ISSN 1883-9606

2017

Vol.135

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2016 ---- March 2017

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 201-March 201

Introduction
This is volume 135(the edition of year 2017) 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, the International Research Center for
Medical Education, 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 150 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.

Kohei Miyazono, Dean
Graduate School of Medicine and Faculty of Medicine
The University of Tokyo
October, 2017

i

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

1

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

2

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

4

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

6

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

8

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

9

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

12

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

14

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

17

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

18

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

21

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

24

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

27

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

28

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

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

48

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

52

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

55

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

56

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

60

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

61

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

69

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

70

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

73

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

75

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

79

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

80

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

83

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

88

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

90

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

91

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

93

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

94

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

97

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

102

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

108

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

109

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

111

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

115

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

116

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

119

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

122

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

123

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

128

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

132

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

137

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

138

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

142

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

148

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

152

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

155

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

158

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

160

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.434] )Department of Transfusion Medicine ·········································································

161

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

164

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

165

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

167

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

170

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

172

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

174

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

175

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

179

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

183

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

184

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

188

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

189

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

193

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

197

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

200

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

205

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

210

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

216

Department of Metabolic Care and Endocrine Surgery ·····················································

219

iv

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

221

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

222

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

225

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

229

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

234

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

239

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

245

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

250

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

253

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

254

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

257

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

262

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

263

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

268

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

274

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

278

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

279

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

282

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

285

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

289

Department of Gerontological Home Care and Long-term Care Nursing/Palliative Care Nursing ···290

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

293

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

296

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

300

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

306

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

307

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

313

v

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

316

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

317

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

320

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

323

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

327

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

329

Department of Biostatistics(See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.268] )Department of Social and Preventive Epidemiology ························································

330

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

333

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

33

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

341

Department of Mental Health(See Department of Mental Health [P.26] )Department of Health Sociology and Health Education(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.342] )Departments of Health and Social Behavior & Health Education and Health Sociology ···············

342

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.274] )3. Health Services Sciences ·························································································

346

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.111] )Department of Healthcare Informatics (See Department of Biomedical Informatics [ P.119] )Department of Clinical Information Engineering ····························································

347

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.116] )Endowed Department ···································································································

349

Department of Bone & Cartilage Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.486] )Department of Cartilage & Bone Regeneration (Fujisoft)(See Central Clinical Facilities Division of Tissue Engineering [P.486] )Department of Clinical Epidemiology and Systems ·························································

350

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

354

Science for joint reconstruction ( See Department of Orthopaedic Surgery [P.234] )Department of Chronic Kidney Disease (CKD) Pathophysiology ········································

356

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

359

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

360

vi

Department of Medical Genomics ·············································································

363

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

365

Department of Youth Mental Health ···········································································

368

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

370

Department of medical research and the management of musculoskeletal pain ························372

AXA Chair on Health and Human Security ( See Department of Global Health Policy [P.307] )Department of Advanced Nephrology and Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.486] )Department of Molecular Sciences on Diabetes·······························································

376

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

378

Department of Osteoimmunology ···············································································

380

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

382

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

383

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

386

Endowed Department (22nd Century Medical and Research Center) ···········································

387

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

388

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

391

Department of Joint Disease Research ········································································

394

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

397

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

400

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

402

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

407

Pharmacology and Pharmacokinetics ·········································································

410

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

412

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

416

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

417

Verbal Analysis of Pathophysiology ···········································································

420

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

422

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

425

Department of Skincare Science(See Department of Gerontological Nursing /Wound Care Management [P.300] )Social Cooperation Program (22nd Century Medical and Research Center) ···································

428

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

429

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University Hospital
Clinical Divisions ····································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.123] )Respiratory Medicine (See Department of Respiratory Medicine [P.128] )Gastroenterology (See Department of Gastroenterology [P.132] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.138] )Diabetes and Metabolic Diseases (See Department of Diabetes and Metabolic Diseases [P.142] )Hematology and Oncology (See Department of Hematology and Oncology [P.148] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.152] )Infectious Diseases (See Department of Infectious Diseases (Internal Medicine) [P.155] )Neurology (See Department of Neurology [P.97] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.184] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.158] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.197] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.210] )Hepatobiliary Pancreatic Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.200] )Vascular Surgery (See Department of Vascular Surgery [P.216] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.219] )Artificial Organ and Transplantation Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.200] )Cardiovascular Surgery (See Department of Cardiac Surgery [P.193] )Thoracic Surgery (See Department of Thoracic Surgery [P.189] )Neurosurgery (See Department of Neurosurgery [P.102] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.254] )Urology and Andrology (See Department of Urology [P.205] )Gynecologic Surgery (See Obstetrics and Gynecology [P.164] )Sensory and Motor System Medicine
Dermatology and Photolaser Medicine (See Department of Dermatology [P.222] )Ophthalmology and Vision Correction (See Department of Ophthalmology [P.239] )

432

viii

Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.234] )Otorhinolaryngology, and Auditory and Voice Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.245] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.250] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.225] )Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.229] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.175] )Pediatrics Surgery (See Department of Pediatric Surgery [P.179] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.165, 167, 170] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.94] )Radiology
Radiology (See Department of Radiology [P.61] )Central Clinical Facilities ···························································································

433

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

434

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

438

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

441

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

443

Department of Emergency Services(See Department of Emergency and Critical Care Medicine [P.257] )Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.161] )Delivery Unit ·····································································································

447

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

448

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

451

Department of Intensive Care Unit
(See Department of Emergency and Critical Care Medicine [P.257] )Division of Diagnostic Pathology ··············································································

454

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

458

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

460

ix

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

462

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

466

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

469

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.52] )Department of Planning, Information, and Management(See Department of Biomedical Informatics [P.119] )University Hospital Medical Information Network (UMIN) Center ······································

476

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

479

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

481

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

486

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

490

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

493

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

497

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

500

Center for Genome Medicine
Department of Genome Informatics ········································································

502

Department of Clinical Genomics, Medical Genome Center ···········································

504

Department of Genome Analysis, Medical Genome Center ············································

506

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

508

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

517

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

519

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

520

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

524

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

525

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

528

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

531

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

533

Laboratory of Environmental Health Sciences ································································

538

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

540

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

543

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

546

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

549

x

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

552

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

554

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

556

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

557

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017xi

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. 135, October 2017

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. 135, October 2017

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.

xiv

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017

Organization Chart
Cell Biology
Cell Biology and Anatomy

Structural Biology
Structural Cell Biology
Cellular Neurobiology

Molecular Cell Biology

Molecular Biology
Biochemistry and Molecular Biology

Cellular Signaling
Physiological Chemistry andMetabolism

Collaborative Department

Clinical Genome Informatics Lipid Science
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
Surgical Pathology

Microbiology
Pathology, Immunology
and Microbiology

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

Radiological Health

Medical Informatics and Economics
Collaborative Department

Cancer Health Services Research

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017

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
Stress Sciences and Psychosomatic
Medicine

Clinical Laboratory Medicine
and Pathology

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
Metabolic Care and Endocrine
Surgery
Dermatology
Plastic and Reconstructive Surgery
Oral and Maxillofacial Surgery
Sensory and Motor System
Medicine

Orthopaedic Surgery
Ophthalmology
Otorhinolaryngology and Head & Neck
Surgery
Rehabilitation Medicine

Vital Care Medicine

Anesthesiology
Emergency and Critical Care Medicine

xvi

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017
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
Nursing Administration
Preventive and Administrative
Nursing

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

Clinical Nursing

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

Collaborative Department

Public Mental Health Policy

International Social Medicine

Global Health Policy
Community and Global HealthInternational Health

Human Genetics
International Biomedical
Sciences

Developmental Medical Sciences
Human Ecology
Biomedical Chemistry

Medical Science (Master’s Program)

Biostatistics

Epidemiology and Health Sciences

Social and Preventive Epidemiology
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

Collaborative Department

Public Health Science

Laboratory of Molecular Biomedicine for Pathogenesis
Laboratory of Structural Physiology
Laboratory of Regenerative Medical Engineering
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. 135, October 2017

xvii

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
Bone & Cartilage Regenerative Medicine
Cartilarge &Bone Regeneration(Fujisoft)
Immunotherapeutics
Advanced Clinical Science and Therapeutics
Health Management and Policy
Computational Diagnostic Radiology and Preventive Medicine
Health Care Safety Management(Tokio Marine & Nichido)
Healthcare Quality Assessment
Clinical Epidemiology and Systems
Clinical Trial Data Management
Pharmacology and Pharmacokinetics
Ubiquitous Preventive Medicine
Science for Joint Reconstruction

Endowed Department

Therapeutic Strategy for Heart Failure
Molecular Structure and Dynamics
Medical Genomics
Continence Medicine
Department of Life Support Technology (Molten)
Youth Mental Health
AXA Chair on Health and Human Security
Department of Advanced Translational Research and Medicine in Management of Pulmonary Hypertension
Department of Immunotherapy Management
Chronic Kidney Disease Pathophysiology
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
Ubiquitous Health Informatics
Lipidomics

Social Cooperation Program

Functional Regulation of Adipocytes
Advanced Nursing Technology
Verbal analysis of pathophysiology
Skincare Science
General Affairs Office
Personnel Office
Research Support Office
Educational Affairs
Graduate Student Affairs

xviiiThe Tokyo Journal of Medical Sciences. Vol. 135, October 2017

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. 135, October 2017

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 and Photolaser Medicine
Ophthalmology and Vision Collection
Orthopaedic Surgery and Spinal Surgery

Sensory and Motor System
Medicine

Otorhinolaryngology, and Auditory and Voice Surgery
Rehabilitation Medicine
Plastic, Reconstructive, and Aesthetic Surgery
Oral-Maxillofacial Surgery, Dentistry andOrthodontics
Pediatrics

Pediatrics, Perinatal and
Women's Medicine

Pediatric Surgery

Neuropsychiatry

NeuropsychiatryRadiology

Obstetrics and Gynecology

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

Office of Management Planning
Office of Medical Accounting

xix

xx

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017
Central Supply Service
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
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

Vascular Board
Perioperative Assessment Center

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017

xxi

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

Hiromi Sanada

Director, Medical Library

Tsuyoshi Takato

Director General, University Hospital

Nobuhito Saito

Director, Center for Disease Biology and Integrative Medicine

Shigeo Okabe

Director, International Research Center for Medical Education

Kazuhiko Yamamoto

Graduate School of Medicine
Molecular Cell Biology
Professor

Masahide Kikkawa

Professor

Shigeo Okabe

Professor

Noboru Mizushima

Professor

Hiroyuki Mano

Professor

Hiroki Kurihara

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

Yasuteru Urano

Professor

Takeshi Iwatsubo

Professor

Haruhiko Bito

Professor

Kenzo Hirose

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

Neuroscience
Department of Basic Neuroscience

xxii

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017

Department of Integrative Medical Neuroscience
Department of Clinical Neuroscience

Professor

Kiyoto Kasai

Professor

Shoji Tsuji

Professor

Nobuhito Saito

Department of Occupational, Environmental and Preventive

Professor

Koji Matsushima

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

Takashi Kadowaki

Professor

Mineo Kurokawa

Professor

Kazuhiko Yamamoto

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

Norihiro Kokudo

Professor

Yukio Homma

Professor

Toshiaki Watanabe

Professor

Shinichi Sato

Professor

Isao Koshima

Professor

Tsuyoshi Takato

Professor

Sakae Tanaka

Professor

Makoto Aihara

Professor

Tatsuya Yamasoba

Professor

Nobuhiko Haga

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. 135, October 2017

Department of Vital Care Medicine

xxiii

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

Chiho Watanabe

Professor

Tomoyoshi Nozaki

Professor

Yutaka Matsuyama

Professor

Satoshi Sasaki

Professor

Hideo Yasunaga

Professor

Takahiro Kiuchi

Professor

Norito Kawakami

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Professor

Yasuki Kobayashi

Professor

Kazuhiko Ohe

Professor

Hiroshi Oyama

Professor

Hirotaro Iwase

Health Sciences and Nursing
Department of Health Sciences

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. 135, October 2017

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 Regenerative Medical Engineering

Professor

Takashi Azuma

Laboratory of Clinical Biotechnology

Professor

Ungil Chung

Laboratory of Animal Resources

Professor

Atsu Aiba

Laboratory of Molecular Radiology

Professor

Kiyoshi Miyagawa

International Research Center for Medical Education

Professor

Kazuhiko Yamamoto

Medical LibraryProfessor

Tsuyoshi Takato

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

Department of Bone & Cartilage Regenerative Medicine

Project Associate professor

Takumi Matsumoto

Department of Cartilage & Bone Regeneration(Fujisoft)

Project Associate professor

Atsuhiko Hikita

Immunotherapeutics

Project Professor

Kazuhiro Kakimi

Department of Advanced Clinical Science andProject Associate professor

Junichi Suzuki

Computational Diagnostic Radiology and Preventive

Project Professor

Naoto Hayashi

Medicine

Project Associate professor

Kansei Uno

Project Associate professor

Takeharu Yoshikawa

Project Associate professor

Masaki Anraku

Project Professor

Hiroaki Miyata

Project Associate professor

Shun Kohsaka

Pharmacology and Pharmacokinetics

Project Associate professor

Masashi Honma

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

Eirin Sai

Continence medicine

Project Professor

Yasuhiko Igawa

Department of Life Support Technology (Molten)

Project Associate professor

Taketoshi Mori

Department of Youth Mental Health

Project Associate professor

Tsuyoshi Araki

Division of Research Resources and Support

Endowed Departments

Therapeutics

Healthcare Safety Management (Tokio Marine &Nichido)
The Department of Healthcare Quality Assessment

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017

Department of Advanced Nephrology and Regenerativexxv

Project Associate professor

Keiichi Hishikawa

AXA Chair on Health and Human Security

Project Professor

Manami Inoue

Department of Advanced Translational Research andProject Associate professor

Hideki Takimoto

Department of Immunotherapy Management

Project Associate professor

Hiroko Kanda

Chronic kidney disease pathophysiology

Project Associate professor

Reiko Inagi

Department of medical research and management for

Project Professor

Koh Matsudaira

musculoskeletal pain

Project Associate professor

Hiroyuki Oka

Department of Molecular Science on Diabetes

Project Associate professor

Hironori Waki

Department of Integrated Molecular Sciences on

Project Associate professor

Masato Iwabu

Department of Osteoimmunology

Project Associate professor

Kazuo Okamoto

Department of medical and pharmaceutical community

Project Associate 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

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

Medicine

Medicine in Management of Pulmonary Hypertension

Metabolic Diseases

healthcare

Organ Disorders
Social Cooperation Program

University Hospital
Clinical Divisions
General Medicine

Head

Mineo Kurokawa

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

Takashi Kadowaki

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Kazuhiko Yamamoto

xxvi

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017

Infectious Diseases

Head

Kyoji Moriya

Neurology

Head

Shoji Tsuji

Geriatric Medicine

Head

Masahiro Akishita

Psychosomatic Medicine

Head

Kazuhiro Yoshiuchi

General Surgery

Head

Norihiro Kokudo

Stomach and Esophagus Surgery

Head

Yasuyuki Seto

Colon and Rectal Surgery

HeadToshiaki Watanabe

Hepatobiliary Pancreatic Surgery

Head

Norihiro Kokudo

Vascular Surgery

HeadToshiaki Watanabe

Breast and Endocrine Surgery

Head

Keiichiro Tada

Artificial organ and Transplantation Surgery

Head

Norihiro Kokudo

Cardiovascular Surgery

HeadMinoru Ono

Thoracic Surgery

Head

Jun Nakajima

Neurosurgery

Head

Nobuhito Saito

Anesthesiology and Pain Relief Center

Head

Yoshitsugu Yamada

Urology and Andrology

Head

Yukio Honma

Gynecologic Surgery

Head

Yutaka Ohsuga

Dermatology and Photolaser Medicine

Head

Shinichi Sato

Ophthalmology and Vision Collection

Head

Makoto Aihara

Orthopaedic Surgery and Spinal Surgery

Head

Sakae Tanaka

Otorhinolaryngology and Auditory and Voice Surgery

Head

Tatsuya Yamasoba

Rehabilitation Medicine

Head

Nobuhiko Haga

Plastic, Reconstructive and Aesthetic Surgery

Head

Isao Koshima

Oral-Maxillofacial Surgery Dentistry and Orthodontics

Head

Tsuyoshi Takato

Pediatrics

Head

Akira Oka

Pediatric Surgery

Head

Jun Fujishiro

Obstetrics and Gynecology

HeadTomoyuki Fujii

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Osamu Abe

Pharmaceutical Department

Head

Hiroshi Suzuki

Department of Clinical Laboratory

Head

Yutaka Yatomi

Surgical Center

Head

Hiroshi Yasuhara

Imaging Center

Head

Osamu Abe

Emergency Service

Head

Naoto Morimura

Department of Blood Transfusion

Head

Hitoshi Okazaki

Perinatal Center

Head

Tomoyuki Fujii

Rehabilitation Center

Head

Nobuhiko Haga

Department of Medical Engineering

Head

Kyouhiro ChouCentral Clinical Facilites

The Tokyo Journal of Medical Sciences. Vol. 135, October 2017

xxvii

Central Supply Service

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Naoto Morimura

Pathology

Head

Masashi Fukayama

Department of Corneal Transplantation

Head

Tomohiko Usui

Department of Cell Therapy and Transplantation Medicine

Head

Mineo Kurokawa

Department of Endoscopy and Endoscopic Surgery

Head

Mitsuhiro FujisiroDepartment 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 Planning, Information and Management

Head

Kazuhiko Ohe

University Hospital Medical Information Network Center

Head

Hirono Ishikawa

Organ Transplantation Service

Head

Norihiro Kokudo

Labor Safety and Health Management Office

HeadTomotaka Yamamoto

Child Psychiatry

Head

Yukiko Kano

Tissue Bank

Head

Sumihito Tamura

Epidemiology and Preventive Medicine

Head

Tsutomu Yamazaki

Cancer Resource Center

Head

Sachiyo Nomura

Center for Liaison and Public Relations

Head

Toshiaki Watanabe

Department of Chemotherapy

HeadNorihiro Kokudo

Department of Medical Record Management

Head

Toshiaki Watanabe

Critical Care Center

Head

Naoto Morimura

Department of 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

Clinical Research Support Center

Head

Tsutomu Yamazaki

22nd Century Medical and Research Center

Head

Tsuyoshi Takato

Department of Tissue Engineering

Head

Tsuyoshi Takato

Cooperative Unit of Medicine and Engineering Research

Head

Minoru Ono

Translational Research Center

Head

Mineo Kurokawa

Center for Genome Medicine

Head

Shoji Tsuji

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 and Associate
Yosuke Tanaka, M. D.,Home page

Noriko Homma, Ph. D.,

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,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 and3molecular genetics and X-ray crystallography.

References
1. Tanaka, Y., S. Niwa, M. Dong, A. Farkhondeh,
Li. Wang, R. Zhou, and N. Hirokawa. The
molecular motor KIF1A transports the trkA
neurotrophin receptor and is essential for sensory
neuron survival and function. Neuron 90: 12151229, 2016.
2. Wang, D., R. Nitta, M. Morikawa, H. Yajima, S.
Inoue, H. Shigematsu, M. Kikkawa, and N.
Hirokawa.
Motility
andmicrotubule
depolymerization mechanisms of the kinesin-8
motor, KIF19A. eLife 2016;5:e18101.doi:10.
7554/eLife.18101
3. Niwa S., DM. Lipton, M. Morikawa, C. Zhao, N.
Hirokawa, H. Lu, and K. Shen. Autoinhibitionof a neuronal kinesin UNC-104/KIF1A regulates
the size and density of synapses. Cell Reports 16:2129-2141, 2016.
4. Ogawa, T., S. Saijo, N. Shimizu, X. Jiang and N.
Hirokawa. Mechanism of Catalytic Microtubule
Depolymerization via KIF2-tubulin Transitional
Conformation. Cell Reports 20: 2626–2638,
2017.

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.

Homepage http://structure.m.u-tokyo.ac.jp
Introduction and Organization
Our laboratory is one of the laboratories in
Department of Cell Biology and Anatomy. Since thereorganization of School of Medicine in 1997, the lab
was named as “Structural Biology”. The current lab
was established in 2009 when Masahide Kikkawa was
appointed as a professor.
Currently the lab members include: Masahide
Kikkawa (professor), Haruaki Yanagisawa, Tsukasa
Makino (research associates), Akihisa Tsutsumi(project research associate), Hiroshi Yamaguchi(project researcher), Yuma Tani, Tatsuki Abe, Genta
Morikawa (MSTP students), Akiko Oosakaya, Akiko
Koikeda, Ayako Ogasawara (technical assistant) and
Mikako Yanagiuchi (assistant clerk).

Teaching activities
Our lab, together with Kanai and Okabe’s lab, is incharge of teaching following courses:
1) Gross Anatomy for medical students.
2) Cell Biology and Histology for medical students.
3) Special training (Free Quarter) for medical students.
4) Advance cell biology course for graduate students.

Research activities
Our lab focuses on the structure and function of
eukaryotic flagella/cilia. Flagella/cilia is both“propeller” and “antenna” of cells, whose diameter isabout 250 nm. From the recent studies, it is becoming
clear that flagella/cilia is involved in various
important cell functions.
To study the functions of flagella/cilia, we employ
various imaging techniques, including cryo-electron
microscopy and 3D-tracking microscope incombination with genetic manipulations.
Cryo-electron microscopy and cryo-electron
tomography
One of our strength is in the high-resolution
cryo-electron microscopy (cryo-EM). This techniqueenables preserving biological samples by quickly
freezing them and observing the frozen samples
without staining. Using electron microscopy, we areable to obtain nano-meter resolution of macromolecular complexes such as axonemes. We havebeen developing new techniques, such as asymmetrichelical reconstruction and Ruby-Helix software.
Cryo-electron tomography is also used for visualizing
more complex cellular structures such as eukaryotic
cilia/flagella. In combination with genetics, it is now
possible to identify the 3D positions of specific geneproduct.
Model Organism
Our lab currently uses Chlamydomonas, zebrafish, andmice as a model organism for studying cilia/flagella.

5

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. Wang D., R. Nitta, M. Morikawa, H. Yajima, S.
Inoue, H. Shigematsu, M. Kikkawa , and N.
Hirokawa“Motility and microtubule depolymerization
mechanisms of the Kinesin-8 motor, KIF19A”.
Elife 2016 Sep 30;5. pii: e18101. doi: 10.7554/
eLife.18101.
2. Yamagishi M., H. Shigematsu, T. Yokoyama, M.
Kikkawa, M. Sugawa, M. Aoki, M. Shirouzu, J.
Yajima, R. Nitta“Structural Basis of Backwards Motion inKinesin-1-Kinesin-14 Chimera: Implication for
Kinesin-14 Motility”.
Structure, 24:1-13, 2016
3. Oda T., T. Abe, H. A. Yanagisawa, and M. Kikkawa“Docking complex-independent alignment of outerdynein arms with 24-nm periodicity in vitro.”
Journal of Cell Science, 129：1547-51, 2016
4. Oda T., T. Abe, H. A. Yanagisawa, and M. Kikkawa“Structure and function of outer dynein arm
intermediate and light chain complex”
Molecular Biology of the Cell, 27:1051-9, 2016

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.
Homepage

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

Introduction and Organization
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 30 members.

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

Research
Brain functions, which are dependent on mutualcommunication of a tremendous number of neuronalcells, regulate the behavior of animals and humans.
The main structure specifically differentiated for
information exchange between neurons is called"synapse". Long-term maintenance of synaptic
properties underlies 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,
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 in7vivo 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. Yokoyama, T., Lee J-K., Miwa, K., Tomoyama,S., Nakanishi, H., Yoshida, A., Yasui, H., Iida, T.,
Miyagawa, S., Okabe, S., Sawa, Y., Sakata, Y.
and I. Komuro
Quantification of sympathetic hyperinnervationand denervation after myocardial infarction by
three-dimensional assessment of the cardiac
sympathetic network in cleared transparent
murine hearts
PLoS One in press.
2. Okabe, S.
Fluorescence imaging of synapse dynamics innormal circuit maturation and in developmental
disorders.
Proceedings of the Japan Academy, Series B. inpress.
3. Nakai, N., Nagano M., Saitow F, Watanabe W.,
Kawamura Y., Kawamoto A., Tamada K.,
Mizuma H., Onoe H., Watanabe Y., Monai H.,
Hirase H., Nakatani J., Inagaki H., Kawada T.,
Miyazaki T., Watanabe M., Sato Y., Okabe S.,
Kitamura K., Kano M., Hashimoto K., Suzuki H.,
and T. Takumi
Serotonin Rebalances Cortical Tuning and
Behavior Linked to Autism Symptoms in
15q11-13 CNV Mice
Science Advances 3, e1603001, 2017, doi;
10.1126/sciadv.1603001
4. Hirai, S., Hotta, K., Kubo, Y., Nishino, A, Okabe,S., Okamura, Y. and H.Okado
AMPA glutamate receptors are required forsensory-organ formation and morphogenesis in
the basal chordate.
Proc. Natl. Acad. Sci. USA 114(15), 3939-3944,
2017 doi: 10.1073/pnas.1612943114
5. Parajuli, L. K., Tanaka, S., and S. Okabe
Insights into age-old questions of new dendritic

spines: From form to function.
Brain Research Bulletin. 129, 3-11, 2017. pii:
S0361-9230(16)30168-X.
doi:10.1016/j.brainresbull.2016.07.014.
6. Miyazaki, J., Tadatsune, I., Tanaka, S., HayashiTakagi, A., Kasai, H., Okabe, S., and T.
Kobayashi
Fast 3D visualization of endogenous brain signals
with high-sensitivity laser scanning photothermal
microscopy.
Biomedical Optics Express 7, 1702-1710, 2016.
doi: 10.1364/BOE.7.001702
7. Ochi, T., Nakatomi, H., Ito, A., Okabe, S. and N.
Saito.
Temporal Changes in the response of SVZ neuralstem cells to intraventricular administration of
growth factors.
Brain Research 1636, 119-129, 2016. doi: 10.
1016/j.brainres.2016.01.046.
8. Hayashi, A., Asanuma, D., Kamiya, M., Urano, U.
and S. Okabe.
High affinity receptor labeling based on basic
leucine zipper domain peptides conjugated with
pH-sensitive fluorescent dye: visualization of
AMPA type glutamate receptor endocytosis inliving neurons.
Neuropharmacology 100, 66-75, 2016. doi: 10.
1016/j.neuropharm.2015.07.026.

Molecular Cell Biology
2. Biochemistry and Molecular Biology

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

Lecturer
Hayashi Yamamoto, Ph.D.

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

Homepage

http://molbiol.umin.jp/

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 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,
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10began 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 (1). In autophagy,
intracellular components are sequestered by
autophagosomes and then degraded upon fusion
with lysosomes. Yeast genetic studies haveidentified more than 30 autophagy-related (ATG)

genes (2). Many of these genes are conserved inhigher eukaryotes, which allow us to performgenetic analysis of autophagy in mammals.
We are currently addressing some of thecentral 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) fusion between the
autophagosome and lysosome, and (5) recognitionof selective substrates.
In 2016, we reported the following novel
findings. Autophagy-related (ATG) conjugation
systems are thought to be important for a late stepof autophagosome formation, their precise
function has been poorly understood because they
are also required for localization of the mostimportant autophagosomal marker LC3. In ourrecent study, we found that, using the
autophagosomal SNARE syntaxin 17 as analternative marker, autophagosome-like structures
were generated in ATG conjugation systemdeficient cells. Those structures could fuse withlysosomes but the degradation of the inner
autophagosomal membrane was significantly
delayed. We suggest that the ATG conjugationdependent closure of autophagosomes causes theinner autophagosomal membrane sensitive tolysosomal degradation.
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.
In 2016, we reported a novel mouse model.
Although Atg5-null mice are neonatal lethal, we
found that these mice can be rescued byneuron-specific transgenic expression of ATG5,

11suggesting that the primary cause of lethality isneuronal dysfunction including suckling failure.
The rescued Atg5-null mouse model, as a novel
resource, allows us to investigate thephysiological roles of autophagy in the wholebody after the neonatal period. These rescued
mice demonstrate previously unappreciatedabnormalities such as hypogonadism andiron-deficiency anemia. These observations
provide new insights into the physiological rolesof the autophagy factor ATG5.
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 probe, GFP-LC3RFP-LC3ΔG, to assess autophagic flux. Upon
intracellular expression, the probe is cleaved by
ATG4 family proteases into equimolar amounts of
GFP-LC3 and RFP-LC3ΔG. The former isdegraded by autophagy while the latter persists as
an internal control in the cytosol. Autophagic flux
can thus be quantified by obtaining the ratio of
GFP:RFP signals. Using this method, we haveidentified several autophagy-modulating drugs byscreening an approved drug library. We have also
demonstrated that induced and basal autophagic
flux can be monitored in zebrafish and mice.

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. Tsuboyama, K., Koyama-Honda, I., Sakamaki, Y.,
Koike, M., Morishita, H., *Mizushima, N. The
ATG conjugation systems are important for
degradation of the inner autophagosomal
membrane. Science 354:1036-1041 (2016).

2. Kaizuka, T., Morishita, H., Hama, Y., Tsukamoto,S., Matsui, T., Toyota, Y., Kodama, A., Ishihara, T.,
Mizushima, T., *Mizushima, N. An autophagic
flux probe that releases an internal control. Mol.
Cell 64: 835-849 (2016).
3. Yoshii, S.R., Kuma, A., Akashi, T., Hara, T.,
Yamamoto, A., Kurikawa, Y., Itakura, E.,
Tsukamoto, S., Shitara, H., Eishi, Y., *Mizushima,
N. Systemic analysis of Atg5-null mice rescued
from neonatal lethality by transgenic ATG5
expression in neurons. Dev. Cell 39: 116-130(2016).
4. Wang, C., Chen, S., Yeo, S., Karsli-Uzunbas, G.,
White, E., Mizushima, N., Virgin, H.W., Guan,
J.L. Elevated p62/SQSTM1 determines the fate of
autophagy-deficient neural stem cells by
increasing superoxide. J. Cell Biol. 212: 545-60(2016).
5. Klionsky, et al. Guidelines for the use andinterpretation of assays for monitoring autophagy(3rd edition). Autophagy. 12: 1-222 (2016).
6. Noda, N.N., Mizushima, N. Atg101: not just anaccessory subunit in the autophagy-initiation
complex. Cell Struct. Funct. 41: 13-20 (2016).

12

Department of Cellular Signaling
Professor
Hiroyuki Mano, M.D., Ph.D.

Associate Professor
Yoshihiro Yamashita, M.D., Ph.D.

Assistant Professors
Manabu Soda, M.D., Ph.D., Toshihide Ueno, Ph.D.

Homepage

http://mano-lab.umin.jp/english/index.html

Introduction and Organization

Research activities

Cancer is the leading cause of adult deaths indeveloped countries. While the incidence of brainstroke– and heart attack–related deaths is rapidly
decreasing, that of cancer-related ones is still linearly
increasing today. More than eight millions of people
die of cancer every year worldwide, and, even only inJapan, >30,000 of people die of cancer.
We aim to discover essential growth driver genes
in cancer, and to develop reliable biomarkers andmolecular targeted therapies by using originalfunctional screening systems as well as genomics
approaches.
In addition to the members shown above, two
postdoctoral fellows, two research fellows, four
graduates, two undergraduates, four researchtechnicians and one secretaries belong to ourdepartment. We are also in a tight collaboration with
Department of Medical Genomics.

Department of Cellular Signaling tries to fulfill ourgoals mainly through two approaches.
(1) Functional screening with the use of retroviral
cDNA expression libraries.
The focus formation assay had been widely usedin 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, such technology is theoretically unable to capture oncogenes
whose promoter/enhancer is silent in recipient cells.
To make every gene expressed sufficiently in recipient
cells, we here developed a highly efficient
retrovirus–mediated cDNA expression library system.
Our system enables to make a library with highcomplexity (containing millions of independent cDNA
clones) even from < 104 of cells.
(2) Cancer genome resequencing
In addition to the functional screening shown
above, we also tried to search for somatically mutatedgenes 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 a cancer specimen even in private
laboratories, it is still a demanding task to conduct
full-genome sequencing for a large number of samples.
Therefore, many laboratories now purify exonic
fragments from a sample genome, and determine their

Teaching activities
We jointly take the responsibility for the lectures ofBiochemistry as well as training of biochemical
experiments. We accept students for Free Quarter andshort laboratory courses. We further deliver lecturesfor Graduate School of Medicine, and accept graduate
students.

13

sequences. However, since gene fusions usually takeplace at intronic regions, such sequencing approachwith 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 mainly use HiSeq2500 and
HiSeq2000 systems for NGS, and have developed
in-house computational pipelines for detecting
somatic single nucleotide variations, insertions/deletions, and chromosomal rearrangemetns.
By coupling such approaches, we have obtained
following findings this year.
Sequencing mRNA of leukemic blasts in acutelymphoblastic leukemia (ALL) of adolescent andyoung adult (AYA) generation revealed that the noveland most frequent oncogene, DUX4-IGH, in B-cell
ALL. Pro-B cells artificially expressing DUX4-IGH
gave rise to B-cell ALL in mice in vivo. Interestingly,
DUX4-IGH is preferentially present in the AYA
generation, less frequently in childhood ALL, butnever in adult ALL. Gene expression profiling of
DUX4-IGHpositive leukemic blasts revealed that it
resembles that of non-Ph-like ALL, indicating that
DUX4-IGH can become a biomarker for better
prognosis.

References
1) Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F,
Kojima S, Ueno T, Imoto N, Kohsaka S, Kunita A,
Doi K, Sakura T, Yujiri T, Kondo E, Fujimaki K,
Ueda Y, Aoyama Y, Ohtake S, Takita J, Sai E,
Taniwaki M, Kurokawa M, Morishita S,
Fukayama M, Kiyoi H, Miyazaki Y, Naoe T and
Mano H. “Recurrent DUX4 fusions in B cell acutelymphoblastic leukemia of adolescents and young
adults” Nat Genet 48:569-574, 2016.
2) Katsura A, Suzuki HI, Ueno T, Mihira H,
Yamazaki T, Yasuda T, Watabe T, Mano H,
Yamada Y and Miyazono K. “MicroRNA-31 is apositive modulator of endothelial-mesenchymaltransition and associated secretory phenotype
induced by TGF-beta” Genes Cells 21:99-116,
2016.

3) Fukumura K, Kawazu M, Kojima S, Ueno T, Sai
E, Soda M, Ueda H, Yasuda T, Yamaguchi H, Lee
J, Shishido-Hara Y, Sasaki A, Shirahata M,
Mishima K, Ichimura K, Mukasa A, Narita Y,
Saito N, Aburatani H, Nishikawa R, Nagane M
and Mano H. “Genomic characterization ofprimary central nervous system lymphoma” Acta
Neuropathol 131:865-875, 2016.
4) Ando M, Kawazu M, Ueno T, Koinuma D, Ando
K, Koya J, Kataoka K, Yasuda T, Yamaguchi H,
Fukumura K, Yamato A, Soda M, Sai E,
Yamashita Y, Asakage T, Miyazaki Y, Kurokawa
M, Miyazono K, Nimer SD, Yamasoba T andManoH.
“Mutational
LandscapeandAntiproliferative Functions of ELF Transcription
Factors in Human Cancer” Cancer Res 76:18141824, 2016.

14

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

Lecturer
Yukiko Kurihara, M.D.

Research Associate
Kazuo Tonami, M.D.

Associate
Yasunobu Uchijima, Ph.D.

URL http://bio.m.u-tokyo.ac.jp/home-j.html
Introduction and Organization
The Department of Physiological Chemistry andNutrition, the predecessor of the present department,
was founded in 1952. Upon the restructuring of theuniversity system in 1997, the department was
renamed ‘Department of Physiological Chemistry andMetabolism’ as one unit of the Specialty of Molecular
Cell Biology. The present members include the above
stuffs, 2 postdoctoral fellows, 3 visiting researchers,
11 graduate students (doctor course 7, master course
4), 1 technical staff and 2 secretaries. 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 an

15endothelium-derived vasoconstrictor peptide, and its
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. Maeda K, Asai R, Maruyama K, Kurihara Y,
Nakanishi T, Kurihara H, Miyagawa-Tomita S.
Postotic and preotic cranial neural crest cells
differently contribute to thyroid development. Dev.
Biol. 409(1):72-83, 2016.
2. Nishio M, Sugimachi K, Goto H, Wang J,
Morikawa T, Miyachi Y, Takano Y, Hikasa H, Itoh
T, Suzuki SO, Kurihara H, Aishima S, Leask A,
Sasaki T, Nakano T, Nishina H, Nishikawa Y,
Sekido Y, Nakao K, Shin-Ya K, Mimori K, Suzuki
A. Dysregulated YAP1/TAZ and TGF-β signaling
mediatehepatocarcinogenesis

inMob1a/1b-

deficient mice. Proc. Natl. Acad. Sci. U. S. A.
113(1):E71-80, 2016.
3. Takechi M, Kitazawa T, Hirasawa T, Hirai T, Iseki
S, Kurihara H, Kuratani S. Developmental
mechanisms of the tympanic membrane in
mammalsandnon-mammalianamniotes.

16

Congenit. Anom. (Kyoto). 56(1):12-17, 2016.
4. Miyazaki T, Tonami K, Hata S, Aiuchi T, Ohnishi
K, Lei XF, Kim-Kaneyama JR, Takeya M, Itabe H,
Sorimachi H, Kurihara H, Miyazaki A. Calpain-6
confers

atherogenicity

tomacrophagesbydysregulating pre-mRNA splicing. J. Clin. Invest.
126(9):3417-3432, 2016.
5. Hanaoka Y, Yamaguchi Y, Yamamoto H, Ishii M,
Nagase T, Kurihara H, Akishita M, Ouchi Y. In
vitro and in vivo anticancer activity of human
β-defensin-3 and its mouse homolog. Anticancer
Res. 36(11): 5999-6004, 2016.
6. Matsuya K, Yura F, Mada J, Kurihara H, Tokihiro
T. A discrete mathematical model for angiogenesis.
SIAM J. Appl. Math. 76(6):2243–2259, 2016.
7. Mada J, Matsuya K, Yura F, Kurihara H, Tokihiro
T. A Mathematical Modeling of Angiogenesis. Jpn.
Soc. Ind. Appl. Math. 26(1): 105-123, 2016.
8. Miyagawa-Tomita S, Arima Y, Kurihara H. The“cardiac neural crest” concept revisited. In:
Etiology and Morphogenesis of Congenital Heart
Disease (eds. Nakanishi T, Markwald RR,
Baldwin HS, Keller BB, Srivastava D, Yamagishi
H. Springer Japan) pp. 227-232, 2016.
9. Asai R, Arima Y, Seya D, Kim KS, Kawamura Y,
Kurihara Y, Miyagawa-Tomita S, Kurihara H.
Endothelin

receptortype

A-expressing

cell

population in the inflow tract contributes tochamber formation. In: Etiology and Morphogenesis of Congenital Heart Disease (eds.
Nakanishi T, Markwald RR, Baldwin HS, Keller
BB, Srivastava D, Yamagishi H. Springer Japan)
pp. 289-290, 2016.
10. Asai R, Haneda Y, Seya D, Arima Y, Fukuda K,
Kurihara Y, Miyagawa-Tomita S, Kurihara H.
Amniogenic somatopleure: a novel origin of
multiple cell lineages contributing to the cardiovascular system. Sci. Rep. (in press).

Functional Biology
1. Physiology

18

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

Homepage

http://www.physiol2.med.kyushu-u.ac.jp

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, Department of Molecular Biology in Graduate
School of Pharmaceutical Sciences and Department ofChemical Pharmacology in Grauate School of
Pharmaceutical Sciences. As part of a teachingactivity for the graduate students, we have anotherweekly seminar, in which the graduate students learn
how to give presentations and hold discussions anddebates.

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system.
(1) Functional columns in the cerebral cortex are
believed to be essential to process sensory informationsuch as orientation selectivity. However, neurons inrodent visual cortex are organized in a mixedsalt-and-pepper fashion for orientation selectivity. If
the connections between neurons are random,

19

information from different orientations would bemixed, and orientation selectivity would be largely
lost. Sharp orientation tuning without functional
clustering suggests the existence of specificconnections among similarly tuned excitatory neurons.
Indeed, networks of specifically connectedsubpopulation of excitatory neurons — subnetworks— have been found in rodent visual cortex, and they
are related to the orientation selectivity of theseneurons. In our lab, we examine whether adevelopmental basis exists for such subnetworks.
It has been long debated to what extent neuronal
functions are determined genetically or by postnatal
experience or neuronal activity. However, how thefunction of neurons in the cortex is influenced byprenatal development is not well understood. In theembryonic stage of cortical development, progenitor
cells in the ventricular zone produce excitatoryneurons that migrate into the cortical plate using radial
glial fibers as a scaffold. Interestingly, in the rodent
cortex, clonally related sister neurons are not tightly
packed. Instead, they are sparsely distributed throughlayers 2–6, spanning several radial minicolumns, insuch a way that sister neurons derived from a given
progenitor are separated from each other by neurons
derived from other progenitors. We wonder whether
there is any relation between the scattered progeny ofsingle progenitors and the scattered salt-and-pepper
orientation map in rodent visual cortex.
Recent studies reported that the progeny of single
progenitor cells are preferentially connected to eachother. These results suggest that clonally related
neurons may participate in specific subnetworks inadult cortex. Since cells with similar response
selectivity also have high probabilities of synaptic
connection, we hypothesize that sister cells may sharesimilar response selectivity.
We image a mouse in which all cells derived from asingle cortical progenitor are labeled. By imaging all
the upper layer cells of a single cortical clone, we
obtain a near-complete picture of the functional
properties of the cells in a cortical clone. We observethat more than half of, but not all, clonally related
cells share response selectivity, indicating that celllineage is partly responsible for the functional
properties of mature neurons.

We find that the orientation preference of sister
cells is not totally determined by clonal identity, assome sister cells show orientation preference different
from the majority of sister cells. We hypothesize thatthe preferential connectivity between sister cells
makes loose scaffolds that accept inputs from thethalamus and give rise to networks that share similarfunctional properties, such as orientation selectivity.
Clonal identity cannot be the only factor determining
the response selectivity of neurons, and othermechanisms, such as activity-dependent processes,
may influence this scaffold and determine the final
selectivity of cortical neurons in adult animals.
Our findings may explain the salt-and-pepper
functional architecture in rodent visual cortex. In mice,neurons derived from the same progenitors tend toshare orientation preference, and neurons derived
from different progenitors are spatially intermingled.
This distribution of clonally related neurons may workas the scaffold to generate the salt-and-pepper
architecture observed in rodents. If so, could lineage
also account for the architecture of the homogeneousfunctional columns observed in higher mammals, suchas carnivores and primates? The distribution of
clonally related cells seems less laterally dispersed
and more radially aligned in the monkey cortex, but
the complete picture of the progeny of single
progenitors has not yet been described. In higher
mammals, a large expansion of the subventricularzone has been reported, with each progenitor giving
rise to a very large number of neurons throughintermediate progenitors. In this scenario, individual
cortical stem cells in higher mammals may produce alarge cohort of neurons that may comprise an entire
functional column with little intermingling of neurons
derived from other clones. Alternatively, in higher
mammals, each single functional column may bederived from multiple clones, and some mechanisms
may group neighboring neurons derived from multiple
clones to give rise to their homogeneous functional
columns.
(2) Neuronal activity is important for the functional
refinement of neuronal circuits in the early visualsystem. At the level of the cerebral cortex, previous
studies have suggested that visual experience
contributes to the maintenance and reorganization of

20

orientation selectivity, but that the initial formation oforientation selectivity is independent of visualexperience.
Synchronous spontaneous activity in the developing
cortex, partly generated intracortically and partly
dependent on retinal activity, has been proposed to be
involved in the formation and maturation oforientation selectivity. This synchronous spontaneous
activity appears approximately 1 week before eye
opening and becomes sparse afterwards. The initialformation and maturation of orientation selectivity isthought to occur during the same period, and this
temporal coincidence may imply that the synchronous
spontaneous activity is involved in the formation
and/or maturation of orientation selectivity. Indeed, aprevious report showed that suppressing spontaneous
activity by infusing tetrodotoxin (a sodium channel
blocker) into the developing visual cortex of ferrets
impairs the maturation of orientation selectivity.
However, as it is technically challenging to suppress
spontaneous activity earlier than the initial formation,
its role in the initial formation of orientation
selectivity remained untested.
Recently, a genetically specified mechanism has
been proposed: cell lineage–derived microcircuit
formation is critically involved in the formation oforientation selectivity in the mouse primary visualcortex (V1). Thus, it is still unknown which of the two
mechanisms — the activity-dependent or theactivity-independent one — is more important for thedevelopment of orientation selectivity.
We use a genetic method to suppress neuronal
activity starting prenatally, which allow us, for the
first time, to investigate the contribution of neuronal
activity to the initial formation of orientation
selectivity. We observe almost normally tuned
orientation selectivity in visual cortical neurons inadults despite a strong suppression of bothspontaneous and visually evoked activity throughout
development. This finding suggests that the initialformation and maturation of orientation selectivity islargely activity independent (Hagihara et al., 2015).
(3) It has been debated whether orientation selectivity
in mouse primary visual cortex (V1) is derived fromtuned lateral geniculate nucleus (LGN) inputs orcomputed from untuned LGN inputs. However, few

studies have measured orientation tuning of LGN
axons projecting to V1. We measure the response
properties of mouse LGN axons terminating in V1 andfind that LGN axons projecting to layer 4 are
generally less tuned for orientation than axons
projecting to more superficial layers of V1. We alsofind several differences in response properties
between LGN axons and V1 neurons in layer 4. These
results suggest that orientation selectivity of mouse
V1 may not simply be inherited from LGN inputs, but
could also depend on thalamocortical or V1 circuits(Kondo and Ohki, 2016).

References(1) Matsui T, Murakami T, Ohki K. Transientneuronal coactivations embedded in globally
propagating
waves
underlie
resting-statefunctional connectivity. Proc Natl Acad Sci U S A.
(2016) 113: 6556-61.
(2) Kondo S, Yoshida T, Ohki K. Mixed functional
microarchitectures for orientation selectivity inthe mouse primary visual cortex. Nat Commun.
（2016) 7: 13210.
(3) Aihara S, Yoshida T, Hashimoto T, Ohki K. Color
Representation Is Retinotopically Biased but
Locally Intermingled in Mouse V1. Front Neural
Circuits. (2017) 11: 22.

21

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

Research Associate
Yoshito Masamizu, Ph.D.
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, 2 technical staff, 3 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, electrophysiology and cellular and molecularphysiology methods for free quarter students. The
department provides also lectures and instructions forlaboratory research for graduate and undergraduate
students in the fields of neurophysiology andmolecular and cellular imaging. Seminars, progress
reports, and journal club for graduate students areroutinely provided. Monthly joint seminars(Functional Biology Seminars) are also provided for
graduate students.

(1) Thalamocortical dynamics mediate learning andexecution of self-initiated movement.
The primary motor cortex (M1) integrates a variety of
information from other brain regions and transmits
motor commands to the spinal cord. Information fromthe basal ganglia and cerebellum, which is thought to22

be critical for motor learning and motor execution, issignaled to the M1 through the thalamus. However,
the temporal dynamics of thalamocortical neuralactivity during motor learning are poorly understood.
To address these issues, we conducted two-photon
calcium imaging in mice M1 during learning of alever-pull task (Hira et al., 2013; Masamizu andTanaka et al., 2014). We found that thalamocorticalaxonal activities in M1 evolve their specificrepresentation for movements through the learningand employ various temporal dynamics depending on
their projecting layers. The population activity of thethalamocortical axons possessed a lever-relevant
sequential structure that was longer in layer 1 than inlayer 3 of M1 in the late stage of learning. Our results
suggest that the layer 1 and layer 3 thalamocortical
dynamics are essential for motor learning andexecution.
(2)
Development ofwide-field
two-photon
microscopy for simultaneous imaging of multiple
cortical areas at cellular resolution.
Understanding the dynamics of cortico-corticalcommunications is essential because information
processing in the brain is not only performed in
intra-areal circuits but also through inter-areal
interactions. To execute voluntary movements, theinteractions between M1 and the secondary motor area(M2) and between M1 and sensory-associated areas
are crucial. Recent advances in two-photon
microscopy have allowed us to image a relatively
large area (up to 1 mm) at cellular resolution.
However, it is still difficult to image a continuous
large field (>2 mm) and two distant (>3 mm) brain
areas at cellular resolution using a single two-photon
microscope.
Wedeveloped
super-wide-field
two-photon microscopy with a single objective, whichallows the imaging of two distant (up to 6 mm apart)
cortical areas and a large continuous area (up to 3mm) at cellular resolution. The method depends on
placing a novel optical device under a high-NA
objective with a long working distance in a standard
two-photon microscope. The device is composed of apair of mirrors and a holder to rotate the mirrors
perpendicular to the optical axis. By controlling therotation timing and angle using custom-made software,

the field of view can be rapidly switched without
moving either the objective or the sample.
By rotating the mirror pair back and forth between
two angles, we conducted sequential two-photon
calcium imaging of neuronal activities in two distantareas up to 6 mm apart and at a depth of up to 800 μm
from the cortical surface. Furthermore, by stitching
the fields of view, we succeeded in imaging a 3 mm ×
1 mm continuous area. We applied it to concurrent
calcium imaging of layer 2/3 and layer 5 neurons in
M2 and M1 while the mice performed a lever-pull task.
We are analyzing how the neural activities in thesefields are coordinated during motor execution.
Importantly, the optical device together with thecontroller can be easily installed on a standard
two-photon
microscope.
Itsadaptationbyneuroscientists should open the door to the study of
information processing in brain networks at cellular
resolution.
(3) Development of two-photon calcium imaging of
the medial frontal cortex without cortical invasion.
In vivo two-photon calcium imaging is a fundamental
method for understanding the function of neuronal
circuits in living animals. The excitation light at
infrared wavelengths can penetrate brain tissue deeply,
so the excitation volume is very small (<1 μm) andphototoxicity is weak. It is currently possible toobserve the activity of multiple neurons at cellular
resolution up to ~900 µm from the cortical surface.
However, even in the mouse, there are many important
brain areas that are located deeper than this. Whenimaging neural activity from areas such as the medial
prefrontal cortex, hippocampus, and striatum,insertion of a lens or aspiration of the upper corticaltissue is necessary. We established a functional
calcium-imaging method that allows us to observe
neuronal activity at depths of 1000–1200 μm from thepia without any cortical invasion. We combined red
genetically encoded calcium indicators andtwo-photon microscopy with an excitation laser atwavelengths of >1000 nm. Using our procedure, we
detected calcium activity from layers 2/3 and 5 of M2
and from the dorsal area of the medial frontal cortex(roughly corresponding to the prelimbic area) inbehaving head-restrained mice over several days. We
found that the pattern of preparatory activity before

23

reward acquisition depended on the depth from thecortical surface. Reducing the invasiveness of
two-photon calcium imaging is an important strategy
for revealing the roles of the medial frontal cortex andother deep brain areas in behaving animals.
(4) Development of marmoset forelimb-movementtasks for two-photon Ca2+ imaging of the motor
cortex.
Recent advances in calcium imaging have revealed
cellular and subcellular mechanisms underlying avariety of brain functions in rodents, fishes, andinvertebrates. However, the calcium imaging
technique is still difficult to apply to awake
non-human primates, especially during forelimb
movement tasks, which are very useful forinvestigating the mechanisms underlying cognitive
behaviors, decision making, motor planning/execution
and motor skill learning. We have extended thetechnique of two-photon calcium imaging, which weestablished in a non-human primate, the common
marmoset, in an anesthetized state (Sadakane et al.,2015), to record neuronal activity in the cerebral
cortex of behaving marmosets.
To do so, we developed a novel lever-manipulation
device with a chair that restrains the head and body,but not forelimbs. Three marmosets were trained withthe device 10–60 min per day for 2–3 weeks. The
marmosets successfully learned a self-initiatedlever-pull task, in which the animals have to pull thelever to get a reward. The marmosets also learned avisual cued lever-pull task, in which the reward isdelivered only when the cue is presented on themonitor and the lever is pulled, with additional 1–2
weeks of the training. We conducted two-photon
calcium imaging in M1 of the marmosets during thetask, using novel marmoset-specific two-photon
microscopy, which allows us to observe any dorsal
cortical area in marmosets sitting on the chair. We
detected calcium transients responding to forelimb
movements from somata and dendrites.
Overall, these results indicate that forelimb
movement tasks for head-restrained marmosets arefeasible and that neural activities can be monitored in
the neocortex of behaving marmosets with cellularand subcellular resolution over days by two-photon
calcium imaging.

