CDDP,
according to multivariable Cox regression analysis(hazard ratio, 0.41; 95% confidence interval,

463

0.26-0.64). Instrumental variable analysis showed asimilar relationship (hazard ratio, 0.19; 95%
confidence interval, 0.038-0.92).
On a large nationwide cohort, adjuvant chemotherapy with oral fluorouracil prolonged recurrencefree survival in patients with postoperative stage
II-IIIA NSCLC, compared with VNR/CDDP. Oral
fluorouracil may thus be a useful alternative to VNR/
CDDP for the adjuvant treatment of these patients.
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. Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Clinical features andpractice patterns of gastroschisis: a retrospective
analysis using a Japanese national inpatient
database. Pediatr Surg Int. 2018.
2. Fujiogi M, Michihata N, Matsui H, Fushimi K,
Yasunaga H, Fujishiro J. Postoperative Small
Bowel Obstruction Following Laparoscopic orOpen Fundoplication in Children: A Retrospective
Analysis Using a Nationwide Database. World J
Surg. 2018.
3. Hiraishi Y, Jo T, Michihata N, Hasegawa W,
Sakamoto Y, Urushiyama H, Matsui H, Fushimi K,
Nagase T, Yasunaga H, Yamauchi Y. Hospital
Volume and Mortality following Diagnostic
Bronchoscopy in Lung Cancer Patients: Data
from a National Inpatient Database in Japan.
Respiration. 2018:1-9.
4. Jo T, Yasunaga H, Michihata N, Sasabuchi Y,
Hasegawa W, Takeshima H, Sakamoto Y, Matsui
H, Fushimi K, Nagase T, Yamauchi Y. Influenceof Parkinsonism on outcomes of elderly
pneumonia patients. Parkinsonism Relat Disord.
2018.
5. Kishimoto M, Yamana H, Inoue S, Noda T,
Akahane M, Inagaki Y, Matsui H, Yasunaga H,
KawaguchiM,ImamuraT.
Suspected
periprosthetic joint infection after total knee
arthroplasty under propofol versus sevoflurane
anesthesia: a retrospective cohort study. Can J
Anaesth. 2018;65(8):893-900.

6. Mitani A, Jo T, Yasunaga H, Sakamoto Y,
Hasegawa W, Urushiyama H, Yamauchi Y, Matsui
H, Fushimi K, Nagase T. Venous thromboembolic
events in patients with lung cancer treated withcisplatin-based versus carboplatin/nedaplatinbased chemotherapy. Anticancer Drugs. 2018;29(6):560-4.
7. 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. 2018.
8. Nakaharai K, Morita K, Jo T, Matsui H, Fushimi
K, Yasunaga H. Early prophylactic antibiotics forsevere acute pancreatitis: A population-based
cohort study using a nationwide database in Japan.
J Infect Chemother. 2018.
9. Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H.
Cholinergic Crisis Caused by Cholinesterase
Inhibitors: a Retrospective Nationwide Database
Study. J Med Toxicol. 2018;14(3):237-41.
10. Ohbe H, Jo T, Yamana H, Matsui H, Fushimi K,
Yasunaga H. Early enteral nutrition for cardiogenic or obstructive shock requiring venoarterial
extracorporeal membrane oxygenation: a nationwide inpatient database study. Intensive Care Med.
2018;44(8):1258-65.
11. Okubo Y, Michihata N, Morisaki N, Sundel RP,
Matsui H, Fushimi K, Yasunaga H. Association
Between Dose of Glucocorticoids and Coronary
Artery Lesions in Kawasaki Disease. Arthritis
Care Res (Hoboken). 2018;70(7):1052-7.
12. Okubo Y, Michihata N, Morisaki N, Yoshida K,
Matsui H, Fushimi K, Yasunaga H. Effects of
Glucocorticoids on Hospitalized Children With
Anaphylaxis. Pediatr Emerg Care. 2018.
13. Sasabuchi Y, Matsui H, Lefor AK, Jo T, Michihata
N, Fushimi K, Yasunaga H. Japanese Herbal
Kampo Hochu-Ekki-To or Juzen-Taiho-To after
Surgery for Hip Fracture Does Not Reduce
Infectious Complications. Evid Based Complement Alternat Med. 2018;2018:8620198.
14. Shinkawa H, Yasunaga H, Hasegawa K, Matsui H,
Fushimi K, Michihata N, Kokudo N. Mortality
and morbidity after hepatic resection in patients
undergoing hemodialysis: analysis of a national
inpatient database in Japan. Surgery. 2018;163(6):464

1234-7.
15. Tadokoro F, Morita K, Michihata N, Fushimi K,
Yasunaga H. Association between sugammadex
and anaphylaxis in pediatric patients: A nested
case-control study using a national inpatient
database. Paediatr Anaesth. 2018.
16. Tsuchiya A, Yamana H, Kawahara T, Tsutsumi Y,
Matsui H, Fushimi K, Yasunaga H. Tracheostomy
and mortality in patients with severe burns: A
nationwide observational study. Burns. 2018.
17. Uda K, Okubo Y, Shoji K, Miyairi I, Morisaki N,
Michihata N, Matsui H, Fushimi K, Yasunaga H.
Trends of neuraminidase inhibitors use in children
with influenza related respiratory infections.
Pediatr Pulmonol. 2018;53(6):802-8.
18. Urushiyama H, Jo T, Yasunaga H, Michihata N,
Matsui H, Hasegawa W, Takeshima H, Sakamoto
Y, Hiraishi Y, Mitani A, Fushimi K, Nagase T,
Yamauchi Y. Oral fluorouracil vs vinorelbine plus
cisplatin as adjuvant chemotherapy for stage
II-IIIA non-small cell lung cancer: Propensity
score-matched and instrumental variable analyses.
Cancer Med. 2018.
19. Urushiyama H, Jo T, Yasunaga H, Michihata N,
Yamana H, Matsui H, Hasegawa W, Hiraishi Y,
Mitani A, Fushimi K, Nagase T, Yamauchi Y.
Effect of Hangeshashin-To (Japanese Herbal
Medicine Tj-14) on Tolerability of Irinotecan:
Propensity Score and Instrumental Variable
Analyses. J Clin Med. 2018;7(9).
20.Yamana H, Kodan M, Ono S, Morita K, Matsui H,
Fushimi K, Imamura T, Yasunaga H. Hospitalquality reporting and improvement in quality ofcare for patients with acute myocardial infarction.
BMC Health Serv Res. 2018;18(1):523.

465

Department of Lipidomics
Professor
Takao Shimizu, M.D., Ph.D.
Yoshiya Oda, Ph.D.

Associate Professor
Fuyuki Tokumasu, Ph.D.

Assistant Professor
Suzumi Tokuoka, Ph.D.

Homepage

http://lipidomics.m.u-tokyo.ac.jp/index-e.html※The following information is the same as that of the previous year for certain reasons.

Introduction and Organization

Research activities

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 and in May 2018, Yoshiya Oda
joined as a professor. In 2014, we had another assistant professor, two guest researchers and two technicalassistants.

Our research interests cover following topics.

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.

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.
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

466

chromatography, develop differential analyses andfeature-extraction methods, and establish an intelligent analytical system linked with lipid database.
Methods for clinical samples
Clinical samples such as blood, urine, feces, andtissue biopsies vary greatly as compared with
controlled animal studies. Furthermore, sampling andstorage conditions are not always optimized for lipid
analysis. We are developing techniques for handlingclinical samples for a practical lipidomics analysis.
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,
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.
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.
Analyses of lipid profile and energy recycling
mechanism in Plasmodium falciparum (humanmalaria parasite)
Human malaria impacts on human healthworld-wide, resulting in close to430,000 victims eachyear. However, developments of anti-malarial drug
have been hampered by quick emergence of drug
resistant parasites. To better understand malaria
parasite biology and drug resistance mechanisms, westudy molecular pathways of lipid metabolism inparasite and biophysical properties of intracellular
membranes that are responsible for malaria protein
delivery to the host erythrocyte membrane. Since
parasites grow inside human erythrocytes, clean
separation of parasites from the host cell and precise
biochemical analyses are often difficult tasks. In ourlaboratory, we combine lipid profiling techniques, ahigh-resolution
fluorescencemicroscopy,
andadvanced biophysical analyses to achieve our research
objectives.

References
1. 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)
2. 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)
3. 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)
4. 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)
5. 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

467

through the aryl hydrocarbon receptor and its
relevance to hepatotoxicity owing to neutrophil
infiltration. J Biol Chem, 292. 10586-10599 (2017)
6. 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)
7. 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.
8. 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)
9. 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)
10. 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)
11. 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)12. 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)
13. 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)
14. Chagas AC, McPhie P, San H, Narum D, Reiter K,
Tokumasu F, Brayner FA, Alves LC, Ribeiro JM,
Calvo E. Simplagrin, a platelet aggregation
inhibitor from Simulium nigrimanum salivary
glands specifically binds to the Von Willebrandfactor receptor in collagen and inhibits carotid
thrombus formation in vivo. PLoS Negl. Trop.
Dis., 8, e2947 (2014)
15. Tokumasu F, Crivat G, Ackerman H, Hwang J,
Wellems TE. Inward cholesterol gradient of themembrane system in P. falciparum -infected
erythrocytes involves a dilution effect fromparasite-produced lipids. Biol. Open, 3, 529-541(2014)
16. Yoshioka W, Kawaguchi T, Fujisawa N, AidaYasuoka K, Shimizu T, Matsumura F, Tohyama C.
Predominant role of cytosolic phospholipase A2α
in dioxin-induced neonatal hydronephrosis inmice. Sci. Rep., 4, 4042 (2014)
17. Tarui M, Shindou H, Kumagai K, Morimoto R,
Harayama T, Hashidate T, Kojima H, Okabe T,
Nagano T, Nagase T, Shimizu T. Selective
inhibitors of a PAF biosynthetic enzyme lysophosphatidylcholine acyltransferase 2. J. LipidRes., 55, 1386-1396 (2014)18. Harayama T, Eto M, Shindou H, Kita Y, Otsubo E,
Hishikawa D, Ishii S, Sakimura K, Mishina M,
Shimizu T. Lysophospholipid acyltransferases
mediate phosphatidylcholine diversification toachieve the physical properties required in vivo.
Cell Metab., 20, 295-305 (2014)
19. Morimoto R, Shindou H, Tarui M, Shimizu T.
rapid production of platelet-activating factor is
induced by protein kinase Cα-mediated phosphorylation of lysophosphatidylcholine acyltransferase 2 protein. J. Biol. Chem., 289, 1556615576 (2014)
20. Liu M, Saeki K, Matsunobu T, Okuno T, Koga T,
Sugimoto Y, Yokoyama C, Nakamizo S,
Kabashima K, Narumiya S, Shimizu T, Yokomizo
T. 12-Hydroxyheptadecatrienoic acid promotes
epidermal wound healing by accelerating
keratinocyte migration via BLT2 receptor. J. Exp.
Med., 211, 1063-1078 (2014)

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

470

Department of Clinical Laboratory
Professor
Yutaka Yatomi, M.D.

Lecturer
Masao Daimon, M.D., Makoto Kurano, M.D.
Daiya Takai, M.D., Masato Yumoto, M.D.,

Associate
Tomoko Nakao, M.D., Masako Nishikawa, M.D
Masaya Sato, M.D., Atsushi Yasumoto, 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 2018, 234,767 outpatient blood
sampling were performed in this section. Furthermore,
255,698 urine samples were examined.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2018, over 5,454,903
serum enzyme tests (such as AST and ALT), and579,702 immunological tests were performed.

The 3rd Section
This section deals with laboratory hematology and
DM-related tests, and gene analysis tests. In 2018,
1,194,808 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 2018, 43,463 ECG, 26,613
pulmonary function tests, and 11,179 EEG were
performed.
The 5th Section
This section deals with ultrasonography. In 2018,
10,524 echocardiography tests, 14,274 abdominal
echography tests, and 9,528 other ultrasonography
tests were performed.

Teaching activities
Lectures are given to the fourth, fifth and sixth grade
medical students on clinical tests including
hematology, chemistry, endocrinology, immunology,
bacteriology, cardiology, and pulmonary function.

471

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. Students
from professional schools also study laboratory
medicine under the guidance of members in ClinicalLaboratory Center.

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) platelet
biology, iii) AI and data mining in laboratory medicine,iv) genetic testing, v) oxidized albumin as a redox
marker, vi) analysis of cardiac functions using
ultrasound, vii) improvement and further clinicalapplication of pulmonary function tests, viii)
elucidation of abnormality in epigenetics in cancer
and its clinical application, and ix) analysis of brain
functionusing
magnetoencephalographyandnear-infrared spectroscopy.

References
Original article:
1. Araoka, H., Baba, M., Okada, C., Kimura, M.,
Sato, T., Yatomi, Y., Moriya, K., and Yoneyama,
A. Risk factors for recurrent Helicobacter cinaedi
bacteremia and the efficacy of selective digestive
decontamination with kanamycin to prevent
recurrence. Clin. Infect. Dis. 67: 573-578, 2018.
2. Araoka, H., Baba, M., Okada, C., Kimura, M.,
Sato, T., Yatomi, Y., Moriya, K., and Yoneyama,
A. First evidence of bacterial translocation fromthe intestinal tract as a route of Helicobacter
cinaedi bacteremia. Helicobacter 23:e12458,
2018.
3. Hikita, H., Sato, M., Sato, M., Soroida, Y.,
Kobayashi, T., Gotoh, H., Iwai, T., Nakagomi, R.,
Tateishi, R., Komuro, T., Sone, S., Koike, K.,
Yatomi, Y., and Ikeda, H. Disappearance of
Perihepatic lymph node enlargement achieving

hepatitis C viral eradication using direct acting
antivirals. J. Viral Hepat. 15: 329-334, 2018.
4. Hiyama, N., Ando, T., Maemura, K., Sakatani, T.,
Amano, Y., Watanabe, K., Kage, H., Yatomi, Y.,
Nagase, T., Nakajima, J., and Takai D.
Glutamate-cysteine ligase catalytic subunit isassociated with cisplatin resistance in lungadenocarcinoma. Jpn. J. Clin. Oncol. 48: 303307, 2018.
5. Honjo, M., Igarashi, N., Kurano, M., Yatomi, Y.,
Igarashi, K., Kano, K., Aoki, J., Weinreb, R.N.,
and Aihara, M. Autotaxin-Lysophosphatidic Acid
Pathway in Intraocular Pressure Regulation and
Glaucoma Subtypes. Invest. Ophthalmol Vis. Sci.
59: 693-701, 2018.
6. Honjo, M., Igarashi, N., Nishida, J., Kurano, M.,
Yatomi, Y., Igarashi, K., Kano, K., Aoki, J., andAihara, M. Role of the Autotaxin-LPA Pathway in
Dexamethasone-Induced Fibrotic Responses andExtracellular Matrix Production in Human
Trabecular Meshwork Cells. Invest. Ophthalmol.
Vis. Sci. 59: 21-30, 2018.
7. Ikeda, H., Kobayashi, M., Kumada, H., Enooku,
K., Koike, K., Kurano, M., Sato, M., , T.,
Kobayashi, T., Ohkawa, R., Shimamoto, S.,
Igarashi, K., Aoki, J., and Yatomi, Y.
Performance of autotaxin as a serum marker ofliver fibrosis. Ann. Clin. Biochem. 55: 469-477,
2018.
8. Igarashi, N., Honjo, M., Kurano, M., Yatomi, Y.,
Igarashi, K., Kano, K., Aoki, J., and Aihara M.
Increased aqueous autotaxin and lysophosphatidic
acid levels are potential prognostic factors after
trabeculectomy in different types of glaucoma. Sci.
Rep. 8: 11304, 2018.
9. Kurano, M., Hasegawa, K., Kunimi, M., Hara, M.,
Yatomi, Y., Teramoto, T., and Tsukamoto, K.
Sitosterol prevents obesity-related chronic
inflammation. Biochim. Biophys. Acta 1863:
191-198, 2018.
10. Kurano, M., Miyagaki, T., Miyagawa, T., Igarashi,K., Shimamoto, S., Ikeda, H., Aoki, J., Sato, S.,
and Yatomi Y. Association between serum
autotaxin or phosphatidylserine-specific phosphorlipase A1 levels and melanoma. J. Dermatol.
45: 571-579, 2018.
11. Kurano, M., Tsuneyama, K., Morimoto, Y.,472

Shimizu, T., Jona, M., Kassai, H.,Nakao, K., Aiba,
A., and Yatomi, Y. Apolipoprotein M Protects
Lipopolysaccharide-Treated Mice from Death andOrgan Injury. Thromb. Haemost. 118: 10211035, 2018.
12. Kurano, M., Ikeda, H., Iso-O, N., Hara, M.,
Tsukamoto, K., and Yatomi, Y. Regulation of themetabolism of apolipoprotein M and sphingosine
1-phosphate by hepatic PPARγ activity. Biochem.
J. 475: 2009-2024, 2018.
13. Kuwajima, K., Sumitani, M., Kurano, M., Kano,
K., Nishikawa, M., Uranbileg, B., Tsuchida, R.,
Ogata, T., Aoki, J., Yatomi, Y., and Yamada, Y.
Lysophosphatidic acid is associated with neuropathic pain intensity in humans: An exploratory
study. PLoS One 13: e0207310, 2018.
14. Lee, S.C., Daimon, M., Di Tullio, M.R., Homma,
S., Hasegawa, T., Chiou, S.H., Nakao, T.,
Hirokawa, M., Mizuno, Y., Yatomi, Y., Yamazaki,T., and Komuro I. Beneficial effect of bodyweight control on left ventricular diastolic
function in the general population: an analysis of
longitudinal data from a health check-up clinic.
Eur. Heart J. Cardiovasc. Imaging 19: 136-142,
2018.
15. Lei, C., Kobayashi, H., Wu, Y., Li, M., Isozaki,
A., Yasumoto, A., Mikami, H., Ito, T., Nitta, N.,
Sugimura, T., Yamada, M., Yatomi, Y., Di Carlo,
D., Ozeki, Y., and Goda, K. High-throughput
imaging flow cytometry by optofluidic timestretch microscopy. Nat. Protoc. 13: 1603-1631,
2018.
16. Maemura, K., Watanabe, K., Ando, T., Hiyama,N., Sakatani, T., Amano, Y., Kage, H., Nakajima,J., Yatomi, Y., Nagase, T., and Takai D. Alteredediting level of microRNAs is a potential
biomarker in lung adenocarcinoma. Cancer Sci.
109: 3326-3335, 2018.
17. Makita, K., Mikami, Y., Matsuzaki, H., Narumoto,O., Takai, D., Yatomi, Y., and Nagase, T. Utilityof bronchoscopy in the definitive diagnosis ofpatients with haematological malignancies
presenting with radiological abnormalities. Clin.
Respir. J. 12: 1381-1388, 2018.
18. Makimoto, H., Shimizu, K., Fujiu, K., Lin, T.,
Oshima, T., Amiya, E., Yamagata, K., Kojima, T.,
Daimon, M., Nagatomo, R., Waki, K., Meyer, C.,

and Komuro, I. Effect of Sympatholytic Therapy
on Circadian Cardiac Autonomic Activity in
Non-Diabetic Chronic Kidney Disease. Int. HeartJ. 59: 1352-1358, 2018.
19. Mishima, Y., Kurano, M., Kobayashi, T.,
Nishikawa, M., Ohkawa, R., Tozuka, M., andYatomi, Y. Dihydro-sphingosine 1-phosphateinteracts with carrier proteins in a manner distinct
from that of sphingosine 1-phosphate. Biosci. Rep.
38: BSR20181288, 2018.
20. Murono, K., Ishihara, S., Kawai, K., Kaneko, M.,
Sasaki, K., Otani, K., Yasuda, K., Nishikawa, T.,
Tanaka, T., Kiyomatsu, T., Hata, K., Nozawa, H.,
Satoh, Y., Kurihara, M., Yatomi, Y., and
Watanabe, T. Significance of carcinoembryonicantigen mRNA in peritoneal lavage determined bytranscription-reverse
transcription
concerted
method in patients with low rectal cancer. Asian J.
Surg. 41: 321-327, 2018.
21. Nakao, T., Yasumoto, A., Tokuoka, S., Kita, Y.,
Kawahara, T., Daimon, M., and Yatomi Y. The
impact of night-shift work on platelet function in
healthy medical staff. J. Occup. Health. 60: 324332, 2018.
22. Nakatani, S., Yasukawa, K., Ishimura, E.,
Nakatani, A., Toi, N., Uedono, H., Tsuda, A.,
Yamada, S., Ikeda, H., Mori, K., Emoto, M.,
Yatomi, Y., and Inaba, M. Non-mercaptalbumin,
Oxidized Form of Serum Albumin, Significantly
Associated with Renal Function and Anemia in
Chronic Kidney Disease Patients. Sci. Rep. 8:16796, 2018.
23. Nitta, N., Sugimura, T., Isozaki, A., Mikami, H.,
Hiraki, K., Sakuma, S., Iino, T., Arai, F., Endo, T.,
Fujiwaki, Y., Fukuzawa, H., Hase, M., Hayakawa,T., Hiramatsu, K., Hoshino, Y., Inaba, M., Ito, T.,
Karakawa, H., Kasai, Y., Koizumi, K., Lee, S.,
Lei, C., Li, M., Maeno, T., Matsusaka, S.,
Murakami, D., Nakagawa, A., Oguchi, Y.,
Oikawa, M., Ota, T., Shiba, K., Shintaku, H.,
Shirasaki, Y., Suga, K., Suzuki, Y., Suzuki, N.,
Tanaka, Y., Tezuka, H., Toyokawa, C., Yalikun,
Y., Yamada, M., Yamagishi, M., Yamano, T.,
Yasumoto, A., Yatomi, Y., Yazawa, M., Di.,
Carlo, D., Hosokawa, Y., Uemura, S., Ozeki, Y.,
and Goda, K. Intelligent Image-Activated Cell
Sorting. Cell 175: 266-276.e13, 2018.

473

24. Ohkawa, R., Kurano, M., Sakai, N., Kishimoto,T., , T., Igarashi, K., Hosogaya, S., Ozaki, Y.,
Dohi, T., Miyauchi, K., Daida, H., Aoki, J.,
Okubo, S., Ikeda, H., Tozuka, M., and Yatomi Y.
Measurement of plasma choline in acute coronary
syndrome: importance of suitable sampling
conditions for this assay. Sci. Rep. 8: 4725, 2018.
25. Sasada, K., Yamamoto, N., Masuda, H., Tanaka,
Y., Ishihara, A., Takamatsu, Y., Yatomi, Y.,
Katsuda, W., Sato, I., and Matsui, H. Interobserver variance and the need for standardizationin the morphological classification of myelodysplastic syndrome. Leuk. Res. 69: 54-59, 2018.
26. Sakoda, M., Kaneko, M., Ohta, S., Qi, P.,
Ichimura, S., Yatomi, Y., and Ito, T. An Injectable
Hemostat Composed of a PolyphosphateConjugated Hyaluronan Hydrogel. Biomacromolecules. 19: 3280-3290, 2018.
27. Shimizu,K., Soroida, Y., Sato, M., Hikita, H.,
Kobayashi, T., Endo, M., Sato, M., Gotoh, H.,
Iwai, T., Tateishi, R., Koike, K., Yatomi, Y., andIkeda H. Eradication of hepatitis C virus isassociated with the attenuation of steatosis as
evaluated using a controlled attenuation parameter.
Sci. Rep. 8: 7845, 2018.
28. Tokuhara, Y., Shukuya, K., Tanaka, M., Sogabe,K., Ejima, Y., Hosokawa, S., Ohsaki, H.,
Morinishi, T., Hirakawa, E., Yatomi, Y., andShimosawa T. Absorbance measurements ofoxidation of homogentisic acid accelerated by theaddition of alkaline solution with sodium
hypochlorite pentahydrate. Sci Rep. 8: 11364,
2018.
29. Uranbileg, B., Nishikawa, T., Ikeda, H., Kurano,M., Sato, M., Saigusa, D., Aoki, J., Watanabe, T.,
and Yatomi, Y. Evidence Suggests Sphingosine
1-Phosphate Might Be Actively Generated,
Degraded, and Transported to ExtracellularSpaces With Increased S1P2 and S1P3 Expressionin Colon Cancer. Clin. Colorectal Cancer 17:e171-e182, 2018.
30. Watanabe, K., Yasumoto, A., Amano, Y., Kage,
H., Goto, Y., Yatomi, Y., Takai, D., and Nagase,T. Mean platelet volume and lymphocyte-tomonocyte ratio are associated with shorter
progression-free survival in EGFR-mutant lungadenocarcinoma treated by EGFR tyrosine kinase

inhibitor. PLoS One 13: e0203625, 2018.
31. Yasukawa, K., Shimosawa, T., Okubo, S., andYatomi, Y. A simple, rapid, and validated
high-performance liquid chromatography method
suitable for clinical measurements of humanmercaptalbumin and nonmercaptalbumin. Ann.
Clin. Biochem. 55: 121-127, 2018.
32. Yasunaga, M., Taoka, K., Nakagawa, H., Yamada,A., Abe, H., Jona, M., Nishikawa, M., Nakazaki,
K., Yatomi, Y., Fukayama, M., Koike, K., andKurokawa, M. Eculizumab treatment for ischemic
enteritis accompanied with paroxysmal nocturnal
hemoglobinuria: a case report and literature
review. Ann. Hematol. 97: 1513-1515, 2018.
33. Xu, B., Kawata, T., Daimon, M., Kimura, K.,
Nakao, T., Lee, S.C., Hirokawa, M., Yoshinaga,A., Watanabe, M., Yatomi, Y., and Komuro I.
Prognostic Value of a Simple Echocardiographic
Parameter, the Right Ventricular Systolic to
Diastolic Duration Ratio, in Patients with
Advanced Heart Failure with Non-Ischemic
Dilated Cardiomyopathy. Int. Heart J. 59:
968-975, 2018.

474

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
Kazuhiko Fukatsu. M.D., Ph.D.

Lecturer
Mitsuaki Muroya, M.D., Ph.D
Satoshi Murakoshi, M.D., Ph.D.
Ryoji Fukushima, M.D., Ph.D.

Associate
Saito Yuhei, M.S.

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 in the Old Central Building until December
1987. The center moved to the new Central Clinical
Service Building 1 in January 1988, when the surgicalcenter had 14 ORs including one bio-clean room. The
administrative staff included 4 doctors, 75 nurses, 6technical officials, 5 part-time employees. The surgical center became to provide managerial services of
the OR to 18 surgical departments after moving into
the new office building. The total number ofoperations remained to be below 6,300 a year between
1999 and 2000 because of the limitation of number of
ORs and nurses.
In July 2001, the branch hospital in Mejiro area wasmerged with the University of Tokyo Hospital in
Hongo area, which opened a new Ward B Building in
October 2001. After the merger, the number ofelective operations markedly increased and becameover 7,300. The 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 orthopedic outpatientswas diverted for the general OR, which was used forthe short-stay and day surgery. In April 2014, one OR
was renovated into a hybrid OR which is equippedwith advanced interventional imaging system for thepatients undergoing interventional surgical treatment.
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.
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 and
11,124 operations were performed in 2006, 2007,2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015,2016, 2017 and 2018 fiscal year, respectively. The
number of operations in 2018 fiscal year counts forapproximately 1.8 times comparing to that in 2001.