(From abstracts in the 40th Annual Meeting of theJapan Neuroscience Meeting)

References
1. Terada S, Matsubara D, Onodera K, Matsuzaki M,
Uemura T, Usui T. Neuronal processing of
noxious thermal stimuli mediated by dendritic
Ca2+ influx in Drosophila sensory neurons. eLife
5: e12959 (2016).
2. Kondo M, Kobayashi K, Ohkura M, Nakai J,
Matsuzaki M. Two-photon calcium imaging of
medial prefrontal cortex and hippocampus without
cortical invasion. bioRxiv doi: https://doi.org/10.
1101/119404 (2017).

24

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

Research Associate
Naofumi Uesaka, Ph.D.
Yuki Hashimotodani, 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
5 faculty members (professor, 3 research associate,
project research associate), 3 postdoctoral fellows, 12
graduate students, 4 undergraduate students and 5
technicians. We teach neurophysiology for medical
undergraduates and for students in the Master andPh.D. courses. Our research aims at elucidating
cellular and molecular mechanisms underlying
regulation of synaptic transmission and postnatal
development of neuronal circuits.

Teaching activities
We
teachneurophysiology
formedicalundergraduates in lectures and practical courses.
Lectures are designed for students to learn basic
mechanisms underlying the generation of electricalsignals, 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 approaches including electrophysiology, pharmacology,
morphology, and genetic engineering of mouse. We

25particularly 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) Kinoshita K, Takahashi H, Hata Y, Nishide K,
Kato M, Fujita H, Yoshida S, Murai K, Mizumaki
K, Nishida K, Yamaguchi Y, Kano M, Tabata T,

Nishida N: SCN5A(K817E), a novel Brugada
syndrome-associated mutation that alters theactivation gating of NaV1.5 channel. Heart
Rhythm 13:1113-1120, 2016 May; (doi:
10.1016/j.hrthm.2016.01.008) (Epub 2016 Jan 8)(2) Matsuda K, Budisantoso T, Mitakidis N, Sugaya Y,
Miura E, Kakegawa W, Yamasaki M, Konno K,
Uchigashima M, Abe M, Watanabe I, Kano M,
Watanabe M, Sakimura K, Radu Aricescu A,
Yuzaki M: Transsynaptic Modulation of Kainate
Receptor Functions by C1q-like Proteins. Neuron
90:752-767, 2016 May 18 (doi: 10.1016/j.neuron.
2016.04.001) (Epub 2016 Apr 28)(3) Matsumoto-Makidono Y, Nakayama H, Yamasaki
M, Miyazaki T, Kobayashi K, Watanabe M, Kano
M, Sakimura K, Hashimoto K: Ionic basis formembrane potential resonance in neurons of theinferior olive. Cell Rep 16: 994-1004, 2016
(DOI:http://dx.doi.org/10.1016/j.celrep.2016.06.0
53) (Epub 2016 July 14)(4) Sugaya Y, Yamazaki M, Uchigashima M,
Kobayashi K, Watanabe M, Sakimura K, Kano M:
Crucial
roles
of
the
endocannabinoid
2-arachidonoylglycerol in the suppression of
epileptic seizures. Cell Rep 16: 1405-1415, 2016
(DOI: http://dx.doi.org/10.1016/j.celrep.2016.06.
083) (Epub 2016 July 21)(5) Narushima M, Uchigashima M, Yagasaki Y,
Harada T, Nagumo Y, Uesaka N, Hashimoto K,
Aiba A, Watanabe M, Miyata M, Kano M: The
metabotropic glutamate receptor subtype 1
mediates experience-dependent maintenance of
mature synaptic connectivity in the visualthalamus. Neuron 91: 1097-1109, 2016 (DOI: 10.
1016/j.neuron.2016.07.035)(6) Dhar M, Brenner JM, Sakimura K, Kano M,
Nishiyama H: Spatiotemporal dynamics oflesion-induced axonal sprouting and its relation tofunctional architecture of the cerebellum. Nat
Commun 7: Article number 12938, 2016 (DOI:
10.1038/ncomms12938)(7) Binda F, Dorgans K, Reibel S, Sakimura K, Kano
M, Poulain B, Isope P: Inhibition promotes
long-term potentiation at cerebellar excitatory
synapses. Sci Rep 6: Article number: 33561, 2016
(doi:10.1038/srep33561)(8) Jung D, Hwang YJ, Ryu H, Kano M, Sakimura K,

26

Cho J: Conditional knockout of Cav2.1 disrupts
the accuracy of spatial recognition of CA1 place
cells and spatial/contextual recognition behavior.
Front. Behav. Neurosci 10: Article 214, 2016
(doi.org/10.3389/fnbeh.2016.00214)(9) Piochon C, Kano M, Hansel C: LTD-likemolecular pathways in developmental synaptic
pruning. Nat Neurosci 19: 1299-1310, 2016
(doi:10.1038/nn.4389)

Functional Biology
2. Pharmacology

28

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

Lecturer
Yohei Okubo, Ph. D.

Research Associate
Kazunori Kanemaru, Ph. D.,

Homepage

Hiroshi Sekiya, M.D.

http://calcium.cmp.m.u-tokyo.ac.jp/index-e.html

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
Our department has a strong background in the fieldof Ca2+ signalling. Ca2+ signal is now known tofunction as a molecular switch in almost every
important cell function including muscle contraction,
exocytosis, cell proliferation, immune responses andregulation of synaptic functions. This is the reason

why this field is expanding rapidly and our research
activity is now diversifying. We are particularlyinterested in Ca2+ signalling in the central nervous
system.
1) Spatiotemporal regulation of Ca2+ signals
Ca2+ signals show very dynamic, temporal andspatial changes within the cell. This property
allows the Ca2+ signal to be an extremely versatile
cellular switch regulating diverse cell functions.
One of the most notable spatiotemporal patterns of
Ca2+ signals is the oscillatory change inintracellular Ca2+ concentration ([Ca2+]i), or Ca2+
oscillation. Many cellular functions are regulatedby the Ca2+ oscillation frequency. However,fundamental questions remain. How and why does
[Ca2+]i oscillate? We have addressed thesequestions. First, we studied inositol 1,4,5trisphosphate (IP3)-induced Ca2+ release mechanism, which is one of the most important Ca2+
mobilizing mechanisms in many types of cell. We
showed that the activity of the IP3 receptor (IP3R)
is dependent on the cytoplasmic Ca2+ concentration. Therefore, Ca2+ release via the IP3R appears
to be under the feedback control of mobilized Ca2+.
We identified the Ca2+ sensor region of the IP3R
and showed that the positive feedback regulationof IP3R via the Ca2+ sensor of IP3R indeed plays

29

an essential role in regulating the Ca2+ signal
dynamics including Ca2+ oscillation.
In order to further study the mechanism
underlying Ca2+ oscillation, we visualized the Ca2+
concentrations within the intracellular organelles(both endoplasmic reticulum and mitochondria)
during Ca2+ oscillations. We found that Ca2+
shuttles between these intracellular organelles inphase with cytoplasmic Ca2+ oscillations. Our
results also indicated that the Ca2+ shuttlingdetermines the Ca2+ oscillation frequency. Thus,
we have shown that mitochondria play animportant role in the generation of Ca2+ oscillation.
These results provide a clue to the mechanism of
Ca2+ oscillation.
Furthermore, we recently generated a family ofgenetically-encoded Ca2+ indicators named CEPIA(for Calcium-measuring organelle-Entrapped
Protein IndicAtors). CEPIA can be used to image
ER and mitochondrial Ca2+ dynamics simultaneously with cytosolic Ca2+ concentration and othercellular processes at high spatiotemporal resolution.
Why then does [Ca2+]i have to oscillate?
Transcription by the nuclear factor of activated T
cells (NFAT) is one of the important cellularfunctions that are regulated by the Ca2+ oscillation
frequency. NFAT is dephosphorylated by Ca2+dependent phosphatase, calcineurin, and translocates from the cytoplasm to the nucleus toinitiate transcription. We analyzed the kinetics ofthe dephosphorylation and translocation of NFAT,
and found that the dephosphorylated form of
NFAT functions as a working memory of transient
increases in [Ca2+]i. With increasing frequency of
Ca2+ oscillation, dephosphorylated NFAT accumulates in the cytoplasm to enhance its nuclear
translocation. This is the molecular basis of themechanism that decodes the Ca2+ oscillation
frequency. We also showed that Ca2+ oscillation ismore cost-effective in regulating cell functions
than a continuous increase in Ca2+. These studies
provide us with an insight into the secrets of Ca2+
signalling.
2)

Imaging of signalling molecules
Our study on Ca2+ signalling made us realize theimportance of visualization of signalling molecules within living cells. Thus, our laboratory has
been involved in the generation of new indicatorsof signalling molecules upstream and downstream
Ca2+ signals. We have succeeded in imaging IP3
signalling in various cells including intact neurons
within cerebellar slice preparations. We also
developed an indicator to detect the phosphorylation of myosin regulatory light chain. The
indicator allowed us to image phosphorylation
state of myosin light chain in living cells.
Furthermore, we generated a nitric oxide (NO)indicator based on the heme-binding domain ofsoluble guanylyl cyclase. This indicator was
successfully used in cerebellar slice preparations
to image NO signals in response to parallel fiber(PF) stimulation. We found that the NO signal
intensity decreases steeply with distance form theactivated synapse and generate synapse-specificlong-term potentiation (LTP) of PF-Purkinje cell
synapses. We also showed that the NO signal
intensity depends biphasically on the frequency of
PF stimulation. Importantly, the LTP depends
similarly on the frequency of PF stimulation. Thus,
our NO indicator provided us with valuable
information regarding the role of NO signals in thecentral nervous system.
Glutamate is the most important excitatory
synaptic transmitter in the brain. We havegenerated a glutamate indicator based on theglutamate-binding domain of the AMPA-typeglutamate receptor. Using this fluorescentglutamate indicator, we have succeeded in imaging
spatiotemporal dynamics of glutamate in theextrasynaptic space in brain slices. This study
demonstrated that bursting synaptic activities
cause glutamate spillover from the synaptic cleft
to activate perisynaptic metabotropic glutamate
receptors, and will provide a basis for the researchof extrasynaptic glutamate transmission that is
involved in many important brain functions.
3) Exploration of previously unrecognized cellularfunctions that are regulated by Ca2+ signals
Although many important cell functions havebeen found to be regulated by Ca2+ signals, not all
the Ca2+-dependent cell functions have been30

identified. We are now searching for new cellfunctions that are regulated by Ca2+ signals.
Cells communicate with each other to form
organized structures by cell-cell adhesion andcell-cell repulsion, but it remains to be clarified
how cell-cell contact information is converted to
intracellular signals. We found that cells in contact
with neighbouring cells generate local transient
intracellular Ca2+ signals (Ca2+ lightning). Ca2+
lightning was exclusively observed near cell-cell
contact regions and was not observed in the central
regions of cells, nor was it found in solitary cells
that are not in contact with other cells. We also
show that Ca2+ lightning is capable of regulatingcell-cell repulsion in a Ca2+-dependent manner.
These results demonstrated that cell-cell contact
information may be transmitted by a new form of
Ca2+ signal, Ca2+ lightning, to regulate intracellular events.
We also clarified a new synaptic maintenancemechanism in the parallel fiber→Purkinje cell
synapse in the cerebellum. We have found that
there is a retrograde signaling mechanism
downstream of metabotropic glutamate receptormediated IP3-Ca2+ signaling in Purkinje cells,
which then generates BDNF (brain-derived
neurotrophic factor) that maintains the glutamaterelease function of the presynaptic terminal ofparallel fibers. This presents a new form ofactivity-dependent synaptic maintenance mechanism.
We have studied the role of IP3-Ca2+ signaling
in astrocytes (the most abundant glial cells) andfound that it regulates the expression of moleculeson the surface of astrocytes that regulate thegrowth of neurons. Our results indicate thatN-cadherin is involved in the regulation of neural
growth in vitro. Furthermore, we recently showedthat IP3-Ca2+ signaling in cerebellar astrocytes(Bergmann glia) regulates glutamate transporter
levels in Bergman glial cells to maintain glutamate
clearance in the mature cerebellum.
In response to brain injury, astrocytes undergo
structural and functional changes (reactive
astrogliosis). We showed that injury-induced Ca2+
responses in astrocytes are important for reactive
astrogliosis and also for neuroprotection. We

studied the molecular mechanism involved in thisreaction, and found that a translational repressor
Pum2 is downregulated in a Ca2+-dependent
manner. We also identified that N-cadherin
mRNA is one of the target mRNAs of Pum2. Thus,
Pum2 down-regulation induces reciprocal upregulation of N-cadherin after brain injury. When
the N-cadherin gene is disrupted in astrocytes,
injury-induced astrogliosis and neuroprotection
were attenuated. These results clarified themolecular events that are responsible for the
astrogliosis and neuroprotection following brain
injury.
We have identified a new NO-dependent Ca2+
signaling mechanism in central neurons. We foundthat synaptically released NO S-nitrosylates theryanodine receptor (RyR) to activate Ca2+ releasethrough the Ca2+ release channel, which we referto as NO-induced Ca2+ release (NICR). NICR isrequired for the NO-dependent LTP at the parallel
fiber-Purkinje cell synapse described above.
Furthermore, NICR has a pathophysiological role,and seems to play an important role in NOdependent neuronal cell death after brain ischemia.
This finding suggests that NICR can be a therapeutic target in certain forms of ischemic brain
diseases.
We have made it possible to image Ca2+ signals
in the fine processes of individual astrocytes invivo using transgenic mice that express anultrasensitive genetically encoded Ca2+ indicator,
YC-Nano50, in an astrocyte-specific manner. Thismethod allowed us to find a previously
unidentified mode of spontaneous astrocytic Ca2+
signals, Ca2+ twinkles, which are preferentiallydisplayed in fine astrocytic processes in living
mice brain. Moreover, a highly sensitive nature ofastrocytic fine processes as a sensitive detector ofneuronal activity was also revealed.

References
1. Mikami, Y., Kanemaru, K., Okubo, Y., Nakaune,T., Suzuki, J., Shibata, K., Sugiyama, H., Koyama,R., Murayama, T., Ito, A., Yamazawa, T., Ikegaya,
Y., Sakurai, T., Saito, N., Kakizawa, S., Iino, M.
Nitric oxide-induced activation of the type 1

31

ryanodine receptor is critical for epileptic
seizure-induced
neuronalcelldeath.
EBioMedicine 11, 253-261, 2016.
2. Kubota, J., Mikami, Y., Kanemaru, K., Sekiya, H.,
Okubo, Y., Iino, M. Whisker experiencedependent mGluR signaling maintains synaptic
strength in the mouse adolescent cortex. Eur. J.
Neurosci. 44, 2004-2014, 2016.

32

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

Lecturer
Kazuki Tainaka, Ph.D. (until Dec.31th), Etsuo A. Susaki, M.D., Ph.D. (from Jan. 1st)

Associate
Koji L. Ode, 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 some 39 lectures per year including
those given by six invited lectures to cover specialized
and currently highlighted fields in pharmacology. We
offer several laboratory courses, and all the membersof the Department participate in the courses to provide
close consultation for the students.
For the graduate students, there are series ofseminars on physiology and neuroscience. We also
have research seminars to discuss and stimulate theresearch activities of the graduate students in the
Department.

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(typically blastocysts) to generate chimera micecomprising a mixture of ES- and host-derived cells. In

33addition, 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 and used for thefollowing experiments. Using this method, multiple
rescue experiments on a circadian clock geneknockout mice (Cry1, Cry2 double-KO mice) were
performed regarding over 20 strains, leading to thediscovery of important phosphorylation sites andprotein structures of the molecule (Ode et al.,
Molecular Cell 2017). Through these experiments, we
showed the efficiency and throughput of theestablished method which facilitates to create
genetically modified mice in just about three months
and use them for subsequent analyses (Susaki et al.
npj Systems Biology and Applications, 2017).
2) System-level identification and analysis of cellular
circuits in the whole-organ and whole-body
The comprehensive identification of molecular
circuits at the organism level also requires accurate(>90%) phenotype analysis. In neuroscience, sleep/
wake behavior is an intriguing phenotype, because
sleep disorders (e.g., insomnia or hypersomnia) are
sensitive and informative symptoms of almost all
psychological disorders. Sleep/wake states have beencharacterized in humans by electroencephalography(EEG) and electromyography (EMG). Characteristic
EEG/EMG patterns during sleep and waking arepreserved in mammals and can be measured byelectrodes surgically implanted in the brain andmuscles. However, such recording requires special
surgical skills, and the surgery is highly invasive,
requiring a long recovery period (more than 10 days)
after implantation before sleep/wake recording.
Furthermore, the EEG/EMG data are often manuallyannotated and classified into sleep/wake phenotypes
by visual assessment, which can be time consuming
and somewhat subjective. Therefore, sleep/wakephenotyping has been a low-throughput method; forcomprehensive 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 automatedsystem, 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 Imaging Cocktails and Computational Analysis),published in Cell, 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; Susaki et al., 2015; Kubota et al. Cell
Reports 2017; Nojima et al. Scientific Reports 2017).
CUBIC provides information on previously
unattainable 3D gene expression profiles and neural34

networks at the systems level. Because of its rapid andhigh-throughput imaging, CUBIC offers extraordinary
opportunity to analyze localized effects of genomic
editing. It also is expected to identify neuralconnections at the whole brain level.
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, we discoverthat Ca2+-dependent neuronal hyperpolarization pathway affects sleep duration in mammals (Sunagawa etal., Cell Reports 2016; Tatsuki et al., Neuron 2016).
We first focused on the firing pattern of cortex
neuron, characterized by alternating bursting andsilent phases. This pattern is the basis of slow-wave
oscillation observed in EEG recording duringslow-wave sleep. We created a computational modelthat simulates the membrane potential of cortex
neuron regulated by a group of ion channels, andfound that Ca2+ influx into neuron and resultant
activation of Ca2+-dependent K+ channel is critical forthe emergence of alternating bursting and silent
phases.
For the experimental verification of this prediction,
we created a series of knock-out mice using thetriple-CRISPR method and analyzed their sleep
phenotype by SSS. We found that knocking out offollowing ion channels results in significant shortsleep duration; Cacna1g, Cacna1h (voltage-dependentcalcium channel), Kcnn2, Kcnn3 (calcium-dependent
potassium channel), Nr3a (NMDA receptor). On theother hand Atp2b3 (plasma membrane calciumtransporting ATPase) knock-out mice showed
increased sleep duration. Overall, these results suggestthat pathways for calcium influx and calciumdependent channels/kinases contribute to increase

sleep duration, while the antagonizing calcium export
pathway contributes to decrease sleep duration.
We further verified the role of NMDA receptors bypharmacological inhibition of the receptor, because
the knocking out of some NMDA receptor subtypes(Nr1 or Nr2b) leads to embryonic lethality. As
expected, administration of NMDA receptor
antagonist shortens the sleep duration. We thenobserved an expression-pattern of marker protein forneuronal excitability in a whole-brain scale with the
CUBIC method, and revealed that the antagonist
administration resulted in the elevated excitability ofcortex pyramidal neurons. This observation consistent
with our hypothesis that Ca2+ influx reduces theexcitability of cortex neuron through the hyper
polarization of membrane potential.
Given these results showing the role of Ca2+ forsleep control, our next challenge is to investigate
molecules that regulate the transition between sleep
and awake phases. We focused on CaMKII(calcium/calmodulin-dependent protein kinase II),protein kinases important for the post-translational
regulation of several neuronal channels. We found thatCamk2a or Camk2b knock-out mice exhibit abnormal
sleep phenotype. These kinases may play an importantrole for the transition between neural activities, whichhappen during milliseconds to seconds, and exchangeof sleep/awake states, which occurs in a time scale ofminutes to hours (Tatsuki et al., Neurosci. Res. 2017;
Ode et al., Curr. Opin. Neurobiol. 2017).
We further revealed the mechanism of temperaturecompensation in circadian clock. The biological clock
regulates 24h animal behavior including sleep andwake. We investigate biochemical mechanisms
underlying
temperature-compensated,
CKIδdependent multi-site phosphorylation in mammals. We
identify two mechanisms for temperature-insensitive
phosphorylation at higher temperature: lower substrateaffinity to CKIδ-ATP complex and higher productaffinity to CKIδ-ADP complex. Our findings suggest
thetemperature-sensitive
substrateandproduct-binding mechanisms underlie temperaturecompensation of circadian clock.
Considering that numbers of researches encompass
model mice for sleep, circadian rhythm and relateddisorders, we envisage that our technologies andresearch outcomes will contribute the understanding

35

of such disorders including psychiatric disorders andneurodegenerative disorders.

References
1. Shinohara Y., Koyama Y.M., Ukai-Tadenuma M.,
Hirokawa T., Kikuchi M., Yamada R.G., Ukai H.,
Fujishima H., Umehara T., Tainaka K., Ueda H.R.
Temperature-Sensitive Substrate and ProductBinding Underlie Temperature- CompensatedPhosphorylation in the Clock. Mol. Cell
2017:67:783–798.
2. Nojima S., Susaki E.A., Yoshida K., Takemoto H.,
Tsujimura N., Iijima S., Takachi K., Nakahara Y.,
Tahara S., Ohshima K., Kurashige M., Hori Y.,
Wada N., Ikeda J., Kumanogoh A., Morii E., Ueda
H.R. CUBIC pathology: three-dimensional
imaging for pathological diagnosis. Sci. Rep.
2017:7:9269.
3. Kubota S.I., Takahashi K., Nishida J., MorishitaY., Ehata S., Tainaka K., Miyazono K., Ueda H.R.
Whole-Body Profiling of Cancer Metastasis with
Single-Cell Resolution. Cell Rep. 2017:20: 236250.
4. Susaki E.A., Ukai H., Ueda H.R. Next-generation
mammalian genetics toward organism-levelsystems biology. npj Syst. Biol. Appl. 2017:3:15.
5. Ode K.L., Katsumata T., Tone D., Ueda H.R. Fastand slow Ca2+-dependent hyperpolarization
mechanisms connect membrane potential andsleep homeostasis. Curr. Opin. Neurobiol. 2017:44:212-221.
6. Sugai S.S., Ode K.L., Ueda H.R. A designprinciple for an autonomous post-translational
pattern formation. Cell Rep. 2017:19:863-874.
7. Tatsuki F., Ode K.L., Ueda H.R. Ca2+-dependent
Hyperpolarization Hypothesis for Mammalian
Sleep. Neurosci. Res. 2017:118:48-55.
8. Ode K.L., Ukai H., Susaki E.A., Narumi R.,
Matsumoto K., Hara J., Koide N., Abe T.,
Kanemaki M.T., Kiyonari H., Ueda H.R.
Knockout-rescue embryonic stem cell-derived
mouse reveals circadian-period control by quality
and quantity of CRY1. Mol. Cell 2017:65:
176-190.

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.

Teppei Morikawa, M.D., Ph.D.

Takeshi Sasaki, M.D., Ph.D. (Chief, Telepathology & Remote Diagnosis Promotion Center)*

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

Associates
Akiko Kunita, Ph.D.,

Mariko Tanaka, M.D., Ph.D.,

Zen-ichi Tanei, M.D., Ph.D.
Yukako Shintani, M.D., Ph.D. *,Shigeki Morita, M.D., Ph.D.*,

Hiroyuki Abe, M.D., Ph.D.*,

Akimasa Hayashi, M.D., Ph.D.*,

Atsushi Tanaka, M.D., Ph.D.*
Ryu Miyagawa, Ph.D.* (Research, Investigation of Health Hazard by Radiation)

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. Shibahara moved as thechairman and professor to Department of Pathology,
Kyorin University, School of Medicine. Lecturer Dr.

Morikawa was promoted to the associate professor,
and lecturer (Hospital) Dr. Aya Ushiku to the lecturer*,
respectively. Dr. Atsushi Tanaka and Dr. Zen-ichi
Tanei were now Associates.
Three postgraduate students (Saito, Hinata,
Mine) finished the course and received Ph.D. In the
new fiscal year, 2017, six new students will enter the
postgraduate course, and there will be 21
postgraduates.
We are responsible for the pathology practice of
the University Hospital, and are carrying forward themorphology-based research targeting human diseases.

38

As for the education of the medical students, we takecharge of the following courses; General Pathology
Course for the 1st grade students in collaboration with
Department of Molecular Pathology, Systemic
Pathology for the 2nd grade, Elective ClinicalClerkship for the 3rd grade, and Clinical Clerkship forthe 4th grade students. Programs for postgraduates andjunior residents are also included in our education
activities.
To promote genomic medicine in clinical care,
we set up Center for Genome Pathology
Standardization (assisted by Japan Agency for
Medical Research and Development). The mission of
the Center is to investigate basic technologies fortissue banking, and to hold seminars for doctors andtechnicians (see the section of Diagnostic Pathology
Division). Clinical Genome Conference started in the
University of Tokyo Hospital for the application ofcancer clinical sequencing to medical practice as a
research project of genome medicine (Project
organizer: Prof. Hiroyuki Mano).
We will join the research project of JapaneseSociety of Pathology “Database of Pathology-Whole
Slide Image (WSI) for Development of Artificial
Intelligence (AI) Technique and AI-based Support
System for Pathology Diagnosis” in 2017.

Clinical activities (diagnostic
pathology and autopsy)
Together with Division of Diagnostic Pathology, we
are responsible for the pathologic diagnosis andautopsy in the University Hospital. We set up
Telepathology & Remote Diagnosis Promotion Center(TRD-PC), and started Outpatient Clinic of Pathology(see the corresponding section of Division of
Diagnostic Pathology).
Surgical pathology conferences are regularly heldwith each clinical division, and the cases of various
tumors are discussed, including thoracic organs, liverand pancreato-biliary tract, urology, gynecology,
breast, and orthopedics, as well as biopsy cases ofkidney, and skin.
Clinico-pathological conferences (CPCs) for two
autopsy cases are held every month in the hospital.
Both CPCs and weekly autopsy conferences are usefulfor the education of clinical residents. Digest versionsof CPC slides are now open in the hospital (Drs.
Shintani and Hayashi), and we also started e-learning
programs for clinical residents to facilitate theunderstanding of the CPC contents (Dr. Ikemura). Allof residents were obligated to take the course for theirtraining once a year.
A model project for the survey analysis of deaths
related to medical treatment (DRMT) started from
September 2005, and finished at the end of 2015 fiscal
A new system for evaluation of deaths related to
medical treatment (DRMT) started from October,
2016.

Teaching activities
We take on General Pathology Course for the 1st gradeof undergraduate students, especially in its morphological 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 pathological exercises, and all slides
used in the course are accessible on our website as
virtual slides (digital images of the slides).
In Clinical Clerkship for 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.
Four students chose the clinical clerkship courserdfor 3 grade medical students. As for the free quarter
program, we received two and five students of M0 and
M1, respectively, 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/Raiology/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. Kunita,
Shinozaki-Ushiku and Abe). We focused on the
immune-escape mechanism of EBV-associated GC

39

this year (ref.1,7). We revealed that PD-L1 isfrequently
expressedincancercells
ofEBV-associated GC (ref.30). Furthermore, gene
amplification of PD-L1 occurs in some of them. We
investigated the relationship of H. pylori infection(ref.31) and molecular mechanism of epigenetic
abnormalities (ref.24) in this specific type of gastriccancer.
The second major theme is ‘translational researchpathology’. We are engaged in search of target
molecules for cancer therapy by global analysis ofvarious cancers, in collaboration with Research Center
for Advanced Science and Technology (RCAST) (Drs.
Ushiku and Morikawa) (ref.20,22). We developed a
new diagnostic technique (ref.21) and evaluatedtherapeutic effect (ref.43) for the molecular target
therapy.
The third theme is to re-evaluate the disease
entities and tumor entities from the standpoint ofhistopathology. Dr. Sibahara proposed Type 1/2
system for the classification of intrahepaticcholangiocarcinoma (ref.4-6), and reassessed thesubset of hepatocellular carcinoma (ref.33). We also
performed investigation of gastric cancers (ref.29, 43),
brain tumor (ref.10) and leukemia (ref.45).

References(including those of Diagnostic Pathology Division)
Case reports are listed in the section of Diagnostic
Pathology Division.
(1) Abe H, Morikawa T, Saito R, Yamashita H, Seto
Y, Fukayama M. In Epstein-Barr virus-associatedgastric
carcinomaahighdensityof
CD66b-positive tumor-associated neutrophils is
associated with intestinal- type histology and low
frequency of lymph node metastasis. VirchowsArch. 2016, 468(5), 539-48.
(2) Akiyama Y, Morikawa T, Maeda D, Shintani Y,
Niimi A, Nomiya A, Nakayama A, Igawa Y,
Fukayama M, Homma Y. Increased CXCR3
expression of infiltrating plasma cells in Hunnertype interstitial cystitis. Sci Rep. 2016, 6, 28652(3) Asada-Hirayama I, Kodashima S, Sakaguchi Y,
Ono S, Niimi K, Mochizuki S, Tsuji Y, Minatsuki
C, Shichijo S, Matsuzaka K, Ushiku T, Fukayama
M, Yamamichi N, Fujishiro M, Koike K.

Magnifying endoscopy with narrow-band
imaging is more accurate for determination ofhorizontal extent of early gastric cancers thanchromoendoscopy. Endosc Int Open. 2016, 4(6),E690-8.
(4) Hayashi A, Misumi K, Shibahara J, Arita J,
Sakamoto Y, Hasegawa K, Kokudo N, Fukayama
M. Distinct Clinicopathologic and Genetic
Features of 2 Histologic Subtypes of Intrahepatic
Cholangio- carcinoma. Am J Surg Pathol. 2016,40(8), 1021-30.
(5) Hayashi A, Misumi K, Shibahara J, Kokudo N,
Kato Y, Fukayama M. Immunohistochemistry
using monoclonal antibody MsMab-2 is useful todetect
IDH1
R132L
in
intrahepaticcholangiocarcinoma. Pathol Int. 2016, 66(10),578-582.
(6) Hayashi A, Shibahara J, Misumi K, Arita J,
Sakamoto Y, Hasegawa K, Kokudo N, Fukayama
M. Histologic Assessment of Intratumoral
Lymphoplasmacytic Infiltration Is Useful in
Predicting
PrognosisofPatients
with
Hepatocellular Carcinoma. PLoS One. 2016,
11(5), e0155744(7) Ichimura T, Abe H, Morikawa T, Yamashita H,
Ishikawa S, Ushiku T, Seto Y, Fukayama M. Low
densityof
CD204-positive
M2-typetumor-associated macrophages in Epstein-Barrvirus- associated gastric cancer: a clinicpathologic study with digital image analysis.
Hum Pathol. 2016, 56, 74-80.
(8) Ichinose J, Shinozaki-Ushiku A, Nagayama K,
Nitadori J, Anraku M, Fukayama M, Nakajima J,
Takai D. Immuno- histochemical pattern analysis
of squamous cell carcinoma: Lung primary andmetastatic tumors of head and neck. Lung Cancer.
2016, 100, 96-101.
(9) Ichinose J, Shinozaki-Ushiku A, Takai D,
Fukayama M, Nakajima J. Differential diagnosis
between primary lung squamous cell carcinoma
and pulmonary metastasis of head and necksquamous cell carcinoma. Review. Expert Rev
Anticancer Ther. 2016, 16(4), 403-10.
(10) Ikemura M, Shibahara J, Mukasa A, Takayanagi S,
Aihara K, Saito N, Aburatani H, Fukayama M.
Utility of ATRX immunohistochemistry indiagnosisof
adult
diffusegliomas.

40

Histopathology. 2016, 69(2), 260-7.
(11) Ishikawa R, Amano Y, Kawakami M, Sunohara M,
Watanabe K, Kage H, Ohishi N, Yatomi Y,
Nakajima J, Fukayama M, Nagase T, Takai D.
The chimeric transcript RUNX1-GLRX5: abiomarker for good postoperative prognosis inStage IA non-small-cell lung cancer. Jpn J Clin
Oncol. 2016, 46(2), 185-9.
(12) Ishiwatari H, Hayashi T, Kawakami H, Isayama
H, Hisai H, Itoi T, Ono M, Kawakubo K,
Yamamoto N, Tanaka M, Itokawa F, Oshiro H,
Sonoda T, Hasegawa T; Japan EZ Port Study
Group. Randomized trial comparing a side-port
needle and standard needle for EUS-guided
histology of pancreatic lesions. Gastrointest
Endosc. 2016, 84(4), 670-8.
(13) Ito T, Matsubara D, Tanaka I, Makiya K, Tanei ZI,
Kumagai Y, Shiu SJ, Nakaoka HJ, Ishikawa S,
Isagawa T, Morikawa T, Shinozaki-Ushiku A,
Goto Y, Nakano T, Tsuchiya T, Tsubochi H,
Komura D, Aburatani H, Dobashi Y, Nakajima J,
Endo S, Fukayama M, Sekido Y, Niki T,
Murakami Y. Loss of YAP1 defines
neuroendocrine differentiation of lung tumors.
Cancer Sci. 2016, 107(10), 1527-1538.
(14) Kasuga J, Kawahara T, Takamoto D, Fukui S,
Tokita T, Tadenuma T, Narahara M, Fusayasu S,
Terao H, Izumi K, Ito H, Hattori Y, Teranishi J,
Sasaki T, Makiyama K, Miyoshi Y, Yao M,
Yumura Y, Miyamoto H, Uemura H. Increased
neutrophil-to- lymphocyte ratio is associated withdisease-specific mortality in patients with penile
cancer. BMC Cancer. 2016, 16, 396-402.
(15) Kishikawa J, Kazama S, Oba K, Hasegawa K,
Anzai H, Harada Y, Abe H, Matsusaka K, Hongo
K, Oba M, Yasuda K, Otani K, Nishikawa T,
Tanaka T, Tanaka J, Kiyomatsu T, Hata K, Kawai
K, Nozawa H, Yamaguchi H, Ishihara S, Sunami
E, Ushiku T, Kitayama J, Fukayama M, Kokudo
N, Watanabe T. CD133 Expression at theMetastatic Site Predicts Patients' Outcome inColorectal Cancer with Synchronous Liver
Metastasis. Ann Surg Oncol. 2016, 23(6),1916-23.
(16) Kida K, Ishikawa T, Yamada A, Shimada K,
Narui K, Sugae S, Shimizu D, Tanabe M, Sasaki
T, Ichikawa Y, Endo I. Effect of ALDH1 on

prognosis and chemoresistance by breast cancer
subtype. Breast Cancer Res Treat. 2016, 156(2),261-9.
(17) Kobayashi R, Miyagawa R, Yamashita H,
Morikawa T, Okuma K, Fukayama M, Ohtomo K,
Nakagawa K. Increased expression of longnon-coding RNA XIST predicts favorable
prognosis of cervical squamous cell carcinoma
subsequent to definitive chemoradiation therapy.
Oncol Lett. 2016, 12(5), 3066-74.
(18) Komura D, Isagawa T, Kishi K, Suzuki R, Sato R,
Tanaka M, Katoh H, Yamamoto S, Tatsuno K,
Fukayama M, Aburatani H, Ishikawa S. CASTIN:
a system for comprehensive analysis ofcancer-stromal interactome. BMC Genomics.
2016, 17(1), 899.
(19) Kondoh H, Nishiyama T, Kikuchi Y, Fukayama M,
Saito M, Kii I, Kudo A. Periostin deficiency
causes severe and lethal lung injury in mice withbleomycin administration. J Histochem Cytochem.
2016, 64(7), 441-53.
(20) Makise N, Morikawa T, Nakagawa T, Ichimura T,
Kawai T, Matsushita H, Kakimi K, Kume H,
Homma Y, Fukayama M. MAGE-A expression,
immune microenvironment, and prognosis inupper urinary tract carcinoma. Hum Pathol. 2016,
50, 62-9.
(21) Matsusaka K, Ishikawa S, Nakayama A, Ushiku T,
Nishimoto A, Urabe M, Kaneko N, Kunita A,
Kaneda A, Aburatani H, Fujishiro M, Seto Y,
Fukayama M. Tumor Content Chart-Assisted
HER2/CEP17 Digital PCR Analysis of Gastric
Cancer Biopsy Specimens. PLoS One. 2016,
11(4), e0154430.
(22) Matsusaka K, Ushiku T, Urabe M, Fukuyo M,
Abe H, Ishikawa S, Seto Y, Aburatani H,
Hamakubo T, Kaneda A, Fukayama M. Coupling
CDH17 and CLDN18 markers for comprehensive
membrane-targeted detection of human gastriccancer. Oncotarget. 2016, 7(39), 64168-64181.
(23) Matsuo K, Sasaki T (19th of 72), et al.
Significance of histologic pattern of carcinoma
and sarcoma components on survival outcomes ofuterine carcinosarcoma. Ann Oncol. 2016, 27(7),1257-66.
(24) Namba-Fukuyo H, Funata S, Matsusaka K,
Fukuyo M, Rahmutulla B, Mano Y, Fukayama M,

41

Aburatani H, Kaneda A. TET2 functions as a
resistance factor against DNA methylationacquisition during Epstein-Barr virus infection.
Oncotarget. 2016, 7(49), 81512-81526.
(25) Okuma H, Gonoi W, Ishida M, Shirota G, Kanno
S, Shintani Y, Abe H, Fukayama M, Ohtomo K.
Comparison of volume and attenuation of thespleen between postmortem and antemortem
computed tomography. Int J Legal Med. 2016,
130(4), 1081-7.
(26) Okushin K, Tsutsumi T, Enooku K, Fujinaga H,
Kado A, Shibahara J, Fukayama M, Moriya K,
Yotsuyanagi H, Koike K. The intrahepatic
expression levels of bile acid transporters areinversely correlated with the histologicalprogression of nonalcoholic fatty liver disease. J
Gastroenterol. 2016, 51(8), 808-18.
(27) Onoyama H, Kamiya M, Kuriki Y, Komatsu T,
Abe H, Tsuji Y, Yagi K, Yamagata Y, Aikou S,
Nishida M, Mori K, Yamashita H, Fujishiro M,
Nomura S, Shimizu N, Fukayama M, Koike K,
Urano Y, Seto Y. Rapid and sensitive detection ofearly esophageal squamous cell carcinoma withfluorescence probe targeting dipeptidyl- peptidase
IV. Sci Rep. 2016, 6, 26399.
(28) Osawa M, Mine S, Ota S, Kato K, Sekizuka T,
Kuroda M, Kataoka M, Fukumoto H, Sato Y,
Kanno T, Hasegawa H, Ueda K, Fukayama M,
Maeda T, Kanoh S, Kawana A, Fujikura Y,
Katano H. Establishing and characterizing a newprimary effusion lymphoma cell line harboring
Kaposi's sarcoma-associated herpesvirus. InfectAgent Cancer. 2016, 11, 37.
(29) Rokutan H, Hosoda F, Hama N, Nakamura H,
Totoki Y, Furukawa E, Arakawa E, Ohashi S,
Urushidate T, Satoh H, Shimizu H, Igarashi K,
Yachida S, Katai H, Taniguchi H, Fukayama M,
Shibata T. Comprehensive mutation profiling of
mucinous gastric carcinoma. J Pathol. 2016
240(2), 137-48.
(30) Saito R, Abe H, Kunita A, Yamashita H, Seto Y,
Fukayama M. Overexpression and gene
amplification of PD-L1 in cancer cells andPD-L1+ immune cells in Epstein-Barrvirus-associated gastric cancer: the prognostic
implications. Mod Pathol. 2016 30(3):427-439(31) Saju P, Murata-Kamiya N, Hayashi T, Senda Y,

Nagase L, Noda S, Matsusaka K, Funata S,
Kunita A, Urabe M, Seto Y, Fukayama M,
Kaneda A, Hatakeyama M. Host SHP1
phosphatase antagonizes Helicobacter pylori
CagA and can be downregulated by Epstein-Barrvirus. Nat Microbiol. 2016, 1, 16026.
(32) Sakai E, Fukuyo M, Ohata K, Matsusaka K, Doi
N, Mano Y, Takane K, Abe H, Yagi K,
Matsuhashi N, Fukushima J, Fukayama M, Akagi
K, Aburatani H, Nakajima A, Kaneda A. Genetic
and epigenetic aberrations occurring in colorectal
tumors associated with serrated pathway. Int J
Cancer. 2016, 138(7), 1634-44.
(33) Shibahara J, Hayashi A, Misumi K, Sakamoto Y,
Arita J, Hasegawa K, Kokudo N, Fukayama M.
Clinicopathologic characteristics of hepatocellular carcinoma with reactive ductule-likecomponents, a subset of liver cancer currently
classified as combined hepatocellular-cholangiocarcinoma with stem-cell features, typicalsubtype. Am J Surg Pathol. 2016, 40(5), 608-16.
(34) Shichijo S, Hirata Y, Niikura R, Hayakawa Y,
Yamada A, Ushiku T, Fukayama M, Koike K.
Histologic intestinal metaplasia and endoscopic
atrophy are predictors of gastric cancer
development after Helicobacter pylori eradication.
Gastrointest Endosc. 2016, 84(4), 618-24.
(35) Shirota G, Ishida M, Shintani Y, Abe H, Ikemura
M, Fukayama M, Gonoi W. Can postmortem
computed tomography detect antemortem
hypoxic-ischemic encephalo- pathy? Forensic Sci
Med Pathol. 2016, 12(3), 267-75.
(36) Taguchi S, Fukuhara H, Morikawa T, Matsumoto
A, Miyazaki H, Nakagawa T, Fujimura T, Kume
H, Igawa Y, Homma Y. Cessation of long-term
adjuvant androgen deprivation therapy afterradical prostatectomy: is it feasible? Jpn J Clin
Oncol. 2016, 46(12), 1143-1147.
(37) Taguchi S, Shiraishi K, Fukuhara H, Nakagawa K,
Morikawa T, Naito A, Kakutani S, Takeshima Y,
Miyazaki H, Nakagawa T, Fujimura T, Kume H,
Homma Y. Optimal timing of salvage radiotherapy for biochemical recurrence after radical
prostatectomy: is ultra-early salvage radiotherapy
beneficial? Radiat Oncol. 2016, 11, 102.
(38) Taguchi S, Shiraishi K, Fukuhara H, Nakagawa K,
Morikawa T, Naito A, Kakutani S, Takeshima Y,42Miyazaki H, Nakagawa T, Fujimura T, Kume H,
Homma Y. Impact of Gleason pattern 5 including
tertiary pattern 5 on outcomes of salvage
treatment for biochemical recurrence in
pT2-3N0M0 prostate cancer. Int J Clin Oncol.
2016, 21(5), 975-980.
(39) Takata M, Amiya E, Watanabe M, Shintani Y,
Sakuma K, Saito A, Fukayama M, Ono M,
Komuro I. Phenotypic differences in aortic
stenosis according to calcification grade. Int J
Cardiol. 2016, 216, 118-20.
(40) Tanaka T, Panthee N, Itoda Y, Yamauchi N,
Fukayama M, Ono M. Negative pressure woundtherapy induces early wound healing by increased
and accelerated expression of vascular endothelial
growth factor receptors. Eur J Plast Surg. 2016,
39, 247-256.
(41) Tanaka Y, Tateishi K, Nakatsuka T, Kudo Y,
Takahashi R, Miyabayashi K, Yamamoto K,
Asaoka Y, Ijichi H, Tateishi R, Shibahara J,
Fukayama M, Ishizawa T, Hasegawa K, Kokudo
N, Koike K. Sharpin promotes hepatocellular
carcinoma progression via transactivation of
Versican expression. Oncogenesis. 2016, 5(12),e277.
(42) Urabe M, Ushiku T, Seto Y, Fukayama M.
Pathologic Response of HER2-positive Gastric
Cancer to Trastuzumab-based Chemotherapy. Am
J Surg Pathol. 2016, 40(10), 1326-33.
(43) Ushiku T, Ishikawa S, Kakiuchi M, Tanaka A,
Katoh H, Aburatani H, Lauwers GY, Fukayama
M. RHOA mutation in diffuse- type gastriccancer: a comparative clinicopathology analysisof 87 cases. Gastric Cancer. 2016, 19(2), 403-11.
(44) Yamamoto K, Tateishi K, Kudo Y, Hoshikawa M,
Tanaka M, Nakatsuka T, Fujiwara H,
Miyabayashi K, Takahashi R, Tanaka Y, Ijichi H,
Nakai Y, Isayama H, Morishita Y, Aoki T,
Sakamoto Y, Hasegawa K, Kokudo N, Fukayama
M, Koike K. Stromal remodeling by the BET
bromodomain inhibitor JQ1 suppresses the
progression of human pancreatic cancer.
Oncotarget. 2016, 7(38), 61469-61484.
(45) Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F,
Kojima S, Ueno T, Imoto N, Kohsaka S, Kunita A,
Doi K, Sakura T, Yujiri T, Kondo E, Fujimaki K,
Ueda Y, Aoyama Y, Ohtake S, Takita J, Sai E,

Taniwaki M, Kurokawa M, Morishita S,
Fukayama M, Kiyoi H, Miyazaki Y, Naoe T,
Mano H. Recurrent DUX4 fusions in B cell acutelymphoblastic leukemia of adolescents and young
adults. Nat Genet. 2016, 48(5), 569-74.

43

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

Associate Professor
Daizo Koinuma, M.D., Ph.D.

Project Associate Professor
Shogo Ehata, M.D., Ph.D. (from July 2016)

Assistant Professors
Caname Iwata, M.D., Ph.D. (until September 2016)
Masato Morikawa, M.D., Ph.D.
Yoko Katsuno, Ph.D. (from October 2016)

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.
Prof. Miyazono is Professor of the Department of
Molecular Pathology from August 2000. In March
2017, the Department consists of a professor, anassociate professor, a project associate professor, two
assistant professors, technical assistants, and someresearch fellows, including 5 graduate students, amaster course student, four post-doctoral fellows, anda guest scientist.

Teaching activities
Our department takes responsibility for lectures on“General Pathology” for the undergraduate students of
the Faculty 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.
Prof. Kohei Miyazono organized the 75th Annual
Meeting of the Japanese Cancer Association as thechairman from October 6 to 8 at Pacifico Yokohama.
Nearly 5,000 participants attended the meeting, andexchanged their research findings.
From 2015, our research projects are mainly
supported by a Grant-in-Aid for Scientific Research(S) on “Transcriptional regulation by TGF-β signaling
and its relation to progression of cancer” from theJapanese Society for the Promotion of Science (JSPS).
We have been doing collaboration with the Ludwig
Institute for Cancer Research, Uppsala, Sweden for
more than 20 years (http://c2ctgfb.umin.jp/). We haveannual TGF-β meeting in Sweden or in the44

Netherlands every year, and three graduate students
participated in the TGF-β meeting in Leiden in 2016.
Four of our graduate students are supported by 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). GPLLI was designed forthe purpose of guiding outstanding students to be
globally active leaders in industry, academia andgovernment. This program also stimulates interaction
between students and scientists in the program as well
as
those
from
other
laboratories(http://square.umin.ac.jp/gplli/).

Research activities
Our major research interest is to elucidate how
members of the TGF-β (transforming growth factor-β)family transduce signals, and how they regulate
growth, differentiation, and apoptosis of various cells.
Ras and TGF-β signaling coordinately enhancecancer progression by promoting the p63transcriptional program: TGF-β-induced cellularresponses are known to be determined bycooperatively acting signaling cascades, including
integrin, Notch, Wnt, and EGF signals. Among thevarious signaling pathways acting in concert with
TGF-β, synergy between TGF-β and Ras/Erk MAP
kinase signaling has been extensively studied. We andothers have previously reported that activation of both
TGF-β and Ras/Erk MAP kinase pathways enhances
the migratory and invasive properties of epithelial
cells through synergistic induction of epithelialmesenchymal transition (EMT).
To identify the downstream effectors of thesynergistic action of TGF-β and Ras/Erk MAP kinase
pathways, we focused on p63, a member of the p53
family of transcription factors and one of the master
regulators of epithelial cell differentiation andmigration. Two different isoforms of p63, TAp63 andΔNp63, have been reported to show opposing
functions.
TAp63
contains
theN-terminaltransactivation (TA) domain, while ΔNp63, an
N-terminal truncated isoform, lacks the TA domain.
ΔNp63 is an amino-terminally truncated isoform, andthe predominant isoform expressed in cancer cells ofepithelial origin. We have determined the
genome-wide binding landscape of p63 in
combination with gene expression profiles in thepresence and absence of TGF-β stimulation and
Ras/Erk MAP kinase activation in HaCaT humankeratinocytes, which have mutant p53 and ΔNp63. We
found that mutant p53 antagonized ΔNp63
transcriptional activity, but that activation of Ras or
TGF-β signaling pathways reduced the amounts ofmutant p53 protein, leading to higher target genebinding of ΔNp63. Among the target proteins ofΔNp63-induced genes, we found that dual-specificity
phosphatase 6 (DUSP6) promoted the degradation ofmutant p53, possibly through dephosphorylation of
p53. Knocking down the expression of p63 or DUSP6
and DUSP7 (DUSP6/7) inhibited the basal or
TGF-β-induced or EGF/Ras-induced migration andinvasion of p53-mutant breast cancer and squamous
skin cancer cells. On the other hand, overexpressionof ΔNp63 in the breast cancer cells increased theirability to form metastatic foci at various tissues upon
intracardiac injection in mice, and this was inhibitedby knocking down the expression of DUSP6/7 in thesecells overexpressing ΔNp63. High expression of
ΔNp63 in various tumors correlated with poor
prognosis in patients, and this correlation was stronger
in patients whose tumors also had a mutation in the
TP53 gene. Thus, oncogenic Ras and TGF-β signaling
coordinately stimulate progression of cancer throughactivation of the ΔNp63 transcriptional program(Vasilaki et al. Science Signaling 2016).
Dual targeting of VEGF and BMP-9/10 impairs
tumor growth through inhibition of angiogenesis:
Tumor microenvironment is composed not only ofcancer cells but also of various types of stroma cells
includingtumor
vessels,which
determinecharacteristics of tumor tissues. Tumor vessels provide
oxygen and nutrient with cancer cells, and become
main routes for cancer cells to metastasize to distantorgans. Therefore, it is crucial to develop effective
strategies to target angiogenic signals in order toinhibit tumor growth and metastasis. Signals mediatedby vascular endothelial growth factor (VEGF) havebeen implicated in tumor angiogenesis. In addition,
we have previously reported that BMP-9 promotes
multiple types of angiogenesis, including tumor

45

angiogenesis, by stimulating the proliferation ofendothelial cells. BMP-10 is structurally similar to
BMP-9 and transduces signals through a similar
mechanism. Previous studies have demonstrated thattargeting the individual signals was not sufficiently
effective in suppression of tumor growth in certain
conditions. We have developed a novel decoy
chimeric receptor which binds both VEGF and
BMP-9/10. Although single targeting of either VEGF
or BMP-9/10 signals reduced the formation of tumor
vessels in a mouse xenograft model of humanpancreatic cancer, it did not exhibit significant effects
on tumor growth. In contrast, dual targeting of theangiogenic signals by VEGF and BMP-9/10 led tomore significant inhibition of tumor angiogenesis,
leading to delay of tumor growth. Thus, simultaneous
blockade of VEGF and BMP-9/10 signals may be
more effective in targeting tumor angiogenesis, and isa promising therapeutic strategy for the cancers thatare resistant to anti-VEGF and BMP-9/10 therapies(Akatsu et al. Cancer Science in press).

References
1. Mizutani, A., Koinuma, D., Seimiya, H., andMiyazono, K. (2016) The Arkadia-ESRP2 axis
suppresses tumor progression: analyses inclear-cell renal cell carcinoma. Oncogene 35 (27),3514-3523.
2. Katsura, A., Suzuki, H. I., Ueno, T., Mihira, H.,
Yamazaki, T., Yasuda, T., Watabe, T., Mano, H.,
Yamada, Y., and Miyazono, K. (2016)
MicroRNA-31 is a positive modulator ofendothelial-mesenchymaltransition
andassociated secretory phenotype induced by TGF-β.
Genes to Cells 21 (1), 99-116.
3. Davis, H., Raja, E., Miyazono, K., Tsubakihara, Y.,
and Moustakas, A. (2016) Mechanisms of actionof bone morphogenetic proteins in cancer.
Cytokine and Growth Factor Reviews 27: 81-92.
4. Morikawa, M., Koinuma, D., Mizutani, A.,
Kawasaki, N., Holmborn, K., Sundqvist, A.,
Tsutsumi, S., Watabe, T., Aburatani, H., Heldin,
C.-H., and Miyazono, K. (2016) BMP sustains
embryonic stem cell self-renewal through distinct
functions of different Krüppel-like factors. Stem
Cell Reports 6 (1), 64-73.

5. Suzuki, H.I., Katsura, A., and Miyazono, K.
(2016) A role of uridylation pathway for blockadeof let-7 microRNA biogenesis by Lin28B. Cancer
Science 106 (9), 1174-1181.
6. Sakurai, T., Isogaya, K., Sakai, S., Morikawa, M.,
Morishita, Y., Ehata, S., Miyazono, K., andKoinuma, D. (2016) RNA-binding motif protein
47 inhibits Nrf2 activity to suppress tumor growth
in lung adenocarcinoma. Oncogene 35 (38),5000-5009.
7. Hosoya, H., Dobroff, A.S., Driessen, W.H.,
Cristini, V., Brinker, L.M., Staquicini, F.I.,
Cardó-Vila, M., D'Angelo, S., Ferrara, F., Proneth,
B., Lin, Y.S., Dunphy, D.R., Dogra, P., Melancon,
M.P., Stafford, R.J., Miyazono, K., Gelovani, J.G.,
Kataoka, K., Brinker, C.J., Sidman, R.L., Arap, W.,
andPasqualini,R.
(2016)
Integrated
nanotechnology platform for tumor-targeted
multimodal imaging and therapeutic cargo release.
Proceedings of the National Academy of Sciencesof USA. 113 (7), 1877-1882.
8. Ando, M., Kawazu, M., Ueno, T., Koinuma, D.,
Ando, K., Koya, J., Kataoka, K., Yasuda, T.,
Yamaguchi, H., Fukumura, K., Yamato, A., Soda,
M., Sai, E., Yamashita, Y., Asakage, T., Miyazaki,
Y., Kurokawa, M., Miyazono, K., Nimer, S.D.,
Yamasoba, T., and Mano, H. (2016) Mutationallandscape and antiproliferative functions of ELF
transcription factors in human cancer. Cancer
Research 76 (7), 1814-1824.
9. Sakai, S., Iwata, C., Tanaka, H.Y., Cabral, H.,
Morishita, Y., Miyazono, K., and Kano, M.R.
(2016) Increased fibrosis and impaired
intratumoral accumulation of macromolecules in amurinemodelofpancreaticcancerco-administered with FGF-2. Journal ofControlled Release 230, 109-115.
10. Morikawa, M., Derynck, R., and Miyazono, K.
(2016) TGF-β and the TGF-β family: Contextdependent roles in cell and tissue physiology.
Cold Spring Harbor Perspectives in Biology 8 (5),pii: a022095.
11. Miyazawa, K. and Miyazono, K. (2016)
Regulation of TGF-β family signaling byinhibitory Smads. Cold Spring Harbor
Perspectives in Biology 9 (3), pii: a021873.

46

12. Vasilaki, E., Morikawa, M., Koinuma, D.,
Mizutani, A., Hirano, Y., Ehata, S., Sundqvist, A.,
Kawasaki, N., Cedervall, J., Olsson, A.K.,
Aburatani, H., Moustakas, A., Miyazono, K., andHeldin, C.-H. (2016) Ras and TGF-β signalingenhance cancer progression by promoting the
ΔNp63 transcriptional program. Science Signaling
9 (442), ra84.
13. Kaneda, A., Nonaka, A., Fujita, T., Yamanaka, R.,
Fujimoto, M., Miyazono, K., and Aburatani, H.
(2016) Epigenomic regulation of Smad1 signaling
during cellular senescence induced by Ras
activation. Methods in Molecular Biology 1344,
341-353.

Pathology, Immunology andMicrobiology
2. Microbiology

48

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

Lecturer
Naoko Kamiya, Ph.D.

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 18 members; 1 professor (Dr. Hatakeyama),
1 senior lecturer (Dr. Kamiya), 2 research associates(Drs. Takahashi and Hayashi), 1 project research
associate (Dr. Fujii), 2 post-doctoral fellows (Drs.
Nishikawa and Kikuchi), 2 academic assistants (Ms.
Shimada and Komatsu), 10 graduate school students(Ms. and Mrs. Hashi, Bingo, Ohki, Nojima, Ben, Lu,
Knight, Inoue, Imai).

Gastric cancer is the second 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 of 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. Collaboration
betweencagA-positive
Helicobacter pylori and Epstein-Barr virus in
gastric carcinogenesis
Most if not all human gastric cancers are caused bychronic infection of the stomach lining with H. pylori
strains that possess the cagA gene. Approximately
10% of gastric cancer cases also harbor Epstein-Barrvirus (EBV) in the cancer cells. Upon delivery into
gastric epithelial cells via type IV secretion, CagA
undergoes tyrosine phosphorylation by Src family
kinases or c-Abl kinase at the Glu-Pro-Ile-Tyr-Ala(EPIYA) motif. Tyrosine-phosphorylated CagA binds
to the pro-oncogenic protein tyrosine phosphatase
SHP2 and thereby aberrantly activates the phosphataseactivity, which has been considered to play animportant role in gastric carcinogenesis.
We identified SHP1, the only homologue of SHP2,
as a tyrosine phosphatase that dephosphorylates CagA.
We showed that SHP1 interacts with CagA
independently of EPIYA motif. The interaction
potentiates the phosphatase activity of SHP1 thatsubverts the oncogenic activity of CagA by
dephosphorylating the CagA EPIYA motifs. Theseobservations indicated that the level of SHP1 ingastric epithelial cells influences the magnitude of
CagA action.
EBV-positive gastric cancers are associated withgenome-wide hypermethylation. Since the most ofpatients with EBV-positive gastric cancer are
co-infected with H. pylori, we investigated the
methylation status of SHP1 (PTPN6) in gastricepithelial cells. In vitro infection of gastric epithelial
cells with EBV induced SHP1 promoter hypermethylation, which reflected the decrease of SHP1mRNA and SHP1 protein expression. Further more,
phosphorylation-dependent CagA activity was
substantially strengthened in EBV-positive gastricepithelial cells. Clinical specimens of EBV-positive
gastric cancers also exhibited SHP1 hypermethylation
with reduced SHP1 expression. This work revealed
that a pathophysiological collaboration between the H.
pylori bacterium and the EBV cooperate in promoting
the development of gastric cancer.

2. Impact of structural polymorphism for the
Helicobacter pylori CagA on binding topolarity-regulating kinase PAR1b
Once inside the host cells, H. pylori CagA also binds
to partitioning-defective 1b (PAR1b)/microtubule
affinity-regulating kinase 2 (MARK2) via the CagA
multimerization (CM) motif in a tyrosine
phosphorylation-independent
manner.
Throughcomplex formation, CagA inhibits kinase activity ofPAR1b, resulting in induction of junctional andpolarity defects. Notably, the polymorphism in the
CM motif has been identified among geographic
variants of CagA, differing in either the copy number
or the sequence composition.
Through quantitative analysis of the complex
formation between CagA and PAR1b, we found thatseveral CagA species have acquired elevated PAR1bbinding activity via duplication of the CM motifs,
while others have lost their PAR1b-binding activity.
We also found that strength of CagA-PAR1b
interaction is proportional to the degrees of stressfiber formation and tight junctional disruption by
CagA in gastric epithelial cells. These results indicatethat the CM polymorphism is a determinant for themagnitude of pathophysiological actions of H. pylori
CagA. Therefore, the CM diversity may contribute to
the different disease manifestations caused bycagA-positive H. pylori infection.
3. Pragmin-Csk interaction creates a positive
feedback regulatory loop of Csk activation that
regulate cell motility
Inside the host cells, tyrosine-phosphorylated CagA
binds to SH2 domain-containing mammalian proteinssuch as SHP2 and the C-terminal Src kinase (Csk), a
negative regulator of Src family kinases. Pragmin is
one of the few mammalian proteins that possess the
Glu-Pro-Ile-Tyr-Ala (EPIYA) motif. Like CagA,
Pragmin also forms a physical complex with Csk.
In the present study, we found that Pragmin directly
binds to Csk by the tyrosine-phosphorylated EPIYA
motif. The complex formation potentiates kinase
activity of Csk, which in turn phosphorylates Pragminon tyrosine-238 (Y238), Y343, and Y391. As Y391 ofPragmin comprises the EPIYA motif, Pragmin-Csk
interaction creates a positive feedback regulatory loopof Csk activation. We also found that Pragmin and Csk

50

are colocalized to focal adhesions. These observations
indicate that the Pragmin-Csk interaction, triggeredby Pragmin EPIYA phosphorylation, robustly
stimulates the kinase activity of Csk at focal
adhesions, which direct cell-matrix adhesion that
regulates cell morphology and cell motility. As aconsequence, expression of Pragmin and/or Csk inepithelial cells induces an elongated cell shape withelevated cell scattering in a manner that is mutuallydependent on Pragmin and Csk. Therefore,
deregulation of the Pragmin-Csk axis may induce
aberrant cell migration that contributes to tumor
invasion and metastasis.

4. Parafibromin is a transcriptional coactivator of
the Wnt/Hedgehog/Notch pathways
The Wnt, Hedgehog (Hh) and Notch signaling
pathways are among only a handful of evolutionallyconserved morphogen pathways mediating embryonicdevelopment as well as homeostasis of adult tissues.
Nevertheless, mechanisms that intracellularly
coordinate these signal inputs remain poorly
understood.
Parafibromin is the human (mammalian) orthologueof budding yeast Cdc73, a component of the RNAPolymerase 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. Here we found thatparafibromin competitively interacts with β-catenin
and Gli1, thereby potentiating transactivation of Wntand Hh-target genes in a mutually exclusive manner.
Parafibromin also binds to the Notch intracellulardomain (NICD), enabling concerted activation of
Wnt- and Notch-target genes. The transcriptional
platform function of parafibromin is potentiated bytyrosine dephosphorylation, mediated by SHP2
phosphatase, while it is attenuated by tyrosine
phosphorylation, mediated by PTK6 kinase.
Consequently, acute loss of parafibromin in micedisorganizes the normal epithelial architecture of theintestine, which requires coordinated activation/
inactivation of Wnt, Hh and/or Notch signaling. This

work revealed that multiple independent morphogen
signaling pathways converge on the transcriptional
platform parafibromin.

Publications
1. Shimoda, A., Ueda, K., Murata-Kamiya, N.,
Mukai, S., Sawada, S., Azuma, T., Hatakeyama,
M* and Akiyoshi, K*. Exosomes as nanocarriers
for systemic delivery of the Helicobacter pylori
virulence factor CagA. Sci. Rep. 6: 18346 (2016)(*Corresponding authors)
2. Senda, M., Hayashi, T., Hatakeyama, M.,
Takeuchi, K., Sasaki, A.T., Senda, T. Use ofmultiple cryoprotectants to improve diffraction
quality from protein crystals. Cryst. Growth Des.
16(3): 1565-1571 (2016)
3. Kameoka, S., Kameyama, T., Hayashi, T., Seto, S.,
Ohnishi, N., Hayashi, T., Murata-Kamiya, N.,
Higashi, H., Hatakeyama, M., Takaoka, A.
Helicobacter pylori induces IL-1β protein
through the inflammasome activation indifferentiated macrophagic cells. Biomed. Res.
37(1): 21-27 (2016)
4. Lang, B.J., Gorrell, R.J., Tafreshi, M.,
Hatakeyama, M., Kwok, T., Price, J.T. The
Helicobacter pylori cytotoxin CagA is essential
for suppressing host heat shock protein
expression. Cell Stress Chaperones 21(3): 523-33(2016)
5. Saju, P., Murata-Kamiya, N., Hayashi, T., Senda,
Y., Nagase, L., Noda, S., Matusaka, K., Funata, S.,
Kunita, A., Urabe, M., Seto, Y., Fukayama, M.,
Kaneda, A., Hatakeyama, M. Host SHP1
phosphatase antagonizes Helicobacter pylori
CagA and can be downregulated by Epstein-Barrvirus. Nat. Microbiol. Article number: 16026(2016)
6. Senda, Y., Murata-Kamiya, N., Hatakeyama, M.
Csk-mediated EPIYA phosphorylation of Pragmin
creates a feed-forward Csk activation loop that
promotes cell motility. Cancer Sci. 107(7):972-80 (2016)
7. Roy, R.K., Hoppe, M.M., Srivastava, S., Samanta,
A., Sharma, N., Tan, K.T., Yang, H., Voon, D.C.,
Pang, B., Teh, M., Murata-Kamiya, N.,
Hatakeyama, M., Chang, Y.T., Young, W.P., Ito,51

Y., Ho, K.Y., Tan, P., Soong, R., Koeffler, P.H.,
Yeoh, K.G., Jeyasekharan, A.D. CEACAM6 isupregulated by Helicobacter pylori CagA and is abiomarker for early gastric cancer. Oncotarget
7(34): 55290-301 (2016)
8. Nishikawa, H., Hayashi, T., Arisaka, F., Senda, T.,
Hatakeyama,M.
Impactofstructuralpolymorphism for the Helicobacter pylori CagA
oncoprotein on binding to polarity-regulating
kinase PAR1b. Sci. Rep. 6, Article Number:
30031 (2016)
9. Kikuchi, I., Takahashi-Kanemitsu, A., Sakiyama,N., Tang, C., Tang, P.J., Noda, S., Nakao, K.,
Kasai, H., Sato, T., Aiba, A., Hatakeyama, M.
Dephosphorylatedparafibrominisatranscriptional coactivator of the Wnt/Hedgehog/
Notch pathways. Nat Commun 7, Article Number:
12887 (2016)
10. Nakano, M., Yahiro, K., Yamasaki, E., Kurazono,
H., Akada, J., Yamaoka, Y., Niidome, T.,
Hatakeyama, M., Suzuki, H., Yamamoto, T., Moss,J., Isomoto, H., Hirayama, T. Helicobacter pylori
VacA, acting through receptor protein tyrosine
phosphatase α, is crucial for CagA phosphorylation in human duodenum carcinoma cell line
AZ-521. Dis. Model Mech. 9(12): 1473-1481(2016)

52

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

Hospital Lecturer
Keita Tatsuno, M.D., Ph.D.
Mahoko Ikeda, M.D., Ph.D.

Research Associate
Nobuhiko Satoh, M.D., Ph.D.
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, six 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 such as mupirocin and vancomycin.
3) Microbiological investigation of wards andenvironment (at request or need).
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

53

the hospital and occupational infection control. We
have been also offering our information and techniqueon occasions of request.

Research
We have been mainly studying on following subjects:
Several studies are now going with the members of
department of pharmacy and of surgery.
1) Development of preemptive strategies for thecontrol of healthcare-associated infection2) Development of new methods in infection control
and treatment of viral hepatitis
3) Molecularpathogenesisofhepatocellular
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 defences to microorganisms
8) Molecular analysis of innate immunity in microorganism infection
9) New detection method and pathogenesis ofopportunistic cytomegaloviral infection10) Mechanism of multi-drug resistant microorganisms11) Epidemiology of Clostridium difficile infection

Publications
1. Uchino K, Tateishi R, Fujiwara N, Minami T,
Sato M, Enooku K, Nakagawa H, Asaoka Y,
Kondo Y, Yoshida H, Moriya K, Shiina S, Omata
M, Koike K. Impact of serum ferritin level on
hepatocarcinogenesis in chronic hepatitis C
patients. Hepatol Res. 2016 Apr;46(4):259-68.
2. Niikura R, Yamada A, Nagata N, Kobayashi Y,
Okamoto M, Mitsuno Y, Ogura K, Yoshida S,
Shimbo T, Hirata Y, Koike K. New predictivemodel of rebleeding during follow-up of patents
with obscure gastrointestinal bleeding: A
multicenter cohort study. J Gastroenterol Hepatol.
2016 Apr;31(4):752-60.
3. Yamamichi N, Hirano C, Takahashi Y, Minatsuki
C, Nakayama C, Matsuda R, Shimamoto T,
Takeuchi C, Kodashima S, Ono S, Tsuji Y,
Fujishiro M, Wada R, Mitsushima T, Koike K.

4.

5.

6.

7.

8.

Comparative analysis of upper gastrointestinalendoscopy, double-contrast upper gastrointestinal
barium X-ray radiography, and the titer of serumanti-Helicobacter pylori IgG focusing on the
diagnosis of atrophic gastritis. Gastric Cancer.
2016 Apr;19(2):670-5.
Yamamichi N, Hirano C, Ichinose M, Takahashi
Y, Minatsuki C, Matsuda R, Nakayama C,
Shimamoto T, Kodashima S, Ono S, Tsuji Y,
Niimi K, Sakaguchi Y, Kataoka Y, Saito I,
Asada-Hirayama I, Takeuchi C, Yakabi S,
Kaikimoto H, Matsumoto Y, Yamaguchi D,
Kageyama-Yahara N, Fujishiro M, Wada R,
Mitsushima T, Koike K. Atrophic gastritis andenlarged gastric folds diagnosed by doublecontrast upper gastrointestinal barium X-ray
radiography are useful to predict future gastriccancer development based on the 3-year
prospective observation. Gastric Cancer. 2016 Jul;
19(3):1016-22.
Sakaguchi Y, Tsuji Y, Fujishiro M, Kataoka Y,
Takeuchi C, Yakabi S, Saito I, Shichijo S,
Minatsuki C, Asada-Hirayama I, Yamaguchi D,
Niimi K, Ono S, Kodashima S, Yamamichi N,
Koike K. Triamcinolone Injection and Shielding
with Polyglycolic Acid Sheets and Fibrin Glue for
Postoperative
Stricture
Prevention
after
Esophageal Endoscopic Resection: A Pilot Study.
Am J Gastroenterol. 2016 Apr;111(4):581-3.
Niimi K, Goto O, Kawakubo K, Nakai Y,
Minatsuki C, Asada-Hirayama I, Mochizuki S,
Ono S, Kodashima S, Yamamichi N, Isayama H,
Fujishiro M, Koike K. Endoscopic ultrasoundguided fine-needle aspiration skill acquisition ofgastrointestinal submucosal tumor by traineeendoscopists: A pilot study. Endosc Ultrasound.
2016 May-Jun;5(3):157-64.
Satoh N, Yamada H, Yamazaki O, Suzuki M,
Nakamura M, Suzuki A, Ashida A, Yamamoto D,
Kaku Y, Sekine T, Seki G, Horita S. A purechloride channel mutant of CLC-5 causes Dent's
disease via insufficient V-ATPase activation.
Pflugers Arch. 2016 Jul;468(7):1183-96.
Ogishi M, Yotsuyanagi H, Moriya K, Koike K.
Delineation of autoantibody repertoire throughdifferential proteogenomics in hepatitis C

54virus-induced cryoglobulinemia. Sci Rep. 2016
Jul 12;6:29532.
9. Asada-Hirayama I, Kodashima S, Sakaguchi Y,
Ono S, Niimi K, Mochizuki S, Tsuji Y, Minatsuki
C, Shichijo S, Matsuzaka K, Ushiku T, Fukayama
M, Yamamichi N, Fujishiro M, Koike K.
Magnifying endoscopy with narrow-band imaging
is more accurate for determination of horizontal
extent of early gastric cancers than chromoendoscopy. Endosc Int Open. 2016 Jun;4(6): E690-8.
10. Okushin K, Tsutsumi T, Enooku K, Fujinaga H,
Kado A, Shibahara J, Fukayama M, Moriya K,
Yotsuyanagi H, Koike K. The intrahepatic
expression levels of bile acid transporters areinversely correlated with the histologicalprogression of nonalcoholic fatty liver disease. J
Gastroenterol, 2016 Aug;51(8):808-18.
11. Minami-Kobayashi Y, Yamada A, Watabe H,
Suzuki H, Hirata Y, Yamaji Y, Yoshida H, Koike
K. Efficacy of repeat review with flexible spectral
imaging color enhancement in patients with nofindings by capsule endoscopy. Saudi J
Gastroenterol,2016 Sep-Oct;22(5):385-390.
12. Nishikawa H, Shiraki M, Hiramatsu A, Moriya K,
Hino K, Nishiguchi S. Japan Society of
Hepatology guidelines for sarcopenia in liverdisease (1st edition): Recommendation from theworking group for creation of sarcopenia
assessment criteria. Hepatol Res. 2016 Sep;
46(10):951-63.
13. Tian Y, Yang Y, Zhang X, Nakajima T, Tanaka N,
Sugiyama E, Kamijo Y, Lu Y, Moriya K, Koike K,
Gonzalez FJ, Aoyama T. Age-dependent PPARα
activation induces hepatic sulfatide accumulationin transgenic mice carrying the hepatitis C virus
core gene. Glycoconj J. 2016 Dec;33(6):927-936.
14. Igawa G, Casey M, Sawabe E, Nukui Y, Okugawa
S, Moriya K, Koike R, Tohda S, Saito R.
Comparison of agar dilution and brothmicrodilution methods for Clostridium difficile
antimicrobial susceptibility testing. J Glob
Antimicrob Resist. 2016, Dec;7:43-45.
15. Tsutsumi T, Okushin K, Enooku K, Fujinaga H,
Moriya K, Yotsuyanagi H, Aizaki H, Suzuki T,
Matsuura Y, Koike K. Nonstructural 5A Proteinof Hepatitis C Virus Interferes with Toll-Like
Receptor Signaling and Suppresses the Interferon

Response in Mouse Liver. PLoS One. 2017 Jan
20;12(1): e0170461.
16. Ota Y, Yamada A, Kobayashi Y, Niikura R,
Shimpoh T, Narita A, Yoshida S, Suzuki N,
Watabe H, Hirata Y, Ishihara S, Sunami E,
Watanabe T, Koike K. Diagnostic capability ofcolon capsule endoscopy for advanced colorectal
cancer: A pilot study. Dig Endosc. 2017 Mar 10.
17. Hatakeyama S, Ohama Y, Okazaki M, Nukui Y,
Moriya K. Antimicrobial susceptibility testing of
rapidly growing mycobacteria isolated in Japan.
BMC Infect Dis. 2017 Mar 7;17(1):197.

Pathology, Immunology andMicrobiology
3. Immunology

56

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

Associate Professor
Takeshi Nitta, Ph.D.

Assistant Professor
Shinichiro Sawa, M.D., Ph.D.; Noriko Komatsu, Ph.D.

Project Assistant Professor
Hiroyuki Takaba, Ph.D.

Homepage

http://www.osteoimmunology.com/

Introduction and Organization

Teaching activities

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

All members of our department take very seriously
their responsibilities to teach and train the next
generation of scientists. Undergraduate students of thefaculty take part in departmental class work throughlectures on immunobiology, immunochemistry andmolecular immunology as well as practical training by
way of laboratory courses on basic immunology
experimental techniques. The education of graduate
students is based on weekly seminars where students
present the progress of their own research projects,
discuss the future directions of their research and theresearch of others, and are exposed to the latest
cutting-edge questions confronting the research fieldof immunology. We also offer a special training course(called ‘free quarter’) of basic and advanced
biological and immunological techniques to medical
students. We are also accepting undergraduate
students as Medical Scientist Training Program infaculty of medicine. In fiscal year 2016, special
lectures for undergraduate students were given byinternationally recognized scientists, Dr. Takehiko
Sasazuki (Prof. of Kyushu Univ.), Dr. Shimon
Sakaguchi (Prof. of Osaka Univ.), Dr. Hajime
Karasuyama (Prof. of Tokyo Medical and Dental
Univ.), and Dr. Tadatsugu Taniguchi (Prof. of the Univ.
of Tokyo).

57

Research activities
The final goal of our research is to develop
epoch-making strategies for the treatment of immune
disorders such as autoimmune diseases and severe
infectious diseases. At the present moment,
knowledge in this field, especially about the molecularmechanisms of immune tolerance are quite limited.
Therefore, initially, we aim to achieve further
understanding about whole immunity, including
hematopoietic cell development and regulation of bothinnate and adaptive immune systems.
1) Bone marrow microenvironment
The bone marrow is a primary lymphoid organ thatplays a critical role in immune cell development. It
has been proposed by several groups that marrow
resident non-hematopoietic cells i.e. osteoblasts,
endothelial cells, neurons or reticular cells (named
CXCL12 expressing CAR cells) play critical roles onhematopoiesis. However, the crucial cell types that
support hematopoietic cell development in the bonemarrow have not been clarified.
Recently we reported the crucial role of osteoblastsin supporting lymphoid lineage development within
the bone marrow microenvironment (Terashima et al.,Immunity 2016). The mice genetically ablated forosteoblasts exhibited a marked reduction of thenumber of common lymphoid progenitor cells in thebone marrow and mature lymphocytes in the periphery.
Our results showed that osteoblasts play a pivotal rolein maintenance of common lymphoid progenitors
through the production of IL-7. Furthermore, using amouse model of sepsis, we showed that sepsis rapidly
ablated osteoblasts, which reduced the common
lymphoid progenitor number and thereby resulted inperipheral lymphopenia. This study demonstrates areciprocal interaction between the immune and bonesystems, in which acute inflammation induces a defectin bone cells resulting in lymphopenia-associatedimmunodeficiency, suggesting that osteoblasts are apotential therapeutic target of the treatment ofinflammatory diseases.
2) Osteoclast and osteoimmunology
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). We
also found that immune complexes in serum activate
osteoclastogenesis and cause bone loss throughbinding to Fcγ receptors (Negishi-Koga et al., Nat
Commun. 2015).
We also reported that, using a bone-fracture modelin mouse, the cytokine IL-17 promotes bone fracture
healing via osteoblastic bone formation and that γδTcells are the major source of IL-17 produced in thebone injury site (Ono et al., Nat Commun. 2016).
Although it has been known that IL-17 enhancesosteoclastic bone resorption in certain pathologicalsituations, our current results clearly show thepromoting effect of IL-17 on bone formation,
providing a new paradigm for physiological interaction between bone and immune system.
Most recently, we studied on the physiologicalsignificance of lysil oxidase (LOX), the enzyme whichwaspreviously
reportedtoinduce‘RANKL-independent’ osteoclastdifferentiation(Tsukasaki et al., J Bone Miner Res. 2017). Our
results demonstrated that LOX failed to substitute for58

RANKL in inducing osteoclastogenesis in vivo, while
LOX facilitated the osteoclast differentiation by
inducing RANKL expression in bone marrow stromalcells.
3) Development and regulation of lymphoid cells
Thymus is the primary lymphoid organ that
supports development of useful T cells (positive
selection) and eliminates self-reactive T cells(negative selection). However, recently it has beenshown that a fraction of self-reactive T cells escapenegative selection in the thymus. This process iscalled “agonistic selection”. We uncovered importance of continuous calcium influx into cytoplasm foragonistic selection of T cells especially regulatory T
cells and iNKT cells (Oh-hora et al., Immunity. 2013).
The microenvironment of the thymus is mainlycomposed of thymic epithelial cells (TEC) that
regulate selections of developing T cells (Nitta et al.,Adv Immunol. 2008; Nitta and Suzuki, Cell Mol Life
Sci. 2016). Using a newly established mouse model of
TEC deficiency, we showed the significant role ofthymic epithelial cells in development, not only of“conventional” αβT cells but also of inflammatory“innate” γδT cells (Nitta et al., EMBO Rep. 2015).
In the mucosal tissues such as gut and lung, thenewly identified innate lymphoid cells (ILCs) play
important roles in pathogen clearance, tissue
homeostasis, and regulation of immune responses(Sawa et al., Science. 2010). We are trying tounderstand the cellular and molecular mechanismsthat underlie development and function of ILCs. We
also aim to identify gut-associated lymphoid tissue
stromal cells that control intestinal immunity againstcommensal and pathogenic microorganisms.
4) Mechanism of autoimmune disease
The IL-17 producing helper T cell subset (Th17cell) plays critical roles in several autoimmune diseasemodels such as collagen induced arthritis (CIA) andexperimental encephalomyelitis (EAE). We haveidentified IκBζ as an indispensable transcription
factor for Th17 cell differentiation (Okamoto et al.,Nature. 2010). However, in both RA and EAE models,effector mechanisms of Th17 cells have been unclear.
Recently, we identified a subset of Th17 cells thatrobustly produces IL-17 and RANKL and exacerbates

both inflammation and bone destruction in CIA mice.
Interestingly these Th17 cells are the progeny of CD4
T cells expressing Foxp3, a master regulator for
immunosuppressive Treg cells (Komatsu et al., Nat
Med. 2014).
We also reported that RANKL
produced by synovial fibroblasts is primarily
responsible for the formation of bone-destructive
osteoclasts in inflammatory arthritis. These results
show that the targeting these cells and/or molecules
could be effective in preventing bone destruction in
RA (Danks et al., Ann Rheum Dis. 2015).
To elucidate a role of RANKL on T cells, we
generated T cell-specific RANKL-deficient mice.
These mice were protected from EAE, a mouse modelof multiple sclerosis, due to an impairment of
infiltration of pathogenic T cells into the central
nervous system (CNS). RANKL on T cells stimulates
the chemokine production by astrocytes, leading to thechronic inflammation in the CNS. Pharmacologicalinhibition of RANKL prevented the development of
EAE, indicating that RANKL is a potential therapeutictarget for treatment of multiple sclerosis (Guerrini etal., Immunity. 2015).
We have also been studying the mechanism of T
cell tolerance induction, because a breakdown of T
cell tolerance induces autoimmune diseases. Selftolerance of T cells is primarily established during
their development in the thymic medulla, where
medullary thymic epithelial cells (mTECs) ectopically
express a variety of tissue-restricted antigens (TRAs)
and thereby TRA-reactive immature T cells aredeleted. It has been known that expression of a set of
TRAs is regulated by the transcriptional regulator Aire,although how the remaining TRAs are regulated has
been unclear. Recently, we identified a novel key
transcription factor Fezf2, which is highly expressedin mTECs and controls the expression of a large
fraction of Aire-independent TRAs (Takaba et al.,Cell. 2015). Mice lacking Fezf2 in mTECs exhibitedsevere autoimmune disorders in peripheral organs, andthe spectrum of autoimmunity in Fezf2-deficient micediffered from that in Aire-deficient mice. These
results indicate that two independent factors, Fezf2
and Aire, play non-redundant and mutually complementary roles in the TRA expression to ensure T cell
tolerance induction. This study represented an important advance in our understanding of the mechanisms

59

underlying the immune tolerance and autoimmune
diseases.

References
1. Gao J, Cheng TS, Qin A, Pavlos NJ, Wang T,
Song K, Wang Y, Chen L, Zhou L, Jiang Q,
Takayanagi H, Yan S, Zheng M. Glucocorticoid
impairscell-cellcommunicationbyautophagy-mediated degradation of connexin 43
in osteocytes. Oncotarget. 7, 26966-26978(2016)
2. Terashima A, Okamoto K, Nakashima T, Akira S,
Ikuta K, Takayanagi H. Sepsis-induced osteoblast
ablation causes immunodeficiency. Immunity. 44,
1434-1443 (2016)
3. Tsukasaki M, Hamada K, Okamoto K Nagashima
K, Terashima A, Komatsu N, Win S, Okamura T,
Nitta T, Yasuda H, Penninger JM, Takayanagi H.
LOX Fails to Substitute for RANKL in
Osteoclastogenesis. J Bone Miner Res. 32,
434-439 (2017)

Radiology and Biomedical
Engineering
1. Radiology

61

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

Associate Professor
Toshimitsu Momose, M.D., Ph.D.,
Akira Kunimatsu, M.D., Ph.D.

Keiichi Nakagawa, M.D., Ph.D.

Lecturer
Harushi Mori, M.D., Ph.D.,
Hidemasa Takao, M.D., Ph.D.,

Jiro Sato, M.D.,
Hideomi Yamashita M.D., Ph.D.

Project Associate Professor
Miwako Takahashi, M.D., Ph.D.,

Takeyuki Watadani, M.D., Ph.D.

Assistant Professor
Shouhei Hanaoka, M.D., Ph.D.,
Kae Okuma, M.D., Ph.D.,
Wataru Gonoi, M.D., Ph.D.,
Masaki Katsura, M.D., Ph.D.,
Kouhei Kamiya, M.D., Ph.D.,

Homepage

Shiori Amemiya, M.D., Ph.D.,
Toshihiro Furuta, M.D., Ph.D.,
Keitaro Koyama, M.D., Ph.D.,
Akihiro Haga, Ph.D.,
Wataru Takahashi, M.D., Ph.D.

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

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 and cardiologists 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 nuclear medicine physicians andcardiologists.
Each year, over 700 new patients receive radiation
therapy in the Radiation Oncology section. Highly

62

accurate 3D radiation therapy is the most outstanding
feature. Stereotactic radiation therapy for small lungor liver tumors has been carried out.
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- andsixth-year students to provide fundamental knowledgeof diagnostic radiology, radiation oncology andnuclear medicine. Professor, associate professors andlecturers as well as specialists assigned as part timelecturers 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-sidelearning (Clinical Clerkship, CC) curriculum, small
groups of the sixth-year students are taking part inmini-lectures and 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 of imaging modalities and technology inradiation therapy against cancer. Postgraduate students
are also welcome to each of subspecialties ofradiology 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. Diagnostic Radiology group in thedepartment promotes research activities aiming at
efficacy improvement of diagnostic imaging andexpansion of its application. Multi-row detector
helical computed tomography (MDCT) enables us totake tomographic images in a three-dimensional (3D)fashion. Using the data acquired by MDCT, various
kinds of diseases in almost all parts of the body, from

cerebral diseases to musculoskeletal diseases, can bedisplayed in 3D images. New 3D software developedin our departments is now widely used in the field of
the gastrointestinal 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 theFaculty of Engineering, the University of Tokyo. Thissection will contribute to development of novelsoftware to abstract clinically useful information fromthe 3D imaging data more sophisticatedly. In the fieldof magnetic resonance (MR) imaging, MR digital
subtraction angiography, perfusion imaging, anddiffusion tensor imaging are the foci of research.
These techniques are aggressively applied to theinvestigation of vascular and neoplastic diseases of thebrain.
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.

63

Nuclear Medicine group promotes clinical researchon functional imaging and the development ofradio-immunotherapy (RIT) by the application ofradioisotope-labeled tracer technology, combinedwith molecular biology. In particular, emission
tomography (PET and SPECT) is applied for theevaluation of cerebral blood flow and metabolism 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 [O-15] H2O, CO2, O2, CO, [F-18]
FDG, [C-11] methionine, [F-18] Dopa, [C-11] NMSP,NMPB, [C-11] raclopride and [C-11] PiB. The studyof dementia using SPECT and the standard brain atlas
has made it possible to categorize the type of dementia.
Evaluation of dopaminergic function by PET is very
important in the differential diagnosis of Parkinsonism.
Cardiac PET and SPECT are also active fields.
Myocardial viability, vascular reserve and sympathetic
nerve denervation in the ischemic heart disease are
evaluated with [F-18] FDG, [N-13] NH3, 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 XCT/MRI would be a routine job
and anatomo-functional images would play animportant role in the clinical management of thepatients.

References
1. Aihara K, Mukasa A, Nagae G, Nomura M,
Yamamoto S, Ueda H, Tatsuno K, Shibahara J,
Takahashi M, Momose T, Tanaka S, Takayanagi S,
Yanagisawa S, Nejo T, Takahashi S, Omata M,
Otani R, Saito K, Narita Y, Nagane M, Nishikawa
R, Ueki K, Aburatani H, Saito N.
Genetic and epigenetic stability of oligodendrogliomas at recurrence.

2.

3.

4.

5.

6.

7.

8.

9.

Acta Neuropathol Commun 5(1): 18, 2017
Akai H, Kiryu S, Shibata E, Maeda E, Sato J,
Tomizawa N, Nojima M, Ohtomo K.
Reducing CT radiation exposure with organ effective modulation: A retrospective clinical study.
Eur J Radiol 85(9): 1569-73, 2016
Akimoto T, Morita A, Shiobara K, Hara M,
Minami M, Shijo K, Nomura Y, Shigihara S, Haradome H, Abe O, Kamei S.
Surgically Cured, Relapsed Pneumococcal Meningitis Due to Bone Defects, Non-invasively Identified by Three-dimensional Multi-detector Computed Tomography.
Intern Med 55(24): 3665-9, 2016
Amemiya S, Takao H, Hanaoka S, Ohtomo K.
Global and structured waves of rs-fMRI signal
identified as putative propagation of spontaneous
neural activity.
Neuroimage 133: 331-40, 2016
Andica C, Hagiwara A, Nakazawa M, Tsuruta K,
Takano N, Hori M, Suzuki H, Sugano H, Arai H,
Aoki S.
The Advantage of Synthetic MRI for the Visualization of Early White Matter Change in an Infant
with Sturge-Weber Syndrome.
Magn Reson Med Sci 15(4): 347-8, 2016
Andica C, Hagiwara A, Nakazawa M, Kumamaru
KK, Hori M, Ikeno M, Shimizu T, Aoki S.
Synthetic MR Imaging in the Diagnosis of Bacterial Meningitis.
Magn Reson Med Sci: Epub ahead of print, 2016
Arnone D, Job D, Selvaraj S, Abe O, Amico F,
Cheng Y, Colloby SJ, O'Brien JT, Frodl T, Gotlib
IH, Ham BJ, Kim M J, Koolschijn PC, Perico CA,
Salvadore G, Thomas AJ, Van Tol MJ, van der
Wee NJ, Veltman DJ, Wagner G, McIntosh AM.
Computational meta-analysis of statistical parametric maps in major depression.
Hum Brain Mapp 37(4): 1393-404, 2016
Ebisawa K, Midorikawa Y, Higaki T, Nakayama
H, Tsuji S, Nishimaki H, Haradome H, Abe O,
Sugitani M, Moriyama M, Takayama T.
Natural history of nonenhancing lesions incidentally detected during the diagnosis of hepatocellular carcinoma. Surgery 160(3): 654-60, 2016
Furuta T, Yamaguchi M, Minami M, Ohtomo K,
Fujii H.
Persistent T2*-hypointensity of the liver paren-

64

chyma after irradiation to the SPIO-accumulated
liver: An imaging marker for responses to radiotherapy in hepatic malignancies.
J Magn Reson Imaging 45(1): 303-12, 2017
10. Goto M, Abe O, Miyati T, Yamasue H, Gomi T,
Takeda T.
Head Motion and Correction Methods in Resting-state Functional MRI.
Magn Reson Med Sci 15(2): 178-86, 2016
11. Goto M, Suzuki M, Mizukami S, Abe O, Aoki S,
Miyati T, Fukuda M, Gomi T, Takeda T.
Repeatability of Brain Volume Measurements
Made with the Atlas-based Method fromT1-weighted Images Acquired Using a 0.4 Tesla
Low Field MR Scanner.
Magn Reson Med Sci 15(4): 365-70, 201612. Hagiwara A, Hori M, Yokoyama K, Takemura MY,
Andica C, Kumamaru KK, Nakazawa M, Takano
N, Kawasaki H, Sato S, Hamasaki N, Kunimatsu
A, Aoki S.
Utility of a Multi-Parametric Quantitative MRI
Model That Assesses Myelin and Edema for
Evaluating Plaques, Periplaque White Matter, andNormal-Appearing White Matter in Patients with
Multiple Sclerosis: A Feasibility Study.
AJNR Am J Neuroradiol 38(2): 237-42, 2017
13. Hagiwara A, Hori M, Yokoyama K, Takemura MY,
Andica C, Tabata T, Kamagata K, Suzuki M, Kumamaru KK, Nakazawa M, Takano N, Kawasaki
H, Hamasaki N, Kunimatsu A, Aoki S.
Synthetic MRI in the Detection of Multiple Sclerosis Plaques.
AJNR Am J Neuroradiol 38(2): 257-63, 2017
14. Hagiwara A, Warntjes M, Hori M, Andica C,
Nakazawa M, Kumamaru KK, Abe O, Aoki S.
SyMRI of the Brain: Rapid Quantification of Relaxation Rates and Proton Density, with Synthetic
MRI, Automatic Brain Segmentation, and Myelin
Measurement.
Invest Radiol: Epub ahead of print, 201715. Hanaoka S, Shimizu A, Nemoto M, Nomura Y,
Miki S, Yoshikawa T, Hayashi N, Ohtomo K,
Masutani Y.
Automatic detection of over 100 anatomical
landmarks in medical CT images: A frameworkwith independent detectors and combinatorial optimization.

Med Image Anal 35:192-214, 2017
16. Hanaoka S, Masutani Y, Nemoto M, Nomura Y,
Miki S, Yoshikawa T, Hayashi N, Ohtomo K,
Shimizu A.
Landmark-guided diffeomorphic demons algorithm and its application to automatic segmentation of the whole spine and pelvis in CT images.
Int J Comput Assist Radiol Surg 12(3): 413-30,
2017
17. Hayashi TY, Matsuda I, Hagiwara K, Takayanagi
T, Hagiwara A.
Massive splenic infarction and splenic venous
thrombosis observed in a patient with acutesplenic syndrome of sickle cell traits on contrast-enhanced thin-slice computed tomography.
Abdom Radiol (NY) 41(9): 1718-21, 201618. Hayashi TY, Gonoi W, Yoshikawa T, Hayashi N,
Ohtomo K.
Ansa pancreatica as a predisposing factor for recurrent acute pancreatitis.
World J Gastroenterol 22(40): 8940-8, 2016
19. Inoue M, Tanaka S, Nakatomi H, Takayanagi S,
Takahashi M, Tanaka M, Momose T, Mukasa A,
Saito N.
Intracranial Infantile Myofibromatosis Mimicking
Malignant Brain Tumor: A Case Report and Literature Review.
World Neurosurg 93: 487.e15-20, 2016
20. Irie R, Tsuruta K, Hori M, Suzuki M, Kamagata K,
Nakanishi A, Kamiya K, Nakajima M, Miyajima
M, Arai H, Aoki S.
Neurite orientation dispersion and density imaging for evaluation of corticospinal tract in idiopathic normal pressure hydrocephalus.
Jpn J Radiol 35(1): 25-30, 2017
21. Ishibashi N, Hata M, Mochizuki T, Ogawa K,
Sugiura H, Takekawa Y, Maebayashi T, Aizawa T,
Sakaguchi M, Abe O.
Radiation therapy for primary breast lymphoma in
male gynecomastia: a rare case report and reviewof the literature.
Int J Hematol 104(4): 519-24, 2016
22. Ishibashi N, Maebayashi T, Aizawa T, Sakaguchi
M, Abe O, Sakanishi K, Endoh Y, Saito T, Kawamori J, Tanaka Y.
Various Regimens of Total Body Irradiation for
Hematopoietic Stem Cell Transplant.

65

Exp Clin Transplant 14(6): 670-75, 2016
23. Iwashiro N, Koike S, Satomura Y, Suga M, Nagai
T, Natsubori T, Tada M, Gonoi W, Takizawa R,
Kunimatsu A, Yamasue H, Kasai K.
Association between impaired brain activity andvolume at the sub-region of Broca's area in ultra-high risk and first-episode schizophrenia: A
multi-modal neuroimaging study.
Schizophr Res 172(1-3): 9-15, 201624. Iwashiro N, Koike S, Satomura Y, Suga M, Nagai
T, Natsubori T, Tada M, Gonoi W, Takizawa R,
Kunimatsu A, Yamasue H, Kasai K.
Letter to the editor; A corrigendum with respect toour research article entitled “Association between
impaired brain activity and volume at the
sub-region of Broca's area in ultra-high risk andfirst-episode schizophrenia: A multi-modal neuroimaging study”
Schizophr Res 176(2-3): 578-9, 2016
25. Kamagata K, Hatano T, Okuzumi A, Motoi Y, Abe
O, Shimoji K, Kamiya K, Suzuki M, Hori M,
Kumamaru KK, Hattori N, Aoki S.
Neurite orientation dispersion and density imaging in the substantia nigra in idiopathic Parkinson
disease.
Eur Radiol 26(8): 2567-77, 2016
26. Kamiya K, Kamagata K, Miyajima M, Nakajima
M, Hori M, Tsuruta K, Mori H, Kunimatsu A,
Arai H, Aoki S, Ohtomo K.
Diffusional Kurtosis Imaging in Idiopathic Normal Pressure Hydrocephalus: Correlation with
Severity of Cognitive Impairment.
Magn Reson Med Sci 15(3): 316-23, 2016
27. Katano A, Yamashita H, Okuma K, Nakagawa K.
Complete response to abdominal bulky lymph
node recurrence in an esophageal cancer patient
treated with S-1 monotherapy: A case report.
Oncol Lett 11(6): 3901-3, 2016
28. Kubo T, Kiryu S, Akai H, Ota Y, Tojo A, Yoshida
H, Kato N, Nakano Y, Ohtomo K.
Hepatic Involvement of Histiocytic Sarcoma: CT
and MRI Findings.
Korean J Radiol 17(5): 758-62, 2016
29. Kunimatsu A, Kunimatsu N, Kamiya K, Katsura
M, Mori H, Ohtomo K.
Variants of meningiomas: a review of imaging
findings and clinical features.