475

These days more and more patients undergo theoperation, using surgical endoscope, such as
laparoscopy/thoracoscopy -assisted operation. There isalso an apparent increase in the number of patients
who are at high risk with critical morbidity or carrierof the particular types of pathogenic bacteria, such as
tuberculosis, MRSA, pseudomonas aeruginosa, HBV,HCV and HIV.

Scope of Activities of Surgical Center
The surgical center covers broad area of clinicalactivities ranging from the operation schedule to theeducation of the medical students and healthcare
workers, and research on healthcare practices.

Operation Schedule
All operations of in-patients are performed in 23
ORs at the surgical center. Computer system has beenutilized in order to handle the information on
operation. In May 1999, the on-line system wasintroduced to order the elective and urgent/emergent
operations through the computer terminal in the wards.
The input of postoperative patient information started
from March in 2000.
The present status of the operation process began to
be seen through the computer monitor from May in1997. 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 photographs of surgical sites, resectedorgans and live video image began to be delivered tothe clinical departments from February in 1997.
The SPD system and the progressive patient caresystem started in the Ward A Building and Central
Clinical Service Building 2 in order to improve theworkflow of hospital in October 2001. In the surgicalcenter, 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 MIDCAB operations for
CABG and endovascular treatment for heart
anomalies such as ASD and VSD. More recently, therobotic surgery has started at the surgical center.
Healthcare-Associated infections (HAIs) are criticalissues in the surgical center. It is mandatory to educate
how to prevent HAIs and occupational infections. As
the number of operation associated with emergenceand re-emergence infectious diseases such as HIV andtuberculosis has increased, all health care staff in thesurgical center are required to adhere to the principles
of standard precautions and transmission-based
precautions.

Teaching Activities
The following lectures or seminar are given to theundergraduates and postgraduates 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 recently
introduced to perform highly advanced operations
such as in the navigation surgery, transplantation
surgery, cardiovascular surgery and robotic surgery.
As a result, the education related to the assist for thosesurgical procedure has become most important
activities in the surgical center. The lectures ofadvanced technologies are in the curriculum for thesurgeons, the nursing staff and clinical engineers sothat they can understand how to use them in a proper
way.
Lectures for the nursing staff consist of a freshmancourse and an advanced course. The freshman course

476

is a basic training course for a scrub nurse or acirculating nurse. 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 thecomplicated and long operations such as transplantation surgery, open-heart surgery, neurosurgery
and robotic surgery.
There is also a training course to clinical 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-job training are given to the non-nursing
staff including technical officials and temporary
employees and performed when they start their careers
in the surgical center. They are given lectures on
aseptic techniques, sterilization/disinfection methods,
prevention of perioperative infections, and maintenance of reusable surgical instruments such as forceps,
scissors and clamps. These subjects are summarized
and stated in the manual. Lectures are also given to
the senior technical officers and temporary employees
to promote their technical knowledge and skills.

microscopy and/or laparoscopy
7) Proper management of equipment of endoscopyassisted surgery8) Centralization of the live video images of thesurgical field
9) Management of surgical devices using UID
10) Perioperative infection control and prevention
related to the sterilization
11) Maintenance of the surgical environment in theOR12) Maintenance and management of the surgicalequipment
13) Perioperative nutritional management of thesurgical patients
14) Others

References（2018）
1.

2.

3.

4.

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 robot-assisted operation
5) Efficient use of human resources6) Introduction of advanced operation assisted by the5.

Higashizono K, Fukatsu K, Watkins A, Watanabe T,
Noguchi M, Tominaga E, Ri M, Murakoshi S,
Yasuhara H, Seto Y. Effects of short-term fasting on
gut-associated lymphoid tissue and intestinal morphology in mice. Clinical Nutrition Experimental
18:6-14, 2018
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. Sep 27. doi: 10.1002/jpen.1446. [Epubahead of print], 2018
Miyakuni T, Fukatsu K, Ri M, Murakoshi S, Inoue
Y, Kurihara S, Takayama T, Yasuhara H. Cystine
and Theanine Improve Survival after Gut IschemiaReperfusion. Ann Nutr Metab. 73(2):131-137,2018
Nakamura K, Fukatsu K, Sasayama A, Yamaji T. An
immune-modulating formula comprising whey peptides and fermented milk improves inflammationrelated remote organ injuries in diet-induced acutepancreatitis in mice. Biosci Microbiota Food Health.
37(1):1-8, 2018
Moriya T, Fukatsu K, Noguchi M, Nishikawa M,
Miyazaki H, Saitoh D, Ueno H, Yamamoto J.
Effects of semielemental diet containing whey
peptides on Peyer's patch lymphocyte number,
immunoglobulin A levels, and intestinal morphology
in mice. J Surg Res. 222:153-159, 2018

477

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.

Homepage

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

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 2002. 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: Ongoing collaborative researches are as follows: image-guided radiation
therapy, clinical PET, multi-detector row CT, 3-Tesla
MRI, flat panel detector.

Clinical activities
1) Diagnostic Radiology:
The section of diagnostic radiology is responsible
for all the clinical examinations of CT, MRI, andangiography and vascular interventional procedures
except for cardiac and peripheral arterial studies. Allof these examinations are performed under therequests of clinicians. Over two hundred CT
examinations are performed using six MDCT scanners
each day. Interventional procedure such as percutaneous biopsy and abscess drainage are also doneby CT guidance. About seventy MR examinations aredone using two of 1.5-Tesla and five of 3-Teslascanners every day. Diagnostic and interventional
procedures are performed using six angiographic
units.
2) Nuclear medicine:
The section of nuclear medicine is responsible forall the radionuclide imaging examinations including
conventional scintigraphy such as bone, kidney,478

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 multileaf collimator systems, which isutilized mainly for non-coplanar radiation therapy inmany patients especially with brain tumor or head andneck tumor. The linear accelerator system with conebeam CT technology has been introduced to our
hospital, which enabled 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.

479

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Lecturer
Tappei Takada, Ph.D.,

Masashi Honma, Ph.D.

Research Associate
Takahiro Amemiya, Ph.D.,

Yuki Ikebuchi, Ph.D.,

Yoshiyuki Ohno, Ph.D.,

Yoshiaki Kariya, Ph.D.,

Tomoko Mayuzumi,

Yoshihide Yamanashi, Ph.D.

Homepage

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

Introduction and Organization
We have 9 faculty members, 80 pharmacy staffs,
and 8 graduate students and 6 undergraduate students
from the faculty of pharmaceutical sciences (as ofJanuary 1st, 2019).

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 (2,515
items), out-patient medicines, anesthetics, muscle
relaxation drugs, psychotropic drugs, poison
medicines.

4805) Narcotic section
Under the supervision of authorized manager fornarcotics (the director of the department ofpharmacy), narcotics are properly managed,
recorded, reported, inspected and directed.
Narcotics are properly arranged and managed at
the dispensing section and each medical caresection.
6) Ward section
They contribute to the team medical care byproviding specialized drug information andsharing them with all the staffs involved in thetreatment as follows;① Supporting the proper use of medication bypharmacists stationed at ICU sections.
② Arrangement and mixing of injections forpatients at the staff station of Hematology andOncology.
③ Investigation of carrying medicines and theadverse effect histories, allergy histories etc. at
the time of hospitalization. Participation for
conferences. Procurement and appraisal ofpatients’ basic information about the disease,compilation of the medicine history. Monitoringof medication guidance and the adverse effectfor patients, and compilation of guidance record.
Offering the doctor with drug information,prescription design support and detailed
contents of medication guidance to each patient.
④ Investigation and management of ward stock
medicine.
⑤ Nutrient support of the patients as a member of
NST.
⑥ Management of proper use of narcotics as amember of palliative care team.
⑦ Management of proper use of antibiotics,
rounds of a hospital ward, and training of thestaffs as members of ICT and AST.
Statistical Data (fiscal year 2018)
Number of items on in-hospital formulary: 2,515
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
374,855 ps.
(outside :319,484 ps.)(inside :55,371 ps.)out-patient chemotherapy:
12,224 ps.

in-patients :244,747 ps.
injection drugs:
184,066 ps.
IVH:
2,666 pp.
chemotherapy:
10,610 pp.
TDM consultations (annual) :18,264 pp.
Numbers of hospital pharmaceutical cares (annual):
18,532 pp.

Education
The department of pharmacy takes various
responsibilities of education with regard to clinicalpharmacy, pharmacology, and pharmacokinetics forstudents and graduate students in the faculty of
medicine, in the faculty of pharmacy, and in theschool of integrated health sciences. We also have ourown half a year post-graduate training course
optimized for new pharmacists.
For students in the faculty of medicine, we are in
charge of "Pathogenetic and Pathology" as an optionalcourse lecture. We are providing a 3-days practicecourse as a part of compulsory clinical practice for theM3 or M4 students and teach clinical pharmaceutics
and practical knowledge of prescription and risk
management to them. For the students in the healthsciences and nursing, we are in charge of clinicalpharmacokinetics lectures as a part of a compulsory
subject, "Pharmacology and Toxicology".
For students in the faculty of pharmacy, we are in
charge of lectures for the undergraduate students:"Clinical Pharmacy" (compulsory subject). They are
educated for the clinical pharmacology andpharmacokinetics. For the graduate students, we are in
charge of “Special Lecture Basic Pharmaceutical
Science IV”, “Special Lecture Clinical Science”,“Advanced Course of Medical Pharmacy" as acooperator of the Clinical Pharmacokinetics. Recent
trends of the medical pharmacy as well as the practicaldevelopments and future visions of the department ofpharmacy are presented in this lecture. In addition tothem, we accept undergraduate and graduate students
from the faculty of pharmaceutical sciences andfaculty of medicine. They are doing various research
activities.
Six year course education system has been launchedin the field of pharmaceutical sciences since 2006. In
this system, the clinical training by pharmacists at the481

hospital is one of the most important curriculums. In
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
2018, 6 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) Ikebuchi Y, Aoki S, Honma M, Hayashi M,
Sugamori Y, Khan M, Kariya Y, Kato G, Tabata Y,
Penninger JM, Udagawa N, Aoki K, Suzuki H.
Coupling of bone resorption and formation by
RANKL reverse signalling. Nature. 2018;561:195200.
(2) Kusunoki T, Nakagawa H, Tsukamoto M, Toyoda Y,
Kamiya K, Okada H, Hara S, Hatakeyama K,
Furukawa M, Ikeda K. Possible association between
middle ear cholesteatoma and a single nucleotide
polymorphism 538G>A in ABCC11, a humanearwax type determinant. J Mol Genet Med. 2018;12:362.
(3) Nakagawa H, Toyoda Y, Albrecht T, Tsukamoto M,
Praetorius M, Ishikawa T, Kamiya K, Kusunoki T,
Ikeda K, Sertel S. Are human ATP-binding cassettetransporter C11 and earwax associated with theincidence of cholesteatoma? Med Hypotheses.
2018;114:19-22.
(4) Nakamura M, Fujita K, Toyoda Y, Takada T,
Hasegawa H, Ichida K. Investigation of the transportof xanthine dehydrogenase inhibitors by the uratetransporter ABCG2. Drug Metab Pharmacokinet.
2018;33:77-81.
(5) Takada T, Yamamoto T, Matsuo H, Tan JK, Ooyama
K, Sakiyama M, Miyata H, Yamanashi Y, Toyoda Y,
Higashino T, Nakayama A, Nakashima A,

1. Elucidation of the molecular mechanism which
controls in vivo disposition of lipids / bile acids /uric acid, and establishment of new therapy forlife-style related diseases based on those
integrated understanding.
2. Elucidation of the dynamic regulatory mechanismof bone resorption / bone formation, and establish-482

Shinomiya N, Ichida K, Ooyama H, Fujimori S,
Suzuki H. Identification of ABCG2 as an exporter of
uremic toxin indoxyl sulfate in mice and as a crucial
factor influencing CKD progression. Sci Rep. 2018;
8:11147.
(6) Tashiro Y, Sakai R, Hirose-Sugiura T, Kato Y,
Matsuo H, Takada T, Suzuki H, Makino T. Effects ofOsthol Isolated from Cnidium monnieri Fruit on
Urate Transporter 1. Molecules. 2018;23.
(7) Yamanashi Y, Takada T, Suzuki H. Associations
between lifestyle-related diseases and transporters
involved in intestinal absorption and biliary excretion of cholesterol. Biological & Pharmaceutical
Bulletin. 2018;41:1-10.

483

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Lecturer
Yusuke Shinoda, M.D.

Research Associate
Yasuaki Karasawa, M.D., Motomu Suga, M.D.,
Sayaka Fujiwara, 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 acupunc-

ture 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
corresponding to needs expansion of service toinpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year

484

medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such ascerebrovascular disturbances, respiratory disorders,
neuromuscular diseases, bone and joint diseases, andpediatric disorders as well as on outline of rehabilitation, and amputation/prostheses. We have provided aclinical practice in small group, so-called clinicalclerkship for 5th and 6th year students from
Wednesday to Friday every week. They experience a
few 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. Endo S, Takahashi T, Sato M, Noya Y, Obana M:
Effects of l-Carnitine Supplementation, Botulinum
Neurotoxin Injection, and Rehabilitation for a
Chronic Stroke Patient. J Stroke Cerebrovasc Dis
27: 3342-3344, 2018
2. 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
Up and Go test for measuring objective functional
impairment in patients with long-standing
rheumatoid arthritis: a cross-sectional study. Int J
Rheum Dis 21: 1793-1800, 2018
3. Taya M, Amiya E, Hatano M, Maki H, Nitta D,
Saito A, Tsuji M, Hosoya Y, Minatsuki S,
Nakayama A, Fujiwara T, Konishi Y, Yokota K,
Watanabe M, Morita H, Haga N, Komuro I:
High-intensity aerobic interval training can lead to
improvement in skeletal muscle power among
in-hospital patients with advanced heart failure.
Heart Vessels 33: 752-759, 2018
4. Tanaka T, Ito H, Oshima H, Haga N, Tanaka S:
Total hip arthroplasty in a patient with otospondylo-megaepiphyseal dysplasia, planned bythree-dimensional motion-analyses and full-scale
three-dimensional plaster model of bones. Case
Reports in Orthopedics 2018 Jan 23; 2018:8384079.
eCollection 2018
5. Sawada Y, Sasabuchi Y, Nakahara Y, Matsui H,
Fushimi K, Haga N, Yasunaga H: Early
rehabilitation and in-hospital mortality incommunity-acquired pneumonia patients admitted
to an intensive care unit: propensity-matchedanalysis. Am J Crit Care 27: 97-103, 2018
6. Mano H, Fujiwara S, Haga N: Adaptive behaviour
and motor skills in children with upper limb
deficiency. Prosthet Orthot Int 42: 236-240, 2018
7. Mano H, Fujiwara S, Takamura K, Kitoh H,
Takayama S, Ogata T, Hashimoto S, Haga N:
Congenital limb deficiency in Japan: A crosssectional nationwide survey on its epidemiology.
BMC Musculoskelet Disord 19: 262, 2018
8. Mano H, Takiakwa K, Haga N: Intellectual
characteristics using WISC-IV in children withmyelomeningocele. Cogent Med 5: 1151827, 2018

485

9. 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 patientswith rheumatoid arthritis: A prospective cohort
study. Int J Rheum Dis 21: 1801-1808, 2018
10. Kaneoka A, Yang S, Inokuchi H, Ueha R,
Yamashita H, Nito T, Seto Y, Haga N: Presentationof oropharyngeal dysphagia and rehabilitativeintervention
followingesophagectomy:asystematic review. Dis Esophagus 31: 1-11, 2018
11. Ueha R, Takano T, Hirata Y, Sato T, Goto T,
Kaneoka A, Nito T. Yamasoba T: Management oflaryngeal cleft in mechanically ventilated children
with severe comorbidities. Auris Nasus Larynx 45:
1121-1126, 2018
12. 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
pii: S0949-2658(18)30317-8, 2018.11
13. 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 of threeconservative treatments in patients with lumbar
spinal stenosis: lumbar spinal stenosis withacupuncture and physical therapy study (LAP
study). BMC Complementary and Alternative
Medicine 18(1):19, 201814. Suga M, Kawakubo Y, Nishimura Y, Hashimoto K,
Yumoto M, Kasai K: Lack of correlation between
phonetic magnetic mismatch field and plasma
D-serine levels in humans. Clinical Neurophysiology 129(7):1444-1448, 2018

486

Central Supply Service
Associate 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 associate professor and one assistantprofessor, one nurse, 8 staff members, and 26
members from external staff sources are the main
members of this division.

Facilities
The following facilities are located in an area of
1,077 square meters :Cleaning equipment : 7 washer disinfectors (WDs), 1
vacuum-ultrasonic cleaning unit.
Drying equipment : 5 system drying units.
Sterilizing equipment : 6 autoclaves, 2 ethylene oxide
gas sterilizers, 1 hydrogen peroxide plasma sterilizer,
1 hydrogen peroxide sterilizer, 1 low temperature
steam formaldehyde sterilizer.

Activities
Used devices are cleaned with automated washer
disinfectors and/or manual washing, then packaged
carefully into container sets or paper bags. The
packaged materials are sterilized with autoclaves,

ethylene oxide gas sterilizer or hydrogen peroxide
plasma sterilizer according to their characteristics. The
cleaning procedure is checked with test device. All
sterilization process is recorded and ensured bychemical indicators and biological indicators.
The number of devices handled in the central
supply service is dramatically increasing withincreased number of operations in the surgical centers(number of containers: 29447 for surgical center in2018).
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. The numberof operations for which the staff re-counted devices
was 5765 in 2018.

Research activities
To establish more efficient procedures forcleaning, intensive trials have been performed and thedata have been presented at academic conferences.
Moreover, basic research on host response to surgicalinsult is another theme of our division. The research isimportant for improving outcome of surgical patientsand our data have been published as original articles

References
1. Higashizono K, Fukatsu K, Watkins A, Watanabe
T, Noguchi M, Tominaga E, Ri M, Murakoshi S,
Yasuhara H, Seto Y. Effects of short-term fastingon gut-associated lymphoid tissue and intestinal

487

2.

3.

4.

5.

morphology in mice. Clinical Nutrition
Experimental 18:6-14, 2018
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. Sep 27. doi: 10.1002/jpen.
1446. [Epub ahead of print], 2018
Miyakuni T, Fukatsu K, Ri M, Murakoshi S,
Inoue Y, Kurihara S, Takayama T, Yasuhara H.
Cystine and Theanine Improve Survival after Gut
Ischemia-Reperfusion. Ann Nutr Metab. 73(2):131-137,2018
Nakamura K, Fukatsu K, Sasayama A, Yamaji T.
An immune-modulating formula comprising whey
peptidesandfermented
milk
improves
inflammation-related remote organ injuries indiet-induced acute pancreatitis in mice. Biosci
Microbiota Food Health. 37(1):1-8, 2018
Moriya T, Fukatsu K, Noguchi M, Nishikawa M,
Miyazaki H, Saitoh D, Ueno H, Yamamoto J.
Effects of semielemental diet containing whey
peptides on Peyer's patch lymphocyte number,
immunoglobulin A levels, and intestinal morphology in mice. J Surg Res. 222:153-159, 2018

488

Division of Diagnostic Pathology
Director (Associate 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.,

Professor
Masashi Fukayama, 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),
Munetoshi Hinata, M.D., Ph.D., Sho Yamazawa, M.D., Ph.D., Kento Misumi, M.D., Ph.D.,
Naoko Yamauchi, M.D., Ph.D., Naohiro Makise, M.D., Ph.D.,

Project Research Associate
Ruri Saito, M.D., Ph.D. ("Tsunagu"- Fukushima-Kanto Pathology- Forensic Pathology
Cooperation Program)

Clinical Fellow
Kayoko Ichimura, M.D., Ph.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.
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 thepathologic diagnosis to the patients with breast cancer.
In February 2018, the University of Tokyo489

Hospital was selected as one of the core hospitals to
promote cancer genomic medicine in Japan. In August,the Hospital began advanced medical care (categoryB) named ‘Trial of a multiplex genomic testing by"Todai OncoPanel" for Geneprofiling of malignant
solid tumors’. We serve as members of expert panel tocontribute to the smooth conduct of genomic medicine.
Several types of cancer panel testing will start next
fiscal year which will be covered by public healthinsurance.
We registered 1000 cases of whole slide images(WSI) in the research project of Japanese Society of
Pathology “Database of Pathology-WSI for Development of Artificial Intelligence (AI) Technique andAI-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 2018
fiscal year consisted of 16,947 surgical cases, 16,212
cytology, 1,108 intraoperative histologic diagnosis,
408 intraoperative cytology, 35 autopsy cases (autopsy
rate, 12.9%), and 3 autopsy cases from outside
hospitals.
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–students. ClinicalClerkship (CC) courses of autopsy and surgicalpathology are for the 4th grade students. We usuallyaccept three to five students in elective clinicalclerkship course (there was no acceptance this year
because of the changes in the curriculum).
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 also started e-learning program forinterns to solve the problems in CPC by themselves,
thereby facilitating their understanding.
The Division of Diagnostic Pathology accepted
eight junior residents (total 19 months) in 2018 fortheir second-year program.

Research activities
Dr. Sasaki is in charge of the research to evaluate
feasibility of telepathology for daily practice ofdiagnostic pathology. We conduct research ofdeveloping artificial intelligence (AI)-system, such as“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
Chinzei, director).
We continue the study to investigate the useful-490

ness 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 in order to 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. Nakagama Y, Inuzuka R, Ichimura K, Hinata M,
Takehara H, Takeda N, Kakiuchi S, Shiraga K,
Asakai H, Shindo T, Hirata Y, Saitoh M, Oka A.
Accelerated Cardiomyocyte Proliferation in theHeart of a Neonate With LEOPARD SyndromeAssociated Fatal Cardiomyopathy. Circ Heart Fail.
2018;11(4)2. Murono K, Kawai K, Hata K, Emoto S, Kaneko
M, Sasaki K, Nishikawa T, Otani K, Tanaka T,
Ikemura M, Nozawa H. A case of anastomotic
stenosis of the small intesine caused bycholesterol cyrstal embolisum. Surg Case Rep.
2018;4(1):29.
3. 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. 2018;59(3):641646.
4. Suzuki Y, Koya J, Ebisawa K, Abe H,
Shinozaki-Ushiku A, Nakamura F, Kurokawa M.
Sequential development of monoclonal B cell
lymphocytosis-derived
small
lymphocytic
lymphoma and plasma cell leukemia. Ann
Hematol. 2018;97(5):917-919.
5. Furuya G, Abe H, Shinozaki-Ushiku A,
Yamashita A, Ihara S, Hirata Y, Chiba A, Fujioka
Y, Kurokawa M, Koike K, Fukayama M.
Extranodal NK/T-cell lymphoma of the nasal
cavity developed in a patient with intestinal
Epstein-Barr virus-positive T/NK-cell lympho-

proliferative disorder. Pathol Res Pract. 2018;
214(7):1051-1055.
6. Suzuki Y, Honda A, Nakazaki K, Mizuno H,
Ikemura M, Shinozaki-Ushiku A, Nakamura F,
Fukayama M, Kurokawa M. Histologicaltransformation of MALT lymphoma to plasma
cell leukemia after rituximab-containing therapy.
Ann Hematol. 2018;97(7):1297-1298.
7. Kage H, Kohsaka S, Shinozaki-Ushiku A, Ushiku
T, Takai D, Nakajima J, Miyagawa K, Aburatani
H, Mano H, Nagase T. Spontaneous Transformation from EGFR and ALK Wild-Type Lung
Adenocarcinoma to Neuroendocrine Carcinoma. J
Thorac Oncol. 2018;13(7):e126-e128.
8. Yasunaga M, Taoka K, Nakagawa H, Yamada A,
Abe H, Jona M, Nishikawa M, Nakazaki K,
Yatomi Y, Fukayama M, Koike K, Kurokawa M.
Eculizumab treatment for ischemic enteritis
accompaniedwithparoxysmal
nocturnal
hemoglobinuria: a case report and literature
review. Ann Hematol. 2018;97(8):1513-1515.
9. Shinozaki-Ushiku A, Higashihara T, Ikemura M,
Sato J, Nangaku M, Ushiku T, Fukayama M.
Glomeruloid hemangioma associated withTAFRO syndrome. Hum Pathol. 2018;82:172176.
10. Fukayama M, Miyagaki T, Akamata K, Suzuki S,
Tanaka M, Sato S. Japanese familial anetoderma:
A report of two cases and review of the publishedwork. J Dermatol. 2018;45(12):1459-1462.
11. Yamagushi N, Mano T, Ohtomo R, Ishiura H,
Almansour MA, Mori H, Kanda J, Shirota Y,
Taira K, Morikawa T, Ikemura M, Yanagi Y,
Murayama S, Shimizu J, Sakurai Y, Tsuji S, Iwata
A. An Autopsy case of familial neuronal
intranuclear inclusion disease with dementia andneuropathy. Intern Med. 2018;57(23):3459-3462..
12. Nejo T, Tanaka S, Ikemura M, Nomura M,
Takayanagi S, Shin M, Ushiku T, Shibahara J,
Saito N, Mukasa A. Maffucci syndrome
complicated by three different central nervous
system tumors sharing an IDH1 R132C mutation:case report. J Neurosurg. 2018. [Epub ahead ofprint]
13. Kume A, Yamashita H, Nishida M, Abe H,
Fukayama M, Seto Y. A mass-forming cystic
appearance of peritoneal recurrence of gastric491

adenocarcinoma Journal of Cancer Research andPractice 2018;5(4):169-171.
14. Sawada N, Nakao T, Daimon M, Nawata K,
Tanaka M, Komuro I. Multiple calcified
amorphous tumors in a patient with end-stage
renal disease. J Echocardiogr. 2019. [Epub aheadof print]
15. Saito K, Nakai Y, Ushiku T, Saito T, Takahara N,
Mizuno S, Kogure H, Koike K. Successful
diagnosis of primary peritoneal serous carcinoma
by endoscopic ultrasound-guided through-theneedle forceps biopsy. J Gastroenterol Hepatol.
2019. [Epub ahead of print]
16. 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,
Yamashita S, Takai D, Ushijima T, Nagase T,
Hoshi K Identification of a metastatic lungadenocarcinoma of the palate mucosa throughgenetic and histopathological analysis: a rare casereport and literature review. BMC Cancer. 2019;19(1):52.
17. Fukayama M, Asano Y, Shinozaki-Ushiku A,
Sato S. Estrogen dermatitis: Case report andexamination of estrogen receptor-β in the skin. J
Dermatol. 2019. [Epub ahead of print]
18. Hakozaki M, Ito S, Fujii T, Kiya Y, Udagawa H,
Fukayama
M,
Fukusato
T.
Combined
hepatocellular-cholangiocarcinoma with angiosarcomatoid change: A case report with immunehistochemical study. Pathol Int. 2019;69(2):110116.
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;14(2):e31-e34.
20. Kadowaki H, Amiya E, Hoshino Y, Tamura M,
Uehara M, Nakayama A, Nawata K, Domoto Y,
Saeki T, Ono M, Komuro I. Enormous Aneurysmin Coronary Artery Fistula With Immunoglobulin
G4-Related Disease. Can J Cardiol. 2019;35(2):230.e1-230.e3.
21. 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.
2019;58(3):411-414.
22. Ebisawa K, Masamoto Y, Tokushige J, Nishi H,
Honda K, Hinata M, Toyama K, Nangaku M,
Kurokawa M. Tocilizumab for focal segmental
glomerulosclerosis secondary to multicentric
Castleman’s disease. Ann Hematol. 2019. [Epubahead of print]

492

Department of Corneal
Transplantation
Professor
Takashi Miyai, M.D., Ph.D.

Lecturer
Makoto Aihara, 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 73
corneal surgeries including keratoplasty were

performed in 2018. 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493

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: Miyai T. Fuchs Endothelial Corneal Dystrophy
and Mitochondria. Cornea. 2018 Nov;37 Suppl 1:
S74-S77.
2: Yoshida J, Murata H, Miyai T, Shirakawa R,
Toyono T, Yamagami S, Usui T. Characteristics
and risk factors of recurrent keratoconus over thelong term after penetrating keratoplasty. Graefes
Arch Clin Exp Ophthalmol. 2018 Dec;
256(12):2377-2383
3: Omoto T, Sakisaka T, Toyono T, Yoshida J,
Shirakawa R, Miyai T, Yamagami S, Usui T.
Descemet Stripping Automated Endothelial
Keratoplasty for Failed Penetrating Keratoplasty:
Influence of the Graft-Host Junction on the Graft
Survival Rate. Cornea. 2018 Apr;37(4):462-465
4: Ohtomo K, Arita R, Shirakawa R, Usui T,
Yamashita H, Seto Y, Yamagami S; TS-1
Multicenter Study Group. Quantitative Analysis
of Changes to Meibomian Gland Morphology Due
to S-1 Chemotherapy. Trans Vis Sci Technol.
2018 Dec 28; 7(6):37.doi: 10.1167/tvst.7.6.37.
eCollection 2018 Nov.

494

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Mitsuteru Hiwatari, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Assistant Professor
Kazuhiro Toyama, M.D., Ph.D. (Hematology-Oncology)
Hiroaki Maki, M.D., Ph.D. (Hematology-Oncology)

Homepage

http://www.h.u-tokyo.ac.jp/mukin/※The following information is the same as that of the previous year for certain reasons.

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 andpatients with organ dysfunction. The development of
this strategy is expanding the eligibility of transplant
recipients. Allogeneic HSCT for the elderly is
performed under the admission of ethical committeeof the Faculty of Medicine.
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

495

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. Hiwatari M, Seki M, Akahoshi S, Yoshida K,
Miyano S, Shiraishi Y, Tanaka H, Chiba K,
Ogawa S, Takita J. Molecular studies reveal
MLL-MLLT10/AF10 and ARID5B-MLL genefusions displaced in a case of infantile acutelymphoblastic leukemia with complex karyotype.
Oncol Lett. 2017; 14:2295-2299.

2. Yanada M, Yano S, Kanamori H, Gotoh M, Emi
N, Watakabe K, Kurokawa M, Nishikawa A, Mori
T, Tomita N, Murata M, Hashimoto H, Henzan H,
Kanda Y, Sawa M, Kohno A, Atsuta Y, Ichinohe
T, Takami A. Autologous hematopoietic celltransplantation for acute promyelocytic leukemia
in second complete remission: outcomes before
and after the introduction of arsenic trioxide. Leuk
Lymphoma. 2017; 58:1061-1067.
3. Arai Y, Kondo T, Shigematsu A, Tanaka J,
Ohashi K, Fukuda T, Hidaka M, Kobayashi N,
Iwato K, Sakura T, Onizuka M, Ozawa Y, Eto T,
Kurokawa M, Kahata K, Uchida N, Atsuta Y,
Mizuta S, Kako S. Improved prognosis withadditional medium-dose VP16 to CY/TBI inallogeneic transplantation for high risk ALL in
adults. Am J Hematol. 2018; 93:47-57.
4. Uryu K, Nishimura R, Kataoka K, Sato Y,
Nakazawa A, Suzuki H, Yoshida K, Seki M,
Hiwatari M, Isobe T, Shiraishi Y, Chiba K,
Tanaka H, Miyano S, Koh K, Hanada R, Oka A,
Hayashi Y, Ohira M, Kamijo T, Nagase H,
Takimoto T, Tajiri T, Nakagawara A, Ogawa S,
Takita J. Identification of the genetic and clinicalcharacteristics of neuroblastomas using genomewide analysis. Oncotarget. 2017; 8:107513107529.
5. Watanabe K, Kato M, Ishimaru T, Hiwatari M,
Suzuki T, Minosaki Y, Takita J, Fujishiro J, Oka
A. Perioperative management of severe congenital
protein C deficiency. Blood Coagul Fibrinolysis.
2017; 28:646-649.

496

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Yousuke Nakai, M.D., Ph.D.

Associate
Shuntaro Yoshida, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kogaku/index.html

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 internal medicine, surgery,gynecology and otorhinolaryngology, participate theendoscopic 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 school year reached to
20,000. In the gastrointestinal tract, image enhanced
endoscopy for detail inspection and therapeuticendoscopy, including endoscopic submucosal dissection for esophageal, gastric and colorectal tumors,
are major advanced fields. Our recent clinicalactivities are summarized in Table 1.
Another important activity of our department is thedisinfection and maintenance of endoscopic
apparatuses used in other units including outpatient
clinic, radiotherapy department, surgery department or
intensive care units. All endoscopes in our hospital arecollected 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 resident or young doctors in a program ofeach department.

497

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

ERCP
EUS†
Enteroscopy
Laryngoscopy
Colposcopy

226
959
518
181
75
307

255
943
551
181
70
361

197
1072
630
282
108
378

196
956
698
282
83
365

169
912
763
375
128
404

218
1035
766
396
102
327

228
946
882
310
105
295

362
1206
1084
86
125
417

350
1137
1023
304
114
430

316
1057
923
138
92
414

Total

17944

18069

18838

19644

20591

20627

21034

22038

20769

20169

**

2018
11699
(2177‡)

5530(109‡)*Esophagogastroduodenoscopy, **Endoscopic ultrasonography, †Endoscopic retrograde cholangiopancreatography,‡performed at Center for Epidemiology and Preventive Medicine

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

5.

References
1. Niikura R, Yamada A, Maki K, Nakamura M,
Watabe H, Fujishiro M, Oka S, Esaki M, Fujimori
S, Nakajima A, Ohmiya N, Matsumoto T, Tanaka
S, Koike K, Sakamoto C Associations between
drugs and small-bowel mucosal bleeding: Multicenter capsule-endoscopy study. Dig Endosc.
2018 Jan;30(1):79-89.
2. Kodashima S, Tanaka K, Matsuda K, Fujishiro M,
Saito Y, Ohtsuka K, Oda I, Katada C, Kato M,
Kida M, Kobayashi K, Hoteya S, Horimatsu T,
Matsuda T, Muto M, Yamamoto H, Ryozawa S,
Iwakiri R, Kutsumi H, Miyata H, Kato M,
Haruma K, Fujimoto K, Uemura N, Kaminishi M,
Tajiri H. First progress report on the Japan
Endoscopy Database project. Dig Endosc. 2018
Jan;30(1):20-28
3. Matsuda K, Tanaka K, Fujishiro M, Saito Y,
Ohtsuka K, Oda I, Katada C, Kato M, Kida M,
4. 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,
Tajiri H. Design paper: Japan Endoscopy
Database (JED): A prospective, large database

6.

7.

8.

project related to gastroenterological endoscopy
in Japan. Dig Endosc. 2018 Jan;30(1):5-19
Kinoshita Y, Kato M, Fujishiro M, Masuyama H,
Nakata R, Abe H, Kumagai S, Fukushima Y,
Okubo Y, Hojo S, Kusano M. Efficacy and safetyof twice-daily rabeprazole maintenance therapy
for patients with reflux esophagitis refractory to
standard once-daily proton pump inhibitor: theJapan-based EXTEND study. J Gastroenterol.
2018 Jul;53(7):834-844
Niikura R, Hayakawa Y, Hirata Y, Yamada A,
Fujishiro M, Koike K. Long-term proton pumpinhibitor use is a risk factor of gastric cancer after
treatment for Helicobacter pylori: a retrospective
cohort analysis. Gut. 2018 Oct;67(10):1908-1910
Arakawa K, Hata K, Yamamoto Y, Nishikawa T,
Tanaka T, Kiyomatsu T, Kawai K, Nozawa H,
Yoshida M, Fukuhara H, Fujishiro M, Morikawa T,
Yamasoba T, Koike K, Fukayama M, Watanabe T.
Nine primary malignant neoplasms-involving theesophagus, stomach, colon, rectum, prostate, andexternal ear canal-without microsatellite instability: a case report. BMC Cancer. 2018 Jan 4;18(1):24.
Hirasawa T, Aoyama K, Tanimoto T, Ishihara S,
Shichijo S, Ozawa T, Ohnishi T, Fujishiro M,
Matsuo K, Fujisaki J, Tada T. Application of
artificial intelligence using a convolutional neuralnetwork for detecting gastric cancer in endoscopic
images. Gastric Cancer. 2018 Jul;21(4):653-660.

498

9. Mizutani H, Ono S, Ushiku T, Kudo Y, Ikemura M,
Kageyama N, Yamamichi N, Fujishiro M, Someya
T, Fukayama M, Koike K, Onodera H.
Transparency-enhancing technology allows threedimensional assessment of gastrointestinal
mucosa: A porcine model. Pathol Int. 2018 Feb;
68(2):102-108.
10. Niikura R, Hayakawa Y, Hirata Y, Konishi M,
Suzuki N, Ihara S, Yamada A, Ushiku T, Fujishiro
M, Fukayama M, Koike K. Distinct
Chemopreventive Effects of Aspirin in Diffuse
and Intestinal-Type Gastric Cancer. Cancer Prev
Res (Phila). 2018 May;11(5):279-286
11. Ohki D, Tsuji Y, Shinozaki T, Sakaguchi Y,
Minatsuki C, Kinoshita H, Niimi K, Ono S,
Hayakawa Y, Yoshida S, Yamada A, Kodashima S,
Yamamichi N, Hirata Y, Ushiku T, Fujishiro M,
Fukayama M, Koike K. Sessile serrated adenoma
detection rate is correlated with adenoma
detection rate. World J Gastrointest Oncol. 2018
Mar 15;10(3):82-90.
12. Niikura R, Yamada A, Hirata Y, Hayakawa Y,
Takahashi A, Shinozaki T, Takeuchi Y, Fujishiro
M, Koike K
Efficacy of Vonoprazan for
Gastroesophageal Reflux Symptoms in Patientswith Proton Pump Inhibitor-resistant Non-erosive
Reflux Disease. Intern Med. 2018 Sep 1;57(17):2443-2450
13. Niikura R, Nagata N, Yamada A, Doyama H,
Shiratori Y, Nishida T, Kiyotoki S, Yada T, Fujita
T, Sumiyoshi T, Hasatani K, Mikami T, Honda T,
Mabe K, Hara K, Yamamoto K, Takeda M, Takata
M, Tanaka M, Shinozaki T, Fujishiro M, Koike K.
A multicenter, randomized controlled trial
comparing the identification rate of stigmata ofrecent hemorrhage and rebleeding rate between
early and elective colonoscopy in outpatient-onset
acute lower gastrointestinal bleeding: study
protocol for a randomized controlled trial. Trials.
2018 Apr 3;19(1):214.
14. Mitsui T, Yamashita H, Aikou S, Niimi K,
Fujishiro M, Seto Y. Non-exposed endoscopic
wall-inversion surgery for gastrointestinal stromal
tumor. Transl Gastroenterol Hepatol. 2018 Mar
16;3:17
15. Takiyama H, Ozawa T, Ishihara S, Fujishiro M,
Shichijo S, Nomura S, Miura M, Tada T.

Automatic anatomical classification of esophagogastroduodenoscopy images using deep convolutional neural networks. Sci Rep. 2018 May
14;8(1):7497.
16. Tsuji Y, Sakaguchi Y, Fujishiro M, Koike K.
Preventive measures against stricture after
esophageal endoscopic submucosal dissection:
Halfway through the journey to the best method.
Dig Endosc. 2018 Sep;30(5):600-601.
17. 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 Feb;54(2):131-140.
18. Minatsuki C, Yamamichi N, Inada KI, Takahashi
Y, Sakurai K, Shimamoto T, Tsuji Y, Shiogama K,
Kodashima S, Sakaguchi Y, Niimi K, Ono S,
Niwa T, Ohata K, Matsuhashi N, Ichinose M,
Fujishiro M, Tsutsumi Y, Koike KExpression of
Gastric Markers Is Associated with Malignant
Potential of Nonampullary Duodenal Adenocarcinoma. Dig Dis Sci. 2018 Oct;63(10):26172625.
19. Matsuda R, Yamamichi N, Shimamoto T, Sumida
H, Takahashi Y, Minatsuki C, Kodashima S, Ono
S, Niimi K, Tsuji Y, Sakaguchi Y, Saito I, Kataoka
Y, Asada-Hirayama I, Kakimoto H, Yakabi S,
Takeuchi C, Matsumoto Y, Tamaki Z, Fujishiro M,
Asano Y, Sato S, Koike K. Gastroesophageal
Reflux Disease-Related Disorders of Systemic
Sclerosis Based on the Analysis of 66 Patients.
Digestion. 2018;98(4):201-208.
20. Suzuki H, Takizawa K, Hirasawa T, Takeuchi Y,
Ishido K, Hoteya S, Yano T, Tanaka S, Endo M,
Nakagawa M, Toyonaga T, Doyama H, Hirasawa
K, Matsuda M, Yamamoto H, Fujishiro M,
Hashimoto S, Maeda Y, Oyama T, Takenaka R,
Yamamoto Y, Naito Y, Michida T, Kobayashi N,
Kawahara Y, Hirano M, Jin M, Hori S, Niwa Y,
Hikichi T, Shimazu T, Ono H, Tanabe S, Kondo H,
Iishi H, Ninomiya M; Ichiro Oda for J-WEB/EGC
group. Short-term outcomes of multicenterprospective cohort study of gastric endoscopic
resection: 'Real-world evidence' in Japan. Dig
Endosc. 2019 Jan;31(1):30-39

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21. 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 Jan;89(1):25-32.
22. Nakayama C, Yamamichi N, Tomida S, Takahashi
Y, Kageyama-Yahara N, Sakurai K, Takeuchi C,
Inada KI, Shiogama K, Nagae G, Ono S, Tsuji Y,
Niimi K, Fujishiro M, Aburatani H, Tsutsumi Y,
Koike K. Transduced caudal-type homeobox(CDX) 2/CDX1 can induce growth inhibition on
CDX-deficient gastric cancer by rapid intestinal
differentiation. Cancer Sci. 2018 Dec;109(12):3853-3864.
23. Oda I, Hoteya S, Fujishiro M. Status ofHelicobacter pylori infection and gastric mucosal
atrophy in patients with gastric cancer: Analysis
based on the Japan Endoscopy Database. Dig
Endosc. 2019 Jan;31(1):103
24. 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 Feb;89(2):416421.e1.
25. 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. 2018 Nov 8:1-10
26. 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 Apr;247(4):494-504.
27. 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 Apr;
16(2):180-187.
28. 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 Feb;89(2):357-363.e2
29. Nishioka Y, Yoshioka R, Gonoi W, Sugawara T,
Yoshida S, Hashimoto M, Shindoh J. Fluorine-18fluorodeoxyglucose positron emission tomography as an objective substitute for CT morphologic response criteria in patients undergoing
chemotherapy for colorectal liver metastases.
Abdom Radiol (NY). 2018 May;43(5):1152-1158.
30. Toyoshima O, Hata K, Yoshida S, Arita M.
New-generation chromoendoscopy may increase
confidence in the DISCARD2 study. Gut. 2018
Sep;67(9):1742-1743.
31. Yamamoto S, Ikeda M, Fujimoto F, Okamoto K,
Wakabayashi Y, Sato T, Tatsuno K, Kaburaki T,
Yoshida S, Okugawa S, Koike K, Moriya K.
Bilateral Candida endophthalmitis accompanying
Candida lusitaniae bloodstream infection: A casereport. J Infect Chemother. 2018 Feb;24(2):147149.
32. Toyoshima O, Tanikawa C, Yamamoto R,
Watanabe H, Yamashita H, Sakitani K, Yoshida S,
Kubo M, Matsuo K, Ito H, Koike K, Seto Y,
Matsuda K. Decrease in PSCA expression caused
by Helicobacter pylori infection may promote
progression to severe gastritis. Oncotarget. 2017
Dec 14;9(3):3936-3945.
33. Toyoshima O, Nishizawa T, Arita M, Kataoka Y,
Sakitani K, Yoshida S, Yamashita H, Hata K,
Watanabe H, Suzuki H. Helicobacter pylori
infection in subjects negative for high titer serum
antibody. World J Gastroenterol. 2018 Apr 7;
24(13):1419-1428.
34. Sakitani K, Nishizawa T, Arita M, Yoshida S,
Kataoka Y, Ohki D, Yamashita H, Isomura Y,
Toyoshima A, Watanabe H, Iizuka T, Saito Y,
Fujisaki J, Yahagi N, Koike K, Toyoshima O.
Early detection of gastric cancer after Helicobac-

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ter pylori eradication due to endoscopic surveillance. Helicobacter. 2018 Aug;23(4):e12503.
35. Nishioka Y, Shindoh J, Inagaki Y, Gonoi W,
Mitsui J, Abe H, Yoshioka R, Yoshida S,
Fukayama M, Tsuji S, Hashimoto M, Hasegawa K,
Kokudo N. Host MICA Polymorphism as a
Potential Predictive Marker in Response to
Chemotherapy for Colorectal Liver Metastases.
Dig Dis. 2018;36(6):437-445
36. Tomita M, Saito S, Makimoto S, Yoshida S,
Isayama H, Yamada T, Matsuzawa T, Enomoto T,
Kyo R, Kuwai T, Hirata N, Shimada M, Hirakawa
T, Koizumi K, Saida Y. Self-expandable metallic
stenting as a bridge to surgery for malignant
colorectal obstruction: pooled analysis of 426
patients from two prospective multicenter series.
Surg Endosc. 2019 Feb;33(2):499-509.
37. Kuwai T, Yamaguchi T, Imagawa H, Yoshida S,
Isayama H, Matsuzawa T, Yamada T, Saito S,
Shimada M, Hirata N, Sasaki T, Koizumi K,
Maetani I, Saida Y. Factors related to difficult
self-expandable metallic stent placement for
malignant colonic obstruction: A post-hoc
analysis of a multicenter study across Japan. Dig
Endosc. 2019 Jan;31(1):51-58.
38. Ishibashi R, Niikura R, Obana N, Fukuda S,
Tsuboi M, Aoki T, Yoshida S, Yamada A, Hirata Y,
Koike K. Prediction of the Clinical Outcomes ofSigmoid Volvulus by Abdominal X-Ray: AXISClassification System. Gastroenterol Res Pract.
2018 Nov 15;2018:8493235

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Department of Hemodialysis andApheresis
Professor
Masaomi Nangaku, M.D.,Ph.D.

Lecturer
Akihiko Matsumoto, 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.
9.

ESRD patients. Please note that our center does
not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasma exchange for neurodegenerative diseases,
collagen diseases, TMA (TTP), and pre/post solidorgan transplant patients.
Double filtration plasmapheresis (DFPP) for
collagen diseases, dermatological disorders,
myasthenia gravis, waldenstrom macroglobulinemia.
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.

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

502

5.

6.

second year residents on request.
Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. English and Chinese version of“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.
9.

Prognostic analysis for post-liver transplantpatients received plasma exchange therapy.
Identification of prognostic factors in AKI/CRRT
patients.
Genome wide association study for Nephrotic
syndrome and those functional analyses.
Associations between factors at the initiation ofrenal replacement therapy and prognosis in
ESRD patients.
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 those clinical significance in
ICU/CCU.
Renal biomarker todetermine clinicalactionability in CKD and type-2 DN.
The potentiality of urine biomarker tests fordeveloping country [JICA-JST: Science andTechnology Research Partnership for Sustainable
Development].

References
1.

2.

Yoshida T, Matsuura R, Komaru Y, Miyamoto Y,
Yoshimoto K, Hamasaki Y, Noiri E, Morimura N,
Nangaku M, Doi K. Kinetic estimated glomerular
filtration rate as a predictor of successful
continuous renal replacement therapy discontinuation. Nephrology (Carlton). 24, 287-293 (2019).
Miyamoto Y, Hamasaki Y, Matsumoto A, Doi K,
Noiri E, Nangaku M. Prediction of immuneglobulin M reduction via therapeutic dose of
simple plasma exchange and double filtration

plasmapheresis using membrane separation inpatients with hyperviscosity syndrome caused by
Waldenstrom macroglobulinemia. J Clin Apher.
33, 611-615 (2018).
3. Nakamura Y, Kurata Y, Hamasaki Y, Nangaku M.
Extraperitoneal Placement of a Peritoneal Dialysis
Catheter. Intern Med. 58, 147-148 (2019).
4. 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).
5. 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)
6. 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)
7. Komaru Y, Inokuchi R, Ueda Y, Nangaku M, Doi
K. Use of the anion gap and intermittent hemodialysis following continuous hemodiafiltration in
extremely high dose acute-on-chronic lithium
poisoning: A case report. Hemodial Int. 22, E15E18 (2018)
8. 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)
9. 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)
10. 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

503

ICU Survivors: A Retrospective Observational
Cohort Study. Shock. 46, 44-51 (2016)
11. 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)12. Hasegawa S, Kato H, Hamasaki Y, Koiwa T,
Nangaku M. Positron emission tomography in the
diagnosis of cyst infections. Kidney Int. 91, 759(2017)
13. 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)
14. 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)
15. 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)
16. 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)
17. 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)18. 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)
19. 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)20. 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)
21. 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)

504

Department of Medical Community
Network and Discharge Planning
Professor
Kiyoto Kasai, M.D.,Ph.D. (concurrently)

Associate Professor
Masahiko Sumitani, M.D., Ph.D. (concurrently)

Assistant Profeesor
Tsukasa Inajima, 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. The Department 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, the505

proportion of such transferring patients to first-visit
patients keeps more than 80%.

Teaching activities
We educate undergraduate students of the Medical
Social Working and Welfare of other university.

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.

506

Clinical Research Support Center
Professor, Director
Masaomi Nangaku M.D., Ph.D. (until April), Takashi Moritoyo M.D., Ph.D. (from May)

Associate Professor, Vice Director
Chie Sakanaka, M.D., Ph.D.

Project Lecturer, Vice Director
Tetsuya Ueda, M.D., Ph.D. (from September)

Assistant Professor
Munenori Takata, M.D., Ph.D. (until June), Yukari Uemura, Ph.D.,
Gaku Oguri, M.D., Ph.D., Takuya Kawahara, Ph.D.

Project Assistant Professor
Mihoko Shibuya, M.D., Ph.D., Keiko Ueda, M.D., Ph.D.

Homepage

http://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 researchcoordination activities. In addition to the existing
Consultation Division, new divisions such as
Operation Division, Biostatistics Division, DataManagement Division, Monitoring Division and
Safety Information Division and Operation Division
have been added to the Central Coordinating Unit.
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 I Unit that can

507

conduct Phase 1 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..
As of March 2019 the Center has 7 teaching staff(1 professor, 1 associate professor, 3 assistantprofessors, 2 project assistant professors, there are 29
full-time staff members assigned to the Site
Coordinating Unit (11 pharmacists, 7 nurses,
3 laboratory technicians, 3 clinical psychologists,
3 project academic support specialist and 2 clericalstaff. The number of full-time staff assigned to theCentral Coordinating Unit is 21. (5 project seniorspecialists,1 project specialist, 1 pharmacist, 1
laboratory technician, 3 project academic support staff,
4 medical technicians, 5 clerical staff assigned to
specific project and 1 clerical staff member. Safety
Information Management Division has 4 pharmacists(2 are concurrent) and 1 clerical staff. The P 1 Unit
consists of 19 staff members (9 nurses, 8 laboratory
technicians, 1 project academic support supecialist
and 1 clerical staff).

508

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)
4) 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.
The number of applications processed by the Centeras the IRB secretariat in fiscal 2018 included, as forindustry-sponsored trials for marketing approval, 27
new protocol applications, 81 study extension
applications since 2017, 359 protocol amendment
applications, 974 SAE/safety information reports, 20
study
closureor
termination
reports,
91
monitoring/audit reports. As for intervention studies,
the Center processed 15 new protocols including thespecified clinical trials defined by the Clinical Trials
Act enforced in 2018, 19 studies as shared facility and
35 studies as main facilities being continued in thetransition measure.
Protocol presentations of industry-sponsored trials
prior to application to IRB totaled 25 applications.
Preliminary
consultation
andguidanceforinvestigator-initiated research application 29 and 66
applications, respectively. Since 2018, we have been
recommending early consultation at the beginning ofplanning a study to give specialized suggestions.
Clinical Research Support Center managed drug/
device inventory for 95 clinical trials (drug 91,
devices 4) for regulatory approval, 6 post marketing
research, 21 investigator-initiated clinical research,and 4 cases of compassionate use, 4 tissue-engineered
medical products in fiscal 2017. The number ofprescriptions processed was 1672 for research forapproval and post marketing research combined, 274
for investigator-initiated clinical research. We
managed trial drugs centrally for 3 multicenter
research shipped them for 7 times. We masked
investigational drugs for 1 double-blind placebocontrolled research studies.
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. The number of research participants that

509

CRCs interacted with was 6122 (outpatient 4344 andinpatient 1788) in 2018. The number of monitoring
visits was 911 in 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. The number ofconsultation cases was 244 in 2018.

<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).
As of fiscal 2018, we have accepted 57 clinicalresearch projects for providing support (21investigator-initiated clinical trials (including 13
studies which the University of Tokyo Hospital
participated as a head institution and 9 Advanced
Medical Care B Programs). We also supported 13
clinical studies initiated by the other institutions(including 8 investigator-initiated clinical trials). Oneof the major achievements is the investigator-initiatedclinical trial of the pediatric ventricular assist device;
the trial was initiated in February 2012, applied forregulatory approval in November 2014, and 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. In 2018, we started
global phase II/III study for subject with risk of
Alzheimer’s disease. We are also continuously
conducting global phase I study of Alzheimer’s
disease drug, independent observational study in
Alzheimer’s disease and mild cognitive impairment
patients, and global phase Ⅲstudy in healthy senior
volunteers for Alzheimer’s disease drug since
September 2016.
<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.
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 and510

project management. UHCT ACReSS can easily becustomized by researchers. The system is being usedpractically by 281 projects as of March 2019.
Currently, we are expanding the use to researchersother than Alliance members.
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. Contract templates were createdfor investigator-initiated research and provided toeach university hospital by the National University
Hospital Council of Japan. Contract templates for theClinical Trials Act has been provided to university
hospitals.
A booklet of unique approach of each participating
university was published and reported on the website
home page.

Education/Training
The Center has been accepting M3/M4 students fortraining course in ‘Clinical Clerkship’ since it become
mandatory in 2013. In addition, we accepted graduate
students (applicants) for 2 day practical training(enrolled in Master’s and Doctoral courses) in the
Faculty of Medicine, Graduate School of Pharmaceutical Sciences and the School of Engineering, whoparticipated in the Medical Innovation Initiative
course. Medical Innovation Initiative is part of“Fostering Medical Researcher of the Future” project
adopted by MEXT (Ministry of Education, Culture,
Sports and Technology). Also, we accepted students
enrolled in graduate school and Faculty of
Pharmaceutical Sciences, both from inside and outside
the university. 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). Currently, 5900
participants are registered for the program.
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. In June 2018, 5-day
training was held under the auspices of the hospital, in
which 99 trainees (including 4 from the UTokyo) fromuniversity hospitals across the country participated.
In addition, we held a joint workshop series with 8
alliance universities in the Kanto Koushinetsu area, (6organized by the UTokyo) which consisted of 1
monitoring workshop, 6 clinical research lecture series.
Workshops were attended by 185, 29 (155, 16
participants from UTokyo) and 457 (140 from
UTokyo) respectively.
Since 2017, Japan Agency for Medical Research andDevelopment (AMED) sponsored training workshop

511

for clinical research personnel has been held at the
University of Tokyo. In 2018, 30 (all participants
outside of UTokyo) participated.
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.
The Center holds annual “Clinical Research
Seminar” in March, nearly 200 people from academia
and companies participated last year.