Jpn J Radiol 34(7): 459-69, 2016
30. Liu X, Watanabe K, Kakeda S, Yoshimura R, Abe
O, Ide S, Hayashi K, Katsuki A, Umene-Nakano
W, Watanabe R, Ueda I, Nakamura J, Korogi Y.
Relationship between white matter integrity andserum cortisol levels in drug-naive patients withmajor depressive disorder: diffusion tensor imaging study using tract-based spatial statistics.
Br J Psychiatry 208(6): 585-90, 201631. Maeda E, Tomizawa N, Kanno S, Yasaka K, Kubo
T, Ino K, Torigoe R, Ohtomo K.
Subjective and objective evaluation of 10–30%
dose reduced coronary artery phantom scans reconstructed with Forward projected model-based
Iterative Reconstruction SoluTion (FIRST).
Data Brief 10: 210–4, 201632. Maeda E, Tomizawa N, Kanno S, Yasaka K, Kubo
T, Ino K, Torigoe R, Ohtomo K.
The feasibility of Forward-projected model-based
Iterative Reconstruction SoluTion (FIRST) for
coronary 320-row computed tomography angiography: A pilot study.
J Cardiovasc Comput Tomogr 11(1): 40-5, 201733. Maeda E, Yamamoto K, Kanno S, Ino K, Tomizawa N, Akahane M, Torigoe R, Ohtomo K.
Diagnostic Phase of Calcium Scoring Scan Applied as the Center of Acquisition Window ofCoronary Computed Tomography Angiography
Improves Image Quality in Minimal Acquisition
Window Scan (Target CTA Mode) Using theSecond Generation 320-Row CT.
ScientificWorldJournal 2016: 1017851, 201634. Matsubara K, Mori H, Hirai N, Yasukawa K,
Honda T, Takanashi JI.
Elevated taurine and glutamate in cerebral juvenile xanthogranuloma on MR spectroscopy.
Brain Dev 38(10): 964-7, 201635. Miki S, Hayashi N, Masutani Y, Nomura Y, Yoshikawa T, Hanaoka S, Nemoto M, Ohtomo K.
Computer-assisted detection of cerebral aneurysms in MR angiography in a routine image-reading environment: Effects on diagnosis byradiologists.
AJNR Am J Neuroradiol 37(6): 1038-43, 2016
36. Mitsui J, Koguchi K, Momose T, Takahashi M,
Matsukawa T, Yasuda T, Tokushige SI, Ishiura H,
Goto J, Nakazaki S, Kondo T, Ito H, Yamamoto Y,

66

Tsuji S.
Three-Year Follow-Up of High-Dose Ubiquinol
Supplementation in a Case of Familial Multiple
System Atrophy with Compound Heterozygous
COQ2 Mutations.
Cerebellum: Epub ahead of print, 201737. Nakamura K, Yoshizaki A, Takahashi T, Saigusa
R, Taniguchi T, Asano Y, Gonoi W, Hinata M,
Shinozaki-Ushiku A, Sato S.
The first case report of fatal acute pulmonary
dysfunction in a systemic sclerosis patient treatedwith rituximab.
Scand J Rheumatol 45(3) 249-50, 2016
38. Nakamura Y, Shimazoe K, Takahashi H, Yoshimura S, Seto Y, Kato S, Takahashi M, Momose T.
Development of a novel handheld intra-operative
laparoscopic Compton camera for (18)F-Fluoro-2deoxy-2-D-glucose-guided surgery.
Phys Med Biol 61(15): 5837-50, 2016
39. Nakashima R, Komori Y, Maeda E, Yoshikawa T,
Yokosawa K.
Temporal Characteristics of Radiologists' andNovices' Lesion Detection in Viewing Medical
Images Presented Rapidly and Sequentially.
Front Psychol 7: 1553, 2016
40. Namiki Y, Maeda E, Gonoi W, Akamatsu N,
Ikemura M, Ohtomo K.
Pancreatic lipoma with a solid nodule mimicking
invasion from adjoining intraductal papillary mucinous neoplasm.
Radiol Case Rep 11(2): 50-3, 201641. Nobusawa S, Hirato J, Sugai T, Okura N, Yamazaki T, Yamada S, Ikota H, Nakazato Y, Yokoo H.
Atypical Teratoid/Rhabdoid Tumor (AT/RT)
Arising From Ependymoma: A Type of AT/RT
Secondarily Developing From Other PrimaryCentral Nervous System Tumors.
J Neuropathol Exp Neurol 75(2): 167-74, 201642. Nobusawa S, Nakata S, Hirato J, Kawashima T,
Sato K, Fujimaki H, Okura N, Ikota H, Yokoo H.
Atypical teratoid/rhabdoid tumor in the sella turcica of an elderly female with a distinct vascularpattern and genetic alterations.
Virchows Arch 469(6): 711-5, 2016
43. Nomura Y, Higaki T, Fujita M, Miki S, Awaya Y,
Nakanishi T, Yoshikawa T, Hayashi N, Awai K.
Effects of iterative reconstruction algorithms on

computer-assisted detection (CAD) software forlung nodules in ultra-low-dose CT for lung cancer
screening.
Acade Radiol 24(2): 124-30, 201744. Numata T, Kiryu S, Maeda T, Egusa C, Tsuboi R,
Harada K.
A pulmonary metastatic model of murine melanoma assessed by Magnetic Resonance Imaging.
Exp Dermatol: Epub ahead of print, 201745. Okuma H, Gonoi W, Ishida M, Shirota G, Kanno
S, Shintani Y, Abe H, Fukayama M, Ohtomo K.
Comparison of the cardiothoracic ratio between
postmortem
andantemortem
computed
tomography.
Leg Med (Tokyo) 24:86-91, 201746. Sakaguchi M, Maebayashi T, Aizawa T, Ishibashi
N, Fukushima S, Abe O, Saito T.
Patient outcomes of monotherapy with hypofractionated three-dimensional conformal radiation
therapy for stage T2 or T3 non-small cell lungcancer: a retrospective study.
Radiat Oncol 11:3, 2016
47. Sakamoto Y, Inagaki F, Omichi K, Ohkura N,
Hasegawa K, Kokudo N.
Associating
Liver
PartialPartition andTransileocecal Portal Vein Embolization forStaged Hepatectomy.
Ann Surg 264(6): e21-2, 2016
48. Sato K, Tanaka T, Sato J, Shibata E, Nagai Y,
Murono K, Yasuda K, Otani K, Nishikawa T,
Tanaka J, Kiyomatsu T, Hata K, Kawai K, Nozawa H, Kazama S, Yamaguchi H, Ishihara S,
Sunami E, Kitayama J, Ohtomo K, Watanabe T.
Usefulness of preoperative CT colonography forcolon cancer.
Asian J Surg: Epub ahead of print, 201649. Shibata E, Takao H, Amemiya S, Ohtomo K.
Perioperative Hemodynamic Monitoring ofCommon Hepatic Artery for Endovascular Embolization of a Pancreaticoduodenal. Arcade Aneurysm with Celiac Stenosis.
Cardiovasc Intervent Radiol 40(3): 465-9, 201750. Shinozaki T, Imamura Y, Kohashi R, Dezawa K,
Nakaya Y, Sato Y, Watanabe K, Morimoto Y,
Shizukuishi T, Abe O, Haji T, Tabei K, Taira M.
Spatial and Temporal Brain Responses to Noxious
Heat Thermal Stimuli in Burning Mouth

67

Syndrome.
J Dent Res 95(10): 1138-46, 2016
51. Shirota G, Ishida M, Shintani Y, Abe H, Ikemura
M, Fukayama M, Gonoi W.
Can postmortem computed tomography detect
antemortem hypoxic-ischemic encephalopathy?
Forensic Sci Med Pathol 12(3): 267-75, 2016
52. Taguchi S, Shiraishi K, Fukuhara H, Nakagawa K,
Morikawa T, Naito A, Kakutani S, Takeshima Y,
Miyazaki H, Nakagawa T, Fujimura T, Kume H,
Homma Y.
Optimal timing of salvage radiotherapy forbiochemicalrecurrence
after
radicalprostatectomy: is ultra-early salvage radiotherapy
beneficial?
Radiat Oncol 11: 102, 2016
53. Taguchi S, Shiraishi K, Fukuhara H, Nakagawa K,
Morikawa T, Kakutani S, Takeshima Y, Miyazaki
H, Fujimura T, Nakagawa T, Kume H, Homma Y.
Impact of Gleason pattern 5 including tertiary
pattern 5 on outcomes of salvage treatment forbiochemical recurrence in pT2-3N0M0 prostatecancer.
Int J Clin Oncol 21(5): 975-80, 2016
54. Takahashi M, Soma T, Mukasa A, Koyama K,
Arai T, Momose T.
An automated voxel-based method for calculating
the reference value for a brain tumour metabolic
index using (18)F-FDG-PET and (11)Cmethionine PET.
Ann Nucl Med 31(3): 250-9, 2017
55. Takano Y, Aoki Y, Yahata N, Kawakubo Y, Inoue
H, Iwashiro N, Natsubori T, Koike S, Gonoi W,
Sasaki H, Takao H, Kasai K, Yamasue H.
Neural basis for inferring false beliefs and social
emotions in others among individuals with schizophrenia and those at ultra-high risk for psychosis.
Psychiatry Res 259: 34-41, 2017
56. Takao H, Shibata E, Ohtomo K.
Double-Balloon-Assisted
n-Butyl-2-Cyanoacrylate Embolization of Intrahepatic Arterioportal Shunt Prior to Chemoembolization of Hepatocellular Carcinoma.
Cardiovasc Intervent Radiol 39(10): 1479-83,
2016
57. Takao H, Amemiya S, Shibata E, Ohtomo K.
Three-Dimensional Printing of Hollow Portal

Vein Stenosis Models: A Feasibility Study.
J Vasc Interv Radiol 27(11): 1755-8, 2016
58. Takao H, Amemiya S, Shibata E, Ohtomo K.
3D printing of preoperative simulation models ofa splenic artery aneurysm: precision and accuracy.
Acad Radiol: Epub ahead of print, 2017
59. Takenaka R, Yamashita H, Toya T, Haga A,
Shibata S, Kurokawa M, Ootomo K, Nakagawa K.
Unique radiation dermatitis related to total body
irradiation by helical tomotherapy.
J Dermatol 43(11): 1376-7, 2016
60. Taniguchi Y, Takahashi M, Matsudaira K, Oka H,
Momose T.
Potential use of (18)F-FDG-PET/CT to visualize
hypermetabolism associated with muscle pain inpatients with adult spinal deformity: a case report.
Skeletal radiol 45(11): 1577-81, 2016
61. Tokushige S, Terao Y, Matsuda S, Inomata-Terada
S, Shimizu T, Tanaka N, Hamada M, Yugeta A,
Hanajima R, Mori H, Tsuji S, Ugawa Y.
Motor neuron disease with saccadic abnormalities
similar to progressive supranuclear palsy.
Neurol Clin Neurosci 4:146-52, 2016
62. Ueda I, Kakeda S, Watanabe K, Yoshimura R,
Kishi T, Abe O, Ide S, Moriya J, Katsuki A, Hori
H, Iwata N, Nakamura J, Korogi Y.
Relationship between G1287A of the NET Gene
Polymorphisms and Brain Volume in Major
Depressive Disorder: A Voxel-Based MRI Study.
PLoS One 11(3): e0150712, 2016
63. Usami K, Kubota M, Kawai K, Kunii N, Matsuo T,
Ibayashi K, Takahashi M, Kamada K, Momose T,
Aoki S, Saito N.
Long-term outcome and neuroradiologic changes
after multiple hippocampal transection combinedwith multiple subpial transection or lesionectomy
for temporal lobe epilepsy.
Epilepsia 57(6): 931-40, 2016
64. Wang F, Kiryu S, Akai H, Yasaka K, Dumin L,
Qing W.
Assessment of the Hepatic Vasculature inOmphalopagus Conjoined Twins Using ContrastEnhanced Dynamic Computed Tomography.
Int J Radiol Radiat Thera 2(2): 0017, 2017
65. Wang F, Kiryu S, Li L, Wang Q, Li D, Zhang L.
Resectable primary pleural myxoid liposarcoma
with a pedicle: report of a rare case and literature

68

review.
J Thorac Dis 9(3): e183-7, 2017
66. Watanabe K, Kakeda S, Igata N, Watanabe R,
Narimatsu H, Nozaki A, Dan Rettmann, Abe O,
Korogi Y.
Utility of real-time prospective motion correction(PROMO) on 3D T1-weighted imaging in
automated brain structure measurements.
Sci Rep 6: 38366, 2016
67. Watanabe T, Otowa T, Abe O, Kuwabara H, Aoki
Y, Natsubori T, Takao H, Kakiuchi C, Kondo K,
Ikeda M, Iwata N, Kasai K, Sasaki T, Yamasue H.
Oxytocin receptor gene variations predict neuraland behavioral response to oxytocin in autism.
Soc Cogn Affect Neurosci 12(3): 496-506, 2017
68. Wise T, Radua J, Via E, Cardoner N, Abe O,
Adams TM, Amico F, Cheng Y, Cole JH, deAzevedo Marques Perico C, Dickstein DP, Farrow
TF, Frodl T, Wagner G, Gotlib IH, Gruber O, Ham
BJ, Job DE, Kempton MJ, Kim MJ, Koolschijn
PC, Malhi GS, Mataix-Cols D, McIntosh AM,
Nugent AC, O'Brien JT, Pezzoli S, Phillips ML,
Sachdev PS, Salvadore G, Selvaraj S, Stanfield
AC, Thomas AJ, van Tol MJ, van der Wee NJ,
Veltman DJ, Young AH, Fu CH, Cleare AJ,
Arnone D.
Common and distinct patterns of grey-mattervolume alteration in major depression and bipolar
disorder: evidence from voxel-based metaanalysis.
Mol Psychiatry: Epub ahead of print, 2016
69. Yamamoto M, Hasegawa K, Arita J, Maeno R,
Akamatsu N, Kaneko J, Watadani T, Okura N,
Hayashi A, Shibahara J, Sakamoto Y, Ohtomo K,
Fukayama M, Kokudo N.
Primary hepatic schwannoma: A case report.
Int J Surg Case Rep 29: 146-50, 2016
70. Yamashita H, Niibe Y, Yamamoto T, Katsui K,
Jingu K, Kanazawa S, Terahara A, Nakagawa K.
Lung stereotactic radiotherapy for oligometastases: comparison of oligo-recurrence and syncoligometastases.
Jpn J Clin Oncol 46(7): 687-91, 2016
71. Yamashita H, Takenaka R, Okuma K, Ootomo K,
Nakagawa K.
Prognostic factors in patients after definitive
chemoradiation using involved-field radiotherapy
for esophageal cancer in a phase II study.

Thorac Cancer 7(5): 564-9, 2016
72. Yamashita H, Jingu K, Niibe Y, Katsui K,
Matsumoto T, Nishina T, Terahara A.
Definitive salvage radiation therapy andchemoradiation therapy for lymph node oligorecurrence of esophageal cancer: a Japanesemulti-institutional study of 237 patients.
Radiat Oncol 12(1): 38, 201773. Yasaka K, Furuta T, Kubo T, Maeda E, Katsura M,
Sato J, Ohtomo K.
Full and hybrid iterative reconstruction to reduce
artifacts in abdominal CT for patients scanned
without arm elevation.
Acta Radiol: 0284185116684675, 201674. Yasaka K, Kamiya K, Irie R, Maeda E, Sato J,
Ohtomo K.
Metal artefact reduction for patients with metallic
dental fillings in helical neck computed tomography: comparison of adaptive iterative dose
reduction 3D (AIDR 3D), forward-projectedmodel-based iterative reconstruction solution(FIRST) and AIDR 3D with single-energy metal
artefact reduction (SEMAR).
Dentomaxillofac Radiol 45(7): 20160114, 2016
75. Yasaka K, Maeda E, Hanaoka S, Katsura M, SatoJ, Ohtomo K.
Single-energy metal artifact reduction for helicalcomputed tomography of the pelvis in patientswith metal hip prostheses.
Jpn J Radiol 34(9): 625-32, 2016
76. Yoshida Y, Nitadori JI, Shinozaki-Ushiku A, SatoJ, Miyaji T, Yamaguchi T, Fukayama M, Nakajima
J.
Micropapillary histological subtype in lungadenocarcinoma of 2 cm or less: impact onrecurrence and clinical predictors.
Gen Thorac Cardiovasc Surg: Epub ahead of print,
2017
77. Yoshikawa N, Shimizu N, Uehara M, Oda A,
Matsumiya R, Matsubara E, Kobayashi H,
Hosono O, Kuribara-Souta A, Baba H, Nagamura
F, Kiryu S, Tanaka H.
The effects of bolus supplementation of branchedchain amino acids on skeletal muscle mass,strength, and function in patients with rheumatic
disorders during glucocorticoid treatment.
Mod Rheumatol: Epub ahead of print, 2016

Radiology and Biomedical
Engineering
2. Biomedical Engineering

70

Department of System Physiology
Associate Professor
Kimiko Yamamoto, M.D., Ph.D.

Homepage

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

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, andBiosystem Construction and Control. The Department
of System Physiology consists of one 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” forpostgraduate students, “Introduction to Medical
Science: Mechanobiology” for master’s students, inthe faculty of Medicine, and “Principles of Medicine”
for postgraduate students in the faculty of Engineering.
We offer practical training of biomedical engineeringresearch to third- and fourth-year students ofundergraduate medical school. A weekly seminar isheld in our laboratory bringing together staff andresearch fellows to discuss journal articles and give
updates on experiments. Our aim is to enhance theresearch skills of 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
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71antithrombotic 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/macrophase-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
stress-responsive genes, a cDNA encoding an
unknown G-protein coupled receptor was cloned. We
showed that the transcription factor SP1 is involved in
the shear 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 vascularremodeling, via both GATA6-mediated downregulation of gene transcription and an acceleration ofmRNA degradation, while turbulent shear stressincreases the uPA gene expression through mRNAstabilization. We demonstrated that shear stress
up-regulates the gene expression of plasminogenactivator inhibitor-1 (PAI-1) through activation oftranscription factors Sp-1 and Ets-1 in humanhepatocytes. We developed a compliant tube-typeflow-loading device that allows simultaneous
application of physiological levels of shear stress andcyclic strain to cultured cells and observed that the
response of endothelial genes to shear stress or cyclicstrain depends on whether the two forces are applied
separately or together.
3. Hemodynamic force-induced cell differentiation
We have revealed that endothelial progenitor cells(EPCs) circulating in human peripheral blood
proliferate and differentiate into mature ECs in
response to shear stress, thereby forming tube-likestructures in collagen gel. Moreover, we revealed thatshear stress increased the gene expression of 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.
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

72

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. Endogeneously 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 andremodeling, indicating that shear stress signal transduction via P2X4 plays a critical role in the regulationof circulatory functions. Our study revealed that cellsurface ATP synthase localized in caveolae/lipid rafts
are involved in the shear-stress-induced ATP releaseby ECs.
Moreover, we recently report that the plasma
membrane itself differentiates between shear stressand stretch by undergoing transitions in its lipid
phases. Shear stress decreased the lipid order ofhuman pulmonary artery EC plasma membranes,
thereby causing a transition from the liquid-orderedphase to the liquid-disordered phase in some areas,
along with an increase in membrane fluidity. In
contrast, uniaxial stretching and hypotonic swellingincreased the membrane lipid order and decreased
membrane fluidity. A similar increase in lipid orderoccurred when the artificial lipid bilayer membranesof giant unilamellar vesicles were stimulated by shear
stress by using a flow-loading apparatus or stretchedby hypotonic swelling, indicating that mechanicalforce-mediated responses 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 by depleting membrane cholesterol with methyl-

β-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. K. Tanishita, K. Yamamoto. “Introduction” inTanishita K, Yamamoto K (eds.). VascularEngineering, Springer, Tokyo, pp 1-11, 2016.
2. T. Aoki, K. Yamamoto. “Fundamentals ofPhysiology and Biology of Vascular System” inTanishita K, Yamamoto K (eds.). VascularEngineering, Springer, Tokyo, pp 47-68, 2016.
3. Yamamoto K and Ando J. Vascular endothelial
cell membranes differentiate between stretch andshear stress through transitions in their lipid
phases. Am. J. Physiol. Heart Circ. Physiol.
309:H1178-H1185, 2015.
4. Yamamoto K and Ando J. Shear stress sensing. J.
Clin. Exp. Med. 257:1008-1014, 2016.
5. Yamamoto K and Ando J. Mechanisms of vascular
dynamic homeostasis. Clin. Calcium 26:17571764, 2016
6. Ando J and Yamamoto K. Mechanosensing in thecirculatory system. Vasc. Biol. Med. 17:315-324,
2016.

73

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

Assistant Professor
Mako Kamiya, Ph.D.

Homepage

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

Introduction and Organization
The Laboratory of Chemical Biology and Molecular
Imaging is one of the laboratories in the department ofRadiology and Biomedical Engineering. Ourlaboratory is located in the annex of the medicalbuilding 3. Our lab members consist of 2 post-doctoral
researchers, 7 PhD students, 2 master course student
and one technical staff by the end of FY2016.

Teaching activities
As for under-graduate education, our laboratory takes
part in medical engineering lectures for the 3rd year
medical students. As for PhD course education, ourlaboratory delivers the lecture of fluorescence imaging
for both master and doctor course students. Ourlaboratory is also accepting Free Quarter students
every year for the opportunity to be trained tosynthesize chemical probes and observe live cells withfluorescent microscopes. Our laboratory is also
accepting under-graduate students as Medical
Scientist Training Program in faculty of medicine.
They are doing their own research under thesupervision of our staffs, and one student was
graduated this program by the end of FY2016.

Research activities
Our lab aims at developing novel fluorescence probes
and applying these molecules to biology and medicine.
So far, we have succeeded in establishing rational

design strategies of fluorescence probes based on
severalmechanism
suchasintramolecularspirocyclization. In FY2016, we have succeeded todevelop several novel fluorescence probes forvisualizing biological analytes or enzyme activities inliving cells and tissues.
For example, a reversible fluorescent probe forglutathione was developed based on the mechanism ofintermolecular nucleophilic addition/dissociation of
glutathione to the fluorophore. This probe enables
live-cell imaging and quantification of intracellularglutathione, and real-time monitoring of fast
glutathione dynamics. Therefore, it is expected toserve as a practical analytical tool for investigating
biological functions of glutathione in living cells(Reference 2).
We also developed a fluorogenic β-galactosidase
substrate suitable for labeling live cells in culture, as
well as in living tissues. This precisely functionalized
fluorescent probe exhibited dramatic activation offluorescence upon reaction with the enzyme, remained
inside cells by anchoring itself to intracellular proteins,and provided single-cell resolution (Reference 4).
We also applied our fluorescence probe librarytargeted for aminopeptidases and glycosidases toclinical specimens resected from cancer patients, inorder to elucidate characteristic features of live cancer
cells and to screen a suitable probe for visualizing
specific cancer. As a result, we found that our probe
for dipeptidylpeptidase IV (DPPIV) is useful for rapid
visualization of early esophageal squamous cell

74

carcinoma in collaboration with Department of
Gastrointestinal Surgery, The University of Tokyo
Hospital (Reference 7). We also found that a probe forhexosaminidase can visualize human colorectal cancer
by collaborating with Department of Surgical
Oncology, The University of Tokyo Hospital(Reference 9), and that a probe for γ-glutamyltranspeptidase (GGT) can visualize primary lung cancer
with sensitivity of 43.8% and specificity of 84.9% bycollaborating with Department of Thoracic Surgery,
The University of Tokyo Hospital (Reference 8). We
are now validating these new probes for the clinicalapplication.
We also demonstrated that our fluorescence probeswith suppressed fluorescence quantum yields areuseful for photoacoustic imaging (Reference 1).

6.

7.

References
1. Hirasawa T, Iwatate JR, Kamiya M, Okawa S,
Urano Y, Ishihara M: Multispectral photoacoustic
imaging of tumours in mice injected with an
enzyme-activatable photoacoustic probe. Journalof Optics. 2017; 19: 14002.
2. Umezawa K, Yoshida M, Kamiya M, Yamasoba T,
Urano Y: Rational design of reversible fluorescentprobes for live-cell imaging and quantification of
fast glutathione dynamics. Nature Chemistry.
2017; 9: 279-286.
3. Mizushima T, Ohnishi S, Shimizu Y, Hatanaka Y,
Hatanaka KC, Hosono H, Kubota Y, Natsuizaka
M, Kamiya M, Ono S, Homma A, Kato M,
Sakamoto N, Urano Y. Fluorescent imaging ofsuperficial head and neck squamous cell
carcinoma using a γ-glutamyltranspeptidaseactivated targeting agent: a pilot study. BMC
Cancer. 2016; 16: 411.
4. Doura T, Kamiya M, Obata F, Yamaguchi Y,
Hiyama TY, Matsuda T, Fukamizu A, Noda M,
Miura M, Urano Y. Detection of LacZ-Positive
Cells in Living Tissue with Single-Cell Resolution.
Angew Chem Int Ed 2016; 55: 9620-9624.
5. Okubo K, Kamiya M, Urano Y, Nishi H, Herter
JM, Mayadas T, Hirohama D, Suzuki K,
Kawakami H, Tanaka M, Kurosawa M, Kagaya S,
Hishikawa K, Nangaku M, Fujita T, Hayashi M,
Hirahashi J. Lactoferrin Suppresses Neutrophil

8.

9.

Extracellular Traps Release in Inflammation.
BioMedicine. 2016; 10: 204-215.
Shinden Y, Ueo H, Tobo T, Gamachi A, Utou M,
Komatsu H, Nambara S, Saito T, Ueda M, Hirata
H, Sakimura S, Takano Y, Uchi R, Kurashige J,
Akiyoshi S, Iguchi T, Eguchi H, Sugimachi K,
Kubota Y, Kai Y, Shibuta K, Kijima Y, Yoshinaka
H, Natsugoe S, Mori M, Maehara Y, Sakabe M,
Kamiya M, Kakareka JW, Pohida TJ, Choyke PL,
Kobayashi H, Ueo H, Urano Y, Mimori K. Rapid
diagnosis of lymph node metastasis in breast
cancer using a new fluorescent method with
γ-glutamyl hydroxymethyl rhodamine green. Sci
Rep. 2016; 6: 27525.
Onoyama H, Kamiya M, Kuriki Y, Komatsu T,
Abe H, Tsuji Y, Yagi K, Yamagata Y, Aikou S,
Nishida M, Mori K, Yamashita H, Fujishiro M,
Nomura S, Shimizu N, Fukayama M, Koike K,
Urano Y, Seto Y. Rapid and sensitive detection ofearly esophageal squamous cell carcinoma withfluorescence probe targeting dipeptidylpeptidase
IV. Sci Rep. 2016; 6: 26399.
Hino H, Kamiya M, Kitano K, Mizuno K, Tanaka
S, Nishiyama N, Kataoka K, Urano Y, Nakajima J.
Rapid Cancer Fluorescence Imaging Using A
γ-Glutamyltranspeptidase-Specific Probe For
Primary Lung Cancer. Translational Oncology.
2016; 9: 203-210.
Matsuzaki H, Kamiya M, Iwatate RJ, Asanuma D,
Watanabe T, Urano Y. Novel HexosaminidaseTargeting Fluorescence Probe for Visualizing
Human Colorectal Cancer. Bioconjug Chem.
2016; 27: 973-981.

75

Department of Biosystem
Construction & Control
Associate Professor
Yusuke Abe, M.D., Ph.D.

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 an associate professor, alecturer, two project researchers, 7 graduate students,
17 visiting researchers, a senior technical specialist,
and a project academic support stuff.
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 to the weekly meeting. They canlearn how to perform the research work and how toreport it through the meeting.

76

The education to train the leaders of medical
engineers and clinical engineers is another importantrole of our laboratory.

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

The HFTAH could be implanted in the goatsuccessfully with good anatomical fitting. To date, thegoat whose heart was replaced with the HFTAH
survived for 100 days. We are expecting to develop an
ideal TAH that surpass the outcome of the hearttransplantation with combination of the technologiesof the physiological control and hybrid materials
described later.
How to control the output of a TAH is primary interest.
We have developed our original physiological control
method of the TAH, named 1/R control. The 1/R
control was developed with a conductance (1/R:
reciprocal of a resistance) parallel circuit model. Withthe 1/R control, the particular problems of a TAH suchas venous hypertension, slight anemia, low thyroid
hormone level and so on, were not observed and theoutput changed in accordance with a metabolic
demand of the animal.
The problem of the 1/R control was a mismatching of
the time constants between the control systems of thedevice and the body. As a consequence, the 1/R
control occasionally diverged in the animal experiment of the UPTAH and HFTAH. To improve theproblem of instability in the 1/R control, a new control
method based on the fluctuation of arterial and venous
pressures (named ΔP control) was developed byreforming the 1/R control function. At present, ΔP
control is tested with the animal experiment.
On the other hand, the 1/R control was applied to the
UPTAH and HFTAH to perform a physiological study
with a nonpulsatile TAH by changing the drive mode
from pulsatile to nonpulsatile in a single goat. The
result showed that, for a period of several weeks, the
1/R control could be promising not only with apulsatile flow, but also with a nonpulsatile flow. The
general conditions and organ functions were notchanged by the application of the nonpulsatile flow.
The cardiac output and the arterial pressure changed
with the condition of the goat in the pulsatile and also
nonpulsatile flow, which seemed almost identical.
However, under the physiological atrial pressure, thesucking effect of atria was more significant in the
nonpulsatile flow than the pulsatile flow. Therefore,
the nonpulsatile TAH with the 1/R control was
considered to be inadequate, unless some pulsatility
would be introduced to avoid the sucking effect for
ensuring sufficient inflow condition.

77

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 thecomponents of living tissue because these components
have insufficient strength and durability, even though
they have excellent tissue compatibility. To overcome
these problems, an insert molding method, which iscommonly used for resin molding in the industrial
field, was introduced. In this method, the mold, inwhich an artificial material was inserted, was
implanted in the animal, and the tissue grew into themold to make a hybrid material. The method was first
applied to the Jellyfish valve that was originally apolymer valve for the artificial hearts. The hybrid
Jellyfish valve demonstrated a good result. Then, we
started to develop the hybrid conduit of the inflow
cannula for the left ventricular assist device (LVAD).
The conduit is inserted into the apex of the left
ventricle where the thrombus often formed. In thismethod, the mold in which the core of the conduit wasinserted was implanted under the skin of a goat. Afterseveral months, the hybrid conduit was extirpated, andthen freeze-dried, sterilized and used. The experimentof the LVAD using the hybrid conduit is going on witha goat. This hybrid technique will be an important
technology for developing the next generation
artificial organs.
A project of the emergency life support system(ELSS) that is a compact and transportable heart
and/or lung assist device has been started in 2004. The
device consists of a blood pump, an oxygenator, adrive and control unit, and a battery unit. To realize
several-months support with the ELSS, a new bloodpump named the sequential flow pump (SFP) has beendeveloped. The SFP in which fluid is given centrifugal
force sequentially twice in a pump was invented in ourlaboratory in 2013. This sequential pressurization
mechanism enables high-pressure output without highimpeller speed, which can reduce the sheer stress ofthe blood. To realize integration of the pump with theartificial lung, inlet and outlet ports are located atlateral side and center of the pump, respectively,
which is the reverse configuration of conventional
centrifugal pumps. In the ELSS, the whole systemcomponents will be packed in a case having 180 mm
in diameter and 390 mm in length. The whole weight

will be about 20 kg.
Our research of the application of ICT (Informationand communication technology) to medicine has been
focused on the home medical care. The research anddevelopment for monitoring the condition of thepatients living at home has been performed utilizing
the miniaturized wireless electrocardiogram (ECG)
unit with low power consumption. The ECG unit is
attached on the patient’s chest at home. The ECG datais transmitted to the laptop computer set in thepatient’s home. The data is then transmitted to the dataserver set at our laboratory through the mobile
Internet communication. The client computers in theclinic or doctor’s smart phone receive the real-timedata through the Internet lines from the data server.
This system has been tested experimentally in a clinic.
The system revealed to be very useful especially fortaking care of the patients who were going to be indeathbed. To obtain more detailed diagnosis of suchpatients, a breathing monitor is necessary. The
transmitter unit contains a three-axis acceleration
sensor that is used usually for detecting the motion or
posture of the patient. We detected the respiratory
frequency using the three-axis acceleration sensor
contained in the unit.

References
1. Terumi Yurimoto, Shintaro Hara, Takashi Isoyama,
Itsuro Saito,Toshiya Ono, Yusuke Abe.
Viscosity-adjusted estimation of pressure headand pump flow with quasi-pulsatile modulation ofrotary blood pump for a total artificial heart.
Journal of Artificial Organs, 2016: 19(3); 219-25,
DOI: 10.1007/s10047-016-0898-5.
2. Tsuyoshi Sekitani, Tomoyuki Yokota, Kazunori
Kuribara, Martin Kaltenbrunner, Takanori
Fukushima, Yusuke Inoue, Masaki Sekino,
Takashi Isoyama, Yusuke Abe, Hiroshi Onodera,
Takao Someya. Ultraflexible organic amplifier
with biocompatible gel electrodes. Nature
Communications, 2016; 7: 11425-11435, DOI :10.1038/ncomms11425.
3. Sungwon Lee, Amir Reuveny, Jonathan Reeder,
Sunghoon Lee, Hanbit Jin, Qihan Liu, Tomoyuki
Yokota, Tsuyoshi Sekitani, Takashi Isoyama,
Yusuke Abe, Zhigang Suo and Takao Someya. A

78transparent bending-insensitive pressure sensor.
Nature Nanotechnology, 2016; 11: 472-479, DOI:
10.1038/nnano.2015.324.

Neuroscience
1. Basic Neuroscience80

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

Project associate professor
Tadafumi Hashimoto, Ph.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

81

PEN-2 is the component that confers proteolytic
activity to this complex. They also showed that PS,
APH-1, nicastrin and PEN-2 are the essential set ofproteins that comprise the γ-secretase complex(Takasugi et al. Nature, 2003). This study ishighlighted as a milestone work that elucidated themechanistic roles of protein cofactors in the formationand function of γ-secretase (see reviews; Iwatsubo
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
CLAC-positive senile plaques constitute a uniquesubset of plaques distinct from the classical,

82

β-sheet-rich amyloid deposits, underscoring thepathobiological role of CLAC in amyloid formation,and that CLAC inhibits fibrillization of Aβ in vitro.
Knockout mice studies have confirmed the role of
CLAC in neuromuscular development (Tanaka et al. J
Neurosci, 2014).
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.

References
1) Taniguchi-Watanabe S, Arai T, Kametani F,
Nonaka T, Masuda-Suzukake M, Tarutani A,
Murayama S, Saito Y, Arima K, Yoshida M,
Akiyama H, Robinson A, Mann DMA, Iwatsubo
T, Hasegawa M: Biochemical classification oftauopathies by immunoblot, protein sequence andmass spectrometric analyses of sarkosyl-insoluble
and trypsin-resistant tau. Acta Neuropathol 131:267-280, 20162) Tominaga A, Cai T, Takagi-Niidome S, Iwatsubo
T, Tomita T: Conformational changes intransmembrane domain 4 of presenilin 1 areassociated with altered Aβ42 production. J
Neurosci 36:1362-1372, 2016
3) Hayashi Y, Nishimune H, Hozumi K, Saga Y,
Harada A, Yuzaki M, Iwatsubo T, Kopan R,
Tomita T: A novel non-canonical Notch signaling
regulates expression of synaptic vesicle proteinsin excitatory neurons. Sci Rep 6:23969, 2016
4) Kuwahara T, Inoue K, D’Agati VD, Saha S,

5)

6)

7)

8)

Wolozin B, Iwatsubo T, Abeliovich A: LRRK2and RAB7L1 coordinately regulate axonal
morphology and lysosome integrity in diverse
cellular contexts. Sci Rep 6:29945, 2016
Ikari Y, Akamatsu G, Nishio T, Ishii K, Ito K,
Iwatsubo T, Senda M: Phantom criteria for
qualification of brain FDG and amyloid PET
across different cameras EJNMMI Physics 3:23,
2016
Kanatsu K, Hori Y, Takatori S, Watanabe T,
Iwatsubo T, Tomita T: Partial loss of CALM
function reduces Aβ42 production and amyloid
deposition in vivo. Hum Mol Genet pii: ddw239,
2016
Miyagawa T, Ebinuma I, Morohashi Y, Hori Y,
Chang MY, Hattori H, Maehara T, Yokoshima S,
Fukuyama T, Tsuji S, Iwatsubo T, Prendergast GC,
Tomita T: BIN1 regulates BACE1 intracellulartrafficking and amyloid-β production. Hum Mol
Genet 25:2948-2958, 2016
Matsukawa K, Hashimoto T, Matsumoto T, Ihara
R, Chihara T, Miura M, Wakabayashi T, Iwatsubo
T: ALS-linked mutations in profilin 1 exacerbate
degeneration in the retina of Drosophilamelanogaster through increasing the cytoplasmic
localization of TDP-43. J Biol Chem 291:
23464-23476, 2016

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, four postdoctoral scholars, one
technical staff member, three Ph.D. graduate students,
three rotating medical students, three technical84

assistants and one administrative assistant.

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 in

85

the cerebellar granule cells played a critical role intuning the pCREB response necessary for
depolarization-mediated neuronal survival, and that infact CaMKIV stability was actively maintained bydepolarization. Loss of depolarizing signal led to a
caspase-mediated proteolytic degradation of CaMKIV.
This in turn severely impaired CREB phosphorylation,
facilitating apoptosis, and conversely rescuing pCREB
by overexpressing an active form of CaMKIV was
sufficient to prevent apoptosis (See et al., FASEB J.,
2001). Consistent with our observation that subtle
CREB regulation may underlie the neuronal cell
survival, CREB-dependent gene expression mechanisms, especially CBP regulation, have actually been
proposed to be affected in one way or another in manyneurodegenerative disorders such as hereditary
polyglutamine diseases. We thus speculated that if
CREB-opathies (or various defects in CREB-mediatedgene activation mechanisms) were critical determinants in exacerbating neurodegeneration, certain
disease forms may actually accompany deficit in
CaMKIV / pCREB signaling (Bito and TakemotoKimura, Cell Calcium 2003). We also identified
kinase/phosphatase signaling responsible for activitydependent nuclear trafficking of CRTC1, a key
cofactor of CREB, and demonstrated its roles in
CREB-dependent transcription and contextual fear
memory in amygdala (Nonaka et al., Neuron 2014).
To elucidate the significance of the genes
regulated downstream of CREB during learning andmemory, we set out to uncover the most elementary
regulatory element required and sufficient to trigger
robust activity-dependent gene induction of theimmediate early gene Arc, whose expression in many
brain areas have been invariably associated with key
cognitive activities mediated by these areas. We
discovered a fundamentally novel synaptic activityresponsive element (SARE) which was present as a
distal regulatory promoter element and was conserved
across most mammalian species (Kawashima et al.
PNAS 2009; Kim et al. Nature 2010; Inoue et al.
Commun. Integr. Biol. 2010). Surprisingly, SARE
contained juxtaposed binding elements for all three
activity-regulated transcription factors, CREB, MEF2
and SRF. The identification of SARE enables us tobuild reporter virus and mouse lines that are expected
to be useful to map the extent of neuronal circuit

activation during various kinds of cognitive activities(Kawashima et al. Nature Methods, 2013).
Inaddition to the transcriptional regulation, we are
currently investigating about the physiological
function and its molecular mechanism of Arc, which isthought to be a key player that contributes activity
dependent neuronal plasticity at post synaptic sites(Okuno et al. Cell 2012).
One parallel branch of CaMK signaling that has
not been widely studied is the CaMKK/CaMKI
pathway. During the search for potential CaMKIV-like
CREB regulatory kinases (CLICKs) (Ohmae et al., J.
Biol. Chem. 2006), we identified a novel CaMKI
isoform that contained a C-terminal CAAX lipid
modification motif (Takemoto-Kimura et al., J. Biol.
Chem., 2003; Takemoto-Kimura et al. Neuron 2007).
This novel membrane-bound CaMK (CLICK-III/
CaMKIγ) is most expressed in the central nucleus of
the amygdala and in the ventral medial hypothalamus,
while also being present at a much weaker amount inmost central neurons. Biochemical and cell biologicalstudies indicated a critical role for lipidification of thiskinase to be properly sorted into specific lipidrestricted membrane microdomains. The function
played by this lipidified, membrane-inserted CaMK in
circuitry formation and maturation was scrutinizedusing RNA interference. Along with the identificationof the critical lipid-modifying enzyme that controls
lipid-anchoring of this kinase, we discovered a novel
activity-regulated mechanism whereby CLICK-III/
CaMKIγ is actively sorted into dendritic lipid rafts,
where it specifically regulates Rac-mediated actin
remodeling that is required for BDNF-stimulated
dendritogenesis (Takemoto-Kimura et al., Neuron,
2007; Takemoto-Kimura et al. Eur. J. Neurosci. 2010).
Similar studies in axonal growth also suggest theactive contribution of CaMKK cascade in this process(Ageta-Ishihara et al., J. Neurosci. 2009; TakemotoKimura et al. Eur. J. Neurosci. 2010).
How do these multiple Ca2+-dependent signaling
molecules process each pattern of intracellular Ca2+
dynamics to induce a cellular response? Recently, we
have developed a method named dFOMA (dual FRET
imaging with optical manipulation) to simultaneously
measure activities of two distinct signaling moleculesin living neurons. Applying originally developed
FRET probes to dFOMA method enabled us to86

measure 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 (Inoueet al., 2015). 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., 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
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 to87

immediately initiate neuritogenesis. This indicatedthat endogenous Rho activators, by titrating ROCK
activity, continuously antagonized process/ branchformation and that local gradient of Rho activators
might play a crucial role in shaping the timing and theextent of process formation (Bito, J. Biochem., 2003).
Consistent with this idea, we found that in cerebellar
granule cells, a chemokine SDF-1α released from thepia mater was likely to be a predominant Rho
activator via stimulation of a cognate and specific
GPCR CXCR4 (Arakawa et al., J. Cell Biol., 2003).
While a true gradient in SDF-1α still remains to be
demonstrated in vivo, it is intriguing to note that mostactive axonal process formation and elongation
actually occur in the inner zone of EGL that is
opposite and most distant from the interface with the
pia mater (Bito, J. Biochem., 2003). Most strikingly,
we demonstrated that axon elongation could actively
occur in an intermediate Rho activity range thatenables ROCK to be weakened enough while allowing
another Rho effector mDia1 to actively mediate its
effect on actin nucleation and polymerization(Arakawa et al., J. Cell Biol., 2003).
Whether similar or distinct mechanisms also
operate during spinogenesis and spine maturation
remains to be determined, though a role for Rho andROCK has already been postulated in control of spinecomplexity and spine stability. However, multiple
small GTPase signaling cascades clearly seem tocontribute together, in a tightly coordinated manner, tospine regulation, since many distinct classes of GEFs
and GAPs have now been shown to be localized in thedendritic spines. We ourselves initially reported thefirst two direct examples for PSD localization for such
Rho small GTPases interacting proteins, Citron(Furuyashiki et al., J. Neurosci., 1999) and Cupidin/
Homer2 (Shiraishi et al., J. Neurosci., 1999).
In an attempt to pin down molecular mechanismsthat link PSD complexes and spine formation, wequantitatively examined the effect of deleting thebinding capacity of single PDZ domains of PSD-95,
one by one, and in combination, by structure-based
amino acid replacements rather than domain deletion.
Such a second-generation structure-function relation
study surprisingly revealed that a quantitative binding
between PSD-95 and synGAP tightly controlled thedegree of PSD protein clustering in a manner that was

inversely correlated with the distance from the spine
head to the shaft. Thus, these results suggest theexistence of a tight coordination between the state of
PSD complex and the morphogenetic activity of eachspine (Nonaka et al. J. Neurosci., 2006).
In parallel with this work, we and others
determined that protein-protein interaction was key todetermining the physical distance between thesynaptic vesicles in the active zone and the voltagegated calcium channels in its vicinity, the opening of
which triggers their release (Kiyonaka et al., Nature
Neurosci., 2007).

Publications by lab members(January 2016- December 2016)
1. Gaffield MA, Amat SB, Bito H, Christie JM. (2016)
Chronic imaging of Purkinje cell calcium activity inawake behaving mice. J Neurophysiol. 115: 413-22.
(DOI: 10.1152/jn.00834.2015.)
2. Horigane S, Ageta-Ishihara N, Kamijo S, Fujii H,
Okamura M, Kinoshita M, Takemoto-Kimura S, Bito
H (2016) Facilitation of axon outgrowth via a
Wnt5a-CaMKK-CaMKIα pathway during neuronalpolarization. Mol Brain. 9:8. (DOI: 10.1186/s13041016-0189-3.)
3. Kim CK, Yang SJ, Pichamoorthy N, Young NP,
Kauvar I, Jennings JH, Lerner TN, Berndt A, Lee SY,
Ramakrishnan C, Davidson TJ, Inoue M, Bito H,
Deisseroth K. (2016) Simultaneous fast measurementof circuit dynamics at multiple sites across the
mammalian brain. Nat Methods. 13:325-8. (DOI:
10.1038/nmeth.3770.)

88

Department of Neurobiology
Professor
Kenzo Hirose, M.D., Ph.D.

Assistant Professor
Shigeyuki Namiki, Ph.D.,

Homepage

Daisuke Asanuma, Ph.D.

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

Introduction and Organization
The forerunner of Department of Neurobiology is
Department of psychology in Institute of Brain
Research, Faculty of Medicine, University of Tokyo.
Department of psychology was changed to
Department of Neurobiology in 1984. In 2008, Dr.
Kenzo Hirose from Department of Cell Physiology in
Nagoya University was appointed as a new professor.

Teaching activities
We accept Free-Quarter students. Students are
expected to experience various experimental
techniques including basic fluorescence imaging
techniques in living cells as well as cutting-edge
technologies developed in our lab, based on theirinterests. For the training of Master and Ph.D. course
graduated school students, we have a monthly
progress report for discussing current research
activities by each member who summarizes his/her
recent experimental data. Further, we have a seminarby domestic and foreign guest researchers to extend
our knowledge.

Research activities
A goal of our research is to elucidate regulation
mechanisms of cell function through newdevelopment of novel technologies. The main subjectsof our research 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 underling 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 exocytosis process
is indispensable. Aiming at imaging neurotransmitter
glutamate, we developed a novel optical glutamate
probe by our high-throughput screening system. By
using this probe, we successfully visualized presynaptically released glutamate following presynaptic
firing with a single synapse resolution. These results
indicate that our glutamate probe is useful to study
presynaptic modulation and plasticity. To clarify the
dynamics of exocytosis in an excitatory synapse, we
tried to quantitatively analyze released glutamate atindividual synapses. Our results suggest that single
hippocampal synapses contain several release units.

893) Analysiins of supra-molecular assemblies ofsynaptic molecules in central synapse
Recently, nanoscale molecular distribution in synapse
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 supereresolution microscopic
analysis and imaging of synaptically released
glutamate. These advanced imaging techniquerevealed that dynamics of neurotransmitter release isprecisely controlled by the highly coordinatednanoscale molecular assemblies of presynaptic
molecules. We are also trying to identify thefunctional changes in nanoscale molecular assemblies
in psychiatric disease model.

References

Neuroscience
2. Integrative Medical Neuroscience91

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.

Teaching activities
In the year of 2016, we had 7 graduate students.
In addition to research training, educational program
including full-year lectures of child psychiatry, caseconference and journal club was arranged.

Research activities
Main subjects of our research are Autism Spectrum
Disorder (ASD), Attention-Deficit/Hyperactivity
Disorder (ADHD), Tourette syndrome which is asevere and chronic tic disorder, and child & adolescentobsessive-compulsive disorder (OCD). We are trying
to combine scientific analysis of objective mental andbehavioral indicators with neuropsychological, brainimaging, and genetic studies into comprehensive andmultidimensional approach to problems in development of brain and mind. We are applying this comprehensive approach to intervention studies including
pharmacotherapy.
Major research projects with full or preliminary
performance in 2016 are as follows:
・ 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 pharmacotherapy andparent training for ADHD
・Effectiveness study of early intervention for autisticpreschoolers and group cognitive behavior therapy
for adults with high-functioning ASD

92

References
1. Ando S, Kuwabara H, Araki T, Kanehara A, Tanaka
S, Morishima R, Kondo S, Kasai K, Mental Health
Problems in a Community After the Great East
Japan Earthquake in 2011: A Systematic Review.
Harv Rev Psychiatrty, 25(1): 15-28, 2017.
2. Watanabe T, Otowa T, Abe O, Kuwabara H, Aoki Y,
Natsubori T, Takao H, Kakiuchi C, Kondo K, Ikeda
M, Iwata N, Kasai K, Sasaki T, Yamasue H.
Oxytocin receptor gene variations predict neural andbehavioral response to oxytocin in autism. Soc Cogn
Affect Neurosci, 12(3): 496-506, 2017.
3. Yamasaki M, Miyagawa T, Toyoda H, Khor SS, Liu
X, Kuwabara H, Kano Y, Shimada T, Sugiyama T,
Nishida H, Sugaya N, Tochigi M, Otowa T, Okazaki
Y, Kaiya H, Kawamura Y, Miyashita A, Kuwano R,
Kasai K, Tanii H, Sasaki T, Honda Y, Honda M,
Tokunaga K. Evaluation of polygenic risks fornarcolepsy and essential hypersomnia. J Hum Genet,
61(10): 873-878, 2016.
4. Takasaki Y, Koide T, Wang C, Kimura H, Xing J,
Kushima I, Ishizuka K, Mori D, Sekiguchi M, Ikeda
M, Aizawa M, Tsurumaru N, Iwayama Y, Yoshimi A,
Arioka Y, Yoshida M, Noma H, Oya-Ito T,
Nakamura Y, Kunimoto S, Aleksic B, Uno Y, Okada
T, Ujike H, Egawa J, Kuwabara H, Someya T,
Yoshikawa T, Iwata N, Ozaki N. Mutation screeningof GRIN2B in schizophrenia and autism spectrum
disorder in a Japanese population. Sci Rep, 6:33311,2016.
5. Yahata N, Morimoto J, Hashimoto R, Lisi G, Shibata
K, Kawakubo Y, Kuwabara H, Kuroda M, Yamada T,
Megumi F, Imamizu H, Náñez JE Sr, Takahashi H,
Okamoto Y, Kasai K, Kato N, Sasaki Y, Watanabe T,
Kawato M. A small number of abnormal brain
connections predicts adult autism spectrum disorder.
Nat Commun, 7: 11254, 2016.
6. Sakakibara E, Homae F, Kawasaki S, Nishimura Y,Takizawa R, Koike S, Kinoshita A, Sakurada H,
Yamagishi M, Nishimura F, Yoshikawa A, Inai A,
Nishioka M, Eriguchi Y, Matsuoka J, Satomura Y,
Okada N, Kakiuchi C, Araki T, Kan C, Umeda M,
Shimazu A, Uga M, Dan I, Hashimoto H,
Kawakami N, Kasai K. Detection of resting statefunctional connectivity using partial correlation
analysis: A study using multi-distance andwhole-head probe near-infrared
Neuroimage, 142: 590-601, 2016.

spectroscopy.

Neuroscience
3. Clinical Neuroscience94

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

Associate Professor
Chihiro Kakiuchi, M.D., Ph.D.

Seiichiro Jinde, 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.

Ryu Takizawa, M.D., Ph.D.

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

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

Tsuyoshi Okamura, M.D., Ph.D.

Tomoko Ando, M.D.

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

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

Fumichika Nishimura, M.D., Ph.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, 4 clinical psychologists and 2 psychiatric social workers. In 2016, approximately 800
new patients visited our outpatient clinic, and the total

visits per day was about 150.
In our inpatient wards, the secluded ward has 26
beds including 3 seclusion rooms, as well as 28 beds
for the open general ward. Approximately 500 patientswith various psychiatric disorders were admitted in2016. 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. We
also have Japan's first child psychiatry day care unit innational university hospitals since 1967, and mainly
patients with pervasive developmental disorders areengaged in clinical and educational activities.

95

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 12 neuropsychiatry Ph.D.
students are studying.

(1) Liu X, Shimada T, Otowa T, Wu YY, Kawamura
Y, Tochigi M, Iwata Y, Umekage T, Toyota T,
Maekawa M, Iwayama Y, Suzuki K, Kakiuchi C,
Kuwabara H, Kano Y, Nishida H, Sugiyama T,
Kato N, Chen CH, Mori N, Yamada K,
Yoshikawa T, Kasai K, Tokunaga K, Sasaki T,
Gau SS. Genome-wide Association Study ofAutism Spectrum Disorder in the East Asian
Populations. Autism Res. 2016 9:340-349.
(2) Inai A, Tochigi M, Kuwabara H, Nishimura F,
Kato K, Eriguchi Y, Shimada T, Furukawa M,
Kawamura Y, Sasaki T, Kakiuchi C, Kasai K,
Kano Y. Analysis of SLITRK1 in Japanesepatients with Tourette syndrome using a nextgeneration sequencer. Psychiatr Genet. 2015 25:
256-258.
(3) Okada N, Fukunaga M, Yamashita F, Koshiyama
D, Yamamori H, Ohi K, Yasuda Y, Fujimoto M,
Watanabe Y, Yahata N, Nemoto K, Hibar DP, van
Erp TG, Fujino H, Isobe M, Isomura S, Natsubori
T, Narita H, Hashimoto N, Miyata J, Koike S,
Takahashi T, Yamasue H, Matsuo K, Onitsuka T,
Iidaka T, Kawasaki Y, Yoshimura R, Watanabe Y,
Suzuki M, Turner JA, Takeda M, Thompson PM,
Ozaki N, Kasai K, Hashimoto R. Abnormal
asymmetries in subcortical brain volume inschizophrenia. Mol Psychiatry. 2016 21:14601466.
(4) Koike S, Satomura Y, Kawasaki S, Nishimura Y,
Takano Y, Iwashiro N, Kinoshita A, Nagai T,
Natsubori T, Tada M, Ichikawa E, Takizawa R,
Kasai K. Association between rostral prefrontal
cortical activity and functional outcome infirst-episode psychosis: a longitudinal functional
near-infrared spectroscopy study. Schizophr Res.
2016 170:304-310.
(5) Iwashiro N, Koike S, Satomura Y, Suga M, Nagai
T, Natsubori T, Tada M, Gonoi W, Takizawa R,
Kunimatsu A, Yamasue H, Kasai K. Association
between impaired brain activity and volume at the
sub-region of Broca's area in ultra-high risk andfirst-episode schizophrenia: A multi-modal
neuroimaging study. Schizophr Res. 2016 172:
9-15.
(6) Araki T, Kirihara K, Koshiyama D, Nagai T, Tada

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).

96

M, Fukuda M, Kasai K. Intact neural activity
during a Go/No-go task is associated with highglobal functioning in schizophrenia. Psychiatry
Clin Neurosci. 2016 70:278-85.
(7) Yahata N, Morimoto J, Hashimoto R, Lisi G,
Shibata K, Kawakubo Y, Kuwabara H, Kuroda M,
Yamada T, Megumi F, Imamizu H, Náñez JE Sr,
Takahashi H, Okamoto Y, Kasai K, Kato N,
Sasaki Y, Watanabe T, Kawato M. A small
number of abnormal brain connections predicts
adult autism spectrum disorder. Nat Commun.
2016 7:11254.
(8) Suga M, Nishimura Y, Kawakubo Y, Yumoto M,
Kasai K. Magnetoencephalographic recording ofauditory mismatch negativity in response to
duration and frequency deviants in a single
session in patients with schizophrenia. Psychiatry
Clin Neurosci. 2016 70:295-302.
(9) Hirata-Mogi S, Koike S, Toriyama R, Matsuoka
K, Kim Y, Kasai K. Reliability of apaper-and-pencil version of the Japanese Adult
Reading Test short version. Psychiatry Clin
Neurosci. 2016 70:362.
(10) Kanata S, Koike S, Ando S, Nishida A, Usami S,
Yamasaki S, Morimoto Y, Toriyama R, Fujikawa
S, Sugimoto N, Sasaki T, Furukawa TA,
Hiraiwa-Hasegawa M, Kasai K. Enuresis andHyperactivity-Inattention in Early Adolescence:
Findings from a Population-Based Survey inTokyo (Tokyo Early Adolescence Survey). PLoS
One. 2016 11:e0158786.
(11) Kinoshita A, Takizawa R, Yahata N, Homae F,
Hashimoto R, Sakakibara E, Kawasaki S,
Nishimura Y, Koike S, Kasai K. Development ofa neurofeedback protocol targeting the frontal
pole using near-infrared spectroscopy. Psychiatry
Clin Neurosci. 2016 70:507-516.
(12) Sakakibara E, Homae F, Kawasaki S, Nishimura
Y, Takizawa R, Koike S, Kinoshita A, Sakurada H,
Yamagishi M, Nishimura F, Yoshikawa A, Inai A,
Nishioka M, Eriguchi Y, Matsuoka J, Satomura Y,
Okada N, Kakiuchi C, Araki T, Kan C, Umeda M,
Shimazu A, Uga M, Dan I, Hashimoto H,
Kawakami N, Kasai K. Detection of resting statefunctional connectivity using partial correlation
analysis: A study using multi-distance andwhole-head probe near-infrared spectroscopy.