3)

4)

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 2018, the Center was involved in 38
presentations in scientific meetings, of which 34 wereas lead presenters, international conferences 7(Sakanaka, Uemura, Kawahara, Oguri, Kageyama,
Koide). The Japan Society of Clinical Pharmacology
and Therapeutics 3 (Sujino, Arayama, Nakamura),
Conference on CRC and Clinical Research 1(Wakabayashi), Japan Society of Clinical Trials andResearch 2 (Uemura, Kawhara), Academic Research
Organization Council 2 (Uemura, Kawahara),
Japanese Society for Pharmacoepidemiology (Uemura,
Kawahara), 42 publications and academic papers etc.
(English papers 32, Japanese papers 10).

5)

6)Publications
1) 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, 24: 1-8, 20182) Suzuki R, Eiki JI, Moritoyo T, Furihata K,
Wakana A, Ohta Y, Tokita S, Kadowaki T. Effectof short-term treatment with sitagliptin or

7)

glibenclamide on daily glucose fluctuation in
drug-naïve Japanese patients with type 2 diabetes
mellitus. Diabetes Obes Metab. 20(9): 2274-2281,
2018
Okimoto N, Uemura Y, Yoshioka T, Arita S,
Tsurukami H, Otomo H, Nishida S, Ogawa T,
Hirao K, Ikeda S, Matsumoto H, Toten Y, Katae Y,
Okazaki Y, Nakagawa T, Sakai A. Treatment with
Once-Weekly Alendronate Oral Jelly Comparedwith Once-Weekly Alendronate Oral Tablet forJapanese Patients with Primary Osteoporosis: an
Open-label, Prospective, Observational Study.
Health Science Reports, 2(1): e107, 2018
Lee Y, Ohno T, Uemura Y, Osanai A, Miura S,
Taketani T, Fukuda S, Ono M, Takamoto S.
Impact of Complete Revascularization on Longterm Outcomes after Coronary Artery Bypass
Grafting in Patients with Left Ventricular
Dysfunction. Circulation Journal, 83(1): 122-129,
2018
Naya M, Uemura Y, Matsumoto N, Momose M,
Kato T, Hida S, Yamauchi T, Nakajima T, Suzuki
E, Tamaki N; J-COMPASS Extended Follow-Up
Study Group. Long-term events after physicianreferred initial tests by myocardial perfusion
imaging or computed tomography coronary
angiography in patients with suspected coronary
artery disease. Coronary Artery Disease, 29(7):539-546, 2018
Higashitani M, Uemura Y, Mizuno A, Utsunomiya
M, Tetsuo Y, Matsui A, Ozaki S, Tobita K, Tosaka
A, Oida A, Suzuki K, Kodama T, Jujo K, Doijiri T,
Takahashi Y, Matsuno S, Kaneko N, Moriguchi A,
Kishi S, Anzai H. Cardiovascular outcome andmortality in patients undergoing endovasculartreatment for symptomatic peripheral arterydisease: short term results of the Toma-CodeRegistry. Circulation Journal, 82(7): 1917-1925,
2018
Yamasue H, Okada T, Munesue T, Kuroda M,
Fujioka T, Uno Y, Matsumoto K, Kuwabara H,
Mori D, Okamoto Y, Yoshimura Y, Kawakubo Y,
Arioka Y, Kojima M, Yuhi T, Owada K, Yassin W,
Kushima I, Benner S, Ogawa N, Eriguchi Y,
Kawano N, Uemura Y, Yamamoto M, Kano B,
Kasai K, Higashida H, Ozaki N, Kosaka H. Effectof intranasal oxytocin on the core social

512

symptoms of autism spectrum disorder: arandomized clinical trial. Molecular Psychiatry,
20188) Matsuoka K, Uemura Y, Kanai T, Kunisaki R,
Suzuki Y, Yokoyama K, Yoshimura N, Hibi T.
Efficacy of Bifidobacterium breve fermented milk
in maintaining remission of ulcerative colitis.
Digestive Diseases and Sciences. 63(7): 19101919, 2018
9) Nakayama A, Morita H, Nagayama M, Hoshina K,
Uemura Y, Tomoike H, Komuro I. The Cardiac
Rehabilitation Protects against the Expansion of
Abdominal Aortic Aneurysm. J Am Heart Assoc.
27: 7(5), 2018
10) Urabe M, Hiroharu Y, Uemura Y, Tanabe A, Yagi
K, Akikou S, Seto Y. Non-linear association
between long-term outcome and preoperative
neutrophil-to-lymphocyte ratio in patients undergoing curative resection for gastric cancer: A
retrospective tetrachotomous analysis of 1335
case. Japanese Clinical Journal of Oncology.
48(4): 343-349, 201811) Hagiwara Y, Shiroiwa T, Shimozuma K,
Kawahara T, Uemura Y, Watanabe T, Taira N,
Fukuda T, Ohashi Y, Mukai H. Impact of adverse
events on health utility and health-related qualityof life in patients receiving first-line chemotherapy for metastatic breast cancer: results from
SELECT BC Study. Pharmacoeconomics. 36(2):215-223, 201812) Matsuoka K, Uemura Y, Kanai T, Kunisaki R,
Suzuki Y, Yokoyama K, Yoshimura N, Hibi T.
Efficacy of Bifidobacterium breve fermented milk
in maintaining remission of ulcerative colitis.
Digestive Diseases and Sciences. 63(7): 19101919, 201813) Nakayama A, Morita H, Nagayama M, Hoshina K,
Uemura Y, Tomoike H, Komuro I. The Cardiac
Rehabilitation Protects against the Expansion of
Abdominal Aortic Aneurysm. J Am Heart Assoc.
7(5): e007959, 201814) Shimoi T, Shimomura A, Shien T, Uemura Y, Kato
H, Kitada M, Toyama T, Aihara T, Mukai H.
Open-label Phase II Study of Everolimus Plus
Endocrine Therapy in Post-Menopausal Women
with ER+, HER2- Metastatic Breast Cancer.
(Chloe trial). Open Access Journal of Clinical

Trials. 10: 13-8, 201815) Sugawara K, Kawaguchi Y, Nomura Y, Kawasaki
K, Uemura Y, Koike D, Nagai M, Furuya T,
Tanaka N. Perioperative Factors Predicting
Prolonged Postoperative Ileus After Major
Abdominal Surgery. J Gastrointest Surg. 22(3):508-515, 201816) Yamada D, Kume H, Miyazaki H, Tanaka M,
Takata M, Uemura Y, Morikawa T, Enomoto Y,
Suzuki M, Nishimatsu H, Nakagawa T, Fujimura
T, Fukuhara H, Igawa Y, Homma Y. A prospective
randomized controlled study on Suppression of
Prostate Cancer by Naftopidil (SNAP). Preventive
Medicine and Community Health, 1(1): 1-6, 201817) Fujimoto C, Egami N, Kawahara T, Uemura Y,
Yamamoto Y, Yamasoba T, Iwasaki S. Noisy
Galvanic Vestibular Stimulation Sustainably
Improves Posture in Bilateral Vestibulopathy.
Frontiers in neurology 9: 900, 201818) Kawahara T, Fukuda M, Oba K, Sakamoto J,
Buyse M. Meta-analysis of randomized clinical
trials in the era of individual patient data sharing.
Int J Clin Oncol. 23(3):403-409, 201819) Kawahara T, Shimozuma K, Shiroiwa T,
Hagiwara Y, Uemura Y, Watanabe T, Taira N,
Fukuda T, Ohashi Y, Mukai H. Patient-reported
outcome results from the open-label randomized
phase III SELECT BC trial evaluating first-line
S-1 therapy for metastatic breast cancer. Oncology.
94(2): 107–115, 201820) Kawahara T, Shimozuma K, Shiroiwac T,
Hagiwarad Y, Uemura Y, Watanabe T, Taira N,
Fukudac T, Ohashi Y, Mukai H. Patient-Reported
Outcome Results from the Open-Label
Randomized Phase III SELECT BC Trial
Evaluating First-Line S-1 Therapy for Metastatic
Breast Cancer. Oncology. 94(2): 107-115, 201821) Fujimoto C, Kawahara T, Kinoshita M, Kikkawa
YS, Sugasawa K, Yagi M, Yamasoba T, Iwasaki S,
Murofushi T. Aging Is a Risk Factor for Utricular
Dysfunction in Idiopathic Benign Paroxysmal
Positional Vertigo. Frontiers in neurology. 9:1049, 201822) Yamamoto K, Kawahara T, Akai A, Isaji T, Akagi
D, Miyahara T, Hoshina K. Increase in skinperfusion pressure predicts amputation-freesurvival after lower extremity bypass surgery for513

critical limb ischemia. Vascular medicine (London,
England) 23(3): 243-249, 201823) Shiozawa Y, Inuzuka R, Shindo T, Mafune R,
Hayashi T, Hirata Y, Shimizu N, Inatomi J,
Yokoyama Y, Namai Y, Oda Y, Takamizawa M,
Harita Y, Kawahara T, Oka A. Effect of i.v.
immunoglobulin in the first 4 days of illness in
Kawasaki disease. Pediatrics international. 60(4):334-341, 201824) Nakao T, Yasumoto A, Tokuoka S, Kita Y,
Kawahara T, Daimon M, Yatomi Y. The impact ofnight-shift work on platelet function in healthy
medical staff. Journal of occupational health.
60(4): 324-332, 201825) Tsuchiya A, Yamana H, Kawahara T, Tsustumi Y,
Matsui H, Fushimi K, Yasunaga H. Tracheostomy
and mortality in patients with severe burns: A
nationwide observational study. Burns 2018;
44(8):1954-1961.
26) Niikura R, Nagata N, Yamada A, Doyama H,
Shiratori Y, Nishida T, Kiyotoki S, Yada T, Fujita
T, Sumiyoshi T, Hasatani K, Mikami T, Honda T,
Mabe K, Hara K, Yamamoto K, Takeda M, Takata
M, Tanaka M, Shinozaki T, Fujishiro M, Koike K.
A multicenter, randomized controlled trial
comparing the identification rate of stigmata ofrecent hemorrhage and rebleeding rate between
early and elective colonoscopy in outpatient-onset
acute lower gastrointestinal bleeding: study
protocol for a randomized controlled trial. Trials.
19(1): 214, 201827) Ueda K & Merabet L. “Chapter 2 Selection of
Research Question” Critical Thinking Skills in
Clinical Research, Edt. Fregni F & Illigens B,
Oxford Medicine, 201828) Ueda K. “Chapter 17: Fetal cardiac disease
Management of fetuses with congenital heartdisease” Maternal and Fetal Cardiovascular
Disease, Edt. Ikeda T & Kamiyta C, Springer
Japan, 201829) Uchino Y, Watanabe M, Takata M, Amiya E,
Tsushima K, Adachi T, Hiroi Y, Funazaki T,
Komuro I. Effect of Oral Branched-Chain Amino
Acids on Serum Albumin Concentration in Heart
Failure Patients with Hypoalbuminemia: Resultsof a Preliminary Study. Am J Cardiovasc Drugs.
18(4): 327-332, 201830) Fujisawa M, Kato H, Yoshida Y, Usui T, Takata M,
Fujimoto M, Wada H, Uchida Y, Kokame K,
Matsumoto M, Fujimura Y, Miyata T, Nangaku M.
Clinical characteristics and genetic backgroundsof Japanese patients with atypical hemolytic
uremic syndrome. Clin Exp Nephrol. 22(5): 10881099, 201831) Ando T, Ooba N, Mochizuki M, Koide D, Kimura
K, Lee SL, Setoguchi S, Kubota K. Positive
predictive value of ICD-10 codes for acute
myocardial infarction in Japan: a validation study
at a single center. BMC Health Serv Res. 18(1):895, 201832) Kubota K, Ooba N, Kamijima Y, Sato K, Koide D.
The use of anticoagulants in patients with nonvalvular atrial fibrillation between 2005 and 2014:
A drug utilization study using claims data in Japan.
PLoS One. 13(9):e0203380, 2018

514

University Hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Hirono Ishikawa, Ph.D.

Lecturer
Masafumi Okada, M.D., Ph.D.

Instructor
Mio Kato, Ph.D.
Tsuyoshi OkuharaHomepage

http://www.umin.ac.jp/※The following information is the same as that of the previous year for certain reasons.

Introduction and Organization
The University hospital Medical Information Network(UMIN) (the original name was the University
Medical Information Network), was established in
1989. While general-use computer systems were
implemented at all national university hospitals
around the end of the Showa era (late 1980s), Dr.
Shigekoto Kaihara, chair and professor at the HospitalComputer Center, University of Tokyo Hospital, led aproject to connect these computer systems in a
network in order to share information for better
communication. Finally, the Ministry of Education,
Culture, Sports, Science and Technology approved abudget to initiate the UMIN Center. The UMIN Center
was founded within the Hospital Computer Center,
University of Tokyo Hospital, and was officiallyopened 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 wasadded 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 datacollection
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.

515

In 1994, we launched a service through the Internet,
and it began to spread in those days. The number of
UMIN users gradually increased, mainly in the E-mailservice.
In 1996, Dr. Takahiro Kiuchi took up a new post while
Dr. Sakurai was promoted to professor at Hokkaido
University. Dr, Kiuchi updated the system to be
web-based. With the rapid spread of the Internet in
Japan, UMIN users dramatically increased.
The UMIN Center subsequently started to provide
three major information services: (1) the ELBIS(Electronic Library for Biomedical Sciences) as of1997, (2) the INDICE (Internet Data and Information
Center of Clinical Research) as of 2000, and (3) the
EPOC (Evaluation System of Postgraduate ClinicalTraining) 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
University of Tokyo Hospital. In 2003, a budget for
a new professor position was officially approved by
the Ministry of Education, Culture, Sports, Scienceand Technology. Then, Dr. Kiuchi was promoted to
become the first professor of the UMIN Center on
April 1, 2004. The UMIN Center became part of theFaculty of Medicine, as the Department of HealthCommunication, School of Public Health, which wasestablished 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

516(3) Communication support
 E-mail Listserv
 Discussion board
 File exchange

Teaching Activities
Please refer to Department of Health Communication
for information about graduate and undergraduate
education.

Research Activities
Please refer to Department of Health Communication
for information about research activities.

References
Please refer to Department of Health Communication.

517

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

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Center for Epidemiology andPreventive Medicine
Director & Associate Professor
Nobutake Yamamichi, M.D., Ph.D.

Associate Professor
Yuichi Ikeda, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

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.,
Chihiro Takeuchi, M.D., Ph.D.,
Yoshiko Mizuno, M.D., Ph.D. (Department of Biostatistics and Bioinformatics)
Kazutaka Ueda, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

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 (Central Care 2) inNovember 2006 (Heisei 18) in the University ofTokyo Hospital, the Center for Epidemiology andPreventive Medicine was established on January 1,
2007, within the Central Clinical Facilities and therelevant regulations were revised. On January 9, theWorking Group for the Establishment of the Center
for Epidemiology and Preventive Medicine wasorganized; on April 1, Steering Committee for the
Establishment of the Center for Epidemiology andPreventive Medicine was organized; on June 4, thedepartment 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 eleven 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 the519

examinations except for MRI and CT scan can be
performed within our floor, which increased theconvenience and comfort for the examinees.

examinee a free consultation so that we can help
him/her understand the results or decide whether tohave further detailed examination.

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
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, Geriatric Medicine, and
Oral-Maxillofacial
Surgery,
DentistryandOrthodontics).
The staff of the Center for Epidemiology andPreventive Medicine is composed of 11 physicians(eight regular physicians and three physicians fromthe related departments). One of the regularphysicians also performs upper gastrointestinalendoscopy and colonoscopy. Our department also hasnine nurses, five assistant clerks, and one medical
clerk.

Teaching activities

Clinical activities

Past activities

In addition to basic examinations, we provide ten
optional examinations: 1) comprehensive cardiovascular examinations, 2) comprehensive cerebrovascular examinations, 3) check up for dementia,4) colorectal cancer screening, 5) uterine cancer
screening, 6) breast cancer screening, 7) lung cancer
screening, 8) tumor marker diagnosis, 9) estimation ofgastric cancer risk, and 10) oral/dental examinations.
While meeting the needs of examinees, we haveincreased the number of the optional 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 eachIn the fiscal year (FY) 2018 (from April 1, 2018 toMarch 31, 2019), the total number of examinees (whohad basic examinations and optional examinations)was 7,152 including 2,742 in basic examinations, 509
in complete cardiovascular examinations, 606 incomplete cerebrovascular examinations, 72 in checkup dementia, 109 in colorectal cancer screening, 543
in uterine cancer screening, 648 in breast cancer
screening, 610 in lung cancer screening, 1,069 intumor marker diagnosis, 226 in estimation of gastriccancer risk, 15 in oral/dental examinations, and three
in upper gastrointestinal endoscopy (later). Oral/dental
examinations was discontinued in August 2018.
Colorectal cancer screening was temporarily
discontinued from August 2018 to March 2019, but
was resumed in April 2019.
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

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.

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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
2018, we issued 867 letters of referral to otherdepartments in our hospital and 33 to other hospitals.
We have expanded our public relations efforts and15,000 brochures were delivered during the FY 2018.
We also prepared posters which were placed within
our hospital and on the campus of the University ofTokyo as well. We have established our original
website (https://www.todai-yobouigaku.com/) andoffering up-to-date information to the examinees.

References
Academic Papers in English
1. Mizutani H, Ono S, Ushiku T, Kudo Y, Ikemura M,
Kageyama N, Yamamichi N, Fujishiro M, Someya
T, Fukayama M, Koike K, Transparencyenhancing technology allows three-dimensional
assessment of gastrointestinal mucosa: A porcine
model. Pathol Int. 2018 Feb; 68(2):102-108. doi:
10.1111/pin.12627. Epub 2018 Jan 17.
2. Matsumoto L, Suzuki K, Mizuno Y, Ohike Y,
Ozeki A, Ono S, Takanashi M, Sawaki D, Suzuki
T, Yamazaki T, Tsuji S, Iwata A. Association of
subclinical carotid atherosclerosis with immediate
memory and other cognitive functions. Geriatrics& Gerontology International 18(1):65-71, 2018.
3. Lee SC, Daimon M, Di Tullio MR, Homma S,
Hasegawa T, Chiou SH, Nakao T, Hirokawa M,
Mizuno Y, Yatomi Y, Yamazaki T, Komuro I.
Beneficial effect of body weight control on left
ventricular diastolic function in the general
population: an analysis of longitudinal data from ahealth check-up clinic. Eur Heart J Cardiovasc
Imaging 19(2):136-142, 2018.
4. Ohki D, Tsuji Y, Shinozaki T, Sakaguchi Y,
Minatsuki C, Kinoshita H, Niimi K, Ono S,
Hayakawa Y, Yoshida S, Yamada A, Kodashima S,
Yamamichi N, Hirata Y, Ushiku T, Fujishiro M,
Fukayama M, Koike K Sessile serrated adenoma
detection rate is correlated with adenoma
detection rate. World J Gastrointest Oncol. 2018

Mar 15; 10(3):82-90.
5. Mitsui T, Yamashita H, Aikou S, Niimi K,
Fujishiro M, Seto Y. Non-exposed endoscopic
wall-inversion surgery for gastrointestinal stromal
tumor. Transl Gastroenterol Hepatol. 2018 Mar
16; 3:17.
6. 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.
2019Feb; 54(2):131-140.doi:10.1007/s00535-0181489-4. Epub 2018 Jun 28.
7. Matsuda R, Yamamichi N, Shimamoto T, Sumida
H, Takahashi Y, Minatsuki C, Kodashima S, Ono
S, Niimi K, Tsuji Y, Sakaguchi Y, Saito I, Kataoka
Y, Asada-Hirayama I, Kakimoto H, Yakabi S,
Takeuchi C, Matsumoto Y, Tamaki Z, Fujishiro M,
Asano Y, Sato S, Koike K. Gastroesophageal
Reflux Disease-Related Disorders of Systemic
Sclerosis Based on the Analysis of 66 Patients.
Digestion.2018; 98(4):201-208.
8. Ito T, Oura S, Nagamine S, Takahashi M,
Yamamoto N, Yamamichi N, Earashi M, Doihara
H, Imoto S, Mitsuyama S, Akazawa K.
Radiofrequency Ablation of Breast Cancer: A
Retrospective Study. Clin Breast Cancer. 2018
Aug; 18(4):e495-e500.
9. Toyoshima O, Nishizawa T, Sakitani K,
Yamakawa T, Takahashi Y, Yamamichi N, Hata K,
Seto Y, Koike K, Watanabe H, Suzuki H. Serumanti-Helicobacter pylori antibody titer and its
association with gastric nodularity, atrophy, andage: A cross-sectional study. World J
Gastroenterol. 2018 Sep 21; 24(35):4061-4068.
10. Takahashi Y, Yamamichi N, Inada KI, Shiogama
K, Sakurai K, Takeuchi C, Mizutani Y, Tsutsumi Y,
Koike K. Nectin1 expression is frequently
decreased in gastric cancers. Pathol Int. 2018 Oct;68(10):557-562.
11. Minatsuki C, Yamamichi N, Inada KI, Takahashi
Y, Sakurai K, Shimamoto T, Tsuji Y, Shiogama K,
Kodashima S, Sakaguchi Y, Niimi K, Ono S,
Niwa T, Ohata K, Matsuhashi N, Ichinose M,
Fujishiro M, Tsutsumi Y, Koike K.Expression of
Gastric Markers Is Associated with Malignant

521

Potential of Nonampullary Duodenal Adenocarcinoma. Dig Dis Sci. 2018 Oct;63(10):26172625.
12. 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 fromdouble-contrast upper gastrointestinal barium
X-ray radiography. J Gastroenterol. 2019 Apr;
54(4):321-329. doi: 10.1007/s00535-018-1514-7.
Epub 2018 Oct 3.
13. Nakayama C, Yamamichi N, Tomida S, Takahashi
Y, Kageyama-Yahara N, Sakurai K, Takeuchi C,
Inada KI, Shiogama K, Nagae G, Ono S, Tsuji Y,
Niimi K, Fujishiro M, Aburatani H, Tsutsumi Y,
Koike K. Transduced caudal-type homeobox(CDX) 2/CDX1 can induce growth inhibition on
CDX-deficient gastric cancer by rapid intestinal
differentiation. CancerSci.2018Dec; 109(12):3853-3864.

522

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.,

Takumi Matsumoto, M.D., Ph.D.,

Research Associates
Yukiyo Asawa, D.V.M., Ph.D.,

Makoto Komura, M.D., Ph.D.,

Fumiko Yano, D.D.S., Ph.D.,

Homepage

http:// square.umin.ac.jp/t-e/

Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo
Hospital, in October 2001 and has a fully equipped
800 m2 laboratory on the 8th floor of the In-patient
Ward B. In May 2016, it moved to Molecular and Life
Innovation building. Division of Tissue Engineering
consists of Department of Bone & Cartilage
Regenerative Medicine, Department of 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 industryuniversity-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.
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.

523

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.

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
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.

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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

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.

2.

3.

4.

Hoshi K, Fujihara Y, Yamawaki T, Harai M,
Asawa Y and Hikita A. Biological aspects oftissue-engineered cartilage. Histochem Cell Biol,2018 Apr, 149(4):375-381.
Sugiyama M, Nakatsuka T, Saijo H, Fujihara Y,
Kanno Y, Hikita A, Takato T and Hoshi K.
Clinical Findings of a Cantilever Iliac Bone Graft
for Secondary Correction of Cleft Lip-Nose
Deformities. J Craniofac Surg, 2018 May, 9(3):741-746.
Inaki R, Fujihara Y, Kudo A, Misawa M, Hikita A,
Takato T, and Hoshi K. Periostin contributes tothe maturation and shape retention of tissueengineered cartilage. Sci Rep, 2018 Jul 25, 8(1):11210
Uto S, Nishizawa S, Hikita A, Takato T and Hoshi
K. Application of induced pluripotent stem cells
for cartilage regeneration in CLAWN miniature

pig osteochondral replacement model. Regenerative Therapy, 2018 Dec 9, 58-70. 9:58-70
5. Komura M, Komura H, Komuro H, Konishi K,
Obana K, Ikebukuro K, Hikita A, Hoshi K and
Takato T. Long-term follow-up of tracheal
cartilage growth promotion by intratracheal
injection of basic fibroblast growth factor. J
Pediatr Surg, 2018 Dec, (12):2394-2398.
6. Chang SH, Mori D, Kobayashi H, Mori Y,
Nakamoto H, Okada K, Taniguchi Y, Sugita S,
Yano F, Chung UI, Kanayama JK, 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 Mar 29, 10(1):1442.
doi: 10.1038/s41467-019-09491-5.
7. 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 and Tanaka S*. Cooperation of PU.1
with IRF8 and NFATc1 defines chromatin
landscapes during RANKL-induced osteoclastogenesis. J Bone Miner Res, e3689, 2019. doi: 10.
1002/jbmr.3689.
8. Chijimatsu R, Yano F, Saito T, Kobayashi M,
Hamamoto S, Kaito T, Kushioka J, Hart DA,
Chung UI, Tanaka S, Yoshikawa H and Nakamura
N*. Effect of the small compound TD-198946 on
glycosaminoglycan synthesis and chondrogenesisof human synovial derived stem cell in vitro. J
Tissue Eng Regen Med, 2019. doi: 10.1002/term.
2795.
9. 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, 85:172-179, 2019. doi: 10.
1016/j.actbio.2018.12.031.
10. Murahashi Y, Yano F, Kobayashi H, Makii Y, Iba
K, Yamashita T, Tanaka S, and Saito T*.
Intra-articular administration of IκBα kinase
inhibitor suppresses mouse knee osteoarthritis via
downregulation of the NF-κB/HIF-2α axis. Sci
Rep 8:16475, 2018. doi: 10.1038/s41598-01834830-9.