Neuroimage. 2016 142:590-601.
(13) Otowa T, Kawamura Y, Tsutsumi A, Kawakami N,
Kan C, Shimada T, Umekage T, Kasai K,
Tokunaga K, Sasaki T. The First Pilot GenomeWide Gene-Environment Study of Depression in
the Japanese Population. PLoS One. 2016 11:e0160823.
(14) Psychiatric intervention and repeated admission
to emergency centres due to drug overdose.
Kanehara A, Yamana H, Yasunaga H, Matsui H,
Ando S, Okamura T, Kumakura Y, Fushimi K,
Kasai K. BJPsych Open. 2015 Nov 9;1(2):158-163.
(15) Fujikawa S, Ando S, Shimodera S, Koike S,
Usami S, Toriyama R, Kanata S, Sasaki T, Kasai
K, Okazaki Y, Nishida A. The Association of
Current Violence from Adult Family Memberswith Adolescent Bullying Involvement andSuicidal Feelings. PLoS One. 2016 11:e0163707(16) Zhao Z, Jinde S, Kakiuchi C, Kasai K.
Extracellular elevation of adrenomedullin, a geneassociated with schizophrenia, suppresses heatshock protein 1A/1B mRNA. Neuroreport. 201627:1312-1316.

97

Department of Neurology
Professor
Shoji Tsuji, M.D., Ph.D.

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

LecturerAtsushi Iwata, M.D. , Ph.D.
Toshihiro Hayashi, M.D.,Ph.D.

Associate
Kaori Sakuishi, M.D., Ph.D., Masashi Hamada, M.D., Ph.D.,
Hiroyuki Ishiura, M.D., PhD., Jun Mitsui, M.D., PhD.,
Toji Miyagawa, M.D., PhD., Akatsuki Kubota, M.D., Ph.D.

Homepage http://square.umin.ac.jp/neurotky/
Introduction and Organization
The Department of Neurology was established by
the founder Professor Yasuo Toyokura in 1964 as one
Department in the Brain Research Institute. The
Department of Neurology was succeeded byProfessors Toru Mannen and Ichiro Kanazawa. 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 thepatients with highly advanced clinical practice as wellas on clinical activities connected to postgraduate
education of Neurology.
We have outpatient clinics covering the broad
fields of Neurology. Furthermore, we also provide
clinics specialized to movement disorders anddementia (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 and5th grade medical students, and clinical clerkship forthe 5th grade medical students.
In the clinical clerkship we include small group
lectures including neurophysiology, and stroke care.
We are also putting our effort for Free Quarters where
we offer various opportunities for medical students to
be involved in research activities, and 2-3 medical
students are conducting their research activities in thelaboratories.
In postgraduate education we offer the integrated
program including Neurology as the part of the
program of Internal Medicine.
Regarding training for board-certified neurologists, we offer the excellent program including
patients’ care, training in Neurophysiology and Neuro-98

pathology, consultation for Neurology, rotation at ER
and supervising of junior trainees. This program is
integrated with clinical practice at the affiliatedhospitals where rich experience is obtained fornumerous cases in Clinical Neurology.
In Graduate School, we offer highly advanced
research activities based on the interest of graduate
students.

Research activities
Our research field covers broad fields related toneurological diseases, with the goals to elucidate themechanisms of neurological diseases, and to eventually develop new therapeutic strategies. Our research
activities include molecular genetics, developmental
biology, cell biology, pharmacology, pathology, andphysiology. We aim to integrate these broad research
fields to better contribute to clinical neurology.
In the field of molecular genetics, we havedeveloped Medical Genome 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
pedigreeanalysesinhereditary
amyotrophic lateral sclerosis, hereditary spastic
paraplegia, hereditary spinocerebellar atrophy, andhereditary multiple system atrophy. As forsporadic neurologic diseases, we perform casecontrol association studies in multiple system
atrophy and amyotrophic lateral sclerosis to
identify genetic factors underlying these diseases.
On the basis of the findings that mutations in
COQ2 are associated with familial as well as
sporadic multiple system atrophy, we are conducting preclinical study using iPSC-derived cells,
searching for peripheral biomarkers in patients,
and in the process of setting up a patient registry
as well as an investigator-initiated clinical trial
using coenzyme Q10 for patients with multiple
system atrophy. Collaborative researches haveachieved multiple accomplishments including
identification of the causative gene for autosomal
recessive Charcot-Marie-Tooth disease (MME),
familial amyotrophic lateral sclerosis (CCNF), andprogressive neurodegenerative encephalopathy

with atypical infantile spinal muscular atrophy(TBCD), development of a reference database ofgenetic variations in the Japanese population, andcase reports of SPG8 and tubular aggregate
myopathy. Application of next generation
sequencers for molecular diagnosis for various
diseases has been intensively investigated. (Tsuji,S., Date, H., Suzuki, K., Mitsui, J., Ishiura, H.,
Matsukawa, T., Sato, N., Yasuda, T., Naruse, H.,
Matsukawa, M., Kanda, J.)
The human neurophysiology section specializes
in studying the physiology of the human motor andsensory systems in awake healthy volunteers and thepathophysiology of neurological disorders using
several non-invasive physiological methods, such as
TMS, EEG, MEG, fMRI, NIRS and EOG. Our final
goal is to devise new therapeutic techniques for
intractable neurological disorders. To this end, thework extends from the study of spinal systems to basal
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 humanbrain 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., Terada, S., ,Tokushige, S., Sasaki, T., Togashi, N., Kodama, S.,
Sugiyama., Y., Sato, K., Otsuka, J., Goto, R., Irie, K.,
and Yamazaki, A)
In the field of neuromuscular diseases, we
provide pathological diagnosis of biopsied materials
from patients with myopathy or neuropathy. We also
provide autoantibody testing for anti-gangliosideantibodies, muscle specific antibodies and paraneoplastic neurological antibodies. In research field,
using biopsied muscles and collected serum samples,
we have been studying the mechanisms of inflammatory myopathies from the view points of pathological changes, myositis specific autoantibodies,
serum cytokines, and expression profiling of muscle
samples. Our aim is to increase understanding of the
etiology and pathogenesis of neuromuscular diseases.
(Shimizu, J., Kubota A., Maeda M., Kadoya M.,

99

Ikenaga C., Uchio N., Taira K., Unuma, A).
Biochemistry lab is currently working on neuroepigenetics using post-mortem brains of Alzheimer’s
disease (AD), Lewy body disease, multiple system
atrophy and amyotrophic lateral sclerosis, which
revealed a novel pathomechanism in AD. Based on the
methylome analysis, we are on the process of verifying the pathomechanism using in vitro AD model ofhuman neural progenitor cell. We are also analyzing
the histone modification through neuron-specific
ChIP-seq assay, which is one of the major transcriptional regulators. We also work on molecularpathology of chronic ischemia using mouse models.
Other activities include development of new imaging
techniques using Raman microspectroscopy. Recently
we visualized spatial distribution of chemical shifts
within Aβ aggregates formed in vitro. We also
observed globotriaosylceramide distribution within
peripheral nerve of Fabry’s disease patient in
non-labeled manner. 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. Clinical study includes preclinical sporadic
Alzheimer’s disease cohort (AMED Preclinical study)
and familial Alzheimer’s disease (DIAN-J) andclinical trial of florbetapir. (Iwata, A., Nagashima, Y.,
Miyagawa, T., Ohtomo, R., Mano, T., Bannai, T.,
Tsuchida, T., Hamada, K., Mano, K, Ohtomo, G.)
Higher brain function section aims to elucidate
pathophysiology and neural basis of the higher brain
dysfunction in neurological disorders by means of two
approaches: neuropsychological analysis of individual
cases and multimodal big-data analysis. (Hayashi, T.).

Publication
1.

2.

Nishikawa A, Mori-Yoshimura M, Segawa K,
Hayashi YK, Takahashi T, Saito Y, Nonaka I, Krahn
M, Levy N, Shimizu J, Mitsui J, Kimura E, Goto J,
Yonemoto N, Aoki M, Nishino I, Oya Y, Murata M.
Respiratory and cardiac function in japanese patientswith dysferlinopathy. Muscle Nerve. 2016 Mar;53(3):394-401.
Nakamura R, Sone J, Atsuta N, Tohnai G, Watanabe

3.

4.

5.

6.

7.

H, Yokoi D, Nakatochi M, Watanabe H, Ito M,
Senda J, Katsuno M, Tanaka F, 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, Tsuji S, Nakashima K, Kaji R,
Sobue G; Japanese Consortium for Amyotrophic
Lateral Sclerosis Research (JaCALS). Nextgeneration sequencing of 28 ALS-related genes in a
Japanese ALS cohort. Neurobiol Aging. 2016 Mar;
39:219.e1-8.
Watanabe H, Atsuta N, Hirakawa A, Nakamura R,
Nakatochi M, Ishigaki S, Iida A, Ikegawa S, Kubo
M, Yokoi D, Watanabe H, Ito M, Katsuno M, Izumi
Y, Morita M, Kanai K, Taniguchi A, Aiba I, Abe K,
Mizoguchi K, Oda M, Kano O, Okamoto K,
Kuwabara S, Hasegawa K, Imai T, Kawata A, Aoki
M, Tsuji S, Nakashima K, Kaji R, Sobue G. A rapidfunctional decline type of amyotrophic lateralsclerosis is linked to low expression of TTN. J
Neurol Neurosurg Psychiatry. 2016 Aug;87(8):851-8.
Qu W, Tsukahara T, Nakamura R, Yurino H,
Hashimoto S, Tsuji S, Takeda H, Morishita S.
Assessing Cell-to-Cell DNA Methylation Variability
on Individual Long Reads. Sci Rep. 2016 Feb 18;
6:21317.
Higasa K, Miyake N, Yoshimura J, Okamura K,
Niihori T, Saitsu H, Doi K, Shimizu M, Nakabayashi
K, Aoki Y, Tsurusaki Y, Morishita S, Kawaguchi T,
Migita O, Nakayama K, Nakashima M, Mitsui J,
Narahara M, Hayashi K, Funayama R, Yamaguchi D,
Ishiura H, Ko WY, Hata K, Nagashima T, Yamada R,
Matsubara Y, Umezawa A, Tsuji S, Matsumoto N,
Matsuda F. Human genetic variation database, areference database of genetic variations in theJapanese population. J Hum Genet. 2016 Jun;61(6):547-53.
Ichinose Y, Koh K, Fukumoto M, Yamashiro N,
Kobayashi F, Miwa M, Nagasaka T, Shindo K,
Ishiura H, Tsuji S, Takiyama DY. Exome sequencing
reveals a novel missense mutation in the KIAA0196
gene in a Japanese patient with SPG8. Clin Neurol
Neurosurg. 2016 May;144:36-8.
Higuchi Y, Hashiguchi A, Yuan J, Yoshimura A,
Mitsui J, Ishiura H, Tanaka M, Ishihara S, Tanabe H,
Nozuma S, Okamoto Y, Matsuura E, Ohkubo R,
Inamizu S, Shiraishi W, Yamasaki R, Ohyagi Y, Kira

100

J, Oya Y, Yabe H, Nishikawa N, Tobisawa S,
Matsuda N, Masuda M, Kugimoto C, Fukushima K,
Yano S, Yoshimura J, Doi K, Nakagawa M,
Morishita S, Tsuji S, Takashima H. Mutations in
MME cause an autosomal-recessive Charcot-MarieTooth disease type 2. Ann Neurol. 2016 Apr;79(4):659-72.
8. Mano KK, Matsukawa T, Mitsui J, Ishiura H,
Tokushige S, Takahashi Y, Sato NS, Nakamoto FK,
Ichikawa Y, Nagashima Y, Terao Y, Shimizu J,
Hamada M, Uesaka Y, Oyama G, Ogawa G,
Yoshimura J, Doi K, Morishita S, Tsuji S, Goto J.
Atypical parkinsonism caused by Pro105Leu
mutation of prion protein: A broad clinical spectrum.
Neurol Genet. 2016 Jan 7;2(1):e48.
9. Okuma H, Saito F, Mitsui J, Hara Y, Hatanaka Y,
Ikeda M, Shimizu T, Matsumura K, Shimizu J, Tsuji
S, Sonoo M. Tubular aggregate myopathy caused bya novel mutation in the cytoplasmic domain of
STIM1. Neurol Genet. 2016 Feb 1;2(1):e50.
10. Williams KL, Topp S, Yang S, Smith B, Fifita JA,
Warraich ST, Zhang KY, Farrawell N, Vance C, Hu
X, Chesi A, Leblond CS, Lee A, Rayner SL,
Sundaramoorthy V, Dobson-Stone C, Molloy MP,
van Blitterswijk M, Dickson DW, Petersen RC,
Graff-Radford NR, Boeve BF, Murray ME, Pottier C,
Don E, Winnick C, McCann EP, Hogan A, Daoud H,
Levert A, Dion PA, Mitsui J, Ishiura H, Takahashi Y,
Goto J, Kost J, Gellera C, Gkazi AS, Miller J,
Stockton J, Brooks WS, Boundy K, Polak M,
Muñoz-Blanco JL, Esteban-Pérez J, Rábano A,
Hardiman O, Morrison KE, Ticozzi N, Silani V, deBelleroche J, Glass JD, Kwok JB, Guillemin GJ,
Chung RS, Tsuji S, Brown RH Jr, García-Redondo A,
Rademakers R, Landers JE, Gitler AD, Rouleau GA,
Cole NJ, Yerbury JJ, Atkin JD, Shaw CE, Nicholson
GA, Blair IP. CCNF mutations in amyotrophic
lateral sclerosis and frontotemporal dementia. Nat
Commun. 2016 Apr 15;7:11253.
11. Suzuki Y, Korlach J, Turner SW, Tsukahara T,
Taniguchi J, Qu W, Ichikawa K, Yoshimura J, Yurino
H, Takahashi Y, Mitsui J, Ishiura H, Tsuji S, Takeda
H, Morishita S. AgIn: measuring the landscape of
CpG methylation of individual repetitive elements.
Bioinformatics. 2016 Oct 1;32(19):2911-9.
12. Mitsui J, Matsukawa T, Yasuda T, Ishiura H, Tsuji S.
Plasma Coenzyme Q10 Levels in Patients With

Multiple System Atrophy. JAMA Neurol. 2016 Aug
1;73(8):977-80.
13. Amiya E, Morita H, Hatano M, Nitta D, Hosoya Y,
Maki H, Motozawa Y, Sato N, Ishiura H, Numakura
S, Shintani Y, Kinugawa K, Takeda N, Shimizu J,
Tsuji S, Komuro I. Fukutin gene mutations thatcause left ventricular noncompaction. Int J Cardiol.
2016 Nov 1;222:727-9.
14. Fujimori K, Tezuka T, Ishiura H, Mitsui J, Doi K,
Yoshimura J, Tada H, Matsumoto T, Isoda M,
Hashimoto R, Hattori N, Takahashi T, Morishita S,
Tsuji S, Akamatsu W, Okano H. Modelingneurological diseases with induced pluripotent cells
reprogrammed from immortalized lymphoblastoid
cell lines. Mol Brain. 2016 Oct 3;9(1):88.
15. Mitsui J, Tsuji S. Plasma Coenzyme Q10 Levels andMultiple System Atrophy-Reply. JAMA Neurol.
2016 Dec 1;73(12):1499-1500.
16. Yamaguchi N, Misawa S, Sato Y, Nagashima K,
Katayama K, Sekiguchi Y, Iwai Y, Amino H, Suichi
T, Yokota T, Nishida Y, Kohara N, Hirata K,
Nishiyama K, Yabe I, Kaida KI, Suzuki N, Nodera H,
Tsuji S, Koike H, Kira JI, Hanaoka H, Kusunoki S,
Kuwabara S; JET-GBS Group. A Prospective,
Multicenter, Randomized Phase II Study to Evaluate
the Efficacy and Safety of Eculizumab in Patientswith Guillain-Barré Syndrome (GBS): Protocol ofJapanese Eculizumab Trial for GBS (JET-GBS).
JMIR Res Protoc. 2016 Nov 7;5(4):e210.
17. 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 a causal
gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy.
J Hum Genet. 2017 Apr;62(4):473-480.
18. Udagawa T, Jo T, Yanagihara T, Shimizu A, Mitsui J,
Tsuji S, Morishita S, Onai R, Miura K, Kanda S,
Kajiho Y, Tsurumi H, Oka A, Hattori M, Harita Y.
Altered expression of Crb2 in podocytes expands avariation of CRB2 mutations in steroid-resistantnephrotic syndrome. Pediatr Nephrol. 2017 May;32(5):801-809.
19. 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

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protein deficiency with survival to adulthood
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2017 Jan 15;372:6-10.
20. Yoshida, M., Hayashi, T., Fujii, K., Kawai, K., Tsuji,S., Iwata, A. Recovered recall memory after
decompression of the fornix by surgical removal of
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21. Hida A, Yamashita T, Hosono Y, Inoue M, Kaida K,
Kadoya M, Miwa Y, Yajima N, Maezawa R, Arai S,
Kurasawa K, Ito K, Shimada H, Iwanami T, Sonoo
M, Hatanaka Y, Murayama S, Uchibori A, Chiba A,
Aizawa H, Momoo T, Nakae Y, Sakurai Y, Shiio Y,
Hashida H, Yoshizawa T, Sakiyama Y, Oda A, Inoue
K, Takeuchi S, Iwata NK, Date H, Masuda N,
Mikata T, Motoyoshi Y, Uesaka Y, Maeda MH,
Nakashima R, Tsuji S, Kwak S, Mimori T, Shimizu J.
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Suzuki S, Kondo Y, Nakamura H, Mitsuhashi K,
Maeda MH, Shimizu J, Hayashi YK, Nishino I, Oya
Y, Murata M. Chronic Myopathy Associated With
Anti-Signal Recognition Particle Antibodies Can Be
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Ikenaga C, Uchio N, Kubota A, Kaida K, Miwa Y,
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Y, Uesaka Y, Sakurai Y, Izumi T, Inoue M, Kwak S,
Tsuji S, Shimizu J. Cancer association as a risk
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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.,

Akitake Mukasa, M.D., Ph.D.,

Hideaki Imai, M.D., Ph.D.

Associate
Shota Tanaka, M.D.

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

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

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

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

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

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

Hirotaka Hasegawa, M.D.,

Mariko Kawashima, M.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 15 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research, and education. The staffs
include a professor/chairman, an associate professor,
four lecturers and eight 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 andFriday). The latter is open for patients with brain
tumor, pituitary disease, spinal disease, cerebrovascular disease, endovascular intervention, epilepsy,
and gamma knife treatment. From April 2016 to
March 2017, 18,311 patients were treated at theoutpatient clinics.
The neurosurgery ward has approximately 40 beds
on the seventh floor of the new hospital building
opened in September 2001. In 2016, 996 patients wereadmitted to the neurosurgery ward. 516 surgicalprocedures and 90 gamma knife procedures were
performed in 2016. Our practice covers a wide varietyof neurosurgical diseases including malignant andbenign brain tumors, hemorrhagic and thromboembolic cerebrovascular diseases, spinal disorders,

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epilepsy, pain and movement disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional mapping in epilepsy surgery are frequently used topreserve brain function as much as possible.
State-of-the-art techniques including intraoperative
computer-aided
navigation
andintravascular
procedures help our continuous effort to increase thesafety of surgical treatment.
Our department is affiliated with 34 neurosurgicalinstitutions in and around the city of Tokyo including
5 university medical centers, where our residents andstudents are exposed to various clinical experiences.
Surgical case volume in all hospitals exceeds 11,000
cases.

Teaching activities
Medical students take lectures of clinicalneurosurgery in their second year. Clinical casestudies and bedside teaching are scheduled in the thirdand fourth years. The lecturers introduce general
neurosurgery as well as the state-of-art neurosurgicalpractice to the students. At the bedside teaching andclinical clerkship, they are offered opportunities tolearn clinical management of neurosurgical patients in
the hands-on style, and also are exposed to practice invarious subspecialties in neurosurgery through special
seminars given by experts in the fields.
We accepted 14 residents in 2015, 4 in 2016, and 16
in 2017 in our neurosurgical residency program. These
residents are trained in the university hospital andaffiliated hospitals to experience every aspect ofneurosurgical practice for five years on average. Our
residency training is finalized after the sixth year,
when the finishing residents serve as senior residents
at the university hospital for 6 months. Academic
training is provided through numerous intramuralclinical and research conferences, journal clubs,
seminars as well as quarterly regional meetings of theJapan Neurosurgical Society. After or duringresidency training, our residents can choose to be
admitted into the Ph.D. course at the Graduate Schoolof Medicine, the University of Tokyo, to be involvedin advanced basic research activities for 4 years. Uponcompletion of training, our graduates stay in thedepartment to be associates in our university hospitalor become clinical staffs in our affiliated hospitals.

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

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whole exome sequencing, RNA sequencing,expression profiling, and methylation analysis. Ourparticular interest lies in tumor heterogeneity andmalignant 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 researchlab 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 development of 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
purpose of more precise localization of epileptic fociand elucidation 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
with much higher spatial resolution and SN ratio. We
aim to understand brain mechanisms as complicatednetwork systems and to improve the reliability of
non-invasive techniques. Since ECoG is a strong

candidate for a decoding source of brain-computerinterface (BCI), we are planning to expand theresearch on this field to clinical implementation of
BCI for communication and motor control incooperation with other brain research laboratories andengineering laboratories.
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 themulti-modalities enables to visualize all cortical andsubcortical networks of the motor, language and othercognitive functions in each patient. Furthermore, we
succeeded to import the combined information into a
neuronavigation system (functional neuronavigation),
which quickly and accurately indicates the eloquent
brain areas. We could develop virtual reality operative
simulation using multi-modal fusion threedimensional computer graphics. Then, it was possible
to precisely examine surgical strategy.
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 of

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gamma knife radiosurgery in the future.

References (2015)
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5. Fukushima Y., Yoshikawa G., Takasago M.,
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6. Furuse M., Nonoguchi N., Kuroiwa T., Miyamoto
S., Arakawa Y., Shinoda J., Miwa K., Iuchi T.,
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M., Abe T., Narita Y., Saito N., Mukasa A.,
Ogasawara K., Beppu T., Kumabe T., Nariai T.,
Tsuyuguchi N., Nakatani E., Kurisu S., Nakagawa
Y., Miyatake S. I. A prospective, multicentre,
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practice 3(4):272-280, 2016
7. Hanakita S., Shin M., Koga T., Igaki H., Saito N.
Outcomes of Volume-Staged Radiosurgery for
Cerebral Arteriovenous Malformations Larger
Than 20 cm(3) with More Than 3 Years ofFollow-Up. World Neurosurg 87:242-249, 2016
8. Hanakita S., Shin M., Koga T., Igaki H., Saito N.
Risk Reduction of Cerebral Stroke After
Stereotactic Radiosurgery for Small Unruptured
Brain Arteriovenous Malformations. Stroke
47(5):1247-1252, 2016
9. Hasegawa H., Inoue T., Tamura A., Saito I.
Tailored flow sequestration treatment using
high-flow and low-flow bypass for partiallythrombosed giant internal carotid arteryaneurysm-a technical case report. Neurosurg Rev
39(4):699-705, 2016
10. Ho A. L., Koch M. J., Tanaka S., Eichler A. F.,
Batchelor T. T., Tanboon J., Louis D. N., Cahill D.
P., Chi A. S., Curry W. T., Jr. Impact ofhistopathological transformation and overall
survival in patients with progressive anaplastic
glioma. J Clin Neurosci 31:99-105, 2016
11. Ichimura K., Fukushima S., Totoki Y., MatsushitaY., Otsuka A., Tomiyama A., Niwa T., Takami H.,
Nakamura T., Suzuki T., Fukuoka K., YanagisawaT., Mishima K., Nakazato Y., Hosoda F., Narita Y.,
Shibui S., Yoshida A., Mukasa A., Saito N.,
Kumabe T., Kanamori M., Tominaga T.,
Kobayashi K., Shimizu S., Nagane M., Iuchi T.,
Mizoguchi M., Yoshimoto K., Tamura K.,
Maehara T., Sugiyama K., Nakada M., Sakai K.,
Kanemura Y., Nonaka M., Asai A., Yokogami K.,
Takeshima H., Kawahara N., Takayama T., Yao
M., Kato M., Nakamura H., Hama N., Sakai R.,
Ushijima T., Matsutani M., Shibata T., Nishikawa

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R. Recurrent neomorphic mutations of MTOR in
central nervous system and testicular germ celltumors may be targeted for therapy. Acta
Neuropathol 131(6):889-901, 2016
12. Igarashi T., Shono N., Kin T., Saito T. Interactive
Volume Segmentation with Threshold Field
Painting.
Proceedings of the 29th Annual
Symposium on User Interface Software andTechnology; Tokyo, Japan. 2984537: ACM; 2016.
p. 403-413.
13. Ikemura M., Shibahara J., Mukasa A., Takayanagi
S., Aihara K., Saito N., Aburatani H., Fukayama
M. Utility of ATRX immunohistochemistry indiagnosisof
adult
diffusegliomas.
Histopathology 69(2):260-267, 2016
14. Imai H., Ishii K., Chikuda H., Ohya J., Nakagawa
D., Kondo T., Nomura S., Yoshino M., Miyawaki
S., Kin T., Nakatomi H., Saito N. Successful
surgical strategy for a cervical hemangioblastoma:Case report. Surg Neurol Int 7 (Suppl 25):
S660-s663, 2016
15. Imai H., Watanabe K., Miyagishima T.,
Yoshimoto Y., Kin T., Nakatomi H., Saito N. The
outcome of a surgical protocol based on ischemia
overprotection in large and giant aneurysms of theanterior cerebral circulation. Neurosurg Rev
39(3):505-517, 2016
16. Inoue M., Tanaka S., Nakatomi H., Takayanagi S.,
Takahashi M., Tanaka M., Momose T., Mukasa A.,
Saito N. Intracranial Infantile Myofibromatosis
Mimicking Malignant Brain Tumor: A Case
Report and Literature Review. World Neurosurg
93:487.e415-420, 2016
17. Inoue T., Ohwaki K., Tamura A., Tsutsumi K.,
Saito I., Saito N. Extracranial-intracranial bypass
for internal carotid/middle cerebral atherosclerotic
steno-occlusive diseases in conjunction withcarotid endarterectomy for contralateral cervicalcarotid stenosis: clinical results and cognitive
performance. Neurosurg Rev 39(4):633-641,
2016
18. Inoue T., Ohwaki K., Tamura A., Tsutsumi K.,
Saito I., Saito N. Postoperative transientneurological symptoms and chronic subdural
hematoma after extracranial-intracranial bypass
for internal carotid/middle cerebral atherosclerotic
steno-occlusive diseases: negative effect on

cognitive performance. Acta Neurochir (Wien)
158(1):207-216, 201619. Jiang J., Nakajima Y., Sohma Y., Saito T., Kin T.,
Oyama H., Saito N. Marker-less tracking of brain
surface deformations by non-rigid registration
integrating surface and vessel/sulci features. Int J
Comput Assist Radiol Surg 11(9):1687-1701,
2016
20. Kamiya K., Amemiya S., Suzuki Y., Kunii N.,
Kawai K., Mori H., Kunimatsu A., Saito N., Aoki
S., Ohtomo K. Machine Learning of DTI
Structural Brain Connectomes for Lateralizationof Temporal Lobe Epilepsy. Magn Reson Med
Sci 15(1):121-129, 2016
21. Lan Q., Wang A., Cheng Y., Mukasa A., Ma J.,
Hong L., Yu S., Sun L., Huang Q., Purow B., Li
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EGFRvIII and promotes glioblastoma growth invivo but not in vitro. Oncotarget 7(9):9680-9691,
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22. Mikami Y., Kanemaru K., Okubo Y., Nakaune T.,
Suzuki J., Shibata K., Sugiyama H., Koyama R.,
Murayama T., Ito A., Yamazawa T., Ikegaya Y.,
Sakurai T., Saito N., Kakizawa S., Iino M. Nitric
Oxide-induced Activation of the Type 1
Ryanodine Receptor Is Critical for Epileptic
Seizure-induced
Neuronal
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Death.
EBioMedicine 11:253-261, 201623. Miyawaki S., Imai H., Hayasaka T., Masaki N.,
Ono H., Ochi T., Ito A., Nakatomi H., Setou M.,
Saito N. Imaging mass spectrometry detects
dynamic changes of phosphatidylcholine in rat
hippocampal CA1 after transient global ischemia.
Neuroscience 322:66-77, 201624. Morita A., Sora S., Nakatomi H., Harada K.,
Sugita N., Saito N., Mitsuishi M. Medical
Engineering and Microneurosurgery: Application
and Future. Neurol Med Chir (Tokyo)
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25. Nagaoka A., Takehara H., Hayashi-Takagi A.,
Noguchi J., Ishii K., Shirai F., Yagishita S., Akagi
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dynamics of dendritic spines in a fragile X
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Sato N., Takeuchi Y., Kyotani K., Mukasa A.,

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Mizukawa K., Sakata J., Yamamoto Y., Hosoda K.,
Itoh T., Sasaki R., Kohmura E. Diagnostic valueof glutamate with 2-hydroxyglutarate in magnetic
resonance spectroscopy for IDH1 mutant glioma.
Neuro Oncol 18(11):1559-1568, 2016
27. Nakagawa D., Shojima M., Yoshino M., Kin T.,
Imai H., Nomura S., Saito T., Nakatomi H.,
Oyama H., Saito N. Wall-to-lumen ratio of
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green angiography. Asian J Neurosurg 11(4):361-364, 2016
28. Nakatomi H., Miyawaki S., Kin T., Saito N.
Hearing Restoration with Auditory Brainstem
Implant. Neurol Med Chir (Tokyo) 56(10):597-604, 2016
29. Nakatomi H., Ochi T., Saito N. [Endogenous
neural stem cell mobilization with intraventricular
growth factor administration]. Nihon rinsho
Japanese journal of clinical medicine 74(4):655-660, 2016
30. Ochi T., Nakatomi H., Ito A., Imai H., Okabe S.,
Saito N. Temporal changes in the response of
SVZ neural stem cells to intraventricularadministration of growth factors. Brain Res 1636:
118-129, 2016
31. Ohya J., Chikuda H., Nakatomi H., Sakamoto R.,
Saito N., Tanaka S. Acute obstructivehydrocephalus
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32. Okano A., Ogiwara H. The effectiveness of
microsurgical fenestration for middle fossaarachnoid cysts in children. Childs Nerv Syst
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Saito N. Rat white matter injury model induced byendothelin-1 injection: technical modification andpathological evaluation. Acta Neurobiol Exp(Wars) 76(3):212-224, 2016
34. Takahashi J. C., Funaki T., Houkin K., Inoue T.,
Ogasawara K., Nakagawara J., Kuroda S.,
Yamada K., Miyamoto S. Significance of theHemorrhagic Site for Recurrent Bleeding:
Prespecified Analysis in the Japan Adult
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Solitary Langerhans cell histiocytosis of theoccipital condyle: a case report and review of theliterature. Childs Nerv Syst 32(2):399-404, 2016
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Momose T., Aoki S., Saito N. Long-term outcome
and neuroradiologic changes after multiple
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lobe epilepsy. Epilepsia 57(6):931-940, 2016
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for preoperative planning in patients withposterior fossa hemangioblastoma: technical note.
J Neurosurg:1-9, 2016

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

109

Department of
Molecular Preventive Medicine
Professor
Kouji Matsushima, M.D., Ph.D.

Lecturer
Satoshi Ueha, Ph. D.

Assistant professor
Takeshi Shimaoka, Ph.D.,

Yuya Terashima, Ph.D.

Project Assistant professor
Etsuko Toda, Ph.D.

Homepage

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

Introduction and Organization
The Department of Molecular Preventive Medicine
was originally established in 1885. It was designed tooffer both a high level of hygienic education andfacilities for specialized research. At present, it is our
responsibility to give lectures, seminars and courses
for experiments and practical training on thepreventive medicine to the third grade medical
students. The professor, several invited lecturers(including adjunct staff), and research associates takepart in the education as well as research activities.
There are over twenty members in our department,
including research fellows, graduate and undergraduate students, and guest researchers.

Teaching activities
The field of our department covers the wide area of
preventive medicine. The main scope of our education
includes molecular mechanism of host defense
responses to inciting environmental stimuli, free
radical chemistry, and the environmental medicine
with special reference to the relation between healthand environment. The education is provided for thethird grade medical students. The course is consistedof lectures, seminars, experiments, and practicaltraining which are provided by our own staffs and also
by the experts outside: National Institute of Infectious
Diseases (Dr. Oishi), Kanazawa University (Dr.
Matsugo), Kyoto University (Dr. Koizumi), HealthService Center of The University of Tokyo (Dr.
Okubo), Toyama Medical and Pharmaceutical
University (Dr. Inadera), Kyoto Prefectural Universityof Medicine (Dr. Sakai), Shinshu University (Dr.
Fukushima).

Research activities
We focus on several research fields as follows;
1) Molecular and cellular bases of chronic inflammation associated-organ fibrosis.
2) Role of cancer associated fibroblasts in tumor
development.
3) Elucidation of the cellular and molecular mechanisms that lead to Graft-Versus-Host Disease.
4) Molecular analysis of chemokine receptor signaling pathway and development of novel therapeutic drugs against cancer and inflammatory
diseases.
5) Application of humanized anti-CD4 antibody forcancer.

110

References
1: Shichino S, Abe J, Ueha S, Otsuji M, Tsukui T,
Kosugi-Kanaya M, Shand FH, Hashimoto S,
Suzuki HI, Morikawa T, Inagaki Y, Matsushima K.
Reduced supply of monocyte-derived macrophages leads to a transition from nodular todiffuse lesions and tissue cell activation in silicainduced pulmonary fibrosis in mice. Am J Pathol.
2015 Nov;185(11):2923-38.
2: Tsukui T, Ueha S, Shichino S, Inagaki Y,
Matsushima K. Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis. Am J Pathol. 2015
Nov;185(11):2939-48.
3: Ueha S, Yokochi S, Ishiwata Y, Ogiwara H, Chand
K, Nakajima T, Hachiga K, Shichino S, Terashima
Y, Toda E, Shand FH, Kakimi K, Ito S,
Matsushima K. Robust Antitumor Effects ofCombined Anti-CD4-Depleting Antibody andAnti-PD-1/PD-L1 Immune Checkpoint Antibody
Treatment in Mice. Cancer Immunol Res. 2015
Jun;3(6):631-40.
4: Suenaga F, Ueha S, Abe J, Kosugi-Kanaya M,
Wang Y, Yokoyama A, Shono Y, Shand FH,
Morishita Y, Kunisawa J, Sato S, Kiyono H,
Matsushima K. Loss of lymph node fibroblastic
reticular cells and high endothelial cells is
associated with humoral immunodeficiency inmouse graft-versus-host disease. J Immunol. 2015
Jan 1;194(1):398-406.
5: Tomura M, Hata A, Matsuoka S, Shand FH,
Nakanishi Y, Ikebuchi R, Ueha S, Tsutsui H, Inaba
K, Matsushima K, Miyawaki A, Kabashima K,
Watanabe T, Kanagawa O. Tracking and quantification of dendritic cell migration and antigen
trafficking between the skin and lymph nodes. Sci
Rep. 2014 Aug 12;4:6030.
6: Yoshie O, Matsushima K. CCR4 and its ligands:
from bench to bedside. Int Immunol. 2015 Jan;27(1):11-20.
7: Kanegasaki S, Matsushima K, Shiraishi K,
Nakagawa K, Tsuchiya T. Macrophage inflammatory protein derivative ECI301 enhances thealarmin-associated abscopal benefits of tumor
radiotherapy. Cancer Res. 2014 Sep 15; 74(18):5070-8.
doi:10.1158/0008-5472.CAN-14-0551.

Epub 2014 Jul 18. Erratum in: Cancer Res. 2015
Mar 1;75(5):903.
8: Abe J, Shichino S, Ueha S, Hashimoto S, Tomura
M, Inagaki Y, Stein JV, Matsushima K. Lymphnode stromal cells negatively regulate antigenspecific CD4+ T cell responses. J Immunol. 2014
Aug 15;193(4):1636-44.
9: Shand FH, Ueha S, Otsuji M, Koid SS, Shichino S,
Tsukui T, Kosugi-Kanaya M, Abe J, Tomura M,
Ziogas J, Matsushima K. Tracking of intertissue
migration reveals the origins of tumor-infiltrating
monocytes. Proc Natl Acad Sci U S A. 2014 May
27;111(21):7771-6.
10: Nakamura R, Tsukahara T, Qu W, Ichikawa K,
Otsuka T, Ogoshi K, Saito TL, Matsushima K,
Sugano S, Hashimoto S, Suzuki Y, Morishita S,
Takeda H. Large hypomethylated domains serveas strong repressive machinery for key developmental genes in vertebrates. Development. 2014
Jul;141(13):2568-80.

111Department of Public Health/
Department of Health Policy
Professor
Yasuki Kobayashi, M.D., Ph.D.

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

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

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

Homepage

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

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

The objectives of the Department are botheducation and research of public health. The
Department trains graduate and undergraduate
students through lectures, seminars, field practice, andlaboratory work in public health and occupational
medicine, for the degrees of Medical Doctor (MD),Master of Public Health (MPH), and Doctor of
Medical Sciences (equivalent to PhD). The
Department has conducted research on a wide variety
for public health issues, including health policy andeconomics, occupational medicine, clinical epidemiology, health services research, and so on. In addition,
the staff members of the Department have offeredpublic and occupational health services to the governments, industries, and local communities.
In the academic year of 2016, the Department
consists of four faculty members above listed, one
project lecturer (part-time), one project researcher(part-time), 2 supporting staff, 17 graduate students(15 in PhD program and 1 temporary supervised, 1 in
MPH program), 18 part-time lecturers, and 27 visiting
fellows.

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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 medicine,environmental health, nutritional epidemiology, andhealth services research) is provided. All the above
lectures are given by faculty members and part-time
lectures including governmental officials and healthpractitioners.
Field practice and laboratory work in public healthis due in the summer term of the fifth grade (M3),which is jointly provided by Department of MolecularPreventive Medicine and the other departments related
to public health fields. Averagely four to five students(small group) are assigned to one special topic groupwith a tutor (faculty member or part-time lecturer).
Each group conducts field practice, review work, orlaboratory work, and writes a report in the style oforiginal or review paper. The reports submitted arebound and made available to those students insubsequent 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 (about 35 courses) are given by
those departments affiliated with School of Public
Health. Among them, our Department offers threecourses;“HealthPolicy”,“Public
HealthPreparedness”, 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,occupational stress, and health status of workers invarious occupational settings for the purpose of
preventing occupational and life-style diseases.
3) Others
Other research activities includes, (1) evaluation ofdisaster preparedness in local communities andhealthcare facilities, (2) study on risk communicationin public health emergencies, and (3) epidemiologicalstudy on incidence and survival rate of children withcerebral palsy.

113

References
1. Kuboyama I, Toyokawa S, Tomio J, Inada H,
Tanihara S, Kobayashi Y. The number of patientsand therapeutic profile of spinal stenosis using
health insurance claims in Japan. Spine
41(14):1146-1152, 2016.
2. Touyama M, Touyama J, Toyokawa S, Kobayashi
Y. Trends in the prevalence of cerebral palsy inchildren born between 1988 and 2007 in Okinawa,
Japan. Brain & Development 38(9):792-799,
2016.
3. Zaitsu M, Nakamura F, Toyokawa S, Tonooka A,
Takumi Takeuchi T, Homma Y, Kobayashi Y. Riskof alcohol consumption in bladder cancer:
Case-control study from a nationwide inpatient
database in Japan. Tohoku Journal of
Experimental Medicine 239(1): 9-15, 2016.
4. Higashi K, Itoh M, Toyokawa S, Kobayashi Y.
Subsidy and parental attitudes toward pediatrichealth care in the Tokyo metropolitan area.
Pediatrics International 58(2):132-138, 2016.
5. Hasegawa J, Toyokawa S, Ikenoue T, Asano Y,
Satoh S, Ikeda T, Ichizuka K, Tamiya N, Nakai A,
Fujimori K, Maeda T, Masuzaki H, Suzuki H,
Ueda S. Prevention recurrence committee, Japanobstetric compensation system for cerebral palsy:
Relevant obstetric factors for cerebral palsy: From
the nationwide obstetric compensation system inJapan. PLoS One 11(1): e0148122, doi: 10.1371/journal.pone.0148122, 2016.
6. Okada F, Toyokawa S, Kaneko T, Furuhata T. The
adverse relationship of locomotive syndrome onaccess to social capital, life satisfaction, and selfrated health among retired household elderlies-Survey on dietary environment in relation todifficulty in shopping and current healthconditions of household elderly-. Journal of
Health & Human Ecology 82(5):171-181, 2016.
7. Okamoto M, Kobayashi Y, Nakamura F, Musha T.
Association between nonrestorative sleep and riskof diabetes: A cross-sectional study. Behavioral
Sleep Medicine 2016 May 6. [Epub ahead ofprint], doi: 10.1080/15402002.2016. 1163701.
8. Miyawaki A, Toyokawa S, Inoue K, Miyoshi Y,
Kobayashi Y. Self-reported periodontitis andincident type 2 diabetes among male workers

from a 5-year Follow-Up to MY Health Up Study.
PLoS One 11(4): e0153464, doi: 10.1371/journal.
pone.0153464, 2016.
9. Asada T, Aoki Y, Sugiyama T, Yamamoto M,
Ishii T, Kitsuta Y, Nakajima S, Yahagi N, Doi K.
Organ
SystemNetwork
Disruptionin
Nonsurvivors of Critically Ill Patients. Critical
Care Medicine 44(1):83-90, 2016.
10. Inoue K, Tsujimoto T, Saito J, Sugiyama T.
Association between serum thyrotropin levels andmortality among euthyroid adults in the UnitedStates. Thyroid 26(10): 1457-1465, 2016.
11. Tsujimoto T, Sugiyama T, Yamamoto-Honda R,
Kishimoto M, Noto H, Morooka M, Kubota K,
Kamimura M, Hara H, Kajio H, Kakei M, Noda
M. Beneficial effects through aggressive coronary
screening for type 2 diabetes patients withadvanced vascular complications. Medicine(Baltimore)
95(33):e4307,
doi:10.1097/MD.
0000000000004307, 2016.
12. Tsujimoto T, Sugiyama T, Noda M, Kajio H.
Intensive glycemic therapy in patients with type 2
diabetes on β-blockers. Diabetes Care 39(10):1818-26, 2016.
13. Tsujimoto T, Imai K, Kanda S, Kakei M, Kajio H,
Sugiyama T. Sweet taste disorder and vascularcomplications in patients with abnormal glucose
tolerance. International Journal of Cardiology
5(221): 637-641, 2016.
14. Tsujimoto T, Kajio H, Sugiyama T. Risk for
cardiovascular and cardiac deaths in nonobese
patients with diabetes and coronary disease. Mayo
Clin Proc 91(11):1545-1554, doi:10.1016/j.mayocp.
2016.08.018, 2016.
15. Hori M, Tanaka H, Wakai K, Sasazuki S,
Katanoda K. Secondhand smoke exposure andrisk of lung cancer in Japan: a systematic review
and meta-analysis of epidemiologic studies.
Japanese Journal of Clinical Oncology 46 (10):942-951, doi: 10.1093/jjco/hyw091, 2016.
16. Tanaka H, Tomio J, Sugiyama T, Kobayashi Y.
Process quality of diabetes care under favorable
access to healthcare: a 2-year longitudinal study
using claims data in Japan. BMJ Open Diabetes
Research & Care 4 (1): e000291, doi:10.1136/bmj
drc-2016-000291, 2016.
17. Maeda E, Nakamura F, Boivin J, Kobayashi Y,

114

Sugimori H, Saito H. Fertility knowledge and thetiming of first childbearing: a cross-sectional
study in Japan. Human Fertility 19(4):275-281,
doi.org/10.1080/14647273.2016.1239033, 2016.
18. Sugiyama T, Horino M, Inoue K, Kobayashi Y,
Shapiro MF, McCarthy WJ. Trends of child’s
weight perception by children, parents, andhealthcare professionals during the time ofterminology change in childhood obesity in the
United States, 2005-2014. Childhood Obesity12(6): 463-473, 2016.
19. Okamoto M, Nakamura F, Musha T, Kobayashi Y.
Association between novel arterial stiffness
indices and risk factors of cardiovascular disease.
BMC Cardiovascular Disorders 16: 211. doi:10.
1186/s12872-016-0389-x, 2016.
20. Toyokawa S, Maeda E, Kobayashi Y. Estimationof the number of children with cerebral palsy
using nationwide health insurance claims data inJapan. Developmental Medicine & Child
Neurology 59(3):317-321, doi:10.1111/dmcn.
13278, 2016.
21. Inada H, Tomio J, Nakahara S. National 10-year
trend in road injuries involving school children on
the way to and from school in Japan, 2003-2012.
Injury Prevention 2016 Dec 30 [Epub ahead ofprint] doi:10.1136/injuryprev-2016-042042.
22. Okada F, Toyokawa S, Kaneko T, Furuhata T.
Food purchase and locomotive syndrome amonghousehold elderlies -Survey on dietary environment in relation to difficulty in shopping andhousehold elderly. Bulltein of Social Medicine 33;
1-7, 2016.

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

116

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

Lecturer
Yohsuke Makino, M.D., Ph.D.

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

Homepage

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

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.

117

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 Clinical 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, Saitoh H, Sakuma A, Ishii
N, Yajima D, Inokuchi G, Motomura A, Chiba F,
Yamaguchi R, Hashimoto M, Hoshioka Y, Iwase
H. Stature estimation in a contemporary Japanese
population based on clavicular measurements
using multidetector computed tomography.
Forensic Sci. Int. 2017;275:316.e1-6
2. Torimitsu S, Makino Y, Saitoh H, Sakuma A, Ishii
N, Yajima D, Inokuchi G, Motomura A, Chiba F,
Yamaguchi R, Hashimoto M, Hoshioka Y, Iwase
H. Sex determination based on sacral andcoccygeal measurements using multidetector

118

3.

4.

5.

6.

7.

8.

9.

computed tomography in a contemporary
Japanese population. Journal of Forensic
Radiology and Imaging. 2017;9:8-12
Torimitsu S, Makino Y, Saitoh H, Sakuma A, Ishii
N, Yajima D, Inokuchi G, Motomura A, Chiba F,
Yamaguchi R, Hashimoto M, Hoshioka Y, Iwase
H. Sexual determination based on multidetector
computed tomographic measurements of thesecond cervical vertebra in a contemporary
Japanese population. Forensic Sci. Int. 2016;266:
588.e1-6
Torimitsu S, Makino Y, Saitoh H, Sakuma A, Ishii
N, Yajima D, Inokuchi G, Motomura A, Chiba F,
Yamaguchi R, Hashimoto M, Hoshioka Y, Iwase
H. Sex estimation based on scapula analysis in a
Japanese
populationusing
multidetector
computed tomography. Forensic Sci. Int. 2016;
262:285.e1-5
Chiba F, Makino Y, Motomura A, Inokuchi G,
Ishii N, Torimitsu S, Hoshioka Y, Abe H,
Yamaguchi R, Hashimoto M, Sakuma A,
Nagasawa S, Saito H, Yajima D, Iwase H. A rare
autopsy case of traumatic rhabdomyolysis
associated with intermittent assault. Legal Med(Tokyo). 2016 May;20:40-3.
Ishii N, Sakuma A, Makino Y, Torimitsu S,
Yajima D, Motomura A, Chiba F, Hoshioka Y,
Iwase H, Saitoh H. Incidence of three-rooted
mandibular first molars among contemporary
Japnanese individuals determined using multidetector computed tomography. Legal Med(Tokyo). 2016 Sep;22:9-12.
Makino Y, Itoda N, Ikegaya H, Tanaka N,
Kinoshita H, Motomura A, Uno T, Iwase H.
Search and removal of radioactive seeds: anotherapplication of postmortem computed tomography
prior to autopsy. Int J Legal Med. 130(5):1329-32,
2016.
Nagasawa S, Katagiri N, Nara A, Chiba F, Kubo Y,
Torimitsu S, Yajima D, Akutsu M, Iwase H.
Postmortem
redistribution
mechanismofdonepezil in the rat. Forensic Sci Int. 2016;266:
1-7.
Torimitsu S, Makino Y. Anthropology: Stature
Estimation from the Skeleton. In: Roger Byard,
Jason Payne-James, editors. Encyclopedia of

Forensic and Legal Medicine. 2nd edition.
Oxford: Elsevier; 2016 Vol.1 p.221-226

119

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

Assistant Professor
Katsuya Tanaka, 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.

120

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 FY2016 are five in doctor’s course for
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

121

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, Kawazoe Y, Ida Y, Shinohara E,
Tanaka K, Imai T, Ohe K.: Development of Type
2 Diabetes Mellitus Phenotyping Framework Using Expert Knowledge and Machine Learning
Approach. J Diabetes Sci Technol. 2016 Dec 7.
pii: 1932296816681584.
2. Takeshi Imai, Emiko Shinohara, Masayuki Kajino,
Ryota Sakurai, Kazuhiko Ohe, Kouji Kozaki,
Riichiro Mizoguchi. An Ontological Framework
for Representing Topological Information in Human Anatomy.In Proc. of the 5th Internatinal
Conference on Biomedical Ontology (ICBOBioCreative 2016), CEUR-ws.org Vol. 1747,
IT506, Corvallis, Oregon, USA, Aug. 1-4, 2016.
3. Kawaguchi H, Koike S (2016) Association between the Density of Physicians and Suicide Rates
in Japan: Nationwide Ecological Study Using a

4.

5.

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7.

Spatial Bayesian Model. PLoS ONE 11(2):e0148288. doi:10.1371/journal.pone.0148288
香川璃奈,篠原恵美子,河添悦昌,今井健,大江和彦,病名を介する検査推薦システム構築に向けた同時に行うべき検査項目ペアの自動抽出方法の開発,医療情報学 36(3):113-122,2016.
Kawazoe Y, Imai T, Ohe K. :A Querying Method
over RDF-ized Health Level Seven v2.5 Messages
Using Life Science Knowledge Resources, JMIR
Med Inform .,4(2),2016
Kurasawa H, Hayashi K, Fujino A, Takasugi K,
Haga T, Waki K, Noguchi T, Ohe K.:
Machine-Learning-Based Prediction of a Missed
Scheduled Clinical Appointment by Patients With
Diabetes. J Diabetes Sci Technol. 10(3): 730-6,
2016
Yokota S, Ohe K. Construction and evaluation of
FiND, a fall risk prediction model of inpatientsfrom nursing data. Japan Journal of Nursing
Science.13(2): 247–255,2016

Internal Medicine
1. Medicine Ⅰ

123

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

Lecturer
Masafumi Watanabe, M.D., Ph.D.

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

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

Jiro Andoh, M.D.

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

Homepage

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

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

Introduction and Organization
The Department of Cardiovascular Medicine wasestablished in 1998 by regrouping cardiologists of fiveprevious internal medical departments. After Yoshio
Yazaki, the first professor, and Ryozo Nagai, the second
professor, the present professor Issei Komuro waselected in August, 2012. Our department comprises one
professor, 4 lecturers, 2 hospital lecturers, 15 research
assistants, 11 staff members, and 46 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 2016, a total of 1,926 patients were newly
admitted to our hospital ward of 60 beds. The average
duration of hospitalization was 12.2 days.