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11. Saitou K, Tokunaga M, Yoshino D, Sakitani N,
Maekawa T, Ryu Y, Nagao M, Nakamoto H, Saito
T, Kawanishi N, Suzuki K, Ogata T, Makuuchi M,
Takashima A, Sawada K, Kawamura S, Nakazato
K, Kouzaki K, Harada I, Ichihara Y, and Sawada Y.
Local
CyclicalCompression
Modulates
Macrophage Function In Situ and Alleviates
Immobilization-Induced Muscle Atrophy. Clinical
Science (in press).]
12. Makii Y, Asaka M, Setogawa S, Fujiki S, Hosaka
Y, Yano F, Oka H, Tanaka S, Fukui N, Yanagihara
D, and Saito T*. Alteration of gait parameters in amouse model of surgically-induced knee osteoarthritis. J Orthop Surg (Hong Kong) 2018
May-Aug, 26: 2309499018768017. doi: 10.1177/
2309499018768017.
13. Goto H, Nishio M, To Y, Oishi T, Miyachi Y,
Maehama T, Nishina H, Akiyama H, Mak TW,
Makii Y, Saito T, Yasoda A, Tsumaki N, andSuzuki A. Loss of Mob1a/b in mice results inchondrodysplasia due to YAP1/TAZ-TEADsdependent repression of SOX9. Development.
145(6), 2018. (in press) doi: 10.1242/dev.159244.
14. Oichi T, Taniguchi Y, Soma K, Chang SH, Yano F,
Tanaka S and Saito T*. A Mouse Intervertebral
Disc Degeneration Model by Surgically-Induced
Instability. Spine (Phila Pa 1976), 43:E557-564,
2018. doi: 10.1097/BRS.0000000000002427.
15. Matsumoto T, Maenohara Y, Chang SH, Hirose J,
Takuo J, Ito K and Tanaka S. Lateral collapse of
the tarsal navicular in patients with rheumatoid
arthritis: implications for pes planovarus
deformity. Mod Rheumatol 28(5):800-807, 201816. Matsumoto T, Gross C and Parekh SG: Short-term
radiographic outcome after distal chevron
osteotomy for hallux valgus using intramedullary
plates with an amended algorithm for the surgicalmanagement of hallux valgus. Foot Ankle Spec,
12(1):25-33, 2018
17. Taii T, Matsumoto T*, Tanaka S, akamura I, Ito K
and Juji T. Wrist arthrodesis in rheumatoid
arthritis using an LCP metaphyseal locking plateversus an AO wrist fusion plate. Int J Rheumatol,
2018 Jul 10, 2018:4719634.
18. Hosoi I, Kobayashi E, Chang SH, Matsumoto T,
An Q, Anzai E, Ohta Y and Sakuma I.
Development of intraoperative plantar pressure

measuring system considering weight bearing axis.
Int J Comput Assist Radiol Surg, 14(2):385-395,
2018
19. Chang SH, Matsumoto T, Okajima K, Naito M,
Hirose J and Tanaka S: Heterotopic Ossificationof the Peroneus Longus Tendon in the Retromalleolar Portion with the Peroneus Quartus
Muscle: A Case Report. Case Rep Orthop, 2018:7978369.
20. Matsumoto T, Chang SH, Takeda R, Tanaka S andJuji T: Bilateral stress fractures of the talus
associated with adult-aquired flatfoot deformities.
Case Rep Orthop, 2018:5376384.
21. Maenohara Y, Matsumoto T*, Chang SH, Hirose J
and Tanaka S, Guideposts for Inserting Intercuneiform Joint Arthrodesis Screws: Analysis
Using Multiplanar Reconstructed Computed
Tomography. Foot Ankle Spec, 2018 Nov 28[Epub ahead of print]
22. Izawa N, Hirose J, Fujii T, Oka H, Uehara K,
Naito M, Matsumoto T, Tanaka S, and Tohma S.
The utility 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 Rhematol, 29(2):328-334,
2019
23. Kasai T, Matsumoto T*, Iga T and Tanaka S:
Complications of implant removal in ankle
fractures. J Orthop, 2019 Feb 28, 16(3):191-194.
24. Matsumoto T, Naito M, Hirose J, Tanaka S, et al.
Gorham–Stout syndrome of the shoulder girdle
successfully controlled by antiresorptive agents: A
report of two cases. JBJS Case Connect [In press]
25. Suzuki K, Komura M, Terawaki K, Kodaka T,
Gohara T, Komura H and Nakayama Y. Engineeringand repair of diaphragm using biosheet (acollagenous connective tissue membrane) in rabbits.
J Pediatr Sur, 53(2):330-334, 2018;
26. Komura M, Komura H, Komuro H, Konishi K,
Obana K, Ikebukuro K, Hikita A, Hoshi K and
Takato T. Long-term follow-up of tracheal cartilage
growth promotion by intratracheal injection of basic
fibroblast growth factor. J Pediatr Surg, 53(12):2394-2398, 2018

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【総説】
1. 齋藤琢 最新の骨粗鬆症薬 －次世代創薬の展望－ カレントテラピー 36(10), 2018.
2. 齋藤琢 特集 軟骨研究と変形性関節症（編集）Clinical Calcium 28(6), 2018.
3. 齋藤琢 疾患感受性候補遺伝子 RSPO2 の発現と機能 整形外科 69:517-519, 2018.
【著書】
1. 松本卓巳：整形外科手術 名人の know-how「蹠側板損傷の修復」 整形・災害外科 第 61
巻 第 2 号 2018 年 金原出版
2. 松本卓巳、田中栄：リウマチの痛みと骨粗鬆症の最新治療 医学と薬学 第 75 巻 第 8 号
2018 年 自然科学社

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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528

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).

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

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

Homepage

http://kokoro.umin.jp/

Introduction and Organization
The Department of Child Psychiatry wasestablished in April 2005 as the clinical counterpart to
the Clinical Education Center of Mental Development,
both of which are funded by the special grant forfaculty development. The major aim of the Clinical
Education Center is to train mental health specialists
in various fields with a fundamental grounding inchild psychiatry and neurosciences. Much of theservices provided are based on the 37 years ofexperience in intervention and treatment for developmentally disabled children established in the former
child psychiatry division of Department of Neuropsychiatry. Our department uses a multidisciplinary
approach by working in collaboration not only with
the Department of Neuropsychiatry, Department ofPediatrics and Graduate School of Education in the
University of Tokyo but also several other educational
and/or clinical facilities on mental development ordevelopmental disorders. The Department of Child
Psychiatry complemented the Clinical Education
Center by providing fieldwork for clinical training andoffered clinical services to patients with various
development problems also.
The Clinical Education Center of Mental Development was closed in March 2010 because of time limitof the fund, and Department of Child Neuropsychiatry,
Graduate School of Medicine was established in April
2010. The Department of Child Psychiatry, as theclinical counterpart to the department in graduate
school, focuses on clinical activity related to research
as well as quality practice of child psychiatry andeducation of leading child psychiatrists and allied

professionals. In addition to professors of the graduate
school, 3 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 2018, 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 2018 was 278, and about
40 more than that in 2017. About two thirds of the
new patients consisted of patients with ASD, ADHD
or tic disorders. Out of 278 patients, children ofelementary school age were 114, and children of
junior high school age were 43. In other words,
children of elementary or junior high school age weremore than half of the patients. Number of preschool
children was 85, and slightly higher than that in 2017,
suggesting our response to increasing needs for early
diagnosis and intervention.
The follow-up clinic consisted of general clinic and530

special clinic (Tic/OCD clinic). At the general clinic, arigorous diagnosis based on detailed assessment anddecision about treatment course are provided forchildren and adolescents with any kinds of mental
problems. After fine adjustment of treatment course
within a given period, the patients are referred tocommunity hospitals/clinics or intervention/education
facilities with a detailed report. The special clinic
meets a need for high level services and works withresearch for special diseases.
Services for the general child psychiatry outpatientsare provided by psychiatrists in the areas of pharmacotherapy, psychotherapy, psychoeducation and also
work closely with the schools and community.
Psychologists have charge of psychological consultation as well as psychological examination. Patients
involved in those are mainly individuals with
developmental disabilities, and individualized treatment focusing on developmental viewpoint is plannedfor each. Psychological consultation includes services
in the following areas: (1) evaluation of cognitive andbehavioral development, (2) individualized treatmentof the disabled individual (3) counseling of parents
and providing information to the disabled individual’s
support network (relatives, schools) and environmental coordination. In addition to psychologists,
psychiatric social worker participates in actual
environmental coordination. Cognitive behavior
therapy for obsessive-compulsive symptoms oranxiety is sometimes provided also.
As for intervention for preschool children with ASD,
intensive individualized therapy consisting of weekly
10 sessions was provided for children aged 3 years or
younger.
Parent-training for parents with ADHD children,which started in 2011, was provided. This program
aimed that the parents learn deeper understanding ofdifficult children and appropriate strategy of copingwith them.
In addition to these outpatient services, “inpatient
assessment on developmental disorders” program
started in 2010. This program is provided in theinpatient ward of neuropsychiatry for adolescents oradults who have mental problems such as depression
and wish a detailed examination about possibility ofhidden developmental disorders including ASD and
ADHD.

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 has been held once a year. In 2018, we held
the 59th annual meeting of the Japanese Society forChild and Adolescent Psychiatry in the University ofTokyo and conducted the seminar within the programin October. About 200 medical doctors, psychologists,
and allied professionals attended the seminar.

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 autistic

531

preschoolers 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
ASD the revised program is investigated in arandomized 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. We are analyzing DNA
samples of patients with Tourette syndrome and theirparents also.
Neuroimaging
Studies include structural MRI, Near-Infrared Spectroscopy (NIRS) and functional MRI with exploring
the pathogenesis of developmental disorders such as
ASD. Functional MRI study of adults with ADHD andadults with Tourette syndrome by delayed reward task
has been conducted.

Publications
1. Owada K, Kojima M, Yassin W, Kuroda M,
Kawakubo Y, Kuwabara H, Kano Y, Yamasue H.
Computer-analyzed facial expression as asurrogate marker for autism spectrum social core
symptoms. PLoS One. 2018; 13(1): e0190442.
2. Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Kasai K, Kakiuchi
C. Novel rare variations in genes that regulate
developmental change in N-methyl-d-aspartate
receptor in patients with schizophrenia. Hum
Genome Var. 2018; 5: 17056.
3. Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Ohashi Y, Iwamoto
K, Kasai K, Kakiuchi C. Mutations of the glycinecleavage system genes possibly affect thenegative symptoms of schizophrenia throughmetabolomic profile changes. Psychiatry Clin
Neurosci. 2018; 72(3): 168-179.
4. Todokoro A, Tanaka SC, Kawakubo Y, Yahata N,
Ishii-Takahashi A, Nishimura Y, Kano Y, Ohtake F,
Kasai K. Deficient neural activity subserving
decision-making during reward waiting time inintertemporal choice in adult attention-deficit
hyperactivity disorder. Psychiatry Clin Neurosci.
2018; 72(8): 580-590.
5. Tanaka SC, Yahata N, Todokoro A, Kawakubo Y,
Kano Y, Nishimura Y, Ishii-Takahashi A, Ohtake F,
Kasai K. Preliminary evidence of altered neural
response during intertemporal choice of losses inadult attention-deficit hyperactivity disorder. Sci
Rep. 2018; 8(1): 6703.
6. Sakakibara E, Takizawa R, Kawakubo Y,
Kuwabara H, Kono T, Hamada K, Okuhata S,
Eguchi S, Ishii-Takahashi A, Kasai K. Genetic
influences on prefrontal activation during a verbal
fluency task in children: A twin study usingnear-infrared spectroscopy. Brain Behav. 2018;
8(6): e00980.
7. Kano Y, Matsuda N, Nonaka M, Fujio M, Kono T,
Kaido T. Sensory phenomena and obsessive-532

compulsive symptoms in Tourette syndrome
following deep brain stimulation: Two casereports. J Clin Neurosci. 2018; 56: 199-201.
8. Shaw P, Ishii-Takahashi A, Park MT, Devenyi GA,
Zibman C, Kasparek S, Sudre G, Mangalmurti A,
Hoogman M, Tiemeier H, von Polier G, Shook D,
Muetzel R, Chakravarty MM, Konrad K, Durston
S, White T: A multicohort, longitudinal study of
cerebellar development in attention deficit
hyperactivity disorder. J Child Psychol Psychiatry.
2018; 59(10): 1114-1123.
9. Okada N, Yahata N, Koshiyama D, Morita K,
Sawada K, Kanata S, Fujikawa S, Sugimoto N,
Toriyama R, Masaoka M, Koike S, Araki T, Kano
Y, Endo K, Yamasaki S, Ando S, Nishida A,
Hiraiwa-Hasegawa M, Kasai K. Abnormal
asymmetries in subcortical brain volume in earlyadolescentswithsubclinicalpsychotic
experiences. Transl Psychiatry. 2018; 8(1): 254.

533

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 2016, thenumbers achieved to more than total 900 cases andfurther increased in 2017. 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.

5341) 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

535

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. Fearof movement modulates the feedforward motor
control of the affected limb in complex regional
pain syndrome (CRPS): a single-case study.
Medical Hypotheses 2018; 110: 114-9
2. Yokoshima Y, Sumitani M, Nishizawa D,
Nagashima M, Ikeda K, Kato R, Hozumi J, Abe H,
Azuma K, Tsuchida R, Yamada Y, Japanese
TR-Cancer Pain research Group. Gammaaminobutyric acid transaminase genetic polymorphism is a candidate locus for responsivenessto opioid analgesics in patients with cancer pain:
an exploratory study.
Neuropsychopharmacology Reports 2018; 38:
175-81
3. Sumitani M, Nishizawa D, Ikeda K, Abe H, Kato
R, Ueda H, Yamada Y. Association between
polymorphisms in the purinergic P2Y12 receptor
gene and severity of both cancer pain andpostoperative pain.

Pain Med 2018; 19: 348-54
4. Osumi M, Sumitani M, Otake Y, Morioka S. A
“matched” sensory reference can guide goaldirected movements of the affected hand incentral post-stroke sensory ataxia.
Exp Brain Res 2018; 236: 1263-72
5. Nikaido T, Sumitani M, Sekiguchi M, Konno S.
The Spine painDETECT questionnaire: development and validation of a screening tool forneuropathic pain caused by spinal disorders.
PLoS ONE 2018; 13: e0193987
6. Abe H, Sumitani M, Uchida K, Ikeda T, Matsui H,
Fushimi K, Yasunaga H, Yamada Y. Association
between mode of anaesthesia and severe maternal
morbidity during scheduled caesarean delivery: anationwide population-base study in Japan.
Br J Anaesth 2018; 120: 779-89
7. Sumitani M, Sakai T, Matsuda Y, Abe H,
Yamaguchi S, Hosokoawa T, Fukui S. Executive
summary of the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain: Second by theJapanese Society of Pain Clinicians.
J Anesth 2018; 32: 463-78
8. Matsuishi Y, Hoshino H, Shimojo N, Enomoto Y,
Kido T, Hoshino T, Sumitani M, Inoue Y.
Verifying the validity and reliability of theJapanese version of the Face, Legs, Activity, Cry,
Consolability (FLACC) Behavioral Scale.
PLoS ONE 2018; 13: e0194094
9. Otake Y, Yozu A, Fukui T, Sumitani M, Haga N.
Relationships between toe flexion movement andcenter of pressure position.
Int J Foot Ankle 2018; 2: 15
10. Kuwajima K, Sumitani M, Kurano M, Kano K,
Nishikawa M, Uranbileg B, Tsuchida R, Ogata T,
Aoki J, Yatomi Y, Yamada Y. Lysophosphatidic
acid is associated with neuropathic pain intensity
in humans: an exploratory study.
PLoS ONE 2018; 13: e0207310(And, 20 Japanese articles)536

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,
the government 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 theyneed 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
and where, there are also issues related to medicalcare when receiving treatment, such as medical
expenses, how to get along after being discharged
from hospital, job, and nursing services. The Cancer
Counseling and Support Center provides patients withadvice and support so that they can resolve such social
worries.
Provision of information on second opinions
The Center provides information on how to
get a second opinion and on facilities that provide
second opinions.
Various kinds of advice related to the appearancechanges caused by cancer treatment
Cancer treatment often causes appearancechanges such as hair loss and skin pigmentation. The
center provides patients with practical advice andsupport about wig and cover make-up.
Provision of general information and advice on
cancer
The Center sends out and provides
information to people who do not have cancer but who

537

want to find out about cancer, for instance thetreatment and screening for it.

Open hours
If you have any queries, please contact us on
03-5800-9061 between 9am-4pm weekdays (except 12
noon-1pm).

Research activities
Our research field covers the relation between
appearance changes caused by cancer therapy andPatients’ quality of life.

References and Presentation
1. Female cancer and Appearance care, Publisher
Hoken, Takako Wakeda, Sep 2018
2. The importance of beauty volunteers in hospital,
Wakeda T, Nomura, The 26th Annual Meeting ofJapan Society of Breast Cancer, May. 2018
3. The importance of beauty volunteers in hospital,
Wakeda T, Tsuge M, Haruki H, Miura E, Yasuda
M, Nomura S, The 56th Annual Meeting of Japan
Society of Clinical Oncology, Oct. 2018

538

Department of Genome
Informatics
Director & Professor
Takashi Kadowaki, M.D., Ph.D.

1. Organization
The Department of Genome Informatics started asa special unit conducting research on human genetics
and clinical epidemiology in 2003. Our section
functions as the unit to establish clinical andepidemiological data sampling/management and toaccomplish an appropriate and efficient application of
results of recently advanced human genetics andgenomics. In addition, the unit contributes to training
and educating specialists of clinical epidemiology andhuman genetics. Our section also supported designingof clinical / genetic studies. It consists of one
professor and different specialties participating in thedepartment. They include diabetologists, nephrologist,
cardiologists and epidemiologists.

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 GWAS results

highlighted both ethnically shared and distinct
impacts of a series of pathways on type 2 diabetes.
These findings illustrated the etiology of type 2
diabetes in Japanese and Europeans. We identified 88
type 2 diabetes–associated loci, of which 28 loci werenovel. Twenty-eight missense variants were in linkage
disequilibrium with the lead variants, including
missense variants in genes related to insulin secretion(GLP1R) （Suzuki K et al. Nat Genet. 2019,51(3),379-386）. Recently, Mahajan et al. reported type 2
diabetes genome-wide association study metaanalysis data on approximately 900,000 individuals ofEuropean 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 lessthan 20 novel type 2 diabetes loci that were notassociated with type 2 diabetes in Europeans. This
article is referenced in the position statement fromscience council of Japan.
We are interviewed and contributed to the report by
the project of AMED concerning ethical, legal andsocial issue of secondary findings in genomic research.
We also found that one gene was associated withdiabetic nephropathy and two genes were associatedwith diabetic retinopathy (Taira M, et al. PLoS One.
19, 13(12), e0208654, 2018).
We conducted whole genome sequence andanalyzed the sequence data of the subjects with type 2
diabetes in collaboration with RIKEN and BioBank
Japan. We are exploring the genetic and environmental factors by selecting case and control from
BioBank Japan for genome-wide analysis concerning539

deterioration of diabetes and diabetic complications(diabetic nephropathy and diabetic retinopathy). We
are developing 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 cardiology and vascular medicine, we focused onatherosclerotic diseases such as coronary stenosis andmyocardial infarction. It is important to accumulate
and analyze data obtained in practice and genetic data
to gain insight into a clinical picture. Analyzing datacollected provide detailed genetic factors of thecoronary atherosclerotic diseases and their clinicaloutcome.
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, 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, TsuganeS, 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. 2019, 51(3),379-386, doi:10. 1038/s41588-018-0332-4.
2. Taira M, Imamura M, Takahashi A, Kamatani Y,
Yamauchi T, Araki SI, Tanaka N, van Zuydam
NR, Ahlqvist E, Toyoda M, Umezono T, Kawai
K, Imanishi M, Watada H, Suzuki D, Maegawa H,
Babazono T, Kaku K, Kawamori R; SUMMIT
Consortium, Groop LC, McCarthy MI, Kadowaki
T, Maeda S. A variant within the FTO confers
susceptibility to diabetic nephropathy in Japanesepatients with type 2 diabetes. PLoS One. 2018, 19,
13(12),
e0208654,
doi:10.1371/journal,pone,0208654.
3. Kadowaki T, Nangaku M, Hantel S, Okamura T,

4.

5.

6.

7.

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. 2019
May;10(3):760-770. doi: 10.1111/jdi.12971.
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 Gα12/13-coupled receptor LPA4 limits
proper adipose tissue expansion and remodelingin diet-induced obesity. JCI Insight. 2018 Dec
20;3(24).
pii:
97293.
doi:
10.1172/jci.insight.97293.
門脇孝, 山内敏正, 庄嶋伸浩. 総論 糖尿病の精 密 医 療 の 実 現 に む け て . Medical Science
Digest. 2018, 44, 6, 9-10.
細江隼, 庄嶋伸浩, 山内敏正, 門脇孝. インスリン受容体異常症とインスリン受容体の機能ドメイン. 糖尿病学 2018. 2018, 72-75.
細江隼, 庄嶋伸浩, 山内敏正, 門脇孝. 著明なイ
ンスリン抵抗性を認めた症例におけるインス
リン受容体の遺伝子型―表現型の関連. 内分泌・糖尿病・代謝内科. 2018, 47(1), 60-64.

540

Medical Genome Research Support
CenterDirector and Professor
Masaomi Nangaku, M.D., Ph.D.

The Medical Genome Research Support Centerstarted as a core facility at the University of Tokyo
Hospital in 2011. Next generation sequencers(NGSs) including three Illumina HiSeq2500s, one
Pacific Biosciences RS II, an Oxford Nanopore
MinION system, and one Illumina MiSeq, and a
Droplet Digital PCR system have been installed.
Robotics for preparation of samples has also been
installed. Computer servers for processing ofmassive amount of genome data have been installedin the server room, which are connected to NGs via
network system isolated from the internet.

Publications
1.

2.

Activities
The core facility offers genome sequencing
employing NGSs for other laboratories in the
University of Tokyo Hospital. The core facility
further offers genome sequencing employing NGSs
for laboratories outside of the University of Tokyo.
Approximately 2,000 samples per year have been
analyzed.

3.

Research Accomplishments
Collaborative researches have achieved multiple
accomplishments in molecular genetic studies on
Charcot–Marie–Tooth diseases types 2A2A, 2K, and2Z, spinocerebellar ataxia type 42, focal segmental
glomerulosclerosis 9, candidate genes involved insporadic Tourette syndrome, and the causative genefor progressive neurodegenerative encephalopathy
with atypical infantile spinal muscular atrophy(TBCD). Five case reports based on mutational
analyses have also been published.

4.

5.

Ando M, Hashiguchi A, Okamoto Y, Yoshimura
A, Hiramatsu Y, Yuan J, Higuchi Y, Mitsui J,
Ishiura H, Umemura A, Maruyama K,
Matsushige T, Morishita S, Nakagawa M, Tsuji
S, Takashima H. Clinical and genetic diversities
of Charcot-Marie-Tooth disease with MFN2
mutations in a large case study. J Peripher Nerv
Syst. 2017 Sep;22(3):191-199.
Yoshimura A, Yuan J.-H., Hashiguchi A,
Hiramatsu Y, Ando M, Higuchi Y, Nakamura T,
Okamoto Y, Matsumura K, Hamano T, Sawaura
N, Shimatani Y, Kumada S, Okumura Y,
Miyahara J, Yamaguchi Y, Kitamura S,
Haginoya K, Mitsui J, Ishiura H, Tsuji S,
Takashima H. Clinical and mutational spectrumof Japanese patients with Charcot-Marie-Tooth
disease caused by GDAP1 variants. Clin Genet.
2017 Sep;92(3):274-280.
Ando M, Okamoto Y, Yoshimura A, Yuan J-H,
Hiramatsu Y, Higuchi A, Hashiguchi a, Mitsui J,
Ishiura H, FukumuracS, Matsushima M, Ochi N,
Tsugawa J, Morishita S, Tsuji S and Takashima
H. Clinical and mutational spectrum of Charcot–
Marie–Tooth disease type 2Z caused by
MORC2 variants in Japan. Eur J Neurol. 2017
Oct;24(10):1274-1282.
Kimura M, Yabe I, Hama Y, Eguchi K, Ura S,
Tsuzaka K, Tsuji S, Sasaki H. SCA42 mutation
analysis in a case series of Japanese patientswith spinocerebellar ataxia. J Hum Genet. 2017
Sep;62(9):857-859.
Udagawa T, Jo T, Yanagihara T, Shimizu A,
Mitsui J, Tsuji S, Morishita S, Onai R, Miura K,

541

Kanda S, Kajiho Y, Tsurumi H, Oka A, Hattori
M, Harita Y. Altered expression of Crb2 in
podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome.
Pediatr Nephrol. 2017 May;32(5):801-809.
6. Eriguchi Y, Kuwabara H, Inai A, Kawakubo Y,
Nishimura F, Kakiuchi C, Tochigi M, Ohashi J,
Aoki N, Kato K, Ishiura H, Mitsui J, Tsuji S,
Doi K, Yoshimura J, Morishita S, Shimada T,
Furukawa M, Umekage T, Sasaki T, Kasai K,
Kano Y. Identification of candidate genes
involved in the etiology of sporadic Tourette
syndrome by exome sequencing. Am J Med
Genet B Neuropsychiatr Genet. 2017 Oct;174(7):712-723.
7. Ikeda T, Nakahara A, Nagano R, Utoyama M,
Obara M, Moritake H, Uechi T, Mitsui J, Ishiura
H, Yoshimura J, Doi K, Kenmochi N, Morishita
S, Nishino I, Tsuji S, Nunoi H. TBCD may be acausal gene in progressive neurodegenerative
encephalopathy with atypical infantile spinal
muscular atrophy. J Hum Genet. 2017 Apr;
62(4):473-480.
8. Hosoe J, Kadowaki H, Miya F, Aizu K,
Kawamura T, Miyata I, Satomura K, Ito T, Hara
K, Tanaka M, Ishiura H, Tsuji S, Suzuki K,
Takakura M, Boroevich KA, Tsunoda T,
Yamauchi T, Shojima N, Kadowaki T.
Structural Basis and Genotype-Phenotype Correlations of INSR Mutations Causing Severe
Insulin Resistance. Diabetes. 2017 Oct;66(10):2713-2723.
9. Sato NS, Maekawa R, Ishiura H, Mitsui J,
Naruse H, Tokushige SI, Sugie K, Tate G,
Shimizu J, Goto J, Tsuji S, Shiio Y. Partial
duplication of DHH causes minifascicular
neuropathy: A novel mutation detection of DHH.
Ann Clin Transl Neurol. 2017 May 22;4(6):415-421.
10. Yamashita T, Mitsui J, Shimozawa N,
Takashima S, Umemura H, Sato K, Takemoto M,
Hishikawa N, Ohta Y, Matsukawa T, Ishiura H,
Yoshimura J, Doi K, Morishita S, Tsuji S, Abe
K. Ataxic form of autosomal recessive PEX10related peroxisome biogenesis disorders with anovel compound heterozygous gene mutationand characteristic clinical phenotype. J Neurol

Sci. 2017 Apr 15;375:424-429.
11. Harigaya Y, Matsukawa T, Fujita Y, Mizushima
K, Ishiura H, Mitsui J, Morishita S, Shoji M,
Ikeda Y, Tsuji S. Novel GBE1 mutation in a
Japanese family with adult polyglucosan bodydisease. Neurol Genet. 2017 Feb 24;3(2):e138.
12. Matsukawa T, Koshi KM, Mitsui J, Bannai T,
Kawabe M, Ishiura H, Terao Y, Shimizu J,
Murayama K, Yoshimura J, Doi K, Morishita S,
Tsuji S, Goto J. Slowly progressive dbifunctional protein deficiency with survival toadulthood diagnosed by whole-exome sequencing. J Neurol Sci. 2017 Jan 15;372:6-10.

542

Department of Clinical Genomics
Director & Professor
Masaomi Nangaku, M.D., Ph.D.
※The following information is the same as that of the previous year for certain reasons.

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 and to support anappropriate and efficient application of results ofgenetic testing. The department also provides a
training program for physicians preparing for boardcertified clinical geneticists. Many medical staffs withdiverse specialties including pediatricians, obstetricians, neurologists, cardiologists diabetologists andsurgeons participate in the activities of the
Department.