Because we are an authorized facility for heart transplantation, the use of left ventricular assist device incases of severe heart failure has been increasing. In
2006, the first patient with heart failure from ourdepartment underwent a heart transplant procedure atthe Department of Cardiovascular Surgery. In 2016, 12
patients underwent heart transplant (total 78 cases). In
March 2014, our facility was also authorized to perform
lung transplantation. Cardiovascular angiography was
performed in 1,647 patients, of which 523 patients
underwent interventional procedures. CT coronary
angiography and cardiovascular MRI were performed
in 409 and 76 patients, respectively. With regard toarrhythmias, there were 331 cases of catheter ablation,
68 cases of implantation or replacement of pacemakers
and other specialized pacemaker devices, including 19
cases of implantation or replacement of implantablecardioverter-defibrillator and 10 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
208.3 patients visit each day. The disease profile includes ischemic heart disease, heart failure, arrhythmia.
hypertension and peripheral artery disease, There are
special outpatient clinics for pulmonary hypertension,

124congenital heart disease, 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.

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

Research activities
From a research perspective, our interests include all
fields of cardiovascular medicine, ranging frommolecular biology to clinical research, including
genomics. Importantly, our research interests are aimed
at facilitating new diagnostic and treatment methods
for cardiovascular diseases. Our areas of interest
include the following:
1. Cardiac hypertrophy and heart failure: analyses ofpathogenic mechanisms and development of novel
therapies (e.g., gene therapy)
2. Nitric oxide and endothelial function
3. Interplay between organs, cells, and molecules inchronic inflammation
4. Mechanisms underlying cardiorenal association
5. Role of hypoxia signaling in cardiovascular diseases
6. Investigation of disease pathophysiology anddevelopment of novel therapies (severe heart
failure, cardiac transplantation, congenital heartdisease, etc.)
7. New treatments for structural heart disease
8. Diagnosis and treatment of Marfan’s syndrome andadult congenital heart disease
9. New treatments for pulmonary hypertension
10. New treatments for congenital heart disease
11. Aerobic threshold and cardiac rehabilitation
12. Imaging techniques (echocardiography, MRI, CT,

and SPECT) in cardiovascular diseases

Publications (2016)
1. Amiya E, Morita H, Hatano M, Nitta D, Hosoya Y,
Maki H, et al. Fukutin gene mutations that cause
left ventricular noncompaction. Int J Cardiol.
2016;222:727-9.
2. Amiya E, Watanabe M, Watanabe S, Takata M,
Komuro I. Enhancement of arterial pulsation
during flow-mediated dilation is impaired in thepresence of ischemic heart disease. Springerplus.
2016;5(1):1103.
3. Fujino T, Kinugawa K, Nitta D, Imamura T, Maki
H, Amiya E, et al. Donor age is a predictor of early
low output after heart transplantation. J Cardiol.
2016;67(5):477-82.
4. Hara M, Sakata Y, Nakatani D, Suna S, Nishino M,
Sato H, et al. Subclinical elevation of highsensitive troponin T levels at the convalescentstage is associated with increased 5-year mortality
after ST-elevation myocardial infarction. J Cardiol.
2016;67(4):314-20.
5. Hara M, Sakata Y, Nakatani D, Suna S, Nishino M,
Sato H, et al. Impact of coronary collaterals on inhospital and 5-year mortality after ST-elevation
myocardial infarction in the contemporary
percutaneous coronary intervention era: aprospective observational study. BMJ Open. 2016;
6(7):e011105.
6. Hashimoto A, Naito AT, Lee JK, KitazumeTaneike R, Ito M, Yamaguchi T, et al. Generationof Induced Pluripotent Stem Cells From Patients
With Duchenne Muscular Dystrophy and Their
Induction to Cardiomyocytes. Int Heart J. 2016;
57(1):112-7.
7. Hasumi E, Fujiu K, Imamura T, Iwata H, Sawaki
D, Hosoya Y, et al. Cardiac Arrest Triggered bySubepicardial Aneurysm Without Cardiac Rupture.
Circ J. 2016;80(2):538-40.
8. Hirokawa M, Daimon M, Lee SL, Nakao T,
Kawata T, Kimura K, et al. Early menopause does
not influence left ventricular diastolic dysfunction:
A clinical observational study in healthy subjects.
J Cardiol. 2016;68(6):548-53.
9. Ichibori Y, Ohtani T, Nakatani D, Tachibana K,
Yamaguchi O, Toda K, et al. Optical coherence

125

tomography
andintravascularultrasoundevaluation of cardiac allograft vasculopathy withand without intimal neovascularization. Eur HeartJ Cardiovasc Imaging. 2016;17(1):51-8.
10. Ikeda Y, Kumagai H, Motozawa Y, Suzuki J,
Akazawa H, Komuro I. Understanding Vascular
Diseases: Lessons From Premature Aging
Syndromes. Can J Cardiol. 2016;32(5):650-8.
11. Imamura T, Kinugawa K, Komuro I. Tolvaptan
Prolongs Blockage of the Vasopressin Type II
Receptor Over 24 Hours in Responders With StageD Heart Failure. Int Heart J. 2016;57(1):41-6.
12. Imamura T, Kinugawa K, Nitta D, Komuro I.
Tolvaptan Reduces Long-Term Total Medical
Expenses and Length of Stay in AquaporinDefined Responders. Int Heart J. 2016;57(5):5939.
13. Imamura T, Kinugawa K, Nitta D, Komuro I. RealTime Assessment of Autonomic Nerve Activity
During Adaptive Servo-Ventilation Support or
Waon Therapy. Int Heart J. 2016;57(4):511-4.
14. Imamura T, Kinugawa K, Nitta D, Komuro I.
Shorter Heart Failure Duration Is a Predictor of
Left Ventricular Reverse Remodeling During
Adaptive Servo-Ventilator Treatment in Patients
With Advanced Heart Failure. Int Heart J. 2016;
57(2):198-203.
15. Imamura T, Kinugawa K, Nitta D, Komuro I.
Long-Term Adaptive Servo-Ventilator Treatment
Prevents Cardiac Death and Improves Clinical
Outcome. Int Heart J. 2016;57(1):47-52.
16. Ito M, Doi K, Takahashi M, Koyama K, Myojo M,
Hosoya Y, et al. Plasma neutrophil gelatinaseassociated lipocalin predicts major adverse
cardiovascular events after cardiac care unit
discharge. J Cardiol. 2016;67(2):184-91.
17. Iwasa T, Amiya E, Ando J, Watanabe M,
Murasawa T, Komuro I. Different Contributions ofPhysical Activity on Arterial Stiffness between
Diabetics and Non-Diabetics. PLoS One.
2016;11(8):e0160632.
18. Kanda M, Nagai T, Takahashi T, Liu ML, Kondou
N, Naito AT, et al. Leukemia Inhibitory Factor
Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction. PLoS One. 2016;
11(5):e0156562.
19. Kanzaki M, Asano Y, Ishibashi-Ueda H, Oiki E,

Nishida T, Asanuma H, et al. A Development of
Nucleic Chromatin Measurements as a New
Prognostic Marker for Severe Chronic Heart
Failure. PLoS One. 2016;11(2):e0148209.
20. Katagiri M, Takahashi M, Doi K, Myojo M,
Kiyosue A, Ando J, et al. Serum neutrophil
gelatinase-associated lipocalin concentrationreflects severity of coronary artery disease inpatients without heart failure and chronic kidneydisease. Heart Vessels. 2016;31(10):1595-602.
21. Kido Y, Takahashi M, Fukuma N, Kawata T,
Tanaka A, Hayashi A, et al. Heart Failure
Complicated by Alveolar Hemorrhage due toVascular Collapse and Amyloid Deposits in WildType Transthyretin Amyloidosis. Cardiology.
2016;135(4):216-20.
22. Kimura K, Morita H, Daimon M, Horio M, Kawata
T, Nakao T, et al. Utility of Cystatin C for
Estimating Glomerular Filtration Rate in Patients
With Muscular Dystrophy. Int Heart J. 2016;
57(3):386-8.
23. Ko T, Hatano M, Nitta D, Muraoka H, Minatsuki
S, Imamura T, et al. A case of interferon-alphainduced pulmonary arterial hypertension after
living donor liver transplantation. Heart Vessels.
2016;31(7):1206-8.
24. Kobayashi N, Suzuki JI, Aoyama N, Sato H,
Akimoto S, Wakayama K, et al. Toll-like receptor
4 signaling has a critical role in Porphyromonas
gingivalis-accelerated neointimal formation afterarterial injury in mice. Hypertens Res. 2016;
39(10):717-22.
25. Konta A, Ozaki K, Sakata Y, Takahashi A,
Morizono T, Suna S, et al. A functional SNP in
FLT1 increases risk of coronary artery disease in a
Japanese population. J Hum Genet. 2016;61(5):435-41.
26. Kubota A, Takano H, Wang H, Hasegawa H,
Tadokoro H, Hirose M, et al. DPP-4 inhibition has
beneficial effects on the heart after myocardial
infarction. J Mol Cell Cardiol. 2016;91:72-80.
27. Lee SL, Daimon M, Di Tullio MR, Homma S,
Nakao T, Kawata T, et al. Relationship of Left
Ventricular Diastolic Function to Obesity and
Overweight in a Japanese Population With
Preserved Left Ventricular Ejection Fraction. Circ
J. 2016;80(9):1951-6.

126

28. Lee SL, Daimon M, Nakao T, Singer DE,
Shinozaki T, Kawata T, et al. Factors influencing
left atrial volume in a population with preserved
ejection fraction: Left ventricular diastolic
dysfunction or clinical factors? J Cardiol. 2016;
68(4):275-81.
29. Maemura S, Amiya E, Seki H, Ueda K, Nitta D,
Imamura T, et al. Endomyocardial Fibrosis
Associated With Apical Calcification and High
Uptake on Myocardial Gallium-67 Scintigraphy.
Circ J. 2016;80(9):2053-5.
30. Masuda M, Nakatani D, Hikoso S, Suna S, Usami
M, Matsumoto S, et al. Clinical Impact ofVentricular Tachycardia and/or Fibrillation During
the Acute Phase of Acute Myocardial Infarction on
In-Hospital and 5-Year Mortality Rates in the
Percutaneous Coronary Intervention Era. Circ J.
2016;80(7):1539-47.
31. Masumura Y, Higo S, Asano Y, Kato H, Yan Y,
Ishino S, et al. Btg2 is a Negative Regulator of
Cardiomyocyte Hypertrophy through a Decrease in
Cytosolic RNA. Sci Rep. 2016;6:28592.
32. Matsubara TJ, Fujiu K, Asada K, Kojima T, Hisaki
M, Yamagata K, et al. Direct left atrial ICE
imaging guided ablation for atrial fibrillation
without employing contrast medium. Int J Cardiol.
2016;203:733-9.
33. Matsumura T, Amiya E, Tamura N, Maejima Y,
Komuro I, Isobe M. A novel susceptibility locus
for Takayasu arteritis in the IL12B region can be a
genetic marker of disease severity. Heart Vessels.
2016;31(6):1016-9.
34. Miura M, Yamasaki M, Uemura Y, Yoshikawa M,
Miyauchi K, Tanaka H, et al. Effect of Statin
Treatment
and Low-Density
LipoproteinCholesterol on Short-Term Mortality in Acute
Myocardial Infarction Patients UndergoingPrimary Percutaneous Coronary Intervention Multicenter Registry From Tokyo CCU Network
Database. Circ J. 2016;80(2):461-8.
35. Morita H, Komuro I. A Strategy for Genomic
Research on Common Cardiovascular Diseases
Aiming at the Realization of Precision Medicine:
Personal Insights and Perspectives. Circ Res. 2016;
119(8):900-3.
36. Morita H, Komuro I. Periostin Isoforms andCardiac Remodeling After Myocardial Infarction:

Is the Dispute Settled? Hypertension. 2016;67(3):504-5.
37. Nakagawa A, Naito AT, Sumida T, Nomura S,
Shibamoto M, Higo T, et al. Activation ofendothelial beta-catenin signaling induces heart
failure. Sci Rep. 2016;6:25009.
38. Nakayama A, Morita H, Hayashi N, Nomura Y,
Hoshina K, Shigematsu K, et al. Inverse
Correlation Between Calcium Accumulation andthe Expansion Rate of Abdominal Aortic
Aneurysms. Circ J. 2016;80(2):332-9.
39. Nishizaki Y, Shimada K, Tani S, Ogawa T, Ando
J, Takahashi M, et al. Association between the
docosahexaenoic acid to arachidonic acid ratio andacute coronary syndrome: a multicenter
observational study. BMC Cardiovasc Disord.
2016;16(1):143.
40. Nitta D, Kinugawa K, Imamura T, Endo M, Amiya
E, Hatano M, et al. Successful Pregnancy and
Delivery in a Heart Transplantation Recipient. Int
Heart J. 2016;57(3):383-5.
41. Nitta D, Kinugawa K, Imamura T, Kato NP,
Komuro I. High Dose beta-Blocker Therapy
Triggers Additional Reverse Remodeling in
Patients With Idiopathic Non-Ischemic Cardiomyopathy. Int Heart J. 2016;57(6):717-24.
42. Niwa R, Hasumi E, Fujiu K, Uehara M, Nitta D,
Hatano M, et al. A Case of Multiple Coronary
Artery-Left
Ventricular
Micro
FistulaeComplicated With Hepatic Arteriovenous Fistulae.
Int Heart J. 2016;57(1):123-6.
43. Oka T, Morita H, Komuro I. Novel molecularmechanisms and regeneration therapy for heart
failure. J Mol Cell Cardiol. 2016;92:46-51.
44. Ono S, Saito I, Ikeda Y, Fujishiro M, Komuro I,
Koike K. Current Practices in the Management of
Antithrombotic Therapy During the Periendoscopic Period for Patients With Cardiovascular
Disease. Int Heart J. 2016;57(5):530-4.
45. Sakamoto A, Ishizaka N, Imai Y, Uehara M, Ando
J, Nagai R, et al. Relationship between serum IgG4
concentrations and atherosclerotic coronary
plaques assessed by computed tomographic
angiography. J Cardiol. 2016;67(3):254-61.
46. Semba H, Takeda N, Isagawa T, Sugiura Y, Honda
K, Wake M, et al. HIF-1alpha-PDK1 axis-induced
active glycolysis plays an essential role in127

macrophage migratory capacity. Nat Commun.
2016;7:11635.
47. Shiheido Y, Maejima Y, Suzuki JI, Aoyama N,
Kaneko M, Watanabe R, et al. Porphyromonas
gingivalis, a periodontal pathogen, enhances
myocardial vulnerability, thereby promoting postinfarct cardiac rupture. J Mol Cell Cardiol. 2016;
99:123-37.
48. Suzuki J, Imai Y, Aoki M, Fujita D, Takeda N,
Aoyama N, et al. Periodontitis May Deteriorate
Sinus of Valsalva Dilatation in Marfan Syndrome
Patients. Int Heart J. 2016;57(4):456-60.
49. Suzuki J, Shimamura M, Suda H, Wakayama K,
Kumagai H, Ikeda Y, et al. Current therapies andinvestigational drugs for peripheral arterial disease.
Hypertens Res. 2016;39(4):183-91.
50. Takamura C, Suzuki J, Ogawa M, Watanabe R,
Tada Y, Maejima Y, et al. Suppression of murine
autoimmune myocarditis achieved with direct
renin inhibition. J Cardiol. 2016;68(3):253-60.
51. Takata M, Amiya E, Watanabe M, Shintani Y,
Sakuma K, Saito A, et al. Phenotypic differences
in aortic stenosis according to calcification grade.
Int J Cardiol. 2016;216:118-20.
52. Takata M, Amiya E, Watanabe M, Yamada N,
Watanabe A, Kawarasaki S, et al. The association
between orthostatic increase in pulse pressure andischemic heart disease. Clin Exp Hypertens. 2016;
38(1):23-9.
53. Takeda N, Yagi H, Hara H, Fujiwara T, Fujita D,
Nawata K, et al. Pathophysiology and Managementof Cardiovascular Manifestations in Marfan and
Loeys-Dietz Syndromes. Int Heart J. 2016;57(3):271-7.
54. Ueda K, Kasao M, Shimamura M, Haruta H, Nitta
S, Kaneko M, et al. Impact of Oral Treatment on
Physical Function in Older Patients Hospitalizedfor Heart Failure: A Randomized Clinical Trial.
PLoS One. 2016;11(12):e0167933.
55. Ueshima K, Itoh H, Kanazawa N, Komuro I, Nagai
R, Takeuchi M, et al. Rationale and Design of theStandard Versus Intensive Statin Therapy for
Hypercholesterolemic Patients with Diabetic
Retinopathy (EMPATHY) Study: a Randomized
Controlled Trial. J Atheroscler Thromb. 2016;23(8): 976-90.
56. Watanabe R, Suzuki J, Wakayama K, Kumagai H,

Ikeda Y, Akazawa H, et al. Angiotensin II receptor
blocker irbesartan attenuates cardiac dysfunction
induced by myocardial infarction in the presenceof renal failure. Hypertens Res. 2016;39(4):237-44.
57. Yasuda S, Nakao K, Nishimura K, Miyamoto Y,
Sumita Y, Shishido T, et al. The Current Status of
Cardiovascular Medicine in Japan- Analysis of a
Large Number of Health Records From a
Nationwide Claim-Based Database, JROAD-DPC.
Circ J. 2016;80(11):2327-35.
58. Yasui T, Masaki T, Arita Y, Ishibashi T, Inagaki T,
Okazawa M, et al. Molecular Characterization ofStriated Muscle-Specific Gab1 Isoform as a
Critical Signal Transducer for Neuregulin-1/ErbB
Signaling in Cardiomyocytes. PLoS One. 2016;
11(11):e0166710.
59. Yokota J, Fujiu K, Kojima T, Komuro I. PseudoReentry of Atrial Tachycardia After Surgical
Repair of Congenital Heart Disease. J Cardiovasc
Electrophysiol. 2016;27(7):876-7.
60. Zempo H, Suzuki J, Watanabe R, Wakayama K,
Kumagai H, Ikeda Y, et al. Cacao polyphenols
ameliorate autoimmune myocarditis in mice.
Hypertens Res. 2016;39(4):203-9.
61. Zempo H, Suzuki JI, Watanabe R, Wakayama K,
Kumagai H, Ikeda Y, et al. Corrigendum: Cacao
polyphenols ameliorate autoimmune myocarditis
in mice. Hypertens Res. 2016;39(11):828.
62. Zhan H, Aizawa K, Sun J, Tomida S, Otsu K,
Conway SJ, et al. Ataxia telangiectasia mutated in
cardiac fibroblasts regulates doxorubicin-induced
cardiotoxicity. Cardiovasc Res. 2016;110(1):85-95.

128

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

Lecturer
Goh Tanaka, M.D.,Ph.D., Yasuhiro Yamauchi, M.D.,Ph.D.

Associate
Hidenori Kage, M.D.,Ph.D.,

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.,

Azusa Yamato, M.D.,Ph.D.,

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

Homepage

http://kokyuki.umin.jp/

Introduction and Organization

Clinical activities

The staff of the Department of Respiratory Medicine,
Graduate School of Medicine, University of Tokyo,
consists of 1 professor, 2 lecturers, and 8 associates. In
the University of Tokyo, affiliated hospitals andforeign institutions, approximately 60 members
belong to the Department. In the University of Tokyo
Hospital, about 23 respiratory physicians are doingclinical works.
Based on the fact that the number of patients withrespiratory diseases such as primary lung cancer and
COPD is tremendously increasing, advancement andfruitful results of researches on respiratory medicine
are more and more expected. In this era, we areconducting basic and clinical researches for wide
variety of respiratory disorders including primary lungcancer, COPD, asthma and interstitial lung diseases.
Especially, we have been intensively studying themolecular mechanisms underlying the pathogenesis oflung disorders. Our research goal is to develop novel
diagnostic and therapeutic modalities for better
management of these pulmonary diseases.

The Department of Respiratory Medicine is responsible for the out-patient care as well as care of
in-patients (35 cases on average), which is taken at the13th floor of the hospital ward A of the University ofTokyo Hospital. Our practice is performed by thethree-member system of a junior resident, a seniorresident and an experienced associate.
Main diseases of in-patients are primary lung cancer,
respiratory infections, interstitial pneumonia, and
COPD. Many patients with primary lung cancer also
have interstitial pneumonia or COPD as their background pulmonary diseases. There are many
emergency visits and admissions with pneumonia,
respiratory failure due to exacerbation of COPD orinterstitial pneumonia, progression of lung cancer, andso on. In cases of severe respiratory failure such as
severe pneumonia and ARDS, we conduct ventilatory
support of such patients in collaboration with ICU
staff in an effort to rescue them. A specialized clinicalconference for respiratory disease has been held oncea week since late 1990s, where staff of our department,
department of thoracic surgery and department of129radiology join and discuss together to make best
diagnostic and therapeutic approach to individual
patients. This conference has been highly appreciatedas prototype of Cancer Board of the University ofTokyo Hospital, and, is now held as Respiratory
Cancer Board. This conference is still one of themost frequently held Cancer Board in our hospital.
Our department contributes to the pre- and postsurgical evaluation of respiratory functions, and also
receives consultation about respiratory complications
from almost every department in our hospital
At present, there increase highlighted interests in
respiratory medicine. Primary lung cancer is now
leading cause of cancer death, and is one of the major
medical and social problem to be overcome. Recently,
the new developments and their remarkable effectiveness of molecular-targeted therapies in primary lungcancer attract much attention in the fields of bothbasic science and clinical practice. Respiratory
infections are now the 3rd leading cause of all deathand COPD also will be major leading cause of alldeath in the near future. Among respiratory diseases,
there are several disorders to which no effective
therapeutic modalities are currently available. For
example, ARDS is an acute lung injury and themortality rate for ARDS is extremely high despite ofintensive care using currently available tools.
Idiopathic pulmonary fibrosis is a progressive andfatal inflammatory and fibrotic disorder of the lungparenchyma, while only a few medications are
currently available to treat the disease. We would liketo make every effort to develop a novel and potential
therapeutic approach to these diseases.
Number of in-patients in 2016
1. Primary lung cancer
2. Abnormal chest X-ray
3. Respiratory Infection
4. Interstitial pneumonia
5. Sarcoidosis
6. COPD
7. Malignancy other than
primary lung cancer

154
81
59
57
10
6
5

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

Teaching activities
As for under-graduate education, our department takes
part in systematic lectures and specific learning for
diagnosis and treatment of respiratory diseases for the
4th year medical students, clinical clerkship for the 5thyear medical students, and clinical lectures for the 5th
and 6th year medical students. Elective clerkship forthe 5th year students is actively performed in collaboration with expert respiratory physicians from several
leading affiliated hospitals.
In systematic lectures, comprehensive presentation for
the understanding of basic knowledge about theconcept, pathogenesis, pathology, diagnosis and treatment of common respiratory diseases is performed.
In clinical lectures, we present clinical cases ofimportant diseases such as primary lung cancer andpneumothorax, and try to discuss several important
points on the diagnostic evaluation and treatment incollaboration with the Faculty of the Department ofThoracic Surgery. Recent major advance in therelevant fields are also reviewed.
During the period of clinical clerkship, each student,
as a member of medical care team, has opportunities
to experience the daily clinical care with junior andsenior residents as well as with the Faculty. Eachstudent can learn how to make a medical interview,
check physical findings and make the actual plans forthe diagnosis and treatment. The respiratory specialists provide lecture on fundamental chest radiology as
one of essential elements in clinical clerkship and thislecture is highly appreciated by the students.
Elective clerkship at the 5th year of the educational
program is actively performed to facilitate theexposure to a wide range of clinical practice both at
the University of Tokyo Hospital and at one of theaffiliated hospitals for a relatively long period (eachfor two weeks). Several lectures on the specialized

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theme on respiratory diseases are also provided.
As for post-graduate education, respiratory physicians(one senior resident and one associate) assemble ateam with one junior resident, and provide medical
cares for patients with various respiratory diseases.
Under these processes, residents are able to acquire
the knowledge and skills required for diagnosis andtreatment of respiratory diseases. Seminars on
important themes such as medical treatment of lungcancer, diagnostic chest imaging, and so on are held at
regular interval.

remodeling, especially epithelial-mesenchymal transition, and the roles of various cytokines andchemokines, in asthma and COPD.
Detection of small airway disease using impulse
oscillometry and its clinical application.
Search for predictive factors for responses to chemotherapy in malignancy including primary lung cancer.
Epidemiological study of respiratory diseases, using
Diagnosis Procedure Combination database.
Takahide Nagase is working as a GOLD National
Leader.

Research activities
Our department is conducting basic and clinicalresearches for various respiratory disorders including
primary lung cancer, COPD, asthma, interstitial
pneumonia, respiratory infections and others.
Epidemiological, clinical, cellular and molecularbiological techniques are utilized for the elucidation ofpathogenic mechanisms and for the development ofnovel diagnostic and therapeutic modalities in
respiratory medicine. Postgraduate students as well as
the Faculty members make considerable effort tostudy about genetic alterations in primary lung cancer,
cell biological analysis using airway epithelial cells,
fibroblast and smooth muscle cells, both incollaboration with the Faculty of the Department ofThoracic Surgery, analysis of genetically-engineered
mice as disease-models and so on. These results havebeen presented and/or published in the Scientific
Meeting and/or peer-review Journals. Our main
research projects are as follows.
Search for diseases-susceptibility genes and elucidation of their pathophysiological roles in respiratory
diseases.
Analysis of disease-models using genetically engineered mice.
Analysis of DNA methylation, histone modificationand miRNA in primary lung cancer and their clinicalapplications.
Search for previously unidentified oncogenic driver
mutations in lung cancer and elucidation of resistantmechanisms against molecular-targeted dugs.
Analysis of functional alterations of airway epithelial
cells and fibroblasts in relation to tissue repair andReferences
1. Mitani A, Ito K, Vuppusetty C, Barnes PJ,
Mercado N. Restoration of Corticosteroid
Sensitivity in Chronic Obstructive Pulmonary
Disease by Inhibition of Mammalian Target ofRapamycin. Am J Respir Crit Care Med.
2016;193(2): 143-53.
2. Ishikawa R, Amano Y, Kawakami M, Sunohara M,
Watanabe K, Kage H, Ohishi N, Yatomi Y,
Nakajima J, Fukayama M, Nagase T, Takai D. The
chimeric transcript RUNX1-GLRX5: a biomarker
for good postoperative prognosis in Stage IA
non-small-cell lung cancer. Jpn J Clin Oncol.
2016 Feb;46(2):185-9.
3. Horie M, Tamiya H, Goto Y, Suzuki M, Matsuzaki
H, Hasegawa WT, Noguchi S, Kawakami M,
Matsuta K, Nagase T, Sakamoto Y. Nonspecificelevation of serum Aspergillus galactomannan
antigen levels in patients with rheumatoid arthritis.
Respir Investig. 2016;54(1):44-9.
4. Okuda K, Noguchi S, Narumoto O, Ikemura M,
Yamauchi Y, Tanaka G, Takai D, Fukayama M,
Nagase T. A case of Meigs' syndrome withpreceding pericardial effusion in advance of
pleural effusion. BMC Pulm Med. 2016 May 10;
16(1):71.
5. Kirita K, Izumo T, Matsumoto Y, Hiraishi Y,
Tsuchida T. Bronchoscopic Re-biopsy for
Mutational Analysis of Non-small Cell Lung
Cancer. Lung. 2016 Jun;194(3):371-8.
6. Kibinge N, Ono N, Horie M, Sato T, Sugiura T,
Altaf-Ul-Amin M, Saito A, Kanaya S. Integrated
pathway-based transcription regulation network

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mining and visualization based on gene
expression profiles. J Biomed Inform 2016 Jun;
61:194-202.
7. Yamauchi Y, Yasunaga H, Hasegawa W, Sakamoto
Y, Takeshima H, Jo T, Matsui H, Fushimi
K, Nagase T. Effect of outpatient therapy withinhaled corticosteroids on decreasing in-hospitalmortality from pneumonia in patients with COPD.
Int J Chron Obstruct Pulmon Dis. 2016 Jun 23;
11:1403-11
8. Mikami Y, Matsuzaki H, Takeshima H, Makita K,
Yamauchi Y, Nagase T. Development of an In
Vitro Assay to Evaluate Contractile Function ofMesenchymal Cells that Underwent EpithelialMesenchymal Transition. J Vis Exp. 2016 Jun 10;(112).
9. Djureinovic D, Hallström BM, Horie M, Mattsson
JS, La Fleur L, Fagerberg L, Brunnström H,
Lindskog C, Madjar K, Rahnenführer J, Ekman S,Ståhle E, Koyi H, Brandén E, Edlund K,
Hengstler JG, Lambe M, Saito A, Botling J,
Pontén F, Uhlén M, Micke P. Profiling cancer
testis antigens in non-small-cell lung cancer. JCIInsight 2016 Jul 7;1(10):e86837.
10. Horie M, Yamaguchi Y, Saito A, Nagase T, Lizio
M, Itoh M, Kawaji H, Lassmann T, Carninci P,
Forrest AR, Hayashizaki Y, Suzutani T, Kappert K,
Micke P, Ohshima M. Transcriptome analysis ofperiodontitis -associated fibroblasts by CAGE
sequencing identified DLX5 and RUNX2 long
variant as novel regulators involved inperiodontitis. Sci Rep 2016;6: 33666.
11. Yamauchi Y, Yasunaga H, Sakamoto Y, Hasegawa
W, Takeshima H, Urushiyama H, Jo T, Matsui H,
Fushimi K, Nagase T. Mortality associated withbone fractures in COPD patients. Int J Chron
Obstruct Pulmon Dis. 2016 Sep 21;11:2335-2340.
12. Chino H, Amano Y, Yamauchi Y, Matsuda J,
Takeda N, Tanaka G, Takai D, Nagase T.
Cardiogenic syncope possibly related tobevacizumab-containing combination chemotherapy for advanced non-small cell lung cancer. J
Thorac Dis. 2016 Sep;8(9):2646-2650.
13. Flodby P, Kim YH, Beard LL, Gao D, Ji Y, Kage
H, Liebler JM, Minoo P, Kim KJ, Borok Z,
Crandall ED. Knockout Mice Reveal a Major
Role for Alveolar Epithelial Type I Cells in

Alveolar Fluid Clearance. Am J Respir Cell Mol
Biol 2016 Sep; 55(3): 395-406.
14. Kobayashi K, Koyama K, Suzukawa M, Igarashi
S, Hebisawa A, Nagase T, Ohta K. Epithelialmesenchymal transition promotes reactivity ofhuman lung adenocarcinoma A549 cells to CpG
ODN. Allergol Int 2016 Sep; 65 Suppl: S45-52.
15. Nakamoto K, Watanabe M, Sada M, Inui T,
Nakamura M, Honda K, Wada H, Mikami Y,
Matsuzaki H, Horie M, Noguchi S, Yamauchi Y,
Koyama H, Kogane T, Kohyama T, Takizawa H.
Serum Reactive Oxygen Metabolite Levels
Predict Severe Exacerbations of Asthma. PLoS
One. 2016 Oct 24;11(10):e0164948.
16. Hiraishi Y, Nambu A, Shibui A, Nakanishi W,
Yamaguchi S, Morita H, Iikura M, McKenzie
A.N.J, Matsumoto K, Sudo K, Yamasoba T,
Nagase T, and Nakae S. TIM-3 is not essential fordevelopment of airway inflammation induced by
house
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Allergology
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17. Hiraishi Y, Izumo T, Matsumoto Y, Chavez C,
Sasada, S, Tsuchida T. Evaluation of
bronchoalveolar lavage for differentiating
between Pneumocystis jiroveci pneumonia anddrug-induced pulmonary parenchymal disease
after chemotherapy for solid tumors. Internal
Medicine, Review 2016, 2(11).
18. Hanaoka Y, Yamaguchi Y, Yamamoto H, Ishii M,
Nagase T, Kurihara H, Akishita M, Ouchi Y. In
Vitro and In Vivo Anticancer Activity of Human
β-Defensin-3 and Its Mouse Homolog. Anticancer
Res 2016; 36(11): 5999-6004.
19. Kage H, Goto Y, Amano Y, Makita K, Isago H,
Kobayashi K, Narumoto O, Okudaira R, Tanaka G,
Takami K, Ohishi N, Nagase, T. Development of
pulmonary artery aneurysms due to Behcet’s
disease and resolution after treatment. Intern Med
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T. YAP and TAZ modulate cell phenotype in a
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107(12):1755-1766.

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

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

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

Yoshihiro Hirata, M.D., Ph.D.

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

Nobutake Yamamichi, M.D., Ph.D.

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

Yousuke Nakai, M.D., Ph.D.

Yoshinari Asaoka, M.D., Ph.D.

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

Saburo Matsubara, M.D., Ph.D.

Shinya Kodashima, 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.

Satoshi Ono, M.D., Ph.D.

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

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

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

Hiroto Kinoshita, M.D., Ph.D.

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

Tatsuya Minami, 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, 2 lecturers, 21
associates, 12 fellows, 67 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, fourth and fifth
floors of Ward B also take important part forproviding rooms for inpatients. Laboratories of thedepartment are scattered in each floor, mainly ofClinical Research Center and First Research Building
as in the other departments.

Clinical Activities
The Department of Gastroenterology is in chargeof about 90 inpatients on average, which are about
2,900 in total per year. We receive about 110 new
patients in and out of the hospital each week, with anaverage hospital stay of 11 days. Resident, junior andsenior staff members bear the responsibility for a
medical management of each inpatient, in collaboration with subspecialty groups concerned. The staff
members examine about 5,700 outpatients withvarious digestive diseases in a month. Professor’s

133

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 2016). Number of treatments forhepatocellular carcinoma treatments, represented by
percutaneous radiofrequency ablation, exceeded 400
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, ERCP is performed
1000 cases per year. The cumulative number of endoscopic papillary balloon dilation (EPBD) for treatmentof bile duct stones exceeds 1,500. In addition, EST(endoscopic sphincterotomy) or EPLBD (endoscopic
papillary large balloon dilation) is also applied toachieve the best outcomes for every case. Endoscopic
placement of a metal stent is the standard of care formalignant obstructive jaundice and our group has led
the development of covered metal stents. Pancreaticinterventions such as pancreatic stenting, cystic
drainage and stone extraction are also performed,
which are often technically challenging. In addition tothese conventional ERCPs, a numbers of advanced
procedures are performed in our department: 200
balloon-assisted ERCPs for surgically altered anatomy
cases, 200 EUS-FNAs and 50 EUS-guided
interventions. In combination with these interventions,clinical trials of chemotherapy are conducted to
improve the prognosis of pancreatobiliary cancer.
In the gastrointestinal field, ESD (endoscopic
submucosal dissection) is performed as a curativeendoscopic treatment for neoplasms in esophagus,
stomach or colon (more than 360 patients a year).
Non-exposed endoscopic wall-inversion surgery(NEWS), which was developed with the Department
of Gastrointestinal Surgery, now expanded its clinicalapplication from the resection of GIST to thetreatment of gastric cancer. Double-balloon endoscopy
and capsule endoscopy enabled the examination ofwhole small intestines (320 cases in 2016). All thoseinterventions are performed by the members of ourdepartment, who were specially trained for eachtechnique. In addition, for the management against
inoperative malignancies, we effectively combine theinterventional treatments with various chemotherapy
regimens including new molecular-targeting drugs.
Onoutpatientbasis,
ultrasonography,
gastroduodenal endoscopy, and colonoscopy is
performed on 12,500 patients, 9,700 patients, and6,200 patients per year respectively. In the endoscopy
examinations, we diagnose about 760 cases of gastriccancer and 1300 cases of colorectal tumor annually,
and about 50% of them are treated endoscopically.
Using these resected tissues, we perform various basic
studies in order to feed the new finding back to actual
clinical activities.

Educational Activities
The undergraduate medical students regularly
have the opportunity taking systematic and clinicallectures on gastroenterology from the staffs of ourdepartment. Several courses of practical teaching arealso provided for the students. Particularly, in theclinical clerkship program for the fourth gradestudents, each student joins in the team of staff
physicians and learns digestive diseases practically via
the communication with the inward patients. At theend of period, the students make a summary
presentation of the patient to the professor, and also
outline articles from world’s leading medical journals.
The residents of internal medicine participate in
the training in the Department of Gastroenterology for
1-4 months in the first year. They learn the therapeutics and diagnostics in gastroenterology as well as
general internal medicine. Depending on their interestin gastroenterology, they can learn advanced
techniques in gastroenterology in the affiliated134

hospitals for next few years. They come back to thedepartment as a graduate student, and start medical
researches either in basic or clinical research area.
Currently, 67 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 molecular elucidation of carcinogenesis in gastroenterological neoplasms, metabolic
aspects of viral hepatitis, mechanisms of replication ofhepatitis viruses, pathogenesis of NASH, mechanismsof liver regeneration and fibrosis, pathogenesis of
Helicobacter pylori infection, molecular characterization of gastrointestinal morphology, establishing
new animal models for various diseases in our area,etc. Based on such new concepts as non-coding RNA,
cancer stem, or organoid, we performed various
experiments.
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, a combination
therapy of gemcitabine/S-1/leucovorin for unresectable or borderline resectable pancreatic cancer, arandomized controlled trial of covered metallic stent
with anti-reflux system, endoscopic treatment ofwalled off necrosis a large bore covered metal stent,
efficacy of polyglycolic acid sheets for artificial
endoscopic ulcers, personalized salvage therapy of
Helicobacter infection.
Our department always tries to show the newest
and highest-level clinical activities, based on thevarious data of many patients especially sufferingfrom malignant diseases. Furthermore, we aim to findthe new aspects of diseases and create a new strategy
against it, which are based on clinical, basic, andepidemiological studies in our area.

References
1. Nakai Y, Isayama H, Yamamoto N, Matsubara S,
Kogure H, Mizuno S, Hamada T, Takahara N,
Uchino R, Akiyama D, Takagi K, Watanabe T,
Umefune G, Ishigaki K, Tada M, Koike
K.Indications for endoscopic ultrasonography(EUS)-guided biliary intervention: Does EUS
always come after failed endoscopic retrograde
cholangiopancreatography? Dig Endosc. 2017;29:
218-225.
2. Saito T, Hirano K, Isayama H, Nakai Y, Saito K,
Umefune G, Akiyama D, Watanabe T, Takagi K,
Hamada T, Takahara N, Uchino R, Mizuno S,
Kogure H, Matsubara S, Yamamoto N, Tada M,
Koike K. The Role of Pancreatic Enzyme
Replacement Therapy in Unresectable Pancreatic
Cancer: A Prospective Cohort Study. Pancreas.
2017;46:341-346.
3. Hayakawa Y, Sakitani K, Konishi M, Asfaha S,
Niikura R, Tomita H, Renz BW, Tailor Y,
Macchini M, Middelhoff M, Jiang Z, Tanaka T,
Dubeykovskaya ZA, Kim W, Chen X, Urbanska
AM, Nagar K, Westphalen CB, Quante M, Lin CS,
Gershon MD, Hara A, Zhao CM, Chen D,
Worthley DL, Koike K, Wang TC. Nerve Growth
Factor Promotes Gastric Tumorigenesis through
Aberrant Cholinergic Signaling. Cancer Cell.
2017;31:21-34.
4. Yoshikawa T, Wu J, Otsuka M, Kishikawa T,
Suzuki N, Takata A, Ohno M, Ishibashi R,
Yamagami M, Nakagawa R, Kato N, Miyazawa M,
Han J, Koike K. Repression of MicroRNA
Function
Mediates
Inflammation-associatedColon Tumorigenesis. Gastroenterology. 2017;
152:631-643.
5. Umefune G, Kogure H, Hamada T, Isayama H,
Ishigaki K, Takagi K, Akiyama D, Watanabe T,
Takahara N, Mizuno S, Matsubara S, Yamamoto
N, Nakai Y, Tada M, Koike K. Procalcitonin is a
useful biomarker to predict severe acutecholangitis: a single-center prospective study. J
Gastroenterol. 2017;52:734-745.
6. Nakai Y, Hamada T, Isayama H, Itoi T, Koike K.
Endoscopic management of combined malignant
biliary and gastric outlet obstruction. Dig Endosc.
2017;29:16-25.

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7. Hamada T, Isayama H, Nakai Y, Togawa O,
Takahara N, Uchino R, Mizuno S, Mohri D,
Yagioka H, Kogure H, Matsubara S, Yamamoto N,
Ito Y, Tada M, Koike K. ntireflux Metal Stent as aFirst-Line Metal Stent for Distal Malignant
Biliary Obstruction: A Pilot Study. Gut Liver.
2017;11:142-148.
8. Otsuka M, Kishikawa T, Yoshikawa T, Yamagami
M, Ohno M, Takata A, Shibata C, Ishibashi R,
Koike K. MicroRNAs and liver disease. J Hum
Genet. 2017;62:75-80.
9. 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, based on a national
survey. Hepatol Res. 2017;47:E35-E43.
10. Tanaka Y, Tateishi K, Nakatsuka T, Kudo Y,
Takahashi R, Miyabayashi K, Yamamoto K,
Asaoka Y, Ijichi H, Tateishi R, Shibahara J,
Fukayama M, Ishizawa T, Hasegawa K, Kokudo
N, Koike K. Sharpin promotes hepatocellular
carcinoma progression via transactivation of
Versican expression. Oncogenesis. 2016;5:e277.
11. Isayama H, Nakai Y, Hamada T, Matsubara S,
Kogure H, Koike K. Understanding the Mechanical forces of Self-Expandable Metal Stents in the
Biliary Ducts. Curr Gastroenterol Rep. 2016;18:64.
12. Hirata Y, Serizawa T, Shichijo S, Suzuki N,
Sakitani K, Hayakawa Y, Yamada A, Koike K.
Efficacy of triple therapy with esomeprazole,amoxicillin, and sitafloxacin as a third-line
Helicobacter pylori eradication regimen. Int J
Infect Dis. 2016;51:66-69.
13. Hirata Y, Ihara S, Koike K. Targeting the complex
interactions between microbiota, host epithelial
and immune cells in inflammatory bowel disease.
Pharmacol Res. 2016;113:574-584.
14. Nakai Y, Isayama H, Yamamoto N, Matsubara S,
Ito Y, Sasahira N, Hakuta R, Umefune G,
Takahara N, Hamada T, Mizuno S, Kogure H,
Tada M, Koike K. Safety and effectiveness of along, partially covered metal stent for endoscopic
ultrasound-guided hepaticogastrostomy in patientswith malignant biliary obstruction. Endoscopy.
2016;48:1125-1128.

15. Kishikawa T, Otsuka M, Yoshikawa T, Ohno M,
Yamamoto K, Yamamoto N, Kotani A, Koike K.
Quantitation of circulating satellite RNAs inpancreatic cancer patients. JCI Insight. 2016;1:
e86646.
16. Kishikawa T, Otsuka M, Yoshikawa T, Ohno M,
Ijichi H, Koike K. Satellite RNAs promote pancreatic oncogenic processes via the dysfunction of
YBX1. Nat Commun. 2016;7:13006.
17. Ono S, Saito I, Ikeda Y, Fujishiro M, Komuro I,
Koike K. Current Practices in the Management of
Antithrombotic Therapy During the Periendoscopic Period for Patients With Cardiovascular
Disease. Int Heart J. 2016;57:530-4.
18. Asada-Hirayama I, Kodashima S, Sakaguchi Y,
Ono S, Niimi K, Mochizuki S, Tsuji Y, Minatsuki
C, Shichijo S, Matsuzaka K, Ushiku T, Fukayama
M, Yamamichi N, Fujishiro M, Koike K.
Magnifying endoscopy with narrow-band imaging
is more accurate for determination of horizontal
extent of early gastric cancers than chromoendoscopy. Endosc Int Open. 2016;4:E690-8.
19. Shichijo S, Hirata Y, Niikura R, Hayakawa Y,
Yamada A, Mochizuki S, Matsuo K, Isomura Y,
Seto M, Suzuki N, Suzuki H, Yamamoto S,
Sugimoto T, Omae T, Okamoto M, Watabe H,
Togo G, Takano N, Fukui K, Ito Y, Koike K.
Vonoprazan versus conventional proton pumpinhibitor-based triple therapy as first-line treatment against Helicobacter pylori: A multicenter
retrospective study in clinical practice. J Dig Dis.
2016;17:670-675.
20. Yamamoto K, Tateishi K, Kudo Y, Hoshikawa M,
Tanaka M, Nakatsuka T, Fujiwara H, Miyabayashi
K, Takahashi R, Tanaka Y, Ijichi H, Nakai Y,
Isayama H, Morishita Y, Aoki T, Sakamoto Y,
Hasegawa K, Kokudo N, Fukayama M, Koike K.
Stromal remodeling by the BET bromodomain
inhibitor JQ1 suppresses the progression ofhuman pancreatic cancer. Oncotarget. 2016;7:61469-61484.
21. Minami T, Tateishi R, Nakagomi R, Fujiwara N,
Sato M, Enooku K, Nakagawa H, Asaoka Y,
Kondo Y, Shiina S, Koike K. The impact of
direct-acting antivirals on early tumor recurrence
after radiofrequency ablation in hepatitis
C-related hepatocellular carcinoma. J Hepatol.

136

2016;65:1272-1273.
22. Kataoka Y, Tsuji Y, Sakaguchi Y, Minatsuki C,
Asada-Hirayama I, Niimi K, Ono S, Kodashima S,
Yamamichi N, Fujishiro M, Koike K. Bleeding
after endoscopic submucosal dissection: Risk
factors and preventive methods. World J
Gastroenterol. 2016;22:5927-35.
23. Hamada T, Nakai Y, Isayama H, Yasunaga H,
Matsui H, Takahara N, Mizuno S, Kogure H,
Matsubara S, Yamamoto N, Tada M, Koike K.
Progression-free survival as a surrogate foroverall survival in first-line chemotherapy foradvanced pancreatic cancer. Eur J Cancer. 2016;
65:11-20.
24. Niimi K, Goto O, Kawakubo K, Nakai Y,
Minatsuki C, Asada-Hirayama I, Mochizuki S,
Ono S, Kodashima S, Yamamichi N, Isayama H,
Fujishiro M, Koike K. Endoscopic ultrasoundguided fine-needle aspiration skill acquisition ofgastrointestinal submucosal tumor by traineeendoscopists: A pilot study. Endosc Ultrasound.
2016;5:157-64.
25. Takahara N, Isayama H, Nakai Y, Ishigami H,
Satoi S, Mizuno S, Kogure H, Matsubara S,
Yamamoto N, Yamaguchi H, Tada M, Kitayama J,
Watanabe T, Koike K. Intravenous andintraperitoneal paclitaxel with S-1 for treatment ofrefractory pancreatic cancer with malignant
ascites. Invest New Drugs. 2016;34:636-42.
26. Niikura R, Yasunaga H, Yamada A, Matsui H,
Fushimi K, Hirata Y, Koike K. Factors predicting
adverse events associated with therapeuticcolonoscopy for colorectal neoplasia: a retrospective nationwide study in Japan. Gastrointest
Endosc. 2016;84:971-982.e6.
27. Ihara S, Hirata Y, Serizawa T, Suzuki N, Sakitani
K, Kinoshita H, Hayakawa Y, Nakagawa H, Ijichi
H, Tateishi K, Koike K. TGF-β Signaling in
Dendritic Cells Governs Colonic Homeostasis byControlling Epithelial Differentiation and the
Luminal Microbiota. J Immunol. 2016;196:
4603-13.
28. Shichijo S, Hirata Y, Niikura R, Hayakawa Y,
Yamada A, Ushiku T, Fukayama M, Koike K.
Histologic intestinal metaplasia and endoscopic
atrophy are predictors of gastric cancer
development after Helicobacter pylori eradication.

Gastrointest Endosc. 2016;84:618-24.
29. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Matsui H, Fushimi K, Koike K. Interstitial lungdisease associated with gemcitabine: A Japanese
retrospective cohort study. Respirology. 2016;21:338-43.
30. Nakai Y, Isayama H, Chang KJ, Yamamoto N,
Mizuno S, Mohri D, Kogure H, Matsubara S,
Tada M, Koike K. A pilot study of EUS-guided
through-the-needle forceps biopsy (with video).
Gastrointest Endosc. 2016;84:158-62.
31. Niikura R, Yamada A, Nagata N, Kobayashi Y,
Okamoto M, Mitsuno Y, Ogura K, Yoshida S,
Shimbo T, Hirata Y, Koike K. New predictivemodel of rebleeding during follow-up of patents
with obscure gastrointestinal bleeding: A multicenter cohort study. J Gastroenterol Hepatol.
2016;31:752-60.
32. Yamamichi N, Hirano C, Ichinose M, Takahashi Y,
Minatsuki C, Matsuda R, Nakayama C,
Shimamoto T, Kodashima S, Ono S, Tsuji Y,
Niimi K, Sakaguchi Y, Kataoka Y, Saito I,
Asada-Hirayama I, Takeuchi C, Yakabi S,
Kaikimoto H, Matsumoto Y, Yamaguchi D,
Kageyama-Yahara N, Fujishiro M, Wada R,
Mitsushima T, Koike K. Atrophic gastritis andenlarged gastric folds diagnosed by doublecontrast upper gastrointestinal barium X-ray
radiography are useful to predict future gastriccancer development based on the 3-year
prospective observation. Gastric Cancer. 2016;19:
1016-22.
33. Uchino K, Tateishi R, Fujiwara N, Minami T, Sato
M, Enooku K, Nakagawa H, Asaoka Y, Kondo Y,
Yoshida H, Moriya K, Shiina S, Omata M, Koike
K. Impact of serum ferritin level on hepatocarcinogenesis in chronic hepatitis C patients.
Hepatol Res. 2016;46:259-68.

Internal Medicine
2. Medicine Ⅱ138

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

Associate Professor
Norio Hanafusa, M.D., Ph.D. (-May)

Lecturer
Akihiro Tojo, M.D., Ph.D.,

Noriko Makita, M.D., Ph.D.,

Tetsuhiro Tanaka, M.D., Ph.D.,

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

Hideki Kato, M.D., Ph.D.,

Takahisa Kawakami, 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.

Tetsushi Yamashita, M.D., Ph.D.

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

Homepage

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

139

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

Education
We have responsibility for educating undergraduates, graduate students and residents. Our staffs
take part in several lectures for undergraduate andgraduate students. In addition, our members areactively involved in clinical clerkship for undergraduate students, and other clinical practice. Particularly, we have put emphasis on participation of thestudents in clinical practice including medical
investigations, diagnosis, and treatment. In the wards,
we are also educating residents during daily clinicalworks 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

140

3.
4.

5.
6.
7.
8.
9.

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

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

4.
5.
6.
7.
8.