Activities
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 clinical departments byconducting genome analysis for establishing genetic
diagnosis.
We also participate in Marfan’s Syndrome Clinic,
which is managed collaboratively by the Departmentsof Cardiovascular Surgery, Cardiovascular Medicine,
Pediatrics, Spinal Surgery and Ophthalmology.
Clinical sequencing for incurable malignant solid
tumors is also in progress as an Advanced Medical
Treatment B by using a multiplex genome sequencing,named "Todai OncoPanel”. In collaboration with
Clinical Laboratory Center, Pharmaceutical Services,
DepartmentsofPlanning
Information
andManagement, and several clinical departments,
pharmacogenetics tests including those for proton
inhibitor, warfarin, irinotecan, and tacrolimus, areconducted.

Publications
1. Hosoe J, Kadowaki H, Miya F, Aizu K,
Kawamura T, Miyata I, Satomura K, Ito T, Hara
K, Tanaka M, Ishiura H, Tsuji S, Suzuki K,
Takakura M, Boroevich KA, Tsunoda T,
Yamauchi T, Shojima N, Kadowaki T. Structural
Basis and Genotype-Phenotype Correlations of
INSR Mutations Causing Severe Insulin
Resistance. Diabetes. 2017 Oct;66(10):27132723.
2. Sato NS, Maekawa R, Ishiura H, Mitsui J, Naruse
H, Tokushige SI, Sugie K, Tate G, Shimizu J,
Goto J, Tsuji S, Shiio Y. Partial duplication of
DHH causes minifascicular neuropathy: A novel
mutation detection of DHH. Ann Clin Transl
Neurol. 2017 May 22;4(6):415-421.
3. Yamashita T, Mitsui J, Shimozawa N, Takashima
S, Umemura H, Sato K, Takemoto M, Hishikawa
N, Ohta Y, Matsukawa T, Ishiura H, Yoshimura J,
Doi K, Morishita S, Tsuji S, Abe K. Ataxic formofautosomal
recessive
PEX10-related
peroxisome biogenesis disorders with a novelcompound heterozygous gene mutation andcharacteristic clinical phenotype. J Neurol Sci.
2017 Apr 15;375:424-429.
4. Harigaya Y, Matsukawa T, Fujita Y, Mizushima
K, Ishiura H, Mitsui J, Morishita S, Shoji M,
Ikeda Y, Tsuji S. Novel GBE1 mutation in a
Japanese family with adult polyglucosan bodydisease. Neurol Genet. 2017 Feb 24;3(2):e138.

543

5. Matsukawa T, Koshi KM, Mitsui J, Bannai T,
Kawabe M, Ishiura H, Terao Y, Shimizu J,
Murayama K, Yoshimura J, Doi K, Morishita S,
Tsuji S, Goto J. Slowly progressive d-bifunctional
protein deficiency with survival to adulthood
diagnosed by whole-exome sequencing. J Neurol
Sci. 2017 Jan 15;372:6-10.

544

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

Homepage

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

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 consisted

545

of a portion of the first floor and the basement of an
administration building came to a decision by theconference.
2003 May. The construction of Cooperative Unit ofMedicine and Engineering Research was completed.
The cost of the construction was shared by theparticipation groups.
2003 May 22. The first research meeting of
Cooperative Unit of Medicine and Engineering
Research took place and research activities started.
2004 September 3. The second research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2005 September 13. The third research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2006 December 21. The fourth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2007 December 13. The fifth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2009 December 3. The sixth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 February 2. The seventh research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 December 17. The eighth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place2013 January 25. Development forum of advanced
medical seeds took place
2014 January 24. Development forum of advanced
medical seeds took place
2015 January 22. Development forum of advanced
medical seeds took place
2016 February 2. Development forum of advanced
medical seeds took place2017 February 2. Development forum of advanced
medical seeds took place2018 February 1. Development forum of advanced
medical seeds took place2019 February 18. 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.
Laboratory of Cavitation & Lithotripsy
Department of Urology, Faculty of Medicine
Department of Mechanical Engineering, School ofEngineering

546

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.
Development of diagnostic system of orthopedic
biomechanics
The Department of Orthopaedic Surgery, The
University of Tokyo.
Graduate School of Information Science andTechnology, The University of Tokyo.
To develop a non-invasive method for predicting bonestrength by finite element method analysis. Newly
administration of Teriparatide to the rheumatoid
patients and analyses of its effects by finite element
method with bone metabolic markers, bone density,and computed tomography.
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

547

School of Medicine
Department of Diabetes and Metabolic Diseases,
Graduate School of Medicine
Department of Chemistry and Biotechnology, Schoolof Engineering
To establish the system and methods for engineering
the novel model mice of life style-related diseases
using RNAi technology and biotechnology. To
elucidate the mechanisms by which adipose tissue
derived factors, adipokines, contribute to thedevelopment of the metabolic syndrome. To explore
the molecular mechanisms of sarcopenia.
Development of bone and cartilage regeneration byscaffold and mechanical stress
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Division of Science for Joint Reconstruction,
Graduate School of Medicine, The University of Tokyo
Ishihara & Takai Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Laboratory of Regenerative Medical Engineering,
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.

548

Development and application of biomolecule
visualization probes
Department of Cardiovascular Medicine
Laboratory of Chemistry and Biology, Graduate
School of Pharmaceutical Sciences
We have developed biomolecule visualization probes
and investigated model animals for application. As abiomolecule visualization probe, we are improving
and more applying fluorescent probes for cancer
lesion detection. Moreover, we are going to develop
labeled probes which can elucidate disease treatment
mechanism of microRNA and adipose stem cells. Now
as fundamental study, we are researching diseasemodels for applying these treatments. In particular, we
are investigating diabetic nephropathy, liver fibrosis
and atherosclerosis models as non-coding RNA andadipose stem cells treatment targets.

References (in 2018)
1. Murahashi Y, Yano F, Kobayashi H, Makii Y, Iba
K, Yamashita T, Tanaka S, and Saito T*.
Intra-articular administration of IκBα kinase
inhibitor suppresses mouse knee osteoarthritis via
downregulation of the NF-κB/HIF-2α axis. Sci
Rep. 2018;8:164-75.
2. Makii Y, Asaka M, Setogawa S, Fujiki S, Hosaka
Y, Yano F, Oka H, Tanaka S, Fukui N, Yanagihara
D, and Saito T. Alteration of gait parameters in amouse model of surgically-induced knee
osteoarthritis. J Orthop Surg (Hong Kong). 2018;
26: 2309499018768017.
3. Goto H, Nishio M, To Y, Oishi T, Miyachi Y,
Maehama T, Nishina H, Akiyama H, Mak TW,
Makii Y, Saito T, Yasoda A, Tsumaki N, andSuzuki A. Loss of Mob1a/b in mice results inchondrodysplasia due to YAP1/TAZ-TEADsdependent repression of SOX9. Development.
2018;145(6). (in press)
4. Oichi T, Taniguchi Y, Soma K, Chang SH, Yano F,
Tanaka S, and Saito T. A Mouse Intervertebral
Disc Degeneration Model by Surgically-Induced
Instability. Spine (Phila Pa 1976). 2018; 43:
E557-564.
5. Matsumoto T, Maenohara Y, Chang SH, Hirose J,
Takuo J, 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.
6. Matsumoto T, Gross C, Parekh SG: Short-term
radiographic outcome after distal chevron
osteotomy for hallux valgus using intramedullary
plates with an amended algorithm for the surgicalmanagement of hallux valgus. Foot Ankle Spec.
2018; 12(1):25-33.
7. Taii T, Matsumoto T*, Tanaka S, Nakamura I, Ito
K, Juji T: Wrist arthrodesis in rheumatoid
arthritis using an LCP metaphyseal locking plateversus an AO wrist fusion plate Int J Rheumatol.
2018; 4719634.
8. 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; 14(2):385-395.
9. Chang SH, Matsumoto T, Okajima K, Naito M,
Hirose J, Tanaka S: Heterotopic Ossification ofthePeroneus
LongusTendonintheRetromalleolar Portion with the Peroneus Quartus
Muscle: A Case Report. Case Rep Orthop. 2018;7978369.
10. Matsumoto T, Chang SH, Takeda R, Tanaka S,
Juji T: Bilateral stress fractures of the talus
associated with adult-aquired flatfoot deformities.
Case Rep Orthop. 2018:5376384.
11. Maenohara Y, Matsumoto T*, Chang SH, Hirose J,
Tanaka S: Guideposts for Inserting Intercuneiform
Joint Arthrodesis Screws: Analysis Using
Multiplanar
Reconstructed
Computed
Tomography. Foot Ankle Spec. 2018 Nov 28[Epub ahead of print].
12. Kida S, Nakamoto T, Nakano M, Nawa K, Haga A,
Kotoku J, Yamashita H, Nakagawa K. Cone Beam
Computed
Tomography
Image
Quality
Improvement Using a Deep Convolutional Neural
Network. Cureus. 2018; 10 (4), e2548.
13. Aoki S, Yamashita H, Haga A, Ota T, Takahashi W,
Ozaki S, Nawa K, Imae T, Abe O, Nakagawa K.
Stereotactic body radiotherapy for centrallylocated lung tumors with 56 Gy in sevenfractions: A retrospective study. Oncology Letters.
2018; 16, 4498-4506.
14. Amano Y, Qi P, Nakagawa Y, Kirita K, Ohta S, ItoT. Prevention of peritoneal adhesions by ferric

549

ion-crosslinked hydrogels of hyaluronic acidmodified with iminodiacetic acid. ACS
Biomaterials Science and Engineering. 2018; 4(9),3405-3412.
15. Oba S, Ayuzawa N, Nishimoto M, Kawarazaki W,
Ueda K, Hirohama D, Kawakami-Mori F,
Shimosawa T, Marumo T, Fujita T. Aberrant DNA
methylation of Tgfb1 in diabetic kidney
mesangial cells. Sci Rep. 2018;8(1):16338.
16. Suhara M, Miura Y, Cabral H, Akagi D, Anraku Y,
Kishimura A, Sano M, Miyazaki T, Nakamura N,
Nishiyama A, Kataoka K, Koyama H, Hoshina K.
Targeting ability of self-assembled nanomedicines
in rat acute limb ischemia model is affected bysize. J Control Release. 2018;286:394-401.
17. 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.
18. Kyomoto M, Shoyama Y, Saiga K, Moro T,
Ishihara K: Reducing fretting-initiated crevice
corrosion in hip simulator tests using azirconia-toughened alumina femoral head. J
Biomed Mater Res B Appl Biomater. 2018; 106B:
2815-2826.
19. 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 ss-catenin expression isassociated with histological progression and overt
diabetes emergence in NAFLD patients. J
Gastroenterol. 2018; 53(12): 1261-1275.
20. 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. 2018; 38(16):e00116-18.
21. Kubota T, Inoue M, Kubota N, Takamoto I,
Mineyama T, Iwayama K, Tokuyama K, Moroi M,

Ueki K, Yamauchi T, Kadowaki T. Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype
macrophage activation in obesity. Nat Commun.
2018; 9(1):4863.

550

Department of Disaster Medical
Management
Professor
Naoto Morimura, M.D.,Ph.D.

Lecturer
Masataka Gunshin, M.D.

Homepage

Chiaki Toida M.D.,Ph.D.

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 of Tokyo
Hospital Comprehensive Disaster Drill regularly.
Drills of launching a new earthquake early warning
system, building hospital headquarter for disaster
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

551

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. Naoto Morimura: “Actuals of emergency medical
responses for the multiple acts of terror in Paris in2015” Journal of the Japanese Association for theSurgery of Trauma 31; 1: 56-62. 2017
2. Naoto Morimura: “Fact of medical responses forthe multiple acts of terror in Paris” Journal ofJapan Surgical Association 77; 306. 2016
3. Naoto Morimura, Chiaki Toida, Yasushi Asari, et al.:“Introduction of new index of disaster medicine
supply demand balance, Risk Resource Ratio, forthe purpose of plotting out regional disaster medical
management plan” Japanese Journal of Disaster
Medicine 21; 1: 10-17. 2016
4. Chiaki Toida, Takashi Muguruma, Naoto Morimura,et al.: “Disaster medicine and intensive care
medicine. Problems of pediatric intensive care
medicine at the time of disaster including thebusiness continuity plan” Journal of the JapaneseSociety of Intensive Care Medicine 22; 3. 2016
5. Jun Hattori, Naoto Morimura, Yasushi Asari, et al.:“Planning for the burn patients assumed in case of ahuge earthquake in the metropolitan area, using
disaster medicine risk resource ratio” Japanese
Journal of Disaster Medicine 20; 3: 561. 2016
6. Kohei Takahashi, Naoto Morimura, Hidenori
Nakagawa, et al.: “Planning for the crush
syndrome patients assumed in each disaster center
hospital, using disaster medicine risk resource
ratio” Japanese Journal of Disaster Medicine 20;

3: 561. 2016
7. Kyoko Hattori, Jun Hattori, Naoto Morimura, etal.: “The next disaster medicine. Planning forthe perinatal medical care at the time of disaster,using disaster medicine risk resource ratio”
Japanese Journal of Disaster Medicine 20; 3: 461.
2016
8. Naoto Morimura, Chiaki Toida, Yasushi Asari, etal.: “The next disaster medicine. Calculation ofnecessary quantity of support and patterns ofordering priority of support for disaster center
hospitals, based on disaster medicine risk resource
ratio” Japanese Journal of Disaster Medicine 20;
3: 460. 2016
9. Naoto Morimura: “Emergency medical responsesof APHP and SAMU for the multiple acts of terror
in Paris” Journal of Japanese Society for
Emergency Medicine 19; 2: 205. 2016

552

International Medical Center
Director and Associate Professor
Sumihito Tamura, M.D., Ph.D.

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 launched as a significant step forward inenhancing The University of Tokyo Hospital’s
development as an international hub. Designateddirector 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 sophisticatedtreatment 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 advanced clinical trainees granted

permission by the Ministry of Health, Labor andWelfare under the Exceptional Cases of the Medical
Practitioners ‘Act, Article 17, regarding Advanced
Clinical Training of Foreign Medical Practitioners, etc.
Internal hospital rules to accept consultant level
foreign medical doctors as Invited Faculty member
has also been settled.
Lastly, heightening the capability of physicians andmedical staff to cater to international needs is an
important factor in globalizing The University ofTokyo Hospital. To this end, the International Medical
Center will attempt to cultivate personnel by hosting
various international exchanges so as to further
develop the hospital’s capabilities to become aninternational hub in the field.

553

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, the standard foodservice approval system was abolished, and a diettherapy notification system on admission was set up.
An on-admission nutrition guidance fee was alsoestablished.
In 1998, the first diet therapy exhibit organized by
the Department of Nutrition Management was
conducted as part of the diabetes week events that theTokyo Diabetes Association held to the side of the freespace in the vestibule of the outpatient department. In

554

the first year there were 3527 visitors a week.
In 2001, integration of the branch hospital with themain hospital resulted in an 8-managerial- dietitiansystem. In 2004, the Department of Nutrition
Management was separated from the medical service
division. In 2005, the introduction of the self-pay
system for inpatient meals meant that inpatients began
to be charged for their meals. During the same year one
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 dietitianto the staff (full time) as a full-time employee tocalculate the billing charges for the NST was approved.
In 2011, the inauguration of a nutritional guidanceservice for recipients of health checkups in the
Department of Epidemiology and Preventive Medicine
was accompanied 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 opened on the 1st floor of theInpatients Ward A as part of the expansion of theChildren’s Medical Center. In the same month, thecopayment for the patient food service was changed
from 360 yen to 460 yen. In June 2018, “nutrition
newspaper” for inpatients was started, and in October
2018, the special menu (selectable meals) was resumed.
In March 2019, “grand meals” were newly launched forspecial sickrooms.

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.
The records of achievements in 2015 show that there
were 2819 instances of inpatient nutritional guidance

555(455 without charge) and 5503 instances of outpatient
nutritional guidance (275 without charge). The results
for group nutritional guidance showed that during theyear there had been 292 outpatient diabetes classes and
217 inpatient diabetes classes (for some of which there
was a charge), and that there had been 115 best-weightclasses, classes after gastric cancer operations for 81
patients, and mother’s classes for 139 mothers.
In July 2012, a physician, managerial dietitian, andnurse formed a dialysis prevention team, and started
calculating fees for diabetes and dialysis prevention
guidance and management in the outpatient clinic. The
managerial dietitian and nurse provide guidance on
Wednesday and Thursday afternoons, and there were
131 guidance sessions in 2015.
In April 2014, the department started calculating
charges for NST and counted 1261 instances in the firstfiscal year, which reached 1529 instances in 2015.
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.
When a new electronic health record system wasintroduced in January 2017, food service system(Nutrimate Ver. 9.0) and nutritional guidance system
was also updated. Mobile terminals specific for
managerial dietitian were provided on every floor of
Inpatients ward A&B, which enhanced the practiceefficiency. In the fiscal year of 2017, 8485 instanceswere monitored in the two-step screening and floor
NST system. In fiscal year 2018, a “post-sleeve
gastrectomy diet” was newly launched as a
postoperative diet with the introduction of surgicaltreatment for severe obesity (sleeve gastrectomy). In
July 2018, the frequency of NST rounds was increased
to twice weekly, with relaxation of the full-time
requirement for claims for NST medical fee in the2018 medical fee revision. In fiscal year 2018, there

were 1040 claims for NST operations, and 8554
patients received nutrition intervention. In January
2019, in consultation with the Epilepsy Center, the“ketogenic diet” was instituted.

Educational Activities
The Department accepts managerial dietitian clinicaltrainees. In 2018, the department accepted 47 trainees
from 8 training schools: Ochanomizu University,
Tokyo Kasei University, Otsuma Women’s University,
Kagawa Education Institute of Nutrition, Jissen
Women’s Educational Institute, Japan Women’s
University, and Wayo Women’s University.
In 2011, the Department began accepting NST
trainees. From 1 to 4 or 5 terms are conducted a year (5days/ week/ term). Participants are mainly managerial
dietitians, pharmacists, nurses, medical technologists,and physical therapists, and candidates are trainees
whose aim is acquiring the qualifications certified byacademic societies or to become a full-time employee
to calculate the billing charges for the NST. There were
17 participants (4 managerial dietitians, 7 pharmacists,
5 nurses, 1 physical therapist) in 2017.
In 2017, the department was involved in the
curriculum of Clinical Clerkship, the medical education program of the Faculty of Medicine, the Universityof Tokyo. 115 medical students at M4 grade
participated in the two-day practice course.
To disseminate NST activities widely in the hospital,
the department organizes NST seminars (the name waschanged to Basic Nutrition Therapy series in fiscal year2018) for doctors-in-training and clinical nutrition
seminars throughout the year. 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. The
ratio of completion reached 99.0% in March 2016. In
October 2016, “The Manual of The Department ofClinical Nutrition Therapy 2015-2016” was published.
In December 2016, the exchange training program
between the Department of Nutrition Management of
The Institute of Medical Science and our department
was initiated. At the same month, “The Pocket Manual

556

of The Department of Clinical Nutrition Therapy 20162017” was published. In March 2018, “The Manual of
The Department of Clinical Nutrition Therapy 20172018” was published. In March 2018, “The Manual of
The Department of Clinical Nutrition Therapy 20172019” was published. In December 2018, the “Recordof Kitchen Renovation” was published. In March 2019,“Collection of Nutritional Guidance Media 2018-2022”
was published.

2.

3.

Research・Research topics: “Survey of trends in the nutritional
status of pancreatic cancer patients receiving
chemotherapy”
・Research topics: “Retrospective study using
databases such as medical records in nutritional
guidance”
・Joint research with the Department of Hepatobiliaryand Pancreatic Surgery.
Research topics: “A study on the improvement of theperioperative nutritional status with perioperative
administration of branched-chain amino acids inliver cancer patients with cirrhosis with 
indocyanine green retention rate at 15 minutes(ICGR15) and liver transplant recipients”
・Joint research with the Department of Hepatobiliaryand Pancreatic Surgery.
Research topics: “Exploratory research for efficacy
of home enteral nutrition in patients withpancreaticoduodenectomy”
・Joint research with the University of Chiba.
Research topics: “Study of weight loss intervention
to find effective strategy for obesity management
and the target of weight loss amount for reducing
health disorders (SLIM-TARGET Study)”

References<Publications (English)>
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. 38:e00116-00118,

4.

5.

6.

7.

8.

2018.
Kubota T*, Inoue M*, Kubota N*, Takamoto I,
Mineyama T, Iwayama K, Tokuyama K, Moroi M,
Ueki K, Yamauchi T, Kadowaki T. Downregulationof macrophage Irs2 by hyperinsulinemia impairs
IL-4-indeucedM2a-subtype
macrophageactivation in obesity. Nat. Commun. 9:4863, 2018(*co-first authors, co-corresponding authors).
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 3:97293, 2018.
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.
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 stress andregulates metabolism. Nat. Commun. 10:947, 2019.
Sano M, Ijichi H, Takahashi R, Miyabayashi K,
Fujiwara H, Yamada T, Kato H, Nakatsuka T,
Tanaka Y, Tateishi K, Morishita Y, Moses HL,
Isayama H, Koike K. Blocking CXCLs-CXCR2
axis in tumor-stromal interactions contributes tosurvival in a mouse model of pancreatic ductal
adenocarcinoma through reduced cell invasion/
migration and a shift of immune-inflammatory
microenvironment. Oncogenesis 8(2):8, 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 Apr;60:206211. doi:10.1016/j.nut.2018.10.007. Epub 2018
Oct 10. PubMed PMID: 30616102
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,

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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 Apr;37(2):338-344.
doi:10.1007/s10637-018-0691-9. Epub 2018 Nov
9. PubMed PMID: 30411217
9. Ihara S, Hirata Y, Hikiba Y, Yamashita A, Tsuboi M,
Hata M, Konishi M, Suzuki N, Sakitani K,
Kinoshita H, Hayakawa Y, Nakagawa H, Ijichi H,
Tateishi K, Koike K. Adhesive interactions
between mononuclear phagocytes and intestinal
epithelium perturb normal epithelial differentiationand serve as a therapeutic target in inflammatory
bowel disease. J Crohns Colitis 12(10):1219-1231,
2018
10. Shibata W, Kinoshita H, Hikiba Y, Sato T, Ishii Y,
Sue S, Sugimori M, Suzuki N, Sakitani K, Ijichi H,
Mori R, Endo I, Maeda S. Overexpression of HER2
in the pancreas promotes development of
intraductal papillary mucinous neoplasms in mice.
Sci Rep 8(1):6150, 2018
11. Fujiwara H, Tateishi K, Kato H, Nakatsuka T,
Yamamoto K, Tanaka Y, Ijichi H, Takahara N,
Mizuno S, Kogure H, Matsubara S, Nakai Y, Koike
K. Isocitrate dehydrogenase 1 mutation sensitizes
intrahepatic cholangiocarcinoma to the BET
inhibitor JQ1. Cancer Sci 109(11):3602-3610,
2018
12. Saito K, Isayama H, Sakamoto Y, Nakai Y, Ishigaki
K, Tanaka M, Watadani T, Arita J, Takahara N,
Mizuno S, Kogure H, Ijichi H, Tateishi K, Tada M,
Hasegawa K, Fukayama M, Kokudo N, Koike K.
A phase II trial of gemcitabine, S-1 and LV
combination (GSL) neoadjuvant chemotherapy forpatients with borderline resectable and locallyadvanced pancreatic cancer. Med Oncol 35(7):100,
2018
13. 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 19(2):p135-140, 2019

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)

Official Website

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

Research
Our laboratory focuses on clarification of thepathogenesis of various diseases and the related
physiological machineries in cellular and molecular
aspects. Based on our technical advantage in genemanipulation via gene knockout and transgenesis, wegive high priorities to in vivo analyses. This willdefinitively contribute to the direct therapeutic
application of our findings. Since our rationale is tochallenge to uncharacterized disease mechanisms andphysiologies, we will not restrict our interest, strategy
or technique employed, in certain specific field.
Rather, we will expand our research area by
establishing different collaborations with a broad
spectrum of researchers. We believe this fits to thepolicy of the CDBIM, which aims the development of
a comprehensive science including the fundamental
and clinical medicines, and the biotechnology. Overall,
we will attempt to discover novel biological insights
rather than to study details of previously characterized
physiologies, by targeting molecules newly identified
by ourselves. Now, we are focusing on the following

major projects.
AIM (Apoptosis Inhibitor of Macrophage) as a masterswitch to various modern diseases.
The rapid change in lifestyles and eating habits intoday’s society are thought to be the cause of various
disorders; metabolic syndrome and lifestyle-relateddiseases increase the risk of developing obesity,
diabetes, and cardiovascular disease; a fatty liver leads
to NASH and liver disease, may result in liver cancer;
autoimmune disease followed by obesity, chronic
renal failure, and Alzheimer’s disease are considered
as well. We hypothesize that such various modern
disorders, seemingly unrelated at first sight, share thecommon underlying pathological condition andmechanism, and the group of molecules exists as themaster switch, regulating the varied conditions.
We found a soluble apoptosis inhibitor factor
largely produced by tissue macrophage, named AIM(apoptosis inhibitor of macrophage). Our recent
studies showed that AIM plays an important role inregulating the pathological condition of the modern
diseases.

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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.
Finding the mechanism on the regulation of AIM
activity will shed light on developing a diagnostics
and potential treatments to modern diseases. We will
focus on the details of involvement of AIM to thevarious diseases by generating a mouse model. Also,
cohort study is carried out using and analyzing thehuman specimen, aiming to develop a novel drug
treatment.

Lab Activities
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
system and the structural analysis of AIM.
Joint Meeting
In 2018, several medical laboratories from Shimane
University and our laboratory jointly held summer
seminar in Okuizumo, Shimane. The members fromthe both universities including the teaching staffs,
graduate students and researchers, fully enjoyed thiswork shop, and having intense research sessions withlively discussions, which can lead to futurecollaborations. We could also strike up a friendshipthrough the dinners and recreations during the threedays.
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 (hosted by Shimane
University and the University of Tokyo) and, TaiwanJapan Joint Meeting in 2017 (hosted by National
Taiwan University and the University of Tokyo). We
will keep planning such Joint Meetings in the future.
Seminar hosted by our lab
Title: Regulation of autoimmune diseases by AIM andCoroninⅠ. / Prof. Jean Pieters (University ofBasel, Switzerland)
In June 2018, we organized an invited lecture by
Prof. Jean Pieters. He introduced his research
regarding CoroninⅠ.
Symposium hosted by our lab
In February, 2019, we held a mini symposium
regarding the primary biliary cholangitis (PBC),
inviting Prof. Eric Gershwin (The University ofCalifornia, Davis) as well as some experts in thisresearch field.
DBELS (Disease Biology Excellent Lecture Series)
We present a lecture series by top scientists in avariety of research fields related to disease biology. Sofar, eleven lecturers have been invited from many
places including Kyoto Univ., Hokkaido Univ., Riken
Institute, Tokyo Univ. of Science, Washington Univ.
(USA), Univ. of Basel (Switzerland), and Weill
Medical College of Cornell University (USA).
DBELS-EXTRA
This is a lecture series on the latest experimental
techniques for medical research, founded as anextension of DBELS. We offer monthly lecture series,
each of which convenes twice to four times a month,aiming mostly at graduate students and junior

561

researchers.
This series provides lectures by experts fromcompanies, universities and research institutions
specializing in a wide range of areas such as molecular biology, cellular biology, genetics, immunology
and others.
DBELS WORKSHOPIn 2007, we had a workshop at Unzen, a great resort
place in Nagasaki prefecture. Along the policy for
DBELS, we invited 8 top scientists from Kyoto,
Tokyo, Hokkaido, Okinawa, and Boston as lecturers,
and many young participants as audiences. Staying ina beautiful resort hotel, we all had a scientifically andculturally fruitful time. The next workshop is
scheduled to be held in Switzerland, probably in 2010
summer.
Music and Science
On Jun 6, 2006, to commemorate the foundation of
our lab, we organized an invited recital by Mr Maestro
Krystian Zimerman, a world-famous pianist, followed
by a debate session on music and science between Mr.
Zimerman and Professor Miyazaki at Yasuda
Auditorium with more than 800 audiences.
Visiting Professors
We welcomed Prof. Wakeland from Southwestern
Medical Center at The University of Texas in fiscal
2006, Prof. D. Mathis and Prof. C. Benoist from
Harvard University in fiscal 2007, Prof. Jean Pietersfrom University of Basel in fiscal 2018, all of whom
belonged to our lab as a guest professor for one
months to three months respectively.

Publications
1.

2.

Koyama N, Yamazaki T, Kanetsuki Y, Hirota J,
Asai T, Mitsumoto Y, Mizuno M, Shima T,
Kanbara Y, Arai S, Miyazaki T, Okanoue T.
Activation of apoptosis inhibitor of macrophage
is a sensitive diagnostic marker for NASHassociated hepatocellular carcinoma. J Gastroenterol. 53:770-779, 2018.
Hiramoto E, Tsutsumi A, Suzuki R, Matsuoka S,
Arai S, Kikkawa M, Miyazaki T. The IgM
pentamer is an asymmetric pentagon with an

3.

4.

5.

6.

7.

open groove that binds the AIM protein. Sci Adv.
4:eaau1199, 2018.
Sugisawa R, Komatsu G, Hiramoto E, Takeda N,
Yamamura KI, Arai S, Miyazaki T. Independentmodes of disease repair by AIM protein
distinguished in AIM-felinized mice. Sci Rep. 3:13157, 2018.
Komatsu G, Nonomura T, Sasaki M, Ishida Y,
Arai S, Miyazaki T. AIM-deficient mouse fed ahigh-trans fat, high-cholesterol diet: a new
animal model for nonalcoholic fatty liver disease.
Exp Anim. 68:147-158, 2018.
Arai S, Miyazaki T. A scavenging system againstinternal pathogens promoted by the circulating
protein apoptosis inhibitor of macrophage (AIM).
Semin Immunopathol. 40:567-575, 2018.
Miyazaki, T. Homage to Mechnikov - thephagocytic system: past and present. Semin
Immunopathol. 40:519-521, 2018.
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 glomerulosclerosis in humans and mice. Kidney Int. 95:5761, 2018.

562

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 (D2),
Takeshi Sawada (D2), Yuichi Morimoto (D2),Toshiaki Kume (D1), Hongyu Amy Chang (Mastercourse student, M1), Hitoshi Okazaki (Medical Intern),
Monami Nishio (Medical school student, M0), and astechnical staffs, Haruka Ohno, Arisa Kurabayashi,
Yuki Sakata, Masayoshi Asaumi, Rie Yonemoto andYumiko 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563

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).

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).
We also examined the dynamics of spine
volume in the adult mouse visual cortex using
time-lapse in vivo two-photon imaging with a resonant
Galvano scanner. Contrary to expectations, we foundthat the spines in the adult neocortex showed
fluctuations to a similar degree as that observed inyoung hippocampal preparations, but there weresystematic differences in how the dynamics weredependent on spine volumes, thus allowing for fewerfluctuations in small spines, which could account for
the relatively low turnover rates of neocortical spines
in vivo. We found that spine volumes fluctuated to agreater extent in a mouse model (Fmr1 knockout) offragile X mental retardation than in wild-type mice,and the spine turnover rates were also higher in Fmr1
knockout mice. Such features of spine dynamics inFmr1 knockout mice could be represented by a single
slope factor in our model. Our data and model indicate
a small but significant change in the average spine
volume and more eminent differences in the statistical
distribution in Fmr1 knockout mice even in adulthood,

564

which reflects the abnormal in vivo dynamics of spine
volumes (Ishii,, Kasai, eNeuro, 2018, Ref. 3).
(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.

References
1. Okazaki,H., Hayashi-Takagi, A., Nagaoka, A.,
Negishi, M., Ucar, H., Yagishita, S., Ishii, K.,
Toyoizumi, T., Fox, K., & Kasai, H. (2018)
Calcineurin knockout mice show a selective lossof small spines, Neurosci Lett 671:99-102.
2. Tainaka, K., Murakami, T.C., Susaki, E.A.,
Shimizu, C., Saito, R., Takahashi, K., HayashiTakagi, A., Sekiya, H., Arima, Y., Nojima, S.,
Ikemura, M., Ushiku, T., Shimizu, Y., Murakami,M., Tanaka, K.F., Iino, M., Kasai, H., Sasaoka, T.,
Kobayashi, K., Miyazono, K., Morii, E., Isa, T.,
Fukayama, M., Kakita, A. & Ueda, H.R. (2018).
Chemical Landscape for Tissue Clearing based on
Hydrophilic Reagents. Cell Reports, 24(8):21962210.
3. Ishii, K., Nagaoka, A., Kishida, K., Okazaki, H.,
Yagishita, S., Ucar, H., Saito, N. & Kasai, H.
(2018). Volume dynamics of dendritic spines in
the neocortex of wild type and Fmr1 KO mice invivo. eNeuro 5, e0282-18.2018:1-13.
4. Tse, A, Lee, A.K., Takahashi, N.,Gong, A., Kasai,
H. & Tse, F.W. (2018). Strong stimulation triggers
full-collapse fusion exocytosis and very slow
endocytosis of the small dense core granules incarotid glomus cells, J. Neurogenetics, 32:267278.

565

Laboratory of Biomedical
Equipment and Biomaterials
Professor
Takashi Azuma, Ph.D.

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 is composed of two laboratories, Azuma
laboratory and Ito Laboratory. The Division tightly
collaborates with Faculty of Engineering. Prof. Azuma
is also charged at Department of MechanicalEngineering and Bioengineering, where the laboratory
members include an assistant professor, two associates
and 3 graduate students. Prof. Ito charged at
Department of Chemical System Engineering andBioengineering. The current laboratory members
include one assistant professor, two associates, and 13
graduate students School of Engineering andMedicine.

Teaching activities
Prof. Azuma and Prof. Ito are sharing duties forundergraduate 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. Azuma has also
lectures on Overview of Bioimaging，Overview of
Mechano-Bioengineering, Bioengineering exercise
for social implementation at Graduate School ofEngineering. Prof. Ito gives a lecture concerning
biosystem engineering, separation technology I,
biotechnology II, Basic Biology, and Overview ofChemical Bioengineering at the Chemical System

Engineering course and Bioengineering course at
Graduate School of Engineering School.

Research activities
Prof. Azuma’s laboratory aims to develop clinicalimaging and therapeutic systems. In particular, we aredeveloping an advanced imaging system using
ultrasound with large interaction and low invasivenesswith the living body, minimally invasive treatmentusing ultrasound, and a combination device withdrugs.
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

566

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.
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

References(1) A. Ishijima, K. Minamihata, S. Yamaguchi, S.
Yamahira, R. Ichikawa, E. Kobayashi, M. Iijima, Y.
Shibasaki, T. Azuma, T. Nagamune, I. Sakuma,“Selective intracellular vaporisation of antibodyconjugated phase-change nano-droplets in vitro”,
Sci. Rep. 2017(7) 44077(2) K. Okita, R. Narumi, T. Azuma, H. Furusawa, J.
Shidooka, S. Takagi and Y. Matsumoto, “Effectsof breast structure on high-intensity focusedultrasound focal error”, J. Ther. Ultrasound,2018(6) 4-15.
(3) X. Qu, T. Azuma, T. Yogi, S. Azuma, H. Takeuchi,
S. Tamano, S. Takagi, "Synthetic aperture
ultrasound imaging with a ring transducer array:
preliminary ex vivo results", J. Med. Ultrasonics,
2016(43) 461-471(4) Y. Amano, Y. Nakagawa, S. Ohta, T. Ito, “Ionresponsive fluorescence resonance energy transfer
between grafted polyacrylic acid arms of star block
copolymers” Polymer, 2018, 137(14), 169-172.
(5) 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.
(6) P. Qi, S. Ohba, Y. Hara, M. Fuke, T. Ogawa, S.
Ohta, T. Ito “Fabrication of calcium phosphateloaded carboxymethyl cellulose non-woven sheets
for bone regeneration” Carbohydr. Polym., 2018,
189, 322-330.
(7) 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.
(8) 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.
(9) Y. Amano, P. Qi, Y. Nakagawa, K. Kirita, S. Ohta, T.
Ito, “Prevention of peritoneal adhesions by ferric

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ion-crosslinked hydrogels of hyaluronic acidmodified with iminodiacetic acid” ACS Biomater.
Sci. Eng., 2018, 4(9), 3405-3412.
(10) 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. Res Part B –Appl. Biomater., 2018, 107 (5), 1516-1521.

568

Laboratory of Clinical
Biotechnology
Professor
Yuichi Tei/ Ung-il Chung, M.D.,Ph.D.

Associate Professor
Shinsuke Ohba, D.D.S., Ph.D.

Assistant Professor
Hironori Hojo, Ph.D.

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, such

569

as regenerative medicine and medical devices, is an
important and globally growing research field inwhich medical biology and engineering are integrated
and play important roles. Since the medicineengineering cooperation that has occurred to date has
been mainly research collaborations, the developmentof theoretical systems as well as education systems forthe integrated field have been delayed. This oftencauses a mismatch between clinical needs andtechnological seeds. The delay is likely due todifficulties in identifying basic principles that underlie
both of the quite different fields of medical biology
and engineering, when they are integrated.
Through multi-discipline and cross-sectional
research projects integrating medical biology andengineering, we aim to train biomedical professionals
who themselves integrate medicine and engineering;that is, engineers who understand medical needs andmedical researchers who understand technologicalseeds. We are offering students with varying
backgrounds opportunities to study a broad spectrumof biomedical engineering — from basic principles ofliving organisms to advanced medical systems — on
the basis of each student's expertise. We alsocollaborate with The University of Tokyo COI
Self-Managing Healthy Society, in order to utilize theOpen Innovation Platform in which all stakeholders
from industry, government, academia, and the private
sector join the program as equals from the start, as apractical education tool for developing the aforementioned biomedical professionals.

Research
We pursue two scientific interests with a particularfocus on skeletal tissues (bones and cartilage): (1) the
manipulation of progenitor cell differentiation andproliferation based on the understanding of molecularmechanisms underlying cell fate specification, and (2)the development of novel biomaterials fulfilling thecharacteristics required for in vivo use as scaffolds.
We aim to develop novel systems for skeletal tissue
engineering and regenerative medicine in which celldifferentiation and proliferation are directly regulated
in situ. The following four projects are ongoing.

1. Understanding of epigenome dynamics and gene
regulatory networks during cell fate specification
processes
Organogenesis depends on cell fate specification andthe subsequent differentiation and maturation of
specified cells. Gene transcription underlies a series ofprocesses; appropriate genes are transcribed withappropriate amounts and at the appropriate timing for
inducing cell activities and characteristics. In thiscontext, the epigenome works as a main switch forgene expression. Transcription factors, which bind to
the genome in a sequence-dependent manner, in turnincrease the amount of transcripts, in a manner that is
analogous to turning up the volume of a radio.
Against this background, we seek to understandthe mechanisms of cell fate specification, celldifferentiation, and cell maturation during skeletal
development with a particular focus on epigenome
dynamics and genomic targets of transcription factors.
We also plan to apply the knowledge gained to thedevelopment of regenerative therapies for skeletal
tissue defects. Here we rely on the following
approaches: (1) observations of intracellular events bydirect and comprehensive techniques, (2) the construction of hypotheses driven by these observations,and (3) verification of the hypotheses. Thus, theapproach starts with the collection of genome-scaledata on gene expression, epigenome, and transcription
factor binding sites by taking advantage ofnext-generation sequencers. The data are analyzed bybioinformatics approaches, leading to the constructionof a new biological hypothesis. Each hypothesis isverified by molecular-biological approaches andmouse genetics. With this research strategy, we areinvestigating the regulatory landscape on the genomethat determines the specification of bone- andcartilage-forming cells, osteoblasts and chondrocytes,
respectively, and their phenotypes. A series of studies
reveals transcriptional networks that mediate
pluripotency and the differentiation of pluripotent
stem cells (Stem Cells 31:2667, 2013), epigenome
dynamics and modes of action of master transcription
factors that specify osteoblasts and chondrocytes, andthe gene regulatory networks mediated by thosemaster transcription factors (Cell Reports 12:229,
2015; Developmental Cell 37:238, 2016; Development
143:3012, 2016; Trends in Genetics 32:774, 2016). A570

fuller understanding of cell fate specification
processes during skeletal formation, we believe, will
enable the development of novel therapeutic strategies,in which bone and cartilage repair and regeneration
are induced by the manipulation of the specification
processes.

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
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.

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),

571

through the screening of compound libraries withcell-based sensors enabling the high-throughput
detection of osteoblast and chondrocyte differentiation(Biochemical and Biophysical Research Communications 376:375, 2008; Journal of Bone and Mineral
Metabolism 28:627, 2010).
4. The development of tissue-inductive implant
devices integrating tissue-regeneration signals andhighly functional and biocompatible biomaterials
In the current aging society, the treatment of tissue
defects in locomotive organs is a crucial task toachieve the extension of healthy life expectancy.
There is an urgent need for low-invasive reconstruction therapies that recover lost or damaged tissues
with the same functional and aesthetic qualities as
those in healthy states. The transplantation of donor
tissues obtained from patients’ healthy sites has been
widely used for tissue reconstruction (autologoustransplantation). However, this strategy often causes
post-operative pain and the cosmetic disturbance ofdonor sites. Although reconstruction with biomaterials
avoids donor site problems, its tissue induction
capacity is generally inferior to that of autologoustransplantation.
As signaling networks mediating the formation
and regeneration of tissue and organs are being
elucidated by recent advances in stem cell biology,
some biomaterial-based systems are being developed
for delivering signaling factors to target tissues. We
are studying these approaches as mentioned above. In
addition, the emergence of three-dimensional (3D)
printers has rapidly improved the techniques available
for controlling the shapes of scaffold materials. By
controlling the 3D shape of biomaterials, we havebeen attempting to improve the performance of
biomaterials for tissue repair. We developed custommade calcium phosphate artificial bone (CT-bone) thatis manufactured using 3D printers and have appliedthem to clinical settings in cooperation with the
Department of Oral and Maxillofacial Surgery, The
University of Tokyo Hospital (Journal of Artificial
Organs 9:234, 2006; Journal of Artificial Organs
12:200, 2009; Regenerative Therapy 5:1, 2016). We
have also worked on the development and applicationof tetrapod-shaped calcium phosphate artificial bone
(Tetrabone), which is fabricated at 1-mm size by

injection molding, and a custom-made titanium meshcage fabricated by laser sintering (Acta Biomaterialia
8:2340, 2012; Biomaterials 35:3229, 2014).
However, either signaling factors or biomaterials
alone are not sufficient for the clinically sufficient
regeneration of tissues, and interface units integratingthem are necessary for fully utilizing their performance. A candidate for the integrating interface unit isa high-performance hydrogel unit, which maintains
the spatial arrangement of signaling factors and candeliver them to target cells at a selected timing bytemporally controlled degradation. However, conventional hydrogels do not provide the characteristics
required for an integrating interface unit.
In cooperation with 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. Tan Z, Niu B, Tsang KY, Melhado IG, Ohba S,
He X, Hunag Y, Wang C, McMahon AP, Jauch R,
Chan D, Zhang MQ, Cheah KSE: Synergistic
co-regulation and competition by a SOX9-GLIFOXA phasic transcriptional network coordinate

572

2.

3.

4.

5.

chondrocyte differentiation transitions. PLoS
Genet 2018;14(4):e1007346
Qi P, Ohba S, Hara Y, Fuke M, Ogawa T, Ohta S,
Ito T: Fabrication of calcium phosphate-loaded
carboxymethyl cellulose non-woven sheets forbone regeneration. Carbohydr Polym 2018;189:322-330
Fujii Y, Koga-Kawase Y, Hojo H, Yano F, Sato M,
Chung UI, Ohba S, Chikazu D: Bone regeneration
by human dental pulp cells using a helioxanthinderivative and cell-sheet technology. Stem Cell
Res Ther 2018;9(1):24
Fujiyabu T, Toni F, Li X, Chung UI, Sakai T:
Three Cooperative Diffusion Coefficients
describing Dynamics of Polymer Gels. Chem
Comm 2018;54:6784
Furuya M, Kikuta J, Fujimori S, Seno S, Maeda H,
Shirazaki M, Uenaka M, Mizuno H, Iwamoto Y,
Morimoto A, Hashimoto K, Ito T, Isogai Y, Kashii
M, Kaito T, Ohba S, Chung UI, Lichtler AC,
Kikuchi K, Matsuda H, Yoshikawa H, Ishii M:
Direct cell-cell contact between mature
osteoblasts and osteoclasts dynamically controls
their functions in vivo. Nat Commun. 2018;9(1):
300.

573

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 moved from the 3rd floor of theMedical Faculty of Medicine Building 1 to the 8th floorof the Clinical 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, four
graduate students (two for doctoral course and two formaster course), and three graduation trainees
conducted the researches together during the year of
2018.
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
represent the largest source of energy in livingorganisms, are main components constituting cell
membranes, and also act as signal molecules. Lipids areenvironmental nutritional factors ingested from foods,
as well as tissue microenvironmental regulators thatspatiotemporally 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

574

Quality of Lipids (QOL) for Quality of Life (QOL) andaim at building a theoretical foundation for diagnosis,
prevention and treatment of diseases involving
alteration of lipid metabolism.
We performed following researches in 2018.
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 byfacilitating
WAT
browning.
Mechanistically,
PLA2G2D constitutively supplies a pool of PUFAs in
WAT. Thus, our present findings underscore thecontribution of the M2 macrophage-driven PLA2G2DPUFA axis to metabolic health (submitted in revision).
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 were lean,displayed growth retardation, and died prematurely.

Thus, the methyl group flux from choline endogenously generated through PC breakdown by the
PNPLA7 axis is essential for liver functions andsystemic energy homeostasis.
2) Skin diseases
Lipids play crucial roles in skin homeostasis anddiseases. We have currently reported that PLA2G2F(sPLA2-IIF) mobilizes lysoplasmalogen, a uniquelysophospholipid that promotes epidermal hyperplasic
diseases such as psoriasis and skin cancer (Yamamoto
et al, J Exp Med 2015), and that PNPLA1, a member ofthe intracellular iPLA2 family whose mutations cause
autosomal recessive congenital ichthyosis, acts as atransacylase to produce ω-O-acylceramide, an essential
lipid component for skin barrier function (Hirabayashi
et al, Nat Commun 2017). In this year, by phenotypic
screening (with perturbation of skin barrier function asa readout) using a series of PLA2 knockout strains, aswell as by gene expression profiling of PLA2-related
genes in mouse and human skins, we have identified
several PLA2s (e.g. sPLA2-III, cPLA2 and cPLA2)that appear to be linked to skin diseases. Currently, we
are analyzing the phenotypes in knockout strains forthese PLA2s to clarify their roles and underlying lipid
metabolism in skin homeostasis and diseases.
3) Allergic diseases
We have currently shown that PLA2G3 (sPLA2III) 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.
As another collaborating research with a Koreangroup, we have found that the SIRT1-LKB1-AMPK
pathway negatively regulates FcRI signaling in mast
cells (Li et al, Sci Rep 2017; Li et al, Biochem
Pharmacol 2018; Jin et al, Allergy 2019).
2. Environmental Toxicology (Ohsako’s group)
Ohsako’s group is studying various themes related tothe environmental issues from the point of view ofsocial medicine. The following two researches are575

presented for this year. 1) Epigenetic Molecular
Epidemiology: From the second half of the last century,
genital abnormalities such as hypospadias have been
increasing worldwide, and environmental chemicals
are considered to be partially involved in the cause thisdisease. We are investigating chemical exposure levels,
gene expression, DNA methylation, etc. using foreskin
and blood samples collected at the time of surgery forpatients with hypospadias. 2) Verification of theadverse effects of endocrine disrupters: A large numberof researches on the mechanism on toxicity of
endocrine disruptors has been conducted for several
decades. However, there are many reports which aresuspected to not be reproducible, especially in theexperiments at actual exposure levels for human. We
are conducting multifaceted verification of biologicaleffects on bisphenol A (BPA) that even the Ministry of
Health, Labor and Welfare are still hesitating
regulation of industrial production.

in all over the world. The essence of the problem is thatthe low level exposure experiment equivalent to theactual environment is not sufficiently verified to bereliable. We have also conducted low dose BPA
administration experiments to pregnant C57B6/J mice.
Methylation of the cerebrum hippocampus in offspring
by serial administration (200 μg/kg/day) was comparedwith the control group using MSD-AFLP. However,none of the 43,840 CpGs showed significant difference
was found at all (Aiba et al., Genes Environ 2018).
Furthermore, the measurements for DNA methylation
by tiling array and mRNA expression by microarray
were performed with hippocampus samples obtained
from mice continuously exposed to a low dose of BPA(0, 2, 20, 200 μg/kg/day) during fetal periods. However,
the apparent influence on epigenetic alterations by BPA
could not be detected with a statistically significant
level (in preparation).

Teaching activities
1) Epigenetic Molecular Epidemiology
Many epidemiological studies reported that theabnormal external genitalia of newborns, such as
hypospadias, are increasing since the second half of thelast century in worldwide. We found the CYP1 familygene expression as estimated chemical exposure level,
as well as DNA methylation using foreskin or blood
sample collected at the time of surgical operation of thehypospadias to clarify the relationship between disease
and environmental factors. Expression level of the
CYP1 family in hypospadias group is higher than thatof fimosis group Minimum promoter methylation levelof the SRD5A2 gene is correlated with its expression
levels in hypospadias group. These results suggest that
there is some relation between onset and chemical
exposure (Ohsako et al, AECT, 2017).
2) Verification of the adverse effects of endocrine
disruptors
BPA is a representative example of endocrine
disruptors. In animal studies, there are numerous
reports of adverse effects on reproductive function andthe central nervous system by exposure during fetal
periods. In concern of central nervous system andhigher brain function, a low-dose effects of BPA havebeen reported including DNA methylation. However,global coordination on regulation is insufficient.
Therefore, the production of BPA continues to increase

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 guidances for the dissertation for the Master’s andDoctor’s degrees, have been provided.
Undergraduate education
Lectures on biochemistry and molecular biology, witha focus on the diversity, structures and functions oflipids, for medical students (M0).

Publications
1. Li X, Park SJ, Jin F, Deng Y, Yang JH, Chang JH,
Kim DY, Kim JA, Lee YJ, Murakami M, Son KH,
Chang HW. Tanshinone IIA suppresses FcεRImediated mast cell signaling and anaphylaxis by

576

2.

3.

4.

5.

activation of the Sirt1/LKB1/AMPK pathway.
Biochem. Pharmacol. 152, 362-372 (2018)
Tsukayama I, Toda K, Takeda Y, Mega T, Tanaka
M, Kawakami Y, Takahashi Y, Kimoto M,
Yamamoto K, Miki Y, Murakami M, SuzukiYamamoto T. Preventive effect of Dioscorea
japonica on squamous cell carcinoma of mouseskin involving down-regulation of prostaglandin
E2 synthetic pathway. J. Clin. Biochem. Nutr. 62,
139-147 (2018)
Murakami M, Yamamoto K, Taketomi Y.
Phospholipase A2 in skin biology: new insightsfrom gene-manipulated mice and lipidomics.
Inflamm Regen. 38, 31 (2018) (Review)
Aiba T, Saito T, Hayashi A, Sato S, Yunokawa H,
Maruyama R, Fujibuchi W, Ohsako S. Does theprenatal bisphenol A exposure alter DNA
methylation levels in the mouse hippocampus? :Analysis using a high-sensitivity methylome
technique. Genes Environ 4, 40, 12 (2018)
Yamane J, Aburatani S, Imanishi S, Akanuma H,
Nagano R, Kato T, Sone H, Ohsako S, Fujibuchi W.
Construction of a high-precision chemical
prediction zystem using human ESCs. Yakugaku
Zasshi 138, 815-822 (2018)

577

Laboratory of Animal Resources
Professor
Atsu Aiba, Ph.D.

Associate Professor
Kazuki Nakao, Ph.D., Hidetoshi Kassai, Ph.D.

Assistant Professor
Michinori Koebis, Ph.D., 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 6
teaching staffs, 5 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 945 at the end of academic year 2018.
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 learning and memory. We also study cell
metabolism. We generate knockout mice and transgenic mice of signal transduction molecules including
the glutamate receptors and mammalian target of
rapamycin (mTOR). We applied proteomics analysis
to these mice. We also try to generate murine models
for human genetic diseases. We have also established
new gene targeting technology using the CRISPR/
CRISPR-associated (Cas) system.

578

1. Autologous embryo transfer in marmoset
Common marmoset (Callithrix jacchus) is a nonhuman primate and recently used for human model,
especially focusing on brain function. We haveestablished the techniques for embryo transfer tooviducts. To improve embryo development and toincrease the pregnancy rate, we are trying a novel
protocol in which embryos are collected from alreadymated females by oviduct flushing and immediatelytransferred into the oviduct of the very same donors
following injections with genome-editing components.
We expected the higher efficiency of the developmentof genome edited embryos by this technique.
2. Expression and trafficking of mGluR1 splicevariants exposed by two novel mutant mouse
lines
Metabotropic glutamate receptor subtype 1 (mGluR1)
regulates motor coordination, synaptic plasticity andsynapse elimination. mGluR1 undergoes alternative
splicing giving rise to at least three variants,
mGluR1, , and which differ in their intracellular
C-terminal domains. To study the expression ofmGluR1, we have generated a new knock-in mouseline in which the C-terminus of this variant carries two
epitope tags. We found that mGluR1γ is either
untranslated or in amounts that are undetectable in themouse cerebellum. Therefore, only mGluR1 andmGluR1 are present and active at cerebellar synapses.
The trafficking and function of mGluR1 appears
strongly influenced by scaffold proteins such as
Homers that bind to the intracellular C-terminal
domain of mGluR1. To investigate the role of thisinteraction on the mGluR1 subcellular localization at
cerebellar parallel fiber-Purkinje cell synapses, we
generated a second transgenic mouse line
(mGluR1a-P/E-rescue mouse) carrying a point
mutation in the mGluR1 Homer binding domain.
Disruption of this interaction did not result in an
impaired motor coordination. The typical mGluR1
perisynaptic distribution was not significantly changed
in mGluR1a-P/E-rescue mouse. We extended ourultrastructural analysis of mGluR1 perisynaptic
clustering
using
the
freeze-fracture
replicaimmunolabeling technique to other mouse lines inwhich only one mGluR1 splice variant was
reintroduced into Purkinje cells of mGluR1-knock out

mice. This work revealed that mGluR1 preferentiallyaccumulates closer to the edge of the postsynaptic
density, whereas mGluR1 has a less pronounced
perijunctional distribution. In the absence ofmGluR1, mGluR1 showed an impaired trafficking
to the plasma membrane and accumulated in
intracellular organelles.
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 7% of
patients have a smaller, nested deletion of 1.5 Mb.
Genes of human chromosome 22q11.2 have beenhighly conserved in mouse chromosome 16qA13. This
syndrome has been shown to increase the risk ofdeveloping schizophrenia, intellectual disability,
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.