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

Publications(1) Urinary N-acetyl-β-glucosaminidase and eGFR
may identify patients to be treated withimmuno-suppression at diagnosis in idiopathic
membranous nephropathy. Bazzi C, Usui T,
Rizza V, Casellato D, Gallieni M, Nangaku M.
Nephrology (Carlton). 2016 Oct 20.
(2) Hypoxia-Inducible Factor-1α Activates theTransforming Growth Factor-β/SMAD3 Pathway
in Kidney Tubular Epithelial Cells. Kushida N,
Nomura S, Mimura I, Fujita T, Yamamoto S,
Nangaku M, Aburatani H. Am J Nephrol. 2016;
44(4):276-285.
(3) Umbilical Cord Blood Transplantation-associatedNephrotic Syndrome Successfully Treated by
Low-density Lipoprotein Apheresis. Sugawara Y,
Honda K, Katagiri D, Nakamura M, Kawakami T,
Nasu R, Hayashi A, Shintani Y, Tojo A, Noiri E,
Kurokawa M, Fukayama M, Nangaku M. Intern
Med. 2016;55(19):2831-2836.
(4) Selective plasma exchange can reduce autoantibodies in patients with bullous pemphigoid
without affecting factor XIII and fibrinogen. Nasu
K, Hanafusa N, Nangaku M. J Clin Apher. 2016
Oct 6.
(5) Impact of clinical context on acute kidney injury
biomarker performances: differences between
neutrophil gelatinase-associated lipocalin andL-type fatty acid-binding protein. Asada T,
Isshiki R, Hayase N, Sumida M, Inokuchi R,
Noiri E, Nangaku M, Yahagi N, Doi K. Sci Rep.
2016 Sep 8;6:33077.
(6) Analysis of the V2 Vasopressin Receptor (V2R)
Mutations Causing Partial Nephrogenic Diabetes

141

Insipidus Highlights a Sustainable Signaling by a
Non-peptide V2R Agonist. Makita N, Sato T,
Yajima-Shoji Y, Sato J, Manaka K, EdaHashimoto M, Ootaki M, Matsumoto N, Nangaku
M, Iiri T. J Biol Chem. 2016 Oct 21;291(43):22460-22471.
(7) New insights into molecular mechanisms of
epigenetic regulation in kidney disease. Mimura I,
Tanaka T, Nangaku M. Clin Exp Pharmacol
Physiol. 2016 Dec;43(12):1159-1167.
(8) Clinical guides for atypical hemolytic uremic
syndrome in Japan. Kato H, Nangaku M, et al.;Joint Committee for the Revision of Clinical
Guides of Atypical Hemolytic Uremic Syndromein Japan. Pediatr Int. 2016 Jul;58(7):549-55.
(9) Lactoferrin Suppresses NeutrophilExtracellular
Traps Release in Inflammation. Okubo K,
Kamiya M, Urano Y, Nishi H, Herter JM,
Mayadas T, Hirohama D, Suzuki K, Kawakami H,
Tanaka M, Kurosawa M, Kagaya S, Hishikawa K,
Nangaku M, Fujita T, Hayashi M, Hirahashi J.
EBioMedicine. 2016 Aug;10:204-15.
(10) Clinical guides for atypical hemolytic uremic
syndrome in Japan.Kato H, Nangaku M, et al.;Joint Committee for the Revision of Clinical
Guides of Atypical Hemolytic Uremic Syndromein Japan. Clin Exp Nephrol. 2016 Aug;20(4):536-543.
(11) Impact of end-stage renal disease on hospitaloutcomes among patients admitted to intensive
care units: A retrospective matched-pair cohort
study. Iwagami M, Yasunaga H, Matsui H,
Horiguchi H, Fushimi K, Noiri E, Nangaku M,
Doi K. Nephrology (Carlton). 2016 Jun 1.
(12) No association between dysplasminogenemia
with p.Ala620Thr mutation and atypicalhemolytic uremic syndrome. Miyata T, Uchida Y,
Yoshida Y, Kato H, Matsumoto M, Kokame K,
Fujimura Y, Nangaku M. Int J Hematol. 2016
Aug;104(2):223-7.
(13) Potential Survival Benefit of Polymyxin B
Hemoperfusion in Septic Shock Patients on
Continuous Renal Replacement Therapy: A
Propensity-Matched Analysis. Iwagami M,
Yasunaga H, Noiri E, Horiguchi H, Fushimi K,
Matsubara T, Yahagi N, Nangaku M, Doi K.
Blood Purif. 2016;42(1):9-17.

(14) Ulcerative colitis with hepatitis B virus infection
treated successfully by granulocyte monocyte
apheresis. Saito H, Hanafusa N, Kishikawa J,
Noiri E, Sunami E, Ishihara S, Watanabe T,
Nangaku M.J Clin Apher. 2016 Dec;31(6):584-586.
(15) High serum ALP level is associated withincreased risk of denosumab-related hypocalcemia in patients with bone metastases fromsolid tumors. Kinoshita Y, Arai M, Ito N, Takashi
Y, Makita N, Nangaku M, Shinoda Y, Fukumoto
S. Endocr J. 2016 May 31;63(5):479-84(16) Association of Urinary Neutrophil GelatinaseAssociated Lipocalin With Long-Term Renal
Outcomes in ICU Survivors: A Retrospective
Observational Cohort Study. Isshiki R, Asada T,
Sato D, Sumida M, Hamasaki Y, Inokuchi R,
Matsubara T, Ishii T, Yahagi N, Nangaku M,
Noiri E, Doi K. Shock. 2016 Jul;46(1):44-51.
(17) Impact of continuous renal replacement therapy
intensity. Mayumi K, Yamashita T, Hamasaki Y,
Noiri E, Nangaku M, Yahagi N, Doi K.Shock.
2016 Feb;45(2):133-8.
(18) Correction of Metabolic Alkalosis and ElevatedCalcium Levels by Sodium Chloride in a
Hemodialysis Patient With Inadequate Chloride
Intake. Hirakawa Y, Hanafusa N, Nangaku M.
Ther Apher Dial. 2016 Feb;20(1):86-7.
(19) Interstitial renal fibrosis due to multiple cisplatintreatments is ameliorated by semicarbazidesensitive amine oxidase inhibition. Katagiri D,
Hamasaki Y, Doi K, Negishi K, Sugaya T,
Nangaku M, Noiri E. Kidney Int. 2016 Feb;89(2):374-85.
(20) Erythropoietin concentration in acute kidney
injury is associated with insulin-like growth
factor-binding protein-1. Yamashita T, Noiri E,
Hamasaki Y, Matsubara T, Ishii T, Yahagi N,
Nangaku M, Doi K. Nephrology(Carlton). 2016
Aug;21(8):693-9.
(21) The reduced expression of proximal tubulartransporters in acquired Fanconi syndrome with κlight chain deposition. Tojo A, Asaba K,
Kinugasa S, Ikeda Y, Shintani Y, Fukayama M,
Nangaku M. Med Mol Morphol. 2016 Mar;49(1):48-52.

142

Department of Diabetes andMetabolic Diseases
Professor
Takashi Kadowaki, M.D., Ph.D.

Associate Professor
Toshimasa Yamauchi, M.D., Ph.D.

Lecturer
Ryo Suzuki, M.D., Ph.D.

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

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

Hironori Waki, M.D., Ph.D. (until Aug 2016),

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

Nobuhiro Shojima, M.D., Ph.D.,

Yoshihiko Izumida, M.D., Ph.D. (until Dec 2016),
Satoru Takase, M.D., Ph.D.,

Hirotsugu Suwanai, M.D., Ph.D.,

Michihisa Aoyama, M.D., Ph.D. (since Sep 2016)

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) and Dr.
Toshiro Fujita (2003) and current professor Dr.
Takashi Kadowaki (2003-present), we have been
providing a wide-ranged clinical, teaching andresearch activities. Currently, we hold 28 beds mainlyon the 12th floor of the North Wing Ward A and the
4th floor of the Ward B of the University of Tokyo
Hospital, and take care of 612 new inpatients per year.
Besides the staffs listed above, our division holds
faculties in branches, for example, Department ofClinical Nutrition Therapy (Associate Professor: Dr.
Naoto Kubota), Department of Molecular Sciences on
Diabetes (Project Associate Professor: Dr. Hironori
Waki [since Sep 2016], and Project AssistantProfessor: Dr. Masatoshi Kobayashi), Department ofIntegrated Molecular Science on Metabolic Diseases(Project Associate Professor: Dr. Masato Iwabu, andProject Lecturer: Dr. Miki Okada-Iwabu), Division ofBiophysics, Center for Disease Biology andIntegrative Medicine (Lecturer: Dr. Noriko Takahashi),Ubiquitous Health Informatics (Project Associate
Professor: Dr. Kayo Waki), Clinical Epidemiology and
Systems (Project Assistant Professor: Dr. Mikio
Takanashi), Division for Health Service Promotion,

143

The University of Tokyo (Assistant Professor: Drs.
Sachiko Okazaki and Tomohide Yamada), ClinicalResearch Support Center (Project Assistant Professor:
Dr. Akiko Kishi) and Department of ClinicalLaboratory (Assistant Professor: Dr. Makoto Kurano).
With all these 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 180 patients perday (total 43,155 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 Kadowaki.
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144

collaboration with RIKEN and several cohorts, we
explored the comprehensive catalog of genomic
variations to identify variations conferring susceptibility to type 2 diabetes in the Japanese population.
We are also exploring the signal transduction
pathways and physiological roles of insulin andadipokines in various tissues and the mechanisms ofinsulin secretion under the normal or pathologicalconditions, such as diabetes and obesity disease, using
a number of transgenic and knockout animal models,in parallel with information obtained by wholegenome analysis of human patients. In particular, we
are interested in the physiological and pathophysiological functions of adipokines secreted by adipocytes,
including adiponectin, and the signal transduction
pathway of adiponectin through the receptors,
AdipoR1 and AdipoR2, that we discovered andcharacterized. We have also identified “AdipoRon” asan adiponectin receptor agonist, which will contributeto the development and optimization of AdipoRtargeted therapeutics. In addition, we have beensuccessfully unraveling the molecular mechanisms of
β cell proliferation and inter-tissue communication of
glucose metabolism in obesity disease and type 2
diabetes. Recently, we are investigating brown andwhite adipocyte-specific transcriptional and epigenetic
regulations in obesity. We believe that these findings
and research activities will lead to novel therapeuticstrategies for diabetes and the metabolic syndrome.
2) Pathophysiological roles of lipid storage andatherosclerosis
Our aim is to clarify the significance of metabolic risk
factors in the onset and development of atherosclerosis. We are currently investigating thepathophysiological roles of lipid storage in obesity
disease, fatty liver, diabetes, hyperlipidemia andatherosclerosis using strategies of molecular biology
and genetic engineering techniques. Utilizing theanimal models of lipid disorders and molecularbiological technique, we are analyzing the roles oflipid transporters, nuclear receptors and the antioxidative proteins on the lipid disorders and atherosclerosis. We are currently interested in the cholesterol
and lipid absorption from the intestine and lipid
handling in the cells.

3) Clinical trials and epidemiological studies
We are conducting clinical trials and epidemiologicalstudies including “Japan Diabetes Optimal Integrated
Treatment study for 3 major risk factors ofcardiovascular diseases (J-DOIT3)” follow-up study,"Japan Diabetes compREhensive database projectbased on an Advanced electronic Medical record
System (J-DREAMS)", systematic reviews and metaanalyses with a focus on important issues such as
metabolic syndrome, and investigator initiated clinical
trials targeting for a new class of anti-diabetic agents.

References
1. Kubota N, Kubota T, Kajiwara E, Iwamura T,
Kumagai H, Watanabe T, Inoue M, Takamoto I,
Sasako T, Kumagai K, Kohjima M, Nakamuta M,
Moroi M, Sugi K, Noda T, Terauchi Y, Ueki K,
Kadowaki T: Differential hepatic distribution of
insulin receptor substrates causes selective insulin
resistance in diabetes and obesity. Nat Commun.
2016; 7:12977.
2. Imamura M, Takahashi A, Yamauchi T, Hara K,
Yasuda K, Grarup N, Zhao W, Wang X,
Huerta-Chagoya A, Hu C, Moon S, Long J, Kwak
SH, Rasheed A, Saxena R, Ma RC, Okada Y, Iwata
M, Hosoe J, Shojima N, Iwasaki M, Fujita H, Suzuki
K, Danesh J, Jørgensen T, Jørgensen ME, Witte DR,
Brandslund I, Christensen C, Hansen T, Mercader
JM, Flannick J, Moreno-Macías H, Burtt NP, Zhang
R, Kim YJ, Zheng W, Singh JR, Tam CH, Hirose H,
Maegawa H, Ito C, Kaku K, Watada H, Tanaka Y,
Tobe K, Kawamori R, Kubo M, Cho YS, Chan JC,
Sanghera D, Frossard P, Park KS, Shu XO, Kim BJ,
Florez JC, Tusié-Luna T, Jia W, Tai ES, Pedersen O,
Saleheen D, Maeda S, Kadowaki T: Genome-wide
association studies in the Japanese population
identify seven novel loci for type 2 diabetes. Nat
Commun. 2016; 7:10531.
3. Ueki K, Sasako T, Kato M, Okazaki Y, Okahata S,
Katsuyama H, Haraguchi M, Morita A, Ohashi K,
Hara K, Morise A, Izumi K, Ohashi Y, Noda M,
Kadowaki T, and the J-DOIT3 Study Group: Designof and rationale for the Japan Diabetes Optimal
Integrated Treatment Study for 3 major risk factorsof cardiovascular diseases (J-DOIT3): a multicenter,145

open-label, randomized, parallel-group trial. BMJ
Open Diabetes Res Care. 2016; 4(1):e000123.
4. Sato H, Kubota N, Kubota T, Takamoto I, Iwayama
K, Tokuyama K, Mori M, Sugi K, Nakaya K, Goto
M, Jomori T, Kadowaki T: Anagliptin increases
insulin-induced skeletal muscle glucose uptake via
an NO-dependent mechanism in mice. Diabetologia
2016; 59(11):2426-2434.
5. Kubota T, Kubota N, Sato H, Inoue M, Kumagai H,
Iwamura T, Takamoto I, Kobayashi T, Moroi M,
Terauchi Y, Tobe K, Ueki K, Kadowaki T:
Pioglitazone ameliorates smooth muscle cellproliferation in cuff-induced neointimal formation
by both adiponectin-dependent and -independent
pathways. Sci Rep. 2016; 6:34707.
6. Yamada T, Shojima N, Yamauchi T, Kadowaki T:
J-curve relation between daytime nap duration andtype 2 diabetes or metabolic syndrome: A doseresponse meta-analysis. Sci Rep. 2016; 6:38075.
7. Yamada T, Shojima N, Yamauchi T, Kadowaki T:
Lactic acidosis due to attempted suicide with
metformin overdose: A case report. Diabetes Metab.
2016; 42(4):290-1.
8. Kadowaki T, Jinnouchi H, Kaku K, Hersløv ML,
Hyllested-Winge J, Nakamura S: Efficacy and safetyof once-daily insulin degludec dosed flexibly atconvenient times vs fixed dosing at the same timeeach day in a Japanese cohort with type 2 diabetes:
A randomized, 26-week, treat-to-target trial. J
Diabetes Investig. 2016; 7(5):711-7.
9. Kubota T, Kubota N: Cuff-induced neointimal
formation in mouse models. In Mouse Models of
Vascular Diseases. Springer Japan, 2016;21-41.
10. Yamada T, Shojima N, Noma H, Yamauchi T,
Kadowaki T: Glycemic control, mortality, andhypoglycemia in critically ill patients: a systematic
review and network meta-analysis of randomized
controlled trials. Intensive Care Med. 2017; 43:1-15.
Epub 2016 Sep 16.
11. Yamada T: Achieved glucose level and mortality
risk in randomized clinical trials. Resuscitation.
2017; 110:e3-e4. Epub 2016 Oct 27.
12. Kurano M, Kano K, Dohi T, Matsumoto H, Igarashi
K, Nishikawa M, Ohkawa R, Ikeda H, Miyauchi K,
Daida H, Aoki J, Yatomi Y: Different origins oflysophospholipid mediators between coronary andperipheral arteries in acute coronary syndrome. J
Lipid Res. 2017; 58(2):433-442. Epub 2016 Dec 22.
13. Waki K, Fujiu K, Hayashi A, Kimura S, Kobayashi
H, Nangaku M, Kadowaki T, Ohe K: DialBetics:
Smartphone-based self-management for Type 2
diabetes patients on insulin injections. J Diabetes Sci
Technol. 2016; 10(3):804-5.
14. Hirako S, Wada N, Kageyama H, Takenoya F,
Izumida Y, Kim H, Iizuka Y, Matsumoto A, Okabe
M, Kimura A, Suzuki M, Yamanaka S, Shioda S:
Autonomic nervous system-mediated effects ofgalanin-like peptide on lipid metabolism in liver andadipose tissue. Sci Rep. 2016; 19(6):21481.
15. Jakkampudi S, Abe M, Komori N, Takagi R,
Furukawa K, Katan C, Sawada W, Takahashi N,
KasaiH:
Design and synthesis of a
4-Nitrobromobenzene derivative bearing an ethylene
glycol tetraacetic acid unit for a new generation of
caged calcium compounds with two-photon absorption properties in the near-IR region, and their application in vivo. ACS Omega. 2016; 1(2):193-201.
16. Komori N, Jakkampudi S, Motoishi R, Abe M,
Kamada K, Furukawa K, Katan C, Sawada W,
Takahashi N, Kasai H, Xue B, Kobayashi: Designand synthesis of a new chromophore, 2-(4nitrophenyl) benzofuran,for two-photon uncaging
using near-IR light. Chem Commun (Camb). 2016;
52(2):331-4.
17. Goto A, Noto H, Noda M, Ueki K, Kasuga M,
Tajima N, Ohashi K, Sakai R, Tsugane S, Hamajima
N, Tajima K, Imai K, Nakagama H：Report of theJapan diabetes society/Japanese cancer association
joint committee on diabetes and cancer, Second
report. Cancer Sci. 2016; 107(3):369-71.
18. Kabeya Y, Goto A, Kato M, Matsushita Y,
Takahashi Y, Isogawa A, Inoue M, Mizoue T,
Tsugane S, Kadowaki T, Noda M: Time spentwalking and risk of diabetes in Japanese adults: The
Japan Public Health Center-Based Prospective
Diabetes Study. J Epidemiol. 2016; 26(4):224-32.
19. Goto A, Noda M, Sawada N, Kato M, Hidaka A,
Mizoue T, Shimazu T, Yamaji T, Iwasaki M,
Sasazuki S, Inoue M, Kadowaki T, Tsugane S, for
the JPHC Study Group: High hemoglobin A1c levels
within the non-diabetic range are associated with therisk of all cancers. Int J Cancer. 2016; 138(7):1741-1753.

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20. Jo Y, Okazaki H, Moon YA, Zhao T: Regulation of
Lipid Metabolism and Beyond. Int J Endocrinol,
2016; 2016:5415767.
21. Horikoshi M, Pasquali L, Wiltshire S, Huyghe JR,
Mahajan A, Asimit JL, Ferreira T, Locke AE,
Robertson NR, Wang X, Sim X, Fujita H, Hara K,
Young R, Zhang W, Choi S, Chen H, Kaur I,
Takeuchi F, Fontanillas P, Thuillier D, Yengo L,
Below JE, Tam CH, Wu Y, Abecasis G, Altshuler D,
Bell GI, Blangero J, Burtt NP, Duggirala R, Florez
JC, Hanis CL, Seielstad M, Atzmon G, Chan JC, Ma
RC, Froguel P, Wilson JG, Bharadwaj D, Dupuis J,
Meigs JB, Cho YS, Park T, Kooner JS, Chambers JC,
Saleheen D, Kadowaki T, Tai ES, Mohlke KL, Cox
NJ, Ferrer J, Zeggini E, Kato N, Teo YY, Boehnke
M, McCarthy MI, Morris AP: T2D-GENES
consortium: Transancestral fine-mapping of fourtype 2 diabetes susceptibility loci highlights
potential causal regulatory mechanisms. Hum Mol
Genet. 2016; 25(10):2070-2081.
22. Ikeda Y, Tsukube S, Kadowaki T, Odawara M:
Predictors for achieving target glycemic control inJapanese patients with type2 diabetes after initiationof basal supported oral therapy using insulin
glargine: subanalysis of the ALOHA2 study, drug
use surveillance in Japan. Diabetol Int. 2016; 7(2):188-198.
23. Inada S, Yoshiuchi K, Iizuka Y, Ohashi K, Kikuchi
H, Yamamoto Y, Kadowaki T, Akabayashi A: Pilot
Study for the Development of a Self-Care System
for Type 2 Diabetes Patients Using a Personal
Digital Assistant (PDA). Int J Behav Med. 2016;23(3):295-9.
24. Masamoto Y, Arai S, Sato T, Yoshimi A, Kubota N,
Takamoto I, Iwakura Y, Yoshimura A, Kadowaki T,
Kurokawa M： Adiponectin enhances antibacterial
activity of hematopoietic cells by suppressing bonemarrow inflammation. Immunity. 2016; 44(6):1422-33.
25. Kato A, Fujimaki Y, Fujimori S, Izumida Y, Suzuki
R, Ueki K, Kadowaki T, Hashimoto H: A qualitative
study on the impact of internalized stigma on type2diabetes self-management. Patient Educ Couns.
2016; 99(7):1233-1239.
26. Ohtomo K, Shigeeda T, Hirose A, Ohno T,
Kinoshita O, Fujita H, Ando J, Nagai R, Takamoto S,
Kadowaki T, Kato S: Frequency of diabetic

retinopathy and related factors in patients withdiabetes having coronary artery disease. Diabetes
Res Clin Pract. 2016; 118:154-5.
27. Suyama S, Maekawa F, Maejima Y, Kubota N,
Kadowaki T, Yada T: Glucose level determines
excitatory or inhibitory effects of adiponectin on
arcuate POMC neuron activity and feeding. Sci Rep.
2016; 6:30796.
28. Takeuchi Y, Yahagi N, Aita Y, Murayama Y,
Sawada Y, Piao X, Toya N, Oya Y, Shikama A,
Takarada A, MasudaY, Nishi M, Kubota M, Izumida
Y, Yamamoto T, Sekiya M, Matsuzaka T,
Nakagawa Y, Urayama O, Kawakami Y, Iizuka Y,
Gotoda T, Itaka K, Kataoka K, Nagai R, Kadowaki
T, Yamada N, Lu Y, Jain MK, Shimano H: KLF15
enables rapid switching between lipogenesis andgluconeogenesis during fasting. Cell Rep. 2016;16(9):2373-86.
29. Japan Diabetes Society (JDS)/Japan Geriatrics
Society (JGS) Joint Committee on Improving Carefor Elderly Patients with Diabetes: Glycemic targets
for elderly patients with diabetes. Diabelol Int.
2016; 7(3):331-333.
30. Noguchi J, Hayama T, Watanabe S, Ucar H,
Yagishita S, Takahashi N, Kasai H: State-dependent
diffusion of actin-depolymerizing factor/cofilin
underlies the enlargement and shrinkage of dendritic
spines. Sci Rep. 2016; 6:32897.
31. Oe M, Ohashi Y, Takehara K, Oba M, Doi M, Iizuka
Y, Murayama R, Kadowaki T, Sanada H: Foot
complications in patients with diabetes mellitus
practical report of diabetic foot clinic in Beijing.
Japan J Foot Care. 2016; 14(2):57-61.
32. Song NJ, Kim S, Jang BH, Chang SH, Yun UJ, Park
KM, Waki H, Li DY, Tontonoz P, Park KW: Small
Molecule-Induced Complement Factor D (Adipsin)
Promotes Lipid Accumulation and Adipocyte
Differentiation. PloS one. 2016; 11(9)：e0162228.
33. Kunii M, Ohara-Imaizumi M, Takahashi N,
Kobayashi M, Kawakami R, Kondoh Y, Shimizu T,
Shimizu S, Lin BZ, Nunomura K, Aoyagi K, Ohno
M, Ohmuraya M, Sato T, Yoshimura S, Sato K,
Harada R, Kim YJ, Osada H, Nemoto T, Kasai H,
Kitamura T, Nagamatsu S and Harada A: Opposing
roles for SNAP23 in secretion in exocrine andendocrine pancreatic cells. J Cell Biol. 2016; 215(1):121-138.

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34. Hamatani M, Mori T, Oe M, Noguchi H, Takehara
K, Amemiya A, Ohashi Y, Ueki K, Kadowaki T,
Sanada H: Factors associated with callus in diabetic
patients, focused on plantar shear stress during gait.
J Diabetes Sci Technol. 2016; 10(6):1353-1359.
35. Japan Diabetes Society (JDS)/Japan Geriatrics
Society (JGS) Joint Committee on Improving Carefor Elderly Patients with Diabetes: Glycemic targets
for elderly patients with diabetes. Geriatr Gerontol
Int. 2016; 16 (12):1243-1245.
36. Araki E, Haneda M, Kasuga M, Nishikawa T,
Kondo T, Ueki K, Kadowaki T: New glycemic
targets for patientswith diabetes from the Japan
Diabetes Society. Diabetol Int. 2016; 7:327-330.
37. Amemiya A, Noguchi H, Oe M, Takehara K, Ohashi
Y, Suzuki R, Yamauchi T, Kadowaki T, Sanada H,
Mori T: Shear stress-normal stress (pressure) ratio
decides forming callus in patients with diabetic
neuropathy. J Diabetes Res. 2016; 3157123.

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

Lecturer
Shunya Arai, M.D., Ph.D.

Special Lecturer (Hospital)
Fumihiko Nakamura, M.D., Ph.D.

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

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

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

Takashi Toya, M.D., Ph.D.

Ryo Nasu, M.D., Ph.D.,

Junji Koya, M.D., Ph.D.

Mizuki Ogura, 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 one lecturer, one special
lecturer (hospital), and 7 assistant professors.

Clinical activities
On the average, 55-65 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149

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 andtreatment.
Here we introduce technical aspects on the treatment strategy:
1. High dose chemotherapy with autologous stem
cell transplant: High-dose chemotherapy isadministered for the treatment of hematologicalneoplasms and solid tumors. For the autologous
stem cell support, peripheral blood stem cell isusually selected as a source of stem cells.
2. Allogeneic hematopoietic stem cell transplant:
Bone marrow cells are harvested from healthy
donors by operation under general anesthesia andimmediately infused to a recipient. Peripheral
blood stem cells (PBSCs) are harvested fromhealthy donors by leukapheresis using an
automated continuous flow blood cell separator.
PBSCs are immediately infused to a recipient orpreserved in liquid nitrogen in cooperation with
the Department of Transfusion Medicine.
Allogeneic transplant with non-myeloablative
conditioning (also referred to as reduced-intensity
stem cell transplant (RIST)) is commonly
performed for elderly patients and patients with
impaired organ function. 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. Takagi S, Masuoka K, Uchida N, Kurokawa M,
Nakamae H, Imada K, Iwato K, Ichinohe T,
Atsuta Y, Takami A, Yano S. Allogeneic

150

2.

3.

4.

5.

6.

7.

8.

Hematopoietic Cell Transplantation for Leukemic
Transformation
PrecededbyPhiladelphia
Chromosome-Negative
Myeloproliferative
Neoplasms: A Nationwide Survey by the Adult
Acute Myeloid Leukemia Working Group of theJapan
Societyfor
Hematopoietic
Cell
Transplantation. Biol Blood Marrow Transplant.
2016; 22: 2208-2213.
Takenaka R, Yamashita H, Toya T, Haga A,
Shibata S, Kurokawa M, Ootomo K, Nakagawa K.
Unique radiation dermatitis related to total body
irradiation by helical tomotherapy. J Dermatol.
2016; 43: 1376-1377.
Morita K, Nakamura F, Sakuishi K, Yamamoto T,
Shimizu J, Tsuji S, Kurokawa M. Successful
management of chronic myeloid leukemia with acomplication of anti-SRP antibody-associatedmyopathy. Leuk Lymphoma. 2017; 58:1242-1245.
Koshino S, Hamaya H, Ishii M, Kojima T, Urano
T, Yamaguchi Y, Ogawa S, Morita S, Koya J,
Nakamura F, Kurokawa M, Akishita M. Efficacy
of Fine-Needle Aspiration Cytology in the
Diagnosis of Primary Thyroid Lymphoma for
Elderly Adults. J Am Geriatr Soc. 2016; 64(9):e52-3.
Masamoto Y, Kurokawa M. Inflammation-induced
emergency
megakaryopoiesis:
inflammation
paves the way for platelets. Stem Cell Investig.
2016; 3:16.
Sumitomo Y, Koya J, Nakazaki K, Kataoka K,
Tsuruta-Kishino T, Morita K, Sato T, Kurokawa
M.
Cytoprotective
autophagy
maintains
leukemia-initiating cells in murine myeloid
leukemia. Blood. 2016; 128:1614-24.
Nakamura F, Nakamura F, Ikemura M, Fukayama
M, Kurokawa M. Extraosseous plasmacytoma in
the nasal cavity after rituximab therapy against
pulmonary MALT lymphoma. Ann Hematol.
2016; 95:1733-5.
Omata Y, Nakamura S, Koyama T, Yasui T, Hirose
J, Izawa N, Matsumoto T, Imai Y, Seo S,
Kurokawa M, Tsutsumi S, Kadono Y, Morimoto C,
Aburatani H, Miyamoto T, Tanaka S.
Identification of Nedd9 as a TGF-β-Smad2/3
Target Gene Involved in RANKL-Induced
Osteoclastogenesis by Comprehensive Analysis.
PLoS One. 2016; 11:e0157992.

9. Masamoto Y, Arai S, Sato T, Yoshimi A, Kubota N,
Takamoto I, Iwakura Y, Yoshimura A, Kadowaki T,
Kurokawa M. Adiponectin Enhances Antibacterial
Activity of Hematopoietic Cells by Suppressing
Bone Marrow Inflammation. Immunity. 2016;
44:1422-33.
10. Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F,
Kojima S, Ueno T, Imoto N, Kohsaka S, Kunita A,
Doi K, Sakura T, Yujiri T, Kondo E, Fujimaki K,
Ueda Y, Aoyama Y, Ohtake S, Takita J, Sai E,
Taniwaki M, Kurokawa M, Morishita S,
Fukayama M, Kiyoi H, Miyazaki Y, Naoe T,
Mano H. Recurrent DUX4 fusions in B cell acutelymphoblastic leukemia of adolescents and young
adults. Nat Genet. 2016; 48:569-74.
11. Koya J, Kataoka K, Sato T, Bando M, Kato Y,
Tsuruta-Kishino T, Kobayashi H, Narukawa K,
Miyoshi H, Shirahige K, Kurokawa M. DNMT3A
R882 mutants interact with polycomb proteins toblock haematopoietic stem and leukaemic celldifferentiation. Nat Commun. 2016; 7:10924.
12. Ebisawa K, Koya J, Shinozaki-Ushiku A,
Nakamura F, Kurokawa M. Paraneoplastic limbic
encephalitis in B cell lymphoma unclassifiablewith features intermediate between diffuse large B
cell lymphoma and classical Hodgkin lymphoma.
Ann Hematol. 2016; 95:1011-2.
13. Ando M, Kawazu M, Ueno T, Koinuma D, Ando
K, Koya J, Kataoka K, Yasuda T, Yamaguchi H,
Fukumura K, Yamato A, Soda M, Sai E,
Yamashita Y, Asakage T, Miyazaki Y, Kurokawa
M, Miyazono K, Nimer SD, Yamasoba T, Mano H.
Mutational Landscape and Antiproliferative
Functions of ELF Transcription Factors in Human
Cancer. Cancer Res. 2016; 76:1814-24.
14. Sakata-Yanagimoto M, Yokoyama Y, Muto H,
Obara N, Kurita N, Kato T, Hasegawa Y,
Miyazaki Y, Kurokawa M, Chiba S. A nationwide
survey of co-occurrence of malignant lymphomas
andmyelodysplastic
syndromes/
myeloproliferative neoplasms. Ann Hematol.
2016; 95:829-30.
15. Kitanaka A, Takenaka K, Shide K, Miyamoto T,
Kondo T, Ozawa K, Kurokawa M, Akashi K,
Shimoda K. Splenic irradiation provides transientpalliationfor
symptomatic
splenomegaly
associated with primary myelofibrosis: a report on

151

14 patients. Int J Hematol. 2016; 103:423-8.
16. Yamamoto H, Lu J, Oba S, Kawamata T, Yoshimi
A, Kurosaki N, Yokoyama K, Matsushita H,
Kurokawa M, Tojo A, Ando K, Morishita K,
Katagiri K, Kotani A. miR-133 regulates Evi1
expression in AML cells as a potential therapeutictarget. Sci Rep. 2016; 6:19204.

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Department of Allergy andRheumatology
Professor
Kazuhiko Yamamoto, M.D., Ph.D. (Rheumatology, Allergology)

Lecturer
Keishi Fujio, M.D., Ph.D. (Rheumatology)

Hospital Lecturer
Kanae Kubo, M.D., Ph.D. (Rheumatology)
Hirofumi Syoda、M.D., Ph.D. (Rheumatology)

Research Associate
Syuji Sumitomo，M.D., Ph.D. (Rheumatology)
Mihoko Shibuya，M.D., Ph.D. (Rheumatology)
Yukiko Iwasaki，M.D., Ph.D. (Rheumatology)
Hiroaki Harada, M.D., Ph.D. (Allergology)
Ou Sasaki, M.D., Ph.D. (Allergology)
Yasuo Nagafuchi，M.D., Ph.D. (Rheumatology)

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

Project Research Associate
Tomohisa Okamura, M.D., Ph.D. (Rheumatology)
Shyoko Tateishi, M.D., Ph.D. (Rheumatology)

The Department of Allergy and Rheumatology
presently consists of 13 staffs mentioned above, who
preside over 5 medical staff, 20 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 13th
floor of the Hospital Ward A. The physician's office issituated in the East Hospital Ward and the researchrooms are located in the East Hospital Ward, theCentral Ward and the Clinical Research Center A.

Education
In regard to undergraduate education, the Department is in charge of internal medicine diagnosis andsystemic lectures for M2 students and clinical lecturesand bedside education for M3 and M4 students incooperation with other departments of internal
medicine. The systemic lectures and clinical lectures
cover clinical immunology, connective tissue diseases
and allergy. Bedside education provides students witha good opportunity to learn about patients as well aspractical knowledge through numerous seminars.

153

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 has 5 research laboratories in whichclinical and basic studies are carried out concerning
mainly rheumatology and allergology. Recently themainstream of research has employed various techniques of molecular biology and cellular immunology.
The principal research topics are listed below.
1. Functional genomics in autoimmune diseases
2. Analysis of cell metabolism modification by anobel regulatory T cell subset and inhibitory
cytokines.
3. Analysis of the mechanisms of tolerance breakdown to systemic autoantigens.
4. Analysis of T cell and B cell repertoires in
autoimmune diseases.
5. Analysis of autoimmune susceptable gene functions in mice and human modles.
6. Analysis of signal transduction mechanisms in
autoimmune diseases.
7. Analysis of autoimmune disease-specific iPS cells
8. Exploration of the roles of protein prenylation in
the animal models of lung disease.

9.

Analysis of bone strength in glucocorticoidinduced osteoporosis.
10. Investigation of biomarkers in autoimmune
disease.

References

2016

1. Egr2 and Egr3 in regulatory T cells cooperatively
control systemic autoimmunity through Ltbp3mediated TGF-β3 production. Morita K, Okamura
T, Inoue M, Komai T, Teruya S, Iwasaki Y,
Sumitomo S, Shoda H, Yamamoto K, Fujio K.
Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):E8131-E8140.
2. Emerging roles of Egr2 and Egr3 in the control ofsystemic autoimmunity. Morita K, Okamura T,
Sumitomo S, Iwasaki Y, Fujio K, Yamamoto K.
Rheumatology (Oxford). 2016 Dec;55(suppl 2):
ii76-ii81.
3. Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patientswith rheumatoid arthritis with inadequate
response to methotrexate: 52-week results from aprospective, randomised, controlled study(SURPRISE study). Kaneko Y, Atsumi T, Tanaka
Y, Inoo M, Kobayashi-Haraoka H, Amano K,
Miyata M, Murakawa Y, Yasuoka H, Hirata S,
Nagasawa H, Tanaka E, Miyasaka N, Yamanaka
H, Yamamoto K, Takeuchi T. Ann Rheum Dis.
2016 Nov;75(11):1917-1923.
4. Urinary phagocytic macrophages in hemophagocytic lymphohistiocytosis. Oki R, Kono M,
Kubo K, Tojo A, Yamamoto K. Kidney Int. 2016
Oct;90(4):908.
5. IgG4-related disease. Kubo K, Yamamoto K. Int J
Rheum Dis. 2016 Aug;19(8):747-62.
6. Revisiting the regulatory roles of the TGF-βfamily of cytokines. Fujio K, Komai T, Inoue M,
Morita K, Okamura T, Yamamoto K. Autoimmun
Rev. 2016 Sep;15(9):917-22.
7. Immunophenotyping of rheumatoid arthritis
reveals a linkage between HLA-DRB1 genotype,CXCR4 expression on memory CD4(+) T cells,
and disease activity. Nagafuchi Y, Shoda H,
Sumitomo S, Nakachi S, Kato R, Tsuchida Y,
Tsuchiya H, Sakurai K, Hanata N, Tateishi S,
Kanda H, Ishigaki K, Okada Y, Suzuki A, Kochi Y,

154

Fujio K, Yamamoto K. Sci Rep. 2016 Jul 7;6:29338.
8. Post-hoc analysis showing better clinical responsewith the loading dose of certolizumab pegol inJapanese patients with active rheumatoid arthritis.
Takeuchi T, Yamamoto K, Yamanaka H, Ishiguro
N, Tanaka Y, Eguchi K, Watanabe A, Origasa H,
Kobayashi M, Shoji T, Togo O, Miyasaka N,
Koike T. Mod Rheumatol. 2016 Jul;26(4):473-80.
9. Clinical efficacy, radiographic progression, andsafety through 156 weeks of therapy with
subcutaneous golimumab in combination withmethotrexate in Japanese patients with active
rheumatoid arthritis despite prior methotrexate
therapy: final results of the randomized
GO-FORTH trial. Tanaka Y, Harigai M, Takeuchi
T, Yamanaka H, Ishiguro N, Yamamoto K,
Miyasaka N, Koike T, Baker D, Ishii Y, Yoshinari
T; GO-FORTH study group. Mod Rheumatol.
2016 Jul;26(4):481-90.
10. Characteristics of antisynthetase syndrome
patients with hyperferritinaemia. Kobayashi S,
Shoda H, Seri Y, Nagafuchi Y, Sasaki O, Kubo K,
Fujio K, Yamamoto K. Scand J Rheumatol. 2017
Mar;46(2):161-163. Epub 2016 Jun 16.
11. Decreased severity of experimental autoimmune
arthritis in peptidylarginine deiminase type 4
knockout mice. Suzuki A, Kochi Y, Shoda H, SeriY, Fujio K, Sawada T, Yamada R, Yamamoto K.
BMC Musculoskelet Disord. 2016 May 5;17:205.
12. Sialylation converts arthritogenic IgG into
inhibitors of collagen-induced arthritis. Ohmi Y,
Ise W, Harazono A, Takakura D, Fukuyama H,
Baba Y, Narazaki M, Shoda H, Takahashi N,
Ohkawa Y, Ji S, Sugiyama F, Fujio K,
Kumanogoh A, Yamamoto K, Kawasaki N,
Kurosaki T, Takahashi Y, Furukawa K. Nat
Commun. 2016 Apr 5;7:11205.
13. Therapeutic potential of regulatory cytokines thattarget B cells. Fujio K, Okamura T, Sumitomo S,
Yamamoto K. Int Immunol. 2016 Apr;28(4):189-95.
14. Immune responses to Mycobacterial heat shockprotein 70 accompany self-reactivity to human
BiP in rheumatoid arthritis. Shoda H, Hanata N,
Sumitomo S, Okamura T, Fujio K, Yamamoto K.
Sci Rep. 2016 Mar 1;6:22486.

15. Massive calcinosis cutis associated with primary
Sjögren's syndrome. Tsuchida Y, Sumitomo S,
Fujio K, Yamamoto K. BMJ Case Rep. 2016 Feb
4;2016. pii: bcr2015214006.
16. The first double-blind, randomised, parallel-groupcertolizumab pegol study in methotrexate-naive
early rheumatoid arthritis patients with poor
prognostic factors, C-OPERA, shows inhibition ofradiographic progression. Atsumi T, Yamamoto K,
Takeuchi T, Yamanaka H, Ishiguro N, Tanaka Y,
Eguchi K, Watanabe A, Origasa H, Yasuda S,
Yamanishi Y, Kita Y, Matsubara T, Iwamoto M,
Shoji T, Okada T, van der Heijde D, Miyasaka N,
Koike T. Ann Rheum Dis. 2016 Jan;75(1):75-83.
doi: 10.1136/annrheumdis-2015-207511. Epub2015 Jul 2.
17. Efficacy and safety of rituximab in Japanesepatients with systemic lupus erythematosus andlupus nephritis who are refractory to conventional
therapy. Tanaka Y, Takeuchi T, Miyasaka N,
Sumida T, Mimori T, Koike T, Endo K, Mashino
N, Yamamoto K. Mod Rheumatol. 2016;26(1):
80-6.

155

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

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

Assistant Associate
Yoshitaka Wakabayashi, M.D., Ph.D., Koh Okamoto, M.D.

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

Introduction and Organization
The Department of Infectious Diseases has been
one of the leading academic organizations specialized
for internal medicine, in particular, infectious disease
medicine in Japan since 1998, when the Departmentsof Internal Medicine, established in 1890, wererearranged into new ones according to subspecialty ofinternal medicine. Our department has been chiefly
engaged in clinical, educational and research activities
for infectious diseases including bacterial, fungal andviral infections of all organs including HIV infection,
tuberculosis and viral hepatitis. Our department islocated on 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, two 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 11th floor of the Ward
A of University of Tokyo Hospital. Diseases include
HIV
infection,viralhepatitis,
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

156

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 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 two to three members present theirannual 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
Clostridium difficile infection. Also, various emerging
and re-emerging infectious diseases are covered.
Following themes are currently being investigated in
the department.
(1) Establishment of effective therapy for HIV
infection: we have made a great contribution in
the establishment of the guideline for treatment of
HIV infection in Japan.
(2) Elucidation of the mechanism of hepatocarcinogenesis in hepatitis viral infection: the direct
involvement of both HBV and HCV in hepatocarcinogenesis has been demonstrated using ourtransgenic mouse systems.
(3) Establishment of effective therapy for HCV and
HBV infection: we have made a great contribution
in the establishment of the guideline for treatmentof hepatitis viral infection in Japan.
(4) Establishment of effective therapy for HCV/HIV
co-infection: we have made a great contribution in
the establishment of the guideline for treatment of
HCV/HIV co-infection in Japan.
(5) Innovation of new methods to control viral
hepatitis or prevent the development of hepatocellular carcinoma in chronic viral hepatitis.

Members
Kyoji Moriya, Shu Okugawa, Shintaro Yanagimoto,
Keita Tatsuno, Mahoko Ikeda, Yoshitaka Wakabayashi,
Yuta Okada, Aiko Okazaki, Satoshi Kitaura

References
1.

2.

3.

4.

5.

6.

Igawa G, Casey M, Sawabe E, Nukui Y, Okugawa S,
Moriya K, Koike R, Tohda S, Saito R: Comparisonof agar dilution and broth microdilution methods for
Clostridium difficile antimicrobial susceptibility
testing. J Glob Antimicrob Resist 2016, 7:43-45.
Wakabayashi Y, Okugawa S, Tatsuno K, Ikeda M,
Misawa Y, Koyano S, Tsuji E, Yanagimoto S,
Hatakeyama S, Moriya K et al: Scedosporium
prolificans Endocarditis: Case Report and Literature
Review. Intern Med 2016, 55(1):79-82.
Yuhashi K, Yagihara Y, Misawa Y, Sato T, Saito R,
Okugawa S, Moriya K: Diagnosing Clostridium
difficile-associateddiarrhea
using
enzymeimmunoassay: the clinical significance of toxin
negativity in glutamate dehydrogenase-positive
patients. Infect Drug Resist 2016, 9:93-99.
Aizawa S, Okamoto T, Sugiyama Y, Kouwaki T, Ito
A, Suzuki T, Ono C, Fukuhara T, Yamamoto M,
Okochi M et al: TRC8-dependent degradation ofhepatitis C virus immature core protein regulates
viral propagation and pathogenesis. Nat Commun
2016, 7:11379.
Kishii K, Kikuchi K, Tomida J, Kawamura Y,
Yoshida A, Okuzumi K, Moriya K: The first cases ofhuman bacteremia caused by Acinetobacter seifertii
in Japan. J Infect Chemother 2016, 22(5):342-345.
Okushin K, Tsutsumi T, Enooku K, Fujinaga H,
Kado A, Shibahara J, Fukayama M, Moriya K,
Yotsuyanagi H, Koike K: The intrahepatic
expression levels of bile acid transporters areinversely
correlatedwith
thehistological157

progression of nonalcoholic fatty liver disease. J
Gastroenterol 2016, 51(8):808-818.
7. Wada K, Yoshikawa T, Lee JJ, Mitsuda T, Kidouchi
K, Kurosu H, Morisawa Y, Aminaka M, Okubo T,
Kimura S et al: Sharp injuries in Japanese operating
theaters of HIV/AIDS referral hospitals 2009-2011.
Ind Health 2016, 54(3):224-229.
8. Nishikawa H, Shiraki M, Hiramatsu A, Moriya K,
Hino K, Nishiguchi S: Japan Society of Hepatology
guidelines for sarcopenia in liver disease (1stedition): Recommendation from the working groupfor creation of sarcopenia assessment criteria.
Hepatol Res 2016, 46(10):951-963.
9. Tian Y, Yang Y, Zhang X, Nakajima T, Tanaka N,
Sugiyama E, Kamijo Y, Lu Y, Moriya K, Koike K et
al: Age-dependent PPARalpha activation induces
hepatic sulfatide accumulation in transgenic micecarrying the hepatitis C virus core gene. Glycoconj J
2016, 33(6):927-936.
10. Ogishi M, Yotsuyanagi H, Moriya K, Koike K:
Delineation of autoantibody repertoire throughdifferential proteogenomics in hepatitis C virusinduced cryoglobulinemia. Sci Rep 2016, 6:29532.
11. Uchino K, Tateishi R, Fujiwara N, Minami T, Sato
M, Enooku K, Nakagawa H, Asaoka Y, Kondo Y,
Yoshida H et al: Impact of serum ferritin level on
hepatocarcinogenesis in chronic hepatitis C patients.
Hepatol Res 2016, 46(4):259-268.

158

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

Associate
Makoto Otani, M.D., Ph.D.
Shuji Inada, 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 2 senior residents,
7 graduate students, and 2 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 2016 April to 2017 March, overall 1,802
patients (67 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 byapproximately fifteen physicians. During 2016 April
to 2017 March, the numbers of the new outpatientsand of the overall outpatients in our department were
240 and 4,092, respectively.

Teaching activities
We are giving 6 methodical lectures on
psychosomatic medicine for fourth grade medical
students, ‘clinical clerkship’ for fifth grade students
lasting one week, ‘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, orinterpretation of laboratory data, but also relevantways of clinical interview, doctor-patient relationshipbuilding, 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-

159

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. Foo JC, Nagase K, Naramura-Ohno S, Yoshiuchi K,
Yamamoto Y, Morita K. Rank Among Peers DuringGame Competition Affects the Tendency to Make
Risky Choices in Adolescent Males. Front Psychol
8:16, 2017
2. Horie T, Harashima S, Yoneda R, Hiraide M, Inada
S, Otani M, Yoshiuchi K*. Case series of patientswith anorexia nervosa using “tube vomiting”.
BioPsychoSoc Med 10:32, 2016

3. Kuroki T, Ishitobi M, Kamio Y, Sugihara G, Murai T,
Motomura K, Ogasawara K, Kimura H, Aleksic B,
Ozaki N, Nakao T, Yamada K, Yoshiuchi K, Kiriike
N, Ishikawa T, Kubo C, Matsunaga C, Miyata H,
Asada T, Kanba S. Current viewpoints on DSM-5 inJapan. Psychiatry Clin Neurosci 70:371-93, 2016
4. Shimazu A, Tsutsumi A, Yoshiuchi K. Editorial:
Behavioral Medicine in the Asia Pacific. Int J Behav
Med 23:393-394. 2016
5. Yoshiuchi K. How can psychosomatic physicians
contribute to behavioral medicine? BioPsychoSoc
Med 10:8, 2016
6. Inada S, Yoshiuchi K, Iizuka Y, Ohashi K, Kikuchi
H, Yamamoto Y, Kadowaki T, Akabayashi. A Pilot
study for the development of a self-care system for
type 2 diabetes patients using a personal digitalassistant (PDA). Int J Behav Med 23:295-299, 2016
7. Okamoto Y, Fukui S, Yoshiuchi K, Ishikawa T. Do
symptoms among home palliative care patients withadvanced cancer decide the place of death?
Focusing on the presence or absence of symptoms
during home care. Journal of Palliative Medicine
19:488-495, 2016
8. Fujisawa D, Inoguchi H, Shimoda H, Yoshiuchi K,
Inoue S, Ogawa A, Okuyama T, Akechi T, Mimura
M, Shimizu K, Uchitomi Y. The impact ofdepression on health utility value in cancer patients.
Psycho-Oncology 25:491-495, 2016

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

161

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

Associate
Toshiyuki Ikeda, M.D., Yosuke Masamoto, 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

1621) 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. Development of new materials for medical use.

163

References
1. Nagura Y, Tsuno NH, Kano K, Inoue A, Aoki J,
Hirowatari Y, Kaneko M, Kurano M, Matsuhashi
M, Ohkawa R, Tozuka M, Yatomi Y, Okazaki H.
Regulation of the lysophosphatidylserine andsphingosine 1-phosphate levels in autologous
whole blood by the pre-storage leukocyte
reduction. Transfus Med 26:365-372, 2016
2. Masamoto Y, Arai S, Sato T, Yoshimi A, Kubota
N, Takamoto I, Iwakura Y, Yoshimura A,
Kadowaki T, Kurokawa M. Adiponectin Enhances
Antibacterial Activity of Hematopoietic Cells by
Suppressing Bone Marrow Inflammation.
Immunity 44:1422-33, 2016
3. Fujii Y, Tanaka A, Odaka C, Kato H, Yonemura Y,
Fujishima N, Sasaki S, Narasaki M, Ohsawa T,
Tasaki T, Yoshiba F, Iwao N, Ochi N, Kobayashi
Y, Hashimoto M, Kodama R, Kawano Y,
Takenouchi H, Kaneko Y, Nomaguchi Y, Kino S,
Igarashi S, Ishii H, Ohoya S, Okuma K, Okazaki
H, Kitazawa J, Hino S, Momose S, Hamaguchi
I: Investigattion of adverse transfusion reactions
according to clinical department of university
hospitals in Japan. Japanese Journal ofTransfusion and Cell Therapy 62: 451-458,
2016
4. Okazaki H: TRALI and TACO -Recent progressJapanese Journal of Transfusion and Cell
Therapy 62: 630-634, 2016

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

165

Department of
Reproductive Endocrinology
Professors
Tomoyuki Fujii

Associate Professors
Takeshi Nagamatsu

Homepage http://plaza.umin.ac.jp/ivf/index.html
http://square.umin.ac.jp/tkyobgyn/
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 2016
(1) Sato M, et al. Vaginal Stenosis After
Gonadotropin-Releasing
HormoneAgonistTherapy
DuringTreatmentfor
Acute
Lymphoblastic Leukemia. J Low Genit Tract Dis.
2016 Apr;20(2):e11-3.
(2) Taguchi A, et al. Resveratrol Enhances Apoptosis
in Endometriotic Stromal Cells. Am J Reprod
Immunol. 2016 Apr;75(4):486-92.
(3) Akino N, et al. Vaginal cancer possibly caused bypessary and immunocompromised condition:
Multiple risk factors may influence vaginal
cancer development. J Obstet Gynaecol Res. 2016
Jun;42(6):748-751.