References
1. Sudo A, Kanagawa M, Kondo M, Ito C,
Kobayashi K, Endo M, Minami Y, Aiba A, Toda T.
Temporal requirement of dystroglycan glycosylation during brain development and rescue ofsevere cortical dysplasia via gene delivery in the
fetal stage.
Hum Mol Genet, 27(7), 1174-1185, 2018.
2. Ogonuki N, Inoue H, Matoba S, Kurotaki YK,
Kassai H, Abe Y, Sasaki E, Aiba A, Ogura A.
Oocyte-activating capacity of fresh and frozen-thawed spermatids in the common marmoset(Callithrix jacchus).
Mol Reprod Dev, 85(5), 376-386, 2018.
3. Kurano M, Tsuneyama K, Morimoto Y, Shimizu
T, Jona M, Kassai H, Nakao K, Aiba A, Yatomi Y.
Apolipoprotein M Protects Lipopolysaccharide-Treated Mice from Death and Organ Injury.

579

4.

5.

6.

7.

8.

Thromb Haemost, 118(6), 1021-1035, 2018.
Kudo R, Aiba A, Hashimoto K.
The anatomical pathway from the mesodiencephalic junction to the inferior olive relays
perioral sensory signals to the cerebellum in themouse.
J Physiol, 596(16), 3775-3791, 2018.
Nishio N, Tsukano H, Hishida R, Abe M, Nakai J,
Kawamura M, Aiba A, Sakimura K, Shibuki K.
Higher visual responses in the temporal cortex ofmice.
Sci Rep, 8(1), 11136, 2018.
Kanayama M, Nakao K, Horie S, Aiba A.
Generation of transgenic mouse line withprostate-specific expression of codon-improved
Cre recombinase.
Prostate Int, 6(3), 99-103, 2018.
Notartomaso S, Nakao H, Mascio G, Scarselli P,
Cannella M, Zappulla C, Madonna M, Motolese
M, Gradini R, Liberatore F, Zonta M, Carmignoto
G, Battaglia G, Bruno V, Watanabe M, Aiba A,
Nicoletti F.
mGlu1 Receptors Monopolize the Synaptic
Control of Cerebellar Purkinje Cells by Epigenetically Down-Regulating mGlu5 Receptors.
Sci Rep, 8(1), 13361, 2018.
Naito R, Kassai H, Sakai Y, Schönherr S, Fukaya
M, Schwarzer C, Sakagami H, Nakao K, Aiba A,
Ferraguti F.
New Features on the Expression and Trafficking
of mGluR1 Splice Variants Exposed by Two
Novel Mutant Mouse Lines.
Front Mol Neurosci, 11, 439, 2018.

580

Laboratory of Molecular Radiology
Professor
Kiyoshi Miyagawa, M.D., Ph.D.

Lecturer
Noriko Hosoya, M.D., Ph.D., Atsushi Enomoto, Ph.D.

Associate
Claudia Juliane Krause, Ph.D. (Project)

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 cellularresponse 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

581

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
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

582

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. Hosoya N, Ono M, Miyagawa K: Somatic role of
SYCE2: an insulator that dissociates HP1α from
H3K9me3 and potentiates DNA repair. Life Sci
Alliance 1: e201800021, 2018
2. Yasuhara T, Kato R, Hagiwara Y, Shiotani B,
Yamauchi M, Nakada S, Shibata A, Miyagawa K:
Human Rad52 promotes XPG-mediated R-loop
processing to initiate transcription-associatedhomologous recombination repair. Cell 175:558570, 2018
3. Ariyandy A, Sakai C, Ishida M, Mizuta R,
Miyagawa K, Tashiro S, Kinomura A, Hiraaki K,
Ueda K, Yoshizumi M, Ishida T: XRCC3
polymorphism is associated with hypertensioninduced left ventricular hypertrophy. Hypertens
Res 41:426-434, 2018

583

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 2018, 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. One student in the doctor’s
program, four students in the master’s program andone student in M.D./Ph.D. education program areenrolled in our laboratory in FY2018. Additionally, six
undergraduate students took practice education in ourlaboratory through M3 Elective Clerkship program.

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)584developing
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

585

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. Ma X, Shinohara E, Han H, Ishii M, Imai T, Ohe
K. Extracting Information on Lifestyle Issues
from Clinical Narratives in EHR. Japan Journal of
Medical Informatics. 2018;37(6):313-321.
2. Tashiro N, Imai T. Orthographic Normalization of
Disease Names using Word Embedding and
Syntactic Information. The 6th JAMI-JSAI AIM
joint workshop proceedings. 2018; SIG-AIMED006-03. (In Japanese)
3. Aoki M, Yokota S, Shinohara E, Imai T, Ohe K.
Analysisof
Nursing
Records
Using
Morphological Dictionary Based on the Standard
Terminology for Nursing Observation and Action.
Japan Journal of Medical Informatics. 2018;
38(suppl.): 506-507. (In Japanese)
4. Imai T. Functionality of ICD-11 and its
implementation in Japan. Japan Journal of
Medical Informatics. 2018; 38(suppl.): 216-218.
(In Japanese)
5. Takizawa M, Ogawa T, Imai T, Komatsu M,
Oikawa E, Abe K, Nakayama K, Mori K, Tajima
N, Imamura T. Analyses of the “Unspecifiedcode” and ICD-11 revision. Japan Journal of
Medical Informatics. 2018; 38(suppl.): 796-798.
(In Japanese)
6. Tanigaki T, Imai T, Ohe K, Yoshino T, Watanabe
K. The study of prescription support model ofJapanese Kampo formulas for non-Kampo
medical experts. The 5th JAMI-JSAI AIM joint
workshop proceedings. 2018; SIG-AIMED-00504. (In Japanese)
7. Furubayashi S, Imai T, Ishihara S, Fujiu K, Ohe K.
A Study on Normal Abnormal Determination ofElectrocardiogram Waveform using Deep
Learning. The 5th JAMI-JSAI AIM joint
workshop proceedings. 2018; SIG-AIMED-00505. (In Japanese)

The International Research Center
for Medical Education (IRCME)587

Department of Medical Education
Studies
Professor
Masato Eto, M.D., Ph.D.

Lecturer
Daisuke Son, M.D., Ph.D.
※The following information is the same as that of the previous year for certain reasons.

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.

588

Department of International
Cooperation for Medical
Education
Lecturer
Hirotaka Onishi, M.D., M.H.P.E., Ph.D.

Homepagehttps://www.icme.m.u-tokyo.ac.jp/

History
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 and researchunder the control of Graduate School of Medicine sinceApril 2013. IRCME currently consists of Departmentof Medical Education Studies and Department ofInternational Cooperation for Medical Education.

Overview of the Department
The Department of International Cooperation for
Medical Education is a department handlingcomprehensive practices and research, both in the fieldof international 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.
(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 this areaby 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 seenin the concept of assessment itself. As for research,development of work-based assessment methods,
verification of reliability and validity, improvement ofmethods for setting pass / fail judgment 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 to communitybased integrated care system.

References
1. Onishi H. History of Japanese Medical Education.
Korean J Med Educ, 30(4): 281-292, 2018
2. Snell L, Son D, Onishi H. 6 Instructional Design:
Applying Theory. Understanding Medical
Education: Evidence, Theory, and Practice, pp89100. John Wiley & Sons, Inc., Hoboken, 2018
3. Onishi H, Park YS, Takayanagi R, Fujinuma Y.
Combining Scores Based on Compensatory andNoncompensatory Scoring Rules to Assess
Resident Readiness for Unsupervised Practice:
Implications From a National Primary Care
Certification Examination in Japan. Acad Med,
93(11S), S45-S51, 2018.
4. Kimura S, Onishi H, Kawamata M. Characteristics

589

and perceptions of twice-weekly webinars forprimary care physicians in Japan: a qualitative
study. International journal of medical education, 9,229, 2018
5. Tsuchida T, Onishi H, Ono Y, Machino A, Inoue F,
Kamegai M. Population-based survey regarding
factors contributing to expectation for death athome. Asia Pacific family medicine, 17(1), 7, 2018
6. Ie K, Murata A, Tahara M, Komiyama M, Ichikawa
S, Takemura YC, Onishi H. What determines
medical students’ career preference for generalpractice residency training?: a multicenter survey
in Japan. Asia Pacific Family Medicine, 17(1), 2,
2018

590

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
Mami Takahashi, Ph.D., M.B.A., R.Ph., Hiromi Tobe, R.N., P.H.N., Ph.D.

Project Researcher
Mariko Sakka, R.N., Ph.D., Tamae Urai, R.N., Yohei Okawa, R.N., Hiromi Tobe, P.H.N.,
R.N., Ph.D., Zhang Fengying, R.N., Ph.D.

Homepage

http://gnrc.m.u-tokyo.ac.jp/en/

Introduction and Organization
With a falling birthrate and a super-aging society,Japan is in need of a paradigm shift toward a medical
and nursing care that supports the aging, as well as
those dealing with chronic health conditions, to lead
lives with maximum independence and well-being. In
order to provide a healthy life expectancy for its
people, it will be necessary for Japan to face its
forthcoming challenges and bring about the realizationof a ‘care’ society that lightens the difficulty of theliving and brings a self-reliant way of life to theJapanese nation. Nursing, which plays a central role inproviding care, must develop into a new field as ascience for the realization of this ‘care’ society.
Currently, however, the dominant paradigm employedin various nursing fields embraces a structure that
supports the training of clinical nurses, not thedevelopment of a science aimed at producing a'medical and nursing care that supports.’ Thus, GNRC
seeks to promote research into an innovative,
transdisciplinary nursing science that systematizes thistype of care. In particular, our focus is to create atransdisciplinary research and educational environment that fosters young leaders in nursing research
who will promote care innovation and develop nursing
systems for implementation.
In order to achieve this, we must work toward
integrating nursing with fields it has yet to fully
collaborate with, such as bio-engineering, molecularbiology, human engineering, philosophy, educational
psychology, information science, and policy science.
Moreover, as the field of nursing science continues todevelop, further attention must be paid to both thedevelopment of the necessary human resources thatwill be required to promote this transdisciplinary
research, as well as the networks necessary to create
collaborative relationships among industry, government, and academia. In short, our aim is to create along-term research system that allows young
researchers to conduct transdisciplinary work that
ranges from fundamental research to studies withcommercial application.
Thus, the Global Nursing Research Center has been
established as an affiliated research center, which is591

the first of its kind in nursing science. The GNRC willcontinue to execute the following three goals:
1) Establish an innovative nursing research field basedon transdisciplinary integration;2) Carry out cutting-edge research and present it to theworld with young researchers pursuing the sciences;
3) Build up a foundation of these new fields throughrepeated research trials that will strengthen the newresearch and education systems.

Establishing an Innovative Nursing Research
Field
1. Division of Care Innovation
The Division of Care Innovation promotes various
research activities, such as robotics nursing, biologicalnursing, visualized nursing, clinical nursing technology and reverse translational research, with the aimof ‘developing and producing patient care productsthat lighten unfavorable conditions of daily life due tothe health impairment of each person.’
2. Division of Nursing Systems
The Division of Nursing Systems promotes suchresearch activities as health-quality outcome researchand care quality management, in order to provide‘nursing practice solutions that reflect important
cultural and social concerns, constructing Japan-origin
nursing theories that support high quality practices,and making policy proposals.’
3. Achievements
In 2018, three international joint research projects andan industry-government-academia research projects
were undertaken. In addition, two patent applications
were submitted, and 20 original English articles were
published.

Executing Innovative Research
1. International Invited Faculty
In 2018, we invited three researchers: Prof. Sarah
Hope Kagan (Lucy Walker Honorary Term ProfessorofGerontologicalNursing,
UniversityofPennsylvania), Prof. Margaret Ingrid Wallhagen(Professor, Director, John A. Hartford Center ofGerontological Nursing Excellence, PhysiologicalNursing, School of Nursing, The University ofCalifornia, San Francisco), and Prof. Sally Thorne(Associate Dean, Faculty of Applied Science, The
University of British Columbia). They each gave
post-doctoral seminars. We also invited Dr. Patricia A.
Grady (Director Emeritus of the National Institute of
Nursing Research) and held special lectures.
2. Post-doctoral Program
Post-doctoral (PD) researchers engage in focusedresearch projects, the findings of which will be madeknown to the public. In addition, PD researchers musttake five essential seminars that cover comprehensive
research knowledge, skills, and global awareness forthe training of youth for leadership.
These five required seminars are, as follows: (1) How
to Write a Research Paper in English, (2) Leadershipin Nursing Research, (3) Qualitative Research
Methods, (4) Health Quality Outcome Research, and(5) Introductory Seminar to Nursing Science andEngineering.
Further, there are an additional five optional seminars:(1) Skin Assessment, (2) Ultrasonography, (3)Qualitative Sketch Techniques, (4) Biological Nursing,and (5) 3D Measurement and Modeling Hands-on
Seminar for Nursing Science and Engineering.
In 2018, five PD researchers participated in thisprogram, and completed the program.
3. Other Universities’ Young Researchers
In 2018, our PD seminars were opened to young
researchers from other universities, and by the end of
the year, a total of 366 researchers were able to attend.
Furthermore, we conducted research consultations or
technical assistance and training for 20 of these young
researchers.
We held an international summer program, and 48
young researchers attended it from 13 countries andregions.

Building Future Research
1. Global Nursing Research Center FundThe Global Nursing Research Center Fund wascontinued for the purpose of fostering young
researchers.
2. Visiting Foreign Universities
In 2018, we visited Western Sydney University,
Queensland University, Adelaide University, Deakin

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University and Monash University, which werehigh-ranking universities in Australia, and inspected
their education and research systems. The purpose ofthis visit was to enhance education and researchsupport for young nursing researchers which canpermit high quality and world-class innovative
nursing research in the GNRC.

Accomplishments
1. Yoshida M, Murayama R, Hotta K, Higuchi Y,
Sanada H. Differences in motor learning of pelvic
floor muscle contraction between women with andwithout stress urinary incontinence: Evaluation bytransabdominal
ultrasonography.
Neurourol
Urodyn. 2017;36(1):98-103.
2. Oe M, Takehara K, Noguchi H, Ohashi Y, Fukuda
M, Kadowaki T, Sanada H. Skin hydration of theheel with fissure in patients with diabetes: across-sectional observational study. Chronic
Wound Care Management and Researc. 2018;5:
11-16.
3. Yabunaka K, Matsumoto M, Yoshida M, Tanaka S,
Miura Y, Tsutaoka T, H, a M, Nakagami G,
Sugama J, Sanada H. Assessment of rectal feces
storage condition by a point-of-care pocket-size
ultrasound device for healthy adult subjects: apreliminary study. Drug Discoveries andTherapeutics. 2018;12(1):42-46.
4. Mugita Y, Minematsu T, Nakagami G, Sanada H.
Influence of digestive enzymes on development ofincontinence-associated dermatitis: inner tissue
damage and skin barrier impairment caused bylipidolytic enzymes and proteases in rat macerated
skin. International Wound Journal. 2018.
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. 2017 Oct; (in press)
6. Murayama R, Takahashi T, Tanabe H, Yabunaka K,
Oe M, Komiyama C, Sanada H. Exploring thecauses of peripheral intravenous catheter failure
based on shape of catheters removed from various
insertion sites. Drug Discoveries & Therapeutics.
2018; 12(3):170-177.
7. Abe-Doi M, Oe M, Murayama R, Zushi Y, Tanabe

H, Sanada H. Impact of squeezing condition to
obtain sufficient blood volume for self-monitoringof blood glucose using an automatic puncturing
and sampling system. Journal of Diabetes Scienceand Technology. 2018;12(5):1041-1044.
8. Sato I, Higuchi A, Yanagisawa T, Murayama S,
Kumabe K, Sugiyama K, Mukasa A, Saito N,
Sawamura Y, Terasaki M, Shibui S, Takahashi J,
Nishikawa R, Ishida Y, Kamibeppu K. Employment status and termination among survivors ofpediatric brain tumors: a cross-sectional survey.
International Journal of Clinical Oncology. 2018
Apr; 23: 801-811.
9. 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?. Neurourology and
Urodynamics. 2018;38(1):158-164.
10. Yoshida M, Igawa Y, Higashimura S, Suzuki M,
Sanada H. Effectiveness of a hydrophilic-coatedcompact catheter in preventing urinary tract
infections and improving quality of life in female
patients managed with clean intermittent selfcatheterization: A prospective multicenter
randomized parallel comparative trial. Japanese
Journal of Wound, Ostomy and ContinenceManagement. 2018
11. Kitamura A, Minematsu T, Nakagami G, Sanada
H. Assessment of histopathology of wounds basedon protein distribution detected by wound blotting.
SAGE Open Medicine. 2018; 6: 20503121188122
20.
12. Yabunaka K, Nakagami G, Tabata K, Sugama J,
Matsumoto M, Iuchi T, Kido Y, Sanada H.
Constipation in the elderly in a Japanese
long-term medical facility: An ultrasonographic
investigation. Drug Discoveries and Therapeutics.
2018;12(4):233-238.
13. 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. 2018; (in press)
14. Kita S, Umeshita K, Tobe H, Hayashi M,

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Kamibeppu K. Intimate partner violence, negative
attitudes towards pregnancy, and mother-to-fetus
bonding failure among Japanese pregnant woman.
Violence and Victims. 2018; (in press)
15. 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 ofInterpersonal Violence. 2018; (in press)
16. Lai CKY, Igarashi A, Yu CTK, Chin KCW. Does
life story work improve psychosocial well-being
for older adults in the community? A quasiexperimental study. BMC Geriatr. 2018;18(1):119.
17. Noguchi-Watanabe M, Yamamoto-Mitani N,
Takai Y. A Cyclic Model Describing the Processof Sustaining Meaningfulness in Practice: How
nurses continue working at one home care agency.
Global Qualitative Nursing Research. 2018;5:2333393618788265.
18. Igarashi A, Yamamoto-Mitani N, Morita K,
Matsui H, Lai CKY, Yasunaga H. Classification of
long-term care wards and their functional
characteristics: analysis of national hospital data
in Japan. BMC health services research. 2018;18:655.
19. Yamamoto-Mitani N, Saito Y, Futami A, Takaoka
M, Igarashi A. Nurses’ and care workers’
perception of care quality in Japanese long-termcare wards: A qualitative descriptive study. Global
Qualitative Nursing Research. 2018;5:233339361
8812189.
20. Matsumoto M, Yabunaka K, Yoshida M,
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):22-32.

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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 isunder the direct authority of the Dean of the Faculty of
Medicine. Its three most important roles, as defined by
the Committee on International Academic Affairs, arei) international educational exchange, ii) international
contacts in research and scientific fields, and iii)
international cooperation in health care and medicine.

Activities
This document reports on the office's activities inthese areas over the 2018 academic year (April 1, 2018
through March 31, 2019).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2018, there were 150 foreign students (37countries) officially registered in the Graduate Schoolof Medicine. Many inquiries were received during thisperiod from prospective applicants for foreign student
and trainee status; responses were sent to 30 suchinquiries.
Many currently enrolled foreign students received
counseling at this office concerning their studies andlife at the University of Tokyo and the requirements for
obtaining scholarships and degrees.

In addition, a large number of University of Tokyo
students wish to supplement their training with basic
clinical experience overseas before graduation, as wellas the type of short-term training (1-3 months)
frequently called clinical electives overseas. Inquiries
from these students were either answered by this officeor referred to appropriate centers.
Every year, 25 or more University of Tokyo students
go overseas to study, and the office makes its best
efforts to accommodate their needs.
It has become a tradition to hold a Spring gettogether of foreign students and University of Tokyo
students who will study or have studied abroad. This
event is attended by the Dean of the Faculty of
Medicine, teaching staff, administrative staff, andstudents; about 70 people attended in 2018, at CapoPELLICANO.
A formal agreement for academic exchange between
the University of Pennsylvania and the University ofTokyo was renewed in May 2004. Since that time,seventeen University of Tokyo students have taken
research electives at the University of Pennsylvania,
and two students from the University of Pennsylvania
have taken clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and Johns Hopkins University inDecember 2002. Since the start of the program in 2002,

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thirty University of Tokyo students have visited toattend clinical electives at Johns Hopkins University,and four students from Johns Hopkins University havetaken clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the University of Michigan
Medical School in January 2005. Since the start of the
program in 2005, twenty-three University of Tokyo
students have attended clinical electives at the
University of Michigan Medical School, and twelve
students from the University of Michigan have taken
clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and Munich University in
February 2005. Since the start of the program in 2005,
sixteen University of Tokyo students have visited toattend research electives at Munich University, andeleven students from Munich University have taken
clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the College of Medicine of
National Taiwan University in October 2012. Since thestart of the program in 2012, seven University of Tokyo
students have visited to attend clinical electives at
National Taiwan University and ten students from
National Taiwan University have taken clinicalelectives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the University of Chicago
Medicine in June 2014. Since the start of the programin 2014, four University of Tokyo students have visited
to attend clinical electives at the University of Chicago
Medicine and a student from the University of Chicago
Medicine have taken clinical electives at the Universityof Tokyo.
1.2 Counseling about short-term and longer overseas
study programs for University of Tokyo medical
students and researchers.
Every year, about 35 requests from students forcounseling regarding pre-graduation or post-graduation
studies abroad are received by the Office ofInternational Academic Affairs. The office responds tothese requests by providing information, advice, andletters of recommendation.
2. Education and research
2.1 Education
In 2018, Dr. Green taught courses open to allstudents in the Graduate School of Medicine:
Introduction to Scale Development 1 and 2. Dr. Green
also taught two other graduate-level classes:
International Epidemiology 1 and 2.
Dr. Matsumiya was appointed a full time member ofthe office in December 2018, and is responsible for
Medical English 1 and 2, which are required for all
medical students, having taken over from Mr.
Christopher Holmes who reached retirement age, but
continues to teach part-time. Dr Matsumiya has also
run some Medical English classes for students about togo on their elective placements. He was invited as alecturer on the Cambridge Summer Institute at
Magdelene College, University of Cambridge, UK, andhas been invited again this summer.
Dr. Nanishi taught “Basic tools for Population/
Public Health Research” for graduate students. Dr.
Green and Dr. Nanishi conducted several international
health studies.
2.2 Publications
1: Yasuoka J, Kikuchi K, Nanishi K, Ly P, Thavrin B,
Omatsu T, Mizutani T. Malaria knowledge,
preventive actions, and treatment-seeking
behavior among ethnic minorities in Ratanakiri
Province, Cambodia: a community-based crosssectional survey. BMC Public Health. 2018 Oct
26;18(1):1206.
2: Shibanuma A, Yeji F, Okawa S, Mahama E,
Kikuchi K, Narh C, Enuameh Y, Nanishi K, Oduro
A, Owusu-Agyei S, Gyapong M, Asare GQ,
Yasuoka J, Ansah EK, Hodgson A, Jimba M;
Ghana EMBRACE Implementation Research
Project Team . The coverage of continuum of carein maternal, newborn and child health: a crosssectional study of woman-child pairs in Ghana.
BMJ Glob Health. 2018 Sep 3;3(4):e000786.
3: Kikuchi K, Yasuoka J, Nanishi K, Ahmed A,
Nohara Y, Nishikitani M, Yokota F,Mizutani T,
Nakashima N. Postnatal care could be the key toimproving the continuum of care in maternal and

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4:

child health in Ratanakiri, Cambodia. PLoS One.
2018 Jun 11;13(6):e0198829.
Yasuoka J, Nanishi K, Kikuchi K, Suzuki S, Ly P,
Thavrin B, Omatsu T, Mizutani T. Barriers for
pregnant women living in rural, agriculturalvillages to accessing antenatal care in Cambodia:
A community-based cross-sectional study combined with a geographic information system.
PLoS One. 2018 Mar 19;13(3):e0194103.

597

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
80 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 90
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

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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 2018, a total of 6 students
received the Program’s support for carrying out basic
medical research abroad (in U.S.) and to present theirresearch achievements at international scientificmeetings. We also support exposure to clinicaltraining in foreign hospitals with the Osamu Otsubo
Tetsumon Fellowship, initiated in 2008 with an
Endowment donated by Dr. Osamu Otsubo. In 2018, a
total of 9 students were awarded a fellowship andgained invaluable experience as student clinical clerks
in many university hospitals abroad.
2) Organizing an MD scientist training program
retreat
A MDSTP retreat was held on February, 16-17, 2019to present ongoing research progress in a closed
meeting among peers. More than 60 participants,

mostly medical school students, but also some medical
interns, graduate students and Program-affiliatedprofessors attended it. Lively discussions among peers
were exciting throughout the meeting and thefeedback from all participants was outstanding andunequivocal in emphasizing the critical importance fora research progress retreat to promote their future
research projects. One important aspect of the retreat
was to provide students, interns and professors to
discuss opportunities in various career paths available
in the basic medical research field.
3) Cooperating with other medical universities acrossJapan
With the availability of governmental support from2011 on, the MDSTP at the University of Tokyo has
been in close touch with sister organizations at Kyoto
University, Osaka University and Nagoya University.
With a view to enhancing collaborative efforts inimproving the basic medical research training at the 4
medical schools, Joint Retreats were held to promote
communication and networking among the medical
students with research minds. The latest retreat wasorganized on December, 9-10, 2017 in Kobe, at theoccasion of Consortium of Biological Sciences 2017
(ConBio2017). 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 9 otheruniversities in eastern Japan to organize annual
research students’ retreats. In 2018, this was held on
August, 16-17 in Kanazawa under the auspices ofKanazawa University. More than 70 people
participated in the retreat and presented their ongoing
research progress and future plans.

Activities (2018)
The number of registered students: 99 (3rd and 4th
grade: 49, 5th and 6th: 50)
Lectures for students in Years 1 and 2

599

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: 44 lectures
Presentation of research progress: 2 times (including
the retreat of MD scientist training program in the
University of Tokyo)
The number of students receiving travel supports forresearch and clinical activities abroad: 15
The number of Year 6 students who passed theirhonors thesis defense: 7 (the Dean’s Prize wasawarded to 1 students)

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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”, and the eleventh“Kidney”.
Since the opening of the Museum, more than
127,131 people had visited by the end of FY2017.
It is closed due to preparations for the relocation.

601

After April, 2019, we are going to re-open our
museum.

Overview of operations
The opening hours are 10:00-17:00. 12:00-13:00 is
lunch break. The Museum is closed every Monday andduring the New Year holidays (however, it will open if
Monday is a public holiday). Admission is free.

602

Office for Human Research Studies(OHRS)
Professor (Director of OHRS)
Yutaka Yatomi, M.D., Ph.D.

Professor (Vice Director of OHRS)
Akira Akabayashi, M.D., Ph.D.

Lecturer
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 2018
・Research Ethics Committee (except for clinical
trial, GCP):
382 new applications, 1012 minor alterations ofapproved studies
・Clinical Research Review Board:43
・New clinical documentary examinations: 83

603

by cooperating and consulting with Ethics Consultant
specified by each laboratory.

Research activities
At present, OHRS is a business section. For more
information about the research, see the contents of
Department of Biomedical ethics, which is acooperative department.

Though OHRS adopts various inclusive applications,the number of studies applied to and reviewed by
ethics committees over the last several years is on therise.
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 2018 with 2864 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

604

The Office for Clinical Practice andMedical Education
Professor
Tatsuya Yamasoba, 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
specialist/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.

605

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, being followed in 2019.