166(4) Takahashi N, et al. A potential role of endoplasmic reticulum stress in development ofovarian hyperstimulation syndrome. Mol Cell
Endocrinol. 2016 Jun 15;428:161-9.
(5) Miyashita M, et al. Effects of 1,25-Dihydroxy
Vitamin D3 on Endometriosis. J Clin Endocrinol
Metab. 2016 Jun;101(6):2371-9.
(6) Hirano M, et al. The Emerging Role of FOXL2 inRegulating the Transcriptional Activation
Function of Estrogen Receptor β: An Insight Into
Ovarian Folliculogenesis. Reprod Sci. 2016 Jun 1.
pii: 1933719116651150.
(7) Takahashi N, et al. Usefulness of T2 starweighted imaging in ovarian cysts and tumors. J
Obstet Gynaecol Res. 2016 Oct;42(10):13361342.
(8) Hiraoka T, et al. STAT3 accelerates uterine
epithelial regeneration in a mouse model ofdecellularized uterine matrix transplantation. JCIInsight. 2016 Jun 2;1(8).
(9) Hiraoka T, et al. STAT3 accelerates uterine
epithelial regeneration in a mouse model ofdecellularized uterine matrix transplantation. JCIInsight. 2016 Jun 2;1(8).
(10) Haraguchi H,et al. Development of ovariancancer after excision of endometrioma. Fertil
Steril. 2016 Nov;106(6):1432-1437.
(11) Fujii T,et al. Assisted reproductive technology
pregnancy complications are significantly
associated with endometriosis severity before
conception: a retrospective cohort study. Reprod
Biol Endocrinol. 2016 Nov 3;14(1):73.
(12)Takeuchi A, et al. Dienogest reduces proliferation,
NGF expression and nerve fiber density in humanadenomyosis. Eur J Obstet Gynecol Reprod Biol.
2016 Dec;207:157-161.
(13) Takahashi N,et al. The assessment of
myometrium perfusion in patients with uterine
fibroid by arterial spin labeling MRI.
Springerplus. 2016 Nov 3;5(1):1907.

167

Department of
Gynecologic Oncology
Professor
Yutaka Osuga

Associate Professor
Katsutoshi Oda

Homepage http://square.umin.ac.jp/tkyobgyn/
http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika01/index.html
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 ofTokyo Hospital. For the clinical aspect, they are
engaged with in-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 ofhigh-risk HPVs. The most prevalent of these, types 16
and 18, together account for more than 70% of cases.
HPV infections are very common among young
sexually active women, and the majority of infections
are transient and cleared by their immune system
within a short 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
non-pathological 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 wasclosely associated with the presence of the NAs(p=0.0002). The presence of the NAs was associatedwith low-level copy number of the viral DNA relative
to the NA-negative group (p=0.05). The presence of
the NAs against HPV16 was associated with a higher
regression rate of HPV-related CIN1 lesions. The NAsseem to have a role in deterring HPV-related cervicallesions from progressing to CIN2/3 by inhibiting theinfection with de novo replicated HPV. Then we
designed a placebo-controlled trial in healthy adults toevaluate the safety and immunogenicity of a synthetic
peptide consisting of the aa 108-120 of HPV16 L2(L2-108/120) region, because this region contains across-neutralization 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 orplacebo (n=3) without adjuvant at weeks 0, 4, and 12.
Sera were collected 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/L2-capsids in four of the five recipients in the168

0.5mg group. Sera of the four recipients showedneutralizing activities against HPV16 and 52.
Serological responses to the peptides were not foundin the 0.1mg group and the placebo group recipients.
This study suggests the L2-108/120 peptide istolerable in humans and has the potential as abroad-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 in endometrial cancer. For example,
high expression of survivin, an anti-apoptotic protein,is associated with poor prognosis. We found thatsurvivin inhibitor, YM155, dose-dependently andsignificantly increased the apoptotic cell population inall endometrial cancer cell lines examined. In addition,
we elucidated that the histone methyltransferase EZH2,
a key epigenetic modifier, is significantly overexpressed in endometrial cancers, and that EZH2
inhibitor suppressed endometrial cancer cell growth.
We also investigated molecular biomarkers to predictthe prognosis and/or drug sensitivity in endometrial
cancer, using genome-wide analyses in clinicalsamples. Of note, extensive chromosomal instability
was an independent poor prognostic factor inendometrial cancer.
In ovarian cancer, we also investigated genomewide analyses, including whole-exome sequencing
and gene expression array, in high-grade serous andclear cell carcinomas. As well, we examined various
types of molecular-targeted drugs in ovarian cancer
cell lines. For example, we identified a subgroup in
ovarian clear cell carcinomas, which is associatedwith prognosis and chemosensitivity. We reported
several molecular targets in ovarian clear cell
carcinomas. Targeting the PI3K pathway showedanti-tumor effect through induction of wild-type TP53.
We further identified that MDM2, a negative regulatorof TP53, is frequently overexpressed and that MDM2
inhibitor induced TP53-mediated apoptosis in ovarian
clear cell carcinomas.

(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 theefficacy of modified radical hysterectomy in patientswith tumor diameter 2 cm or less FIGO Stage IB1
uterine cervical cancer, for which the current standard
is radical hysterectomy. This study began in January
2013 and a total of 240 patients will be accrued from44 institutions within 5 years. The primary endpoint is
5-year 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
self-urination 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
single-institution analyses in clinical setting. For
example, to evaluate the efficacy and toxicity ofsystematic 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
includedsystematic
pelvicandaorticlymphadenectomy, whereas pelvic lymphadenectomy
alone was performed to preoperative stage I patientswith superficial myometrial invasion and G1
endometrioid
adenocarcinoma.
PORT
wasadministered to 67 patients with positive lymph nodes,
deep myometrial invasion, or adnexal/peritoneal
metastases. Prior to PORT, 37 patients withadnexal/peritoneal involvement or aortic nodemetastases were treated with chemotherapy. Surgery
was undergone in 247 patients, including with 215
pelviclymphadenectomyand126
aorticlymphadenectomy. 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 the169patients who had received lymphadenectomy, 19(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
subsequenttolymphadenectomy should limit to relatively high-riskpatients.

References published in 2016
(1) Sato M, et al. Clinical significance of Gremlin 1
in cervical cancer and its effects on cancer stem
cell maintenance. Oncol Rep. 2016 Jan;35(1):391-7.
(2) Sato M, et al. Decreased expression of theplasminogenactivator inhibitor type 1 isinvolved in degradation of extracellular matrix
surrounding cervical cancer stem cells. Int J
Oncol. 2016 Feb;48(2):829-35.
(3) Tsuruga T, et al. Radical hysterectomy with orwithout para-aortic lymphadenectomy for patientswith stage IB2, IIA2, and IIB cervical cancer:
outcomes for a series of 308 patients. Int J Clin
Oncol. 2016 Apr;21(2):359-66.
(4) Nishida H,et al. Systemic delivery of siRNA by
actively targeted polyion complex micelles forsilencing the E6 and E7 human papillomavirus
oncogenes. J Control Release. 2016 Jun 10;231:
29-37.
(5) Sato M, et al. Measurement of endometrial
thickness by transvaginal ultrasonography topredict pathological response to medroxyprogesterone acetate in patients with grade 1
endometrioid adenocarcinoma. Mol Clin Oncol.
2016 Apr;4(4):492-496.
(6) Chuwa AH,et al. Significance of survivin as aprognostic factor and a therapeutic target in
endometrial cancer. Gynecol Oncol. 2016 Jun;
141(3):564-9.
(7) Oda K, et al. Characterization of TP53 and PI3K
signaling pathways as molecular targets ingynecologic malignancies. J Obstet Gynaecol Res.
2016 Jul;42(7):757-62.
(8) Inaba K, et al. Synergistic antitumor effects ofcombination PI3K/mTOR and MEK inhibition(SAR245409 and pimasertib) in mucinous
ovarian carcinoma cells by fluorescenceresonance energy transfer imaging. Oncotarget.
2016 May 17;7(20):29577-91.
(9) Sato M, et al. Spheroid cancer stem cells display
reprogrammed metabolism and obtain energy byactively running the tricarboxylic acid (TCA)
cycle. Oncotarget. 2016 May 31;7(22):33297305.
(10) Suzuki K, et al. A case of lymphangioleiomyomatosis associated with endometrial cancer
and severe systemic lupus erythematosus. BMC
Cancer. 2016 Jul 4;16:390.
(11) Yoshida M,et al. Modification of the Tumor
Microenvironment in KRAS or c-MYC-Induced
Ovarian Cancer-Associated Peritonitis. PLoS One.
2016 Aug 2;11(8)(12) Fujimoto A, et al. Inhibition of endoplasmic
reticulum (ER) stress sensors sensitizes cancer
stem-like cells to ER stress-mediated apoptosis.
Oncotarget. 2016 Aug 9;7(32):51854-51864. doi:
10.18632/oncotarget.10126.
(13) Inoue T, et al. Cancer-associated fibroblast
suppresses killing activity of natural killer cells
through downregulation of poliovirus receptor(PVR/CD155), a ligand of activating NK receptor.
Int J Oncol. 2016 Oct;49(4):1297-304.
(14) Fukuda T, et al. Autophagy inhibition augments
resveratrol-induced apoptosis in Ishikawa
endometrial cancer cells. Oncol Lett. 2016
Oct;12(4):2560-2566.
(15) Makii C, et al. MDM2 is a potential therapeutictarget and prognostic factor for ovarian clear cell
carcinomas with wild type TP53. Oncotarget.
2016 Nov 15;7(46):75328-75338.
(16) Nakamura H, et al. STAT3 activity regulatessensitivity to tumor necrosis factor-related
apoptosis-inducing ligand-induced apoptosis in
cervical cancer cells. Int J Oncol. 2016
Nov;49(5):2155-2162.
(17) Nakamura H, et al. Expression of Par3 polarity
protein correlates with poor prognosis in ovariancancer. BMC Cancer. 2016 Nov 17;16(1):897.

170

Department of Perinatal Medicine
Professor
Tomoyuki Fujii

Associate Professor
Kaori Koga

Homepage http://square.umin.ac.jp/tkyobgyn/
http://www.iiosan.umin.jp/index.htm
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.
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.

References published in 20152017
1: Hashimoto A, Iriyama T, Sayama S, Nakayama T,
Komatsu A, Miyauchi A, et al. Adenomyosis andadverse perinatal outcomes: increased risk of171

second trimester miscarriage, preeclampsia, andplacental malposition. The journal of maternalfetal & neonatal medicine. 2017:1-6.
2: Motomura K, Okada N, Morita H, Hara M,
Tamari M, Orimo K, et al. A Rho-associatedcoiled-coil containing kinases (ROCK) inhibitor,
Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro. PloS one. 2017;12(5): e0177994.
3: Machino H, Iriyama T, Nakayama T, Komatsu A,
Nagamatsu T, Osuga Y, et al. A case of a surviving
co-twin diagnosed with porencephaly and renal
hypoplasia after a single intrauterine fetal death at
21 weeks of gestation in a monochorionic monoamniotic twin pregnancy. Oxford medical casereports. 2017;2017 (1):omw096.
4: Aikawa S, Kano K, Inoue A, Wang J, Saigusa D,
Nagamatsu T, et al. Autotaxin-lysophosphatidic
acid-LPA3 signaling at the embryo-epithelial
boundary controls decidualization pathways. The
EMBO journal. 2017;36(14):2146-60.
5: Nitta D, Kinugawa K, Imamura T, Endo M,
Amiya E, Hatano M, et al. Successful Pregnancy
and Delivery in a Heart Transplantation Recipient.
International heart journal. 2016;57(3):383-5.
6: Tanaka S, Kanagawa T, Momma K, Hori S, Satoh
H, Nagamatsu T, et al. Prediction of sustained
fetal toxicity induced by ketoprofen based on
PK/PD analysis using human placental perfusion
and rat toxicity data. British journal of clinicalpharmacology. 2017.
7: Samejima T, Nagamatsu T, Schust DJ, Itaoka N,
Iriyama T, Nakayama T, Komatsu, A, Kawana K,
Osuga Y, Fujii T. Elevated concentration of
secretory leukocyte protease inhibitor in thecervical mucus before delivery. Am J Obstet
Gynecol. 214(6):741.e1-7, 2016
8: Taguchi A, Yamashita A, Kawana K, Nagamatsu T,
Furuya H, Inoue E, Osuga Y, Fujii T. Recent
Progress in Therapeutics for InflammationAssociated Preterm Birth: A Review. Reprod Sci.
2015 Dec 1.
9: Oki S, Nagamatsu T, Iriyama T, Komatsu A,
Osuga Y, Fujii T. A case of pregnancy complicatedwith dilated cardiomyopathy 1X. Oxf Med Case
Reports. 2015(11):351-353, 2015
10: Ichikawa M, Nagamatsu T, Schust DJ,

Kawai-Iwasawa Y, Kawana K, Yamashita T,
Osuga Y, Aoki J, Yatomi Y, Fujii T. Placental
autotaxin expression is diminished in women withpre-eclampsia. J Obstet Gynaecol Res. 41(9):1406-1411, 2015.
11: Furuya H, Taguchi A, Kawana K, Yamashita A,
Inoue E, Yoshida M, Nakamura H, Fujimoto A,
Inoue T, Sato M, Nishida H, Nagasaka K, Adachi
K, Hoya M, Nagamatsu T, Wada-Hiraike O,
Yamashita T, Osuga Y, Fujii T. Resveratrol
Protects Against Pathological Preterm Birth by
Suppression of Macrophage-Mediated Inflammation. Reprod Sci. 22(12):1561-1568, 2015
12: Itaoka N, Nagamatsu T, Schust DJ, Ichikawa M,
Sayama S, Iwasawa-Kawai Y, Kawana K,
Yamashita T, Osuga Y, Fujii T. Cervical
Expression of Elafin and SLPI in Pregnancy and
Their Association With Preterm Labor. Am J
Reprod Immunol. 73(6):536-544, 2015

172

Department of Molecular andCellular Reproductive Medicine
Professor
Yutaka Osuga

Associate Professor
Osamu Hiraike

Homepage http://plaza.umin.ac.jp/ivf/index.html
http://square.umin.ac.jp/tkyobgyn/
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 2016
1) Vaginal Stenosis After Gonadotropin-Releasing
Hormone Agonist Therapy During Treatment for Acute
Lymphoblastic Leukemia.
Sato M, Harada M, Oishi H, Wada-Hiraike O, Hirata T,
Nagasaka K, Koga K, Fujii T, Osuga Y.
J Low Genit Tract Dis. 2016 Apr;20(2):e11-3. doi:
10.1097/LGT.0000000000000175.
2) Resveratrol Enhances Apoptosis in Endometriotic
Stromal Cells.
Taguchi A, Koga K, Kawana K, Makabe T, Sue F,
Miyashita M, Yoshida M, Urata Y, Izumi G, Tkamura
M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O,
Fujii T, Osuga Y.
Am J Reprod Immunol. 2016 Apr;75(4):486-92. doi:
10.1111/aji.12489.
3) The Emerging Role of FOXL2 in Regulating theTranscriptional Activation Function of Estrogen

173

4)

5)

6)

7)

8)

9)

Receptor β: An Insight Into Ovarian Folliculogenesis.
Hirano M, Wada-Hiraike O, Fu H, Akino N, Isono W,
Sakurabashi A, Fukuda T, Morita Y, Tanikawa M,
Miyamoto Y, Nishi Y, Yanase T, Harada M, Oishi H,
Yano T, Koga K, Oda K, Kawana K, Fujii T, Osuga Y.
Reprod Sci. 2016 Jun 1. pii: 1933719116651150.
Vaginal cancer possibly caused by pessary andimmunocompromised condition: Multiple risk factors
may influence vaginal cancer development.
Akino N, Wada-Hiraike O, Matsumoto Y, Arimoto T,
Oda K, Kawana K, Osuga Y, Fujii T.
J Obstet Gynaecol Res. 2016 Jun;42(6):748-751. doi:
10.1111/jog.12958.
Effects of 1,25-Dihydroxy Vitamin D3 on
Endometriosis.
Miyashita M, Koga K, Izumi G, Sue F, Makabe T,
Taguchi A, Nagai M, Urata Y, Takamura M, Harada M,
Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
J Clin Endocrinol Metab. 2016 Jun;101(6):2371-9. doi:
10.1210/jc.2016-1515.
STAT3 accelerates uterine epithelial regeneration in amouse model of decellularized uterine matrix transplantation.
Hiraoka T, Hirota Y, Saito-Fujita T, Matsuo M,
Egashira M, Matsumoto L, Haraguchi H, Dey SK,
Furukawa KS, Fujii T, Osuga Y.
JCI Insight. 2016 Jun 2;1(8). pii: e87591.
A potential role of endoplasmic reticulum stress indevelopment of ovarian hyperstimulation syndrome.
Takahashi N, Harada M, Hirota Y, Zhao L, Yoshino O,
Urata Y, Izumi G, Takamura M, Hirata T, Koga K,
Wada-Hiraike O, Fujii T, Osuga Y.
Mol Cell Endocrinol. 2016 Jun 15;428:161-9. doi:
10.1016/j.mce.2016.03.032.
Neutrophil depletion reduces endometriotic lesion
formation in mice.
Takamura M, Koga K, Izumi G, Urata Y, Nagai M,
Hasegawa A, Harada M, Hirata T, Hirota Y,
Wada-Hiraike O, Fujii T, Osuga Y.
Am J Reprod Immunol. 2016 Sep;76(3):193-8. doi:
10.1111/aji.12540.
Usefulness of T2 star-weighted imaging in ovariancysts and tumors.
Takahashi N, Yoshino O, Maeda E, Naganawa S,
Harada M, Koga K, Hiraike O, Nakamura M, Tabuchi
T, Hori M, Saito S, Fujii T, Osuga Y.
J Obstet Gynaecol Res. 2016 Oct;42(10):1336-1342.

doi: 10.1111/jog.13056.
10) Development of ovarian cancer after excision ofendometrioma.
Haraguchi H, Koga K, Takamura M, Makabe T, Sue F,
Miyashita M, Urata Y, Izumi G, Harada M, Hirata T,
Hirota Y, Wada-Hiraike O, Oda K, Kawana K, Fujii T,
Osuga Y.
Fertil Steril. 2016 Nov;106(6):1432-1437.e2. doi: 10.
1016/j.fertnstert.2016.07.1077.
11) The assessment of myometrium perfusion in patientswith uterine fibroid by arterial spin labeling MRI.
Takahashi N, Yoshino O, Hiraike O, Maeda E,
Nakamura M, Hori M, Harada M, Koga K, Saito S,
Fujii T, Osuga Y.
Springerplus. 2016 Nov 3;5(1):1907.
12) Assisted reproductive technology pregnancy complications are significantly associated with endometriosis
severity before conception: a retrospective cohort study.
Fujii T, Wada-Hiraike O, Nagamatsu T, Harada M,
Hirata T, Koga K, Fujii T, Osuga Y.
Reprod Biol Endocrinol. 2016 Nov 3;14(1):73.
13) Dienogest reduces proliferation, NGF expression andnerve fiber density in human adenomyosis.
Takeuchi A, Koga K, Miyashita M, Makabe T, Sue F,
Harada M, Hirata T, Hirota Y, Fujii T, Osuga Y.
Eur J Obstet Gynecol Reprod Biol. 2016
Dec;207:157-161. doi: 10.1016/j.ejogrb.2016.10.053.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

175

Department ofPediatrics, Department ofDevelopmental Pediatrics
Professor
Akira Oka, M.D.,Ph.D.

Associate Professor
Sachiko Kitanaka, M.D., Ph.D.
Naoto Takahashi, M.D., Ph.D. (Department of Maternal, Fetal and Neonatal Medicine)
Junko Takita, M.D., Ph.D.

Lecturer
Shinya Tsuchida, M.D., Ph.D., Yutaka Harita, M.D., Ph.D., Ryo Inuzuka, M.D., PhD.,
Youichirou Hirata, M.D., Ph.D.,
Mitsuteru Hiwatari, M.D., Ph.D., (Department of Cell Therapy and Transplantation
Medicine)

Associate
Hiroki Yasudo M.D.,Ph.D., Riki Nishimura, M.D.,Ph.D., Satsuki Kakiuchi, M.D.,Ph.D.,
Takahiro Shindo,M.D., Atsushi Satou, M.D., Ph.D., Sho-ichirou Kanda, M.D., Ph.D.,
Shigeru Nomura, Konomi Shimoda, M.D., Hiroko Asakai, M.D., Masafumi Seki, Satoshi
Takenaka, Kousuke Tanaka. M.D., Hiroshi Mutoh, M.D., Yousuke Furukawa, M.D., Mariko
Kasai, Kazuhiro Shiraga, Mayumi Hangai, M.D., Hiroki Takehara, M.D., Yuichi Mitani.
(As of March 31, 2017)

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.

176

Clinical activities

Teaching activities

We have specialized outpatient clinics covering allpediatric fields in addition to general pediatrics. In
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 ourinstitution 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), neuromusculardisorders, 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 withthe patients and help their mothers, providing
enormous comfort to both the patients and theirmothers. Various activities are scheduled for thepatients in the hospital such as the Tanabata festival, a
Christmas party and music concerts. All the residents,
fellows and nurses participate in these activities. We
have two child care specialists in the pediatric ward.

The staff members and the visiting lecturers givelectures of general pediatrics and pediatric diagnosis
for 36 hours to the second year students, and clinicalbedside learning in the inpatient ward for 2 weeks to
the third year students. During bedside learning for 2
weeks, specialized teaching sessions, like seminars areheld every day. In the outpatient learning, medical
students take histories and perform physicalexaminations of patients under the supervision of theteaching staff. On the second and third days of theoutpatient clinic, each student visits the local
pediatricians or local hospitals in and around Tokyo.
On the last day of clinical learning, the Professor andan Associate Professor evaluate the students’achievements. We have an elective clinical clerkshipcourse for the third year students.

Research activities
Our departments have the following researchgroups: nephrology, hematology/oncology, neurology,
cardiology, endocrinology/metabolism, immunology/
allergy, and neonatology. We also have multidisciplinary research groups and laboratories such ascell biology, genetic molecular biology 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, we found novel recurrent SPI1-related
fusions in approximately 4% of T-ALL.
Importantly, this SPI1 fusions were significantly
associated with poor prognosis. In PBL, we found
WNT pathway abnormalities in 100% of cases.
Uniparental disomy of chromosome 11q was alsofrequently observed in PBL. In addition, based on
the genetic signatures, 6 distinct genetic subgroups
were detected in NBL. These subgroups were wellcorrelated with clinical features and outcomes.
② Nephrology group: Our aim is to reveal the177molecular mechanism of pediatric kidney diseases.
We revealed novel causative mutations on several
proteinuric diseases including idiopathic nephrotic
syndrome. We also analyzed pathological changes
in glomerulonephritis and found novel mechanismof the phenotypical changes of mesangial cells inglumerulonephritis.
③ Endocrinology and Metabolism group: We
analyzed genes and mechanisms involved in
endocrinology and bone diseases. We successfully found the responsible gene of a rare congenital
disease using next-generation sequencing. We
found a novel disease entity caused by LMX1B
abnormality. We also determined two novel
genetic mechanisms of hereditary rickets.
④ Cardiology group: We performed genome-wide
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. Neonatal
brain function has been investigated using nearinfra-red spectro-scopy (NIRS) with researchers ofDepartment of Education. A clinical trial offormula supplied with biotin has been conductedwith groups of the other Universities. Cytokine
profiles have been investigated in order toelucidate pathophysiology of several diseases inperinatal period.
⑦ Immunology group: Research area of interest
includes refractory Kawasaki disease and epidemiology of childhood infectious disease.

Referencess
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5. Hayakawa I, et al. Giant Coronary Aneurysms in
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7. Hayashi T, et al. Clinical implications of mitralvalve geometric alterations in children withdilated cardiomyopathy. Cardiol Young 26: 1365,
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8. Hirano Y, et al. Systemic lupus erythematosus
presenting with mixed-type fulminant autoimmune hemolytic anemia. Pediatr Int 58: 527,
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9. Hoshino A, et al. Specific HLA genotypes confer
susceptibility to acute necrotizing encephalopathy.
Genes & Immunity 17: 367, 2016
10. Inuzuka R, et al. Novel, single-beat approach for
determining both end-systolic pressure-dimension
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Open Heart 3: e000451, 2016
11. Inuzuka R, et al. Influence of cardiac function andloading conditions on the myocardial performanceindex-theoretical analysis based on a mathematical model. Circ J 80: 148, 2016
12. Kajiho H, et al. RAB2A controls MT1-MMP
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EMBO Rep 17: 1061, 2016
13. Kamiyoshi N, et al. Genetic, clinical, andpathologic backgrounds of patients with autosomal dominant Alport syndrome. Clin J Am Soc
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14. Kanda S, et al. New-onset diabetes after renaltransplantation in a patient with a novel HNF1B
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178

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16. Kato M, et al. Genomic analysis of clonal originof Langerhans cell histiocytosis following acutelymphoblastic leukaemia. Br J Haematol 175: 169,
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17. Konomoto T, et al. Clinical and histologicalfindings of autosomal dominant renal-limited
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cases with various myeloid neoplasms. Leukemia
30: 2270, 201619. Muraoka M, et al. Adults with germline CBLmutation complicated with juvenile myelomonocytic leukemia at infancy. J Hum Genet 61:
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179

Department of Pediatric Surgery
Associate Professor
Jun Fujishiro, M.D., Ph.D.

Lecturer
Mari Arai, M.D. ,Ph.D.

Akinari Hinoki, M.D. ,Ph.D.

Research Associate
Masahiko Sugiyama, M.D.

Tetsuya Ishimaru, M.D., Ph.D.

Miho Watanabe, M.D. ,Ph.D.

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

Homepage

http://square.umin.ac.jp/pedsurg/index.html

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 four 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180

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, and a tumor clinic.
Recently, a second-opinion clinic opened to provide
careful detailed explanations, and this has received afavorable reception.
Our ward is located on the hospital's second floor,south of the A wing. Other pediatric surgical patients
also are admitted to this ward. We have 16 beds in theward, 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, infantmalignant tumors such as Wilms' tumor andneuroblastoma, biliary tract diseases such as biliary
tract dilatation and biliary atresia, respiratory
anomalies such as tracheal stenosis and lung cysts,
gastrointestinal anomalies, and urological disorders
including hydronephrosis and vesicoureteral reflux.
We work with other pediatric surgery teams at otherinstitutions who perform endoscopic surgery(laparoscopic surgery/thoracoscopic surgery). We
have developed 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, and a new therapeutic method for
lymphangioma, are also being evaluated in ongoing
research.

References(1) Ishimaru T, Sugiyama M, Arai M, Satoh K, Uotani
C, Takahashi M, Takami S, Fujishiro J, Iwanaka T.
Impact of scoliosis on laparoscopic Nissen
fundoplication. J Laparoendosc Adv Surg Tech A.
26(11) 2016. PMID: 27726524(2) Takazawa S, Ishimaru T, Harada K, Deie K,
Fujishiro J, Sugita N, Mitsuishi M, Iwanaka T.
Pediatric thoracoscopic surgical simulation using a
rapid-prototyped chest model and motion sensors
can better identify skilled surgeons than a181conventional box trainer. J Laparoendosc Adv Surg
Tech A. 26(9) 2016. PMID: 27599013(3) Fujishiro J, Ishimaru T, Sugiyama M, Arai M,
Suzuki K, Kawashima H, Iwanaka T. Minimallyinvasive surgery for diaphragmatic diseases inneonates and infants. Surg Today. 46(7) 2016.
PMID: 27246508(4) Takazawa S, Ishimaru T, Fujii M, Harada K, Deie K,
Fujishiro J, Sugita N, Mitsuishi M, Iwanaka T. A
multi-degree-of -freedom needle driver with a short
tip and small shaft for pediatric laparoscopic
surgery: in vivo assessment of multi-directional
suturing on the vertical plane of the liver in rabbits.
Surg Endosc. 30(8) 2016. PMID: 26511118(5) Shirota C, Uchida H, Ono Y, Murase N, Tainaka T,
Yokota K, Oshima K, Shirotsuki R, Hinoki A, Ando
H. Long-term outcomes after revision of Kasai
portoenterostomy for biliary atresia. J Hepatobiliary
Pancreat Sci. 23(11) 2016. PMID: 27591751(6) Yokota K, Uchida H, Tanano A, Shirota C, Tainaka
T, Hinoki A, Murase N, Oshima K, Shirotsuki R,
Chiba K. Steroid pulse therapy prevents restenosis
following balloon dilatation for esophageal stricture.
Pediatr Surg Int. 32(9) 2016. PMID: 27469501(7) Tainaka T, Uchida H, Tanaka Y, Shirota C, Yokota K,
Murase N, Oshima K, Shirotsuki R, Chiba K,
Hinoki A. Comparing surgical outcomes ofcomplete thoracoscopic lobectomy for congenital
cystic lung disease between neonatal and infantile
patients. Nagoya J Med Sci 78(4) 2016. PMID:
28008200(8) Tanaka Y, Uchida H, Kawashima H, Fujiogi M,
Suzuki K, Takazawa S, Deie K, Amano H, Iwanaka
T. More than one-third of successfully nonoperatively treated patients with complicatedappendicitis experienced recurrent appendicitis: Isinterval appendectomy necessary? J Pediatr Surg.
51(12) 2016. PMID: 27666007(9) Deie K, Uchida H, Kawashima H, Tanaka Y, Fujiogi
M, Amano H, Murase N, Tainaka T. Laparoscopic
side-to-side pancreaticojejunostomy for chronicpancreatitis in children. J Minim Access Surg. 12(4)2016. PMID: 27251846(10) Gotoh M, Miyata H, Hashimoto H, Wakabayashi G,
Konno H, Miyakawa S, Sugihara K, Mori M,
Satomi S, Kokudo N, Iwanaka T. National Clinical
Database feedback implementation for quality

improvement of cancer treatment in Japan: fromgood to great through transparency. Surg Today
46(1) 2016. PMID: 25797948(11) Tanaka Y, Kawashima H, Mori M, Fujiogi M,
Suzuki K, Amano H, Morita K, Arakawa Y, Koh K,
Oguma E, Iwanaka T, Uchida H. Contraindications
and image-defined risk factors in laparoscopic
resection of abdominal neuroblastoma. Pediatr Surg
Int 32(9) 2016. PMID: 27461435(12) Nishigaki K, Kanamori Y, Ikeda M, Sugiyama M,
Minowa H, Kamibeppu K. Changes in mother’s
psychosocial perceptions of technology-dependent
children and adolescents at home in Japan:
Acknowledgement of children’s autonomy. Asian
Nurs Res 10(2) 2016. PNID: 27349666(13) Watanabe T, Horikawa R, Masaki H, Yoshioka T,
Matsumoto K, Kanamori Y. Anal canal carcinoma
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Pediatr Blood Cancer 63(7) 2016. PMID:
27037640(14) Yamoto M, Inamura N, Terui K, Nagata K,
Kanamori Y, Hayakawa M, Tazuke Y, Yokoi A,
Takayasu H, Okuyama H, Fukumoto K, Urushihara
N, Taguchi T, Usui N. Echocardiographic predictorsof poor prognosis in congenital diaphragmatic
hernia. J Pediatr Surg. 51(12) 2016. PMID:
27663123(15) Satake R, Komura M, Komura H, Kodaka T,
Terawaki K, Ikebukuro K, Komuro H, Yonekawa H,
Hoshi K, Takato T, Nakayama Y. Patch
tracheoplasty in body tissue engineering using
collagenous
connective
tissuemembranes(biosheets). J Pediatr Surg. 51(2) 2016. PMID:
26628203(16) Takayasu H, Masumoto K, Ishikawa M, Sasaki T,
Ono K. The use of a sternothyroid muscle flap toprevent the re-recurrence of a reccurent
tracheoesophageal fistula found 10 years after the
primary repair. Surg Case Rep 2(1) 2016. PMID:
27589983(17) Tanaka H, Masumoto K, Sasaki T, Sakamoto N,
Gotoh C, Urita Y, Shinkai T, Takayasu H, Nakano N,
Noguchi M, Kudo T. Hypergastrinemia and aduodenal ulcer caused by gastric duplication. Surg
Case Rep. 2(1) 2016. PMID: 27464496(18) Aiyoshi T, Masumoto K, Shinkai T, Tanaka Y, Fujii
S, Sasaki T, Chiba F, Sakamoto N, Gotoh C, Urita Y,

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Nakao M, Takayasu H, Tanaka H, Imai H.
Pulmonary interstitial emphysema due torespiratory syncytial virus infection. Pediatr Int.
58(9) 2016. PMID: 27435178(19) Terui K, Nagata K, Hayakawa M, Okuyama H,
Goishi K, Yokoi A, Tazuke Y, Takayasu H, Yoshida
H, Usui N. Growth assessment and the risk ofgrowth retardation in congenital diaphragmatic
hernia: a long-term follow-up study from theJapanese congenital diaphragmatic hernia study
group. Eur J Pediatr surg. 26(1) 2016. PMID:
26509310(20) Takayasu H, Masumoto K, Goishi K, Hayakawa M,
Tazuke Y, Yokoi A, Terui K, Okuyama H, Usui N,
Nagata K, Taguchi T, Japanese Congenital
Diaphragmatic Hernia Study Group. Musculoskeletal abnormalities in congenital diaphragmatic
hernia survivors: patterns and risk factors: report ofa Japanese multicenter follow-up survey. Pediatr Int.
58(9) 2016. PMID: 26766165(21) Masuko T, Tanaka Y, Kawashima H, Amano H.
Diagnostic laparoscopy for neonatal perforated
Meckel’s diverticulum. J Minim Access Surg. 12(1)2016. PMID: 26917924

Reproductive, Developmental andAging Sciences
3. Aging Sciences

184

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

Associate Professor
Sumito Ogawa, MD, PhD.

Lecturer
Yasuhiro Yamaguchi, MD, PhD.

Tomohiko Urano, MD, PhD.

Research Associate
Taro Kojima, MD.

Yumi Kameyama, MD, PhD.

Shinya Ishii, MD, PhD.

Masaki Ishii, MD, PhD.

Yoko Yamada, MD, PhD.

Koji Shibasaki, 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. 352
new and a total of 18,528 patients visited the outpatient clinic in the last fiscal year.

185

Education
Clinical education is provided for fifth and sixthyear medical students on a man-to-man basis with afaculty staff member. During the period, the student
studies one or two cases, through which the student
learns the techniques of interrogation and physicalexamination, interpretation of laboratory tests, andactual medical procedures. Interpretation of theresults of geriatric assessment is studied throughlectures in a case-oriented manner with an emphasis
placed on the multidisciplinary basis of geriatricpatients.

Research
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. Akiyoshi T, Ota H, Iijima K, Son BK, Kahyo T,
Setou M, Ogawa S, Ouchi Y, Akishita M: A
novel organ culture model of aorta for vascular
calcification. Atherosclerosis 244:51-8，2016.
2. Aihara H, Nakagawa T, Mizusaki H, Yoneda M,
Kato M, Doiguchi M, Imamura Y, Higashi M,
Ikura T, Hayashi T, Kodama Y, Oki M,
Nakayama T, Cheung E, Aburatani H, Takayama
K, Koseki H, Inoue S, Takeshima Y, Ito T:
Histone H2A T120 Phosphorylation Promotes
Oncogenic Transformation via Upregulation of
Cyclin D1. Mol Cell. 64(1):176-188, 2016.
3. Fujimura T, Inoue S, Urano T, Takayama K,
Yamada Y, Ikeda K, Obinata D, Ashikari D,
Takahashi S, Homma Y: Increased expression of
Tripartite Motif (TRIM) 47 is a negative
prognostic predictor in human prostate cancer.
Clin Genitourin Cancer 14(4):298-303, 2016
4. Hanaoka Y, Yamaguchi Y, Yamamoto H, Ishii
M, Nagase T, Kurihara H, Akishita M, Ouchi Y.
In Vitro and In Vivo Anticancer Activity of
Human β-Defensin-3 and Its Mouse Homolog.
Anticancer Res. 36(11)5999-6004.2016
5. Ishii S, Kojima T, Ezawa K, Higashi K, Ikebata
Y, Takehisa Y, Akishita M. The association ofchange in medication regimen and use of
inappropriate medication based on Beers criteriawith adverse outcomes in Japanese long-termcare facilities. Geriatr Gerontol Int. 2016 May 26.
doi: 10.1111/ggi.12761. [Epub ahead of print][PMID: 27228966]
6. Ishii S, Chang C, Tanaka T, Kuroda A, Tsuji T,
Akishita M, Iijima K. The Association between
Sarcopenic Obesity and Depressive Symptoms in186

Older Japanese Adults. PLoS One. 2016 Sep
14;11(9):e0162898 [PMID: 27627756]
7. Kojima T, Mizukami K, Tomita N, Arai H,
Ohrui T, Eto M, Takeya Y, Isaka Y, Rakugi H,
Sudo N, Arai H, Aoki H, Horie S, Ishii S,
Iwasaki K, Takayama S, Suzuki Y, Matsui T,
Mizokami F, Furuta K, Toba K, Akishita M;
Working Group on Guidelines for Medical
Treatment its Safety in the Elderly. Screening
tool for older persons’ appropriate prescriptionsin Japanese: report of the Japan Geriatrics
Society Working Group on “guidelines for
medical treatment and its safety in the elderly.
Geriatr Gerontol Int 2016;16:983-1001.
8. Misawa A#, Takayama K#, Urano T, Inoue S:
Androgen-induced
lncRNA
SOCS2-AS1
promotes cell growth and inhibits apoptosis inprostate cancer cells. J Biol Chem. 291:178611780, 2016. (#co-first author)
10. Nanao-Hamai M, Son BK, Hashizume T, Ogawa
S, Akishita M,. Protective effects of estrogen
against vascular calcification via estrogen
receptor α-dependent growth arrest-specific gene
6 transactivation. Biochemical and BiophysicalResearch Communications. 480(3):429-435;
2016.
11. Niimi A, Suzuki M, Yamaguchi Y, Ishii M,
Fujimura T, Nakagawa T, Fukuhara H, Kume H,
Igawa Y, Akishita M, Homma Y Sleep apnea
and circadian extracellular fluid change as anindependent factor for nocturnal polyuria. J Urol.
196(4):1183-9. doi: 10.1016/j.juro.2016.04.060.
Epub 201612. Obinata D#, Takayama K#, Fujiwara K, Suzuki
T, Tsutsumi S, Fukuda N, Nagase H, Fujimura T,
Urano T, Homma Y, Aburatani H, Takahashi S,
Inoue S: Targeting Oct1 genomic function
inhibits androgen receptor signaling andcastration-resistant prostate cancer growth.
Oncogene 35(49):6350-6358, 2016.
13. Obinata D, Takada S, Takayama K, Urano T, Ito
A, Ashikari D, Fujiwara K, Yamada Y, Murata T,
Kumagai J, Fujimura T, Ikeda K, Horie-Inoue K,
Homma Y, Takahashi S, Inoue S: ABHD2, anandrogen target gene, promotes prostate cancer
cell proliferation and migration. Eur J Cancer
57:39-49, 2016.

14. Sasano H, Suzuki T: TACC2 (transforming
acidic coiled-coil protein 2) in breast carcino
Onodera Y, Takagi K, Miki Y, Takayama K,
Shibahara Y, Watanabe M, Ishida T, Inoue S, ma
as a potent prognostic predictor associated withcell proliferation. Cancer Med 5(8):973-82, 201615. Shieh A, Ishii S, Greendale GA, Cauley JA, Lo
JC, Karlamangla AS. Urinary N-Telopeptide andRate of Bone Loss Over the Menopause
Transition and Early Postmenopause. J Bone
Miner Res. 2016 Jun 20. doi: 0.1002/jbmr.2889.
[Epub ahead of print] [PMID: 27322414]
16. Shieh A, Han W, Ishii S, Greendale GA,
Crandall CJ, Karlamangla AS. Quantifying theBalance Between Total Bone Formation andTotal Bone Resorption: An Index of Net Bone
Formation. J Clin Endocrinol Metab. 2016
Jul;101(7):2802-9. [PMID: 27336357]
17. Tamiya H, Ogawa S, Ouchi Y, Akishita M. Rigid
Cooperation of Per1 and Per2 proteins. Sci
Rep.6:32769,2016
18. Yamaguchi Y, Mori H, Ishii M, Okamoto S,
Yamaguchi K, Iijima S, Ogawa S, Ouchi Y,
Akishita M. Interview- and questionnaire-based
surveys on elderly patients' wishes about
artificial nutrition and hydration during end-oflife care. Geriatr Gerontol Int.16, 1204-1210,
2016.
19. Yamada Y, Nakagawa T, Sugihara T, Horiuchi T,
Yoshizaki U, Fujimura T, ukuhara H, Urano T,
Takayama K, Inoue S, Kume H, Homma Y:
Prognostic value of CD66b positive tumorinfiltrating neutrophils in testicular germ celltumor. BMC Cancer. 16(1):898, 2016.
Reaearch letter
1. Ishii S, Umeda-Kameyama Y, Akishita M. Brain
Health: A Japanese viewpoint. J Am Med Dir
Assoc. 2016 May;17(5):455. [PMID: 26972348]
2. Ishii S, Chang C, Tanaka T, Kuroda A, Tsuji T,
Akishita M, Iijima K. The Association between
Sarcopenic Obesity and Depressive Symptoms inOlder Japanese Adults. PLoS One. 2016 Sep 14;
11(9):e0162898 [PMID: 27627756]
3. Kameyama M and Umeda-Kameyam Y. Strategy
based on kinetics of O-(2-[18F] fluoroethyl)-Ltyrosine ([18F] FET). JEuropean Journal of

187

4.

5.

6.

7.

Nuclear Medicine and Molecular Imaging,;
43(12), 2267-2268. 2016.
Kojima T, Shimada K, Terada A, Nishizawa K,
Matsumoto K, Yoshimatsu Y, Akishita M.
Association between polypharmacy and multiple
uses of medical facilities in nursing homeresidents. Geriatr Gerontol Int. 16:770-1, 2016
Koshino S, Hamaya H, Ishii M, Kojima T, Urano
T, Yamaguchi Y, Ogawa S, Morita S, Koya J,
Nakamura F, Kurokawa M, Akishita M.
Efficacy of Fine-Needle Aspiration Cytology in
the Diagnosis of Primary Thyroid Lymphoma for
Elderly Adults. J Am Geriatr Soc. 2016 Sep;
64(9):e52-3. doi: 10.1111/jgs.14289. Epub 2016
Shibasaki K, Yamada S, Ouchi Y, Akishita M,
Ogawa S. The effect of the rehabilitation on therecovery of the sympathetic nervous activity
measured by heart rate variability in frail elderly.
J Am Geriatr Soc 64:e15-16,2016
Ogawa S, Yakabe M, Akishita M: Age-related
sarcopenia and its pathophysiological bases.
Inflammation and Regeneration 36:17, 2016

Review article
1. Ogawa S, Yakabe M, Akishita M. Age-related
sarcopenia and its pathophysiological bases.
Inflammationand Regeneration. 36:17,2016
2. Takayama K, Inoue S: The emerging role of noncoding RNA in prostate 1 cancer progression andits implication on diagnosis and treatment. Brief
Funct Genomics. 15(3):257-65, 2016.Akiyoshi T,
Ota H, Iijima K, Son BK, Kahyo T, Setou M,
Ogawa S, Ouchi Y, Akishita M: A novel organ
culture model of aorta for vascular calcification.
Atherosclerosis 244:51-8，2016.

Surgical Sciences
1. Surgery

189

Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Sato, Masaaki
Nitadori, Jun-ichi
Nagayama, Kazuhiro
Kuwano, Hideki

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 staffs (Nakajima J, Sato M, Nitadori J,
Nagayama K, and Kuwano H), who are certificated as
members of the Japanese Board of General Thoracic
Surgery, are in charge of the Department of Thoracic
Surgery, University of Tokyo Hospital. They
specialize in surgical treatment for diseases of the190respiratory 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 2015, Ministry of Health, Labour andWelfare documented that number of deaths frommalignant neoplasms was approximately 370 thousandout of 1.29 million total deaths in Japan. Of them, 74
thousand people were killed by tracheal andpulmonary 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 andclinical residents, as well as doing the professional
education for training physicians who wish to becomeboard-certified thoracic surgeons.
We have performed the modern-style video-assisted
thoracoscopy for the diagnosis and treatment of thethoracic disease with less surgical invasiveness since
1992 for safer treatment of older patients withcardiovascular and/or respiratory complications. We
currently conduct a standard surgery for clinical stage
IA/IB NSCLC, i.e. lobectomy and lymphadenectomy
through thoracoscopy: In 2015, more than 90% of
patients with NSCLC was the candidate forthoracoscopic 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 are now
performing a cell-transfer therapy with activatedautologous gammadelta T-lymphocytes which has
been approved by the Ministry of Health, Labour andWelfare.
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 para-

neoplastic 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 hosted the annual meeting ofJapan Association for Research on Thymus (JART)
this year, and we are now actively participating a
multiinstitutional study on malignant thymic epithelial
neoplasms database led by 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 4 lung transplants to
date.

500
450
400
350
300
250
200
150
100
50
0

Inpatient, total
Surgery, total
Lung cancer
Pulm meta(Figure) Number of inpatient, surgery (total), surgery oflung cancer, and surgery of pulmonary metastasis by year. Pulm meta, pulmonary metastasis

Academic education
Medical students in the fifth grade have two-weeks’program 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

191

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 aboard-certified 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. Recently
we conducted clinical studies on the immunotherapy
with adopted gammadelta- T-cell for the treatment of
the patients with unresectable or recurrent NSCLC.
The following are the major themes under research:(1) Minimally invasive surgeries for thoracic
malignant neoplasms.
(2) Identification of small pulmonary lesions throughthoracoscopy.
(3) Image analysis of the lung cancer focusing on its
degree of malignancy.
(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 and malignant
mesothelioma.
(7) Single and multi-institutional studies on thymic
epithelial malignant neoplasms.
(8) Single and multi-institutional studies on surgicaltherapeutics for pulmonary metastasis fromcolorectal cancer.
(9) Analysis on mechanisms of acute or chronic
rejection of the allogeneic lung and trachea after
allogeneic transplantation.
(10) Research on donor lung preservation.

Selected publications
1. Karasaki T, Murakawa T, Nagayama K, et al. New
onset of myasthenia gravis 10 years after proton
beam therapy for thymoma. Gen Thorac
Cardiovasc Surg. 2016;64(5):290-3
2. Nakagawa K, Yokoi K, Nakajima J, et al. Is
Thymomectomy Alone Appropriate for Stage I(T1N0M0) Thymoma? Results of a PropensityScore Analysis. Ann Thorac Surg. 2016;101(2):520-6.
3. Ichinose J, Nagayama K, Hino H, et al. Results ofsurgical treatment for secondary spontaneous
pneumothorax according to underlying diseases.
Eur J Cardiothorac Surg. 2016;49(4):1132-6.
4. Karasaki T, Nagayama K, Kawashima M, et al.
Identification of Individual Cancer-Specific Somatic Mutations for Neoantigen-Based Immunotherapy of Lung Cancer. J Thorac Oncol. 2016;
11(3):324-33.
5. Ichinose J, Shinozaki-Ushiku A, Takai D,
Nakajima J, et al. Differential diagnosis between
primary lung squamous cell carcinoma andpulmonary metastasis of head and neck squamouscell carcinoma. Expert Rev Anticancer Ther.
2016;16(4):403-10
6. Nakajima J, Okumura M, Yano M, et al.
Myasthenia gravis with thymic epithelial tumour:a retrospective analysis of a Japanese database.
Eur J Cardiothorac Surg. 2016;49(5):1510-5
7. Hino H, Kamiya M, Kitano K, et al. Rapid
Cancer Fluorescence Imaging Using A
γ-Glutamyltranspeptidase-Specific Probe For
Primary Lung Cancer. Transl Oncol. 2016;9(3):203-10.
8. Hino H, Nishimura T, Nitadori J, et al. An
uncommon presentation of Kikuchi-Fujimoto
disease as mediastinal lymphadenopathy. J Thorac
Dis. 2016 May;8(5):E330-3
9. Takahashi Y, Ikeda N, Nakajima J, et al.
Prognostic Analysis of Surgical Resection for
Pulmonary Metastasis from Hepatocellular
Carcinoma. World J Surg. 2016;40(9):2178-85.
10. Endo S, Ikeda N, Nakajima J, et al. Developmentof an annually updated Japanese national clinicaldatabase for chest surgery in 2014. Gen Thorac
Cardiovasc Surg. 2016;64(10):569-76.
11. Hino H, Nishimura T, Seki A, et al. Microthymoma in elderly-onset myasthenia gravis
detected preoperatively. Asian Cardiovasc Thorac
Ann. 2016;24(8):818-821
12. Ichinose J, Shinozaki-Ushiku A, Nagayama K, etal. Immunohistochemical pattern analysis ofsquamous cell carcinoma: Lung primary and192

metastatic tumors of head and neck. Lung Cancer.
2016;100:96-101.
13. Yanagiya M, Sato M, Kawashima S, et al. Flat
Chest of Pleuroparenchymal Fibroelastosis
Reversed by Lung Transplantation. Ann Thorac
Surg. 2016 Oct;102(4):e347-9
14. Inui M, Nitadori JI, Tajima S, et al. Mediastinal
seminoma associated with multilocular thymic
cyst. Surg Case Rep. 2017;3(1):7.
15. Sato M, Murayama T, Nakajima J. Techniques ofstapler-based navigational thoracoscopic segmentectomy using virtual assisted lung mapping (VALMAP). J Thorac Dis. 2016;8(Suppl 9):S716-S730.
16. Ichinose J, Murakawa T, Kawashima M, et al.
Prognostic significance of red cell distribution
width in elderly patients undergoing resection for
non-small cell lung cancer. J Thorac Dis. 2016;
8(12):3658-3666
17. Yeh YC, Kadota K, Nitadori J, et al. International
Association for the Study of Lung Cancer/
American Thoracic Society/European Respiratory
Society classification predicts occult lymph nodemetastasis in clinically mediastinal node-negativelung adenocarcinoma. Eur J Cardiothorac Surg.
2016;49(1):e9-e15

193

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

Associate Professor
Yasutaka Hirata, M.D.

Lecturer
Kan Nawata, M.D., Haruo Yamauchi, M.D., Mitsutoshi Kimura , M.D.

Associate
Tetsuhiro Takaoka, M.D., Akihiro Masuzawa, M.D., Osamu Kinoshita, M.D.,
Yoshifumi Itoda, M.D., Shinichi Ozaki, M.D., Akihiro Yamamoto, M.D.,
Tomoyuki Iwase, M.D., Syuichi Yoshitake, 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.
Additional clinical team of treatment of advanced heart
failure was established to cope with an increasing
number of patients who require ventricular assist
device treatment. Present staffs are one Chief Professor,
one Associate Professor and three Lecturer and eight
Associates.

194

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 about 340,
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, ventricular assist device implantation, aortic
valve sparing root replacement, arch replacement using
retrograde cerebral perfusion, treatment of extended
thoracic aortic aneurysm and repair of complex
congenital heart diseases, such as Jatene, Fontan and
Norwood operations. Transcatheter aortic valve
replacement was initiated in 2015. Several high-riskvery old patients with aortic valve stenosis weresuccessfully treated.
The University of Tokyo Tissue Bank was founded
in 1997, based on the Department of Cardiovascular
Surgery. The Bank has been actively promoting
procurement, preservation and shipping of humanvalve and blood vessel allograft in Japan. We take thelead in surgical treatment using allograft for severe
active endocarditis or infection of aortic aneurysm or
vascular prosthesis. Surgical treatment using allograft
was approved as advanced medical technology by theGovernment in 2006. As of March 2017, 80 cases ofheart transplantation and more than 250 cases ofventricular assist device implantation were performedin The University Hospital with excellent long-term
survival.

Teaching Activities
We have the chair of systematic review ofcardiovascular surgery in the spring term at the 2nd
grade of medical course. We also take charge in clinicalpractice on diagnosis of cardiovascular disease in theautumn term at the 2nd grade. We expose the students todaily clinical works as well as research works during

the course 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 10-11th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments, it isessential for cardiothoracic surgical department of the
University to have active research programs in clinicaland basic subjects. The Cardiothoracic Department of
the University of Tokyo has created highly active
research programs in the every field of cardiothoracic
surgery, played an internationally leading role andcontributed to its development. A research meeting isheld once a month on a research project for every
member of the department to understand and to makefree thorough discussions of the subject.
Basic and/or clinical research activities are focusedon 1) establishment of recovery and weaning protocolsof left ventricular assist device, 2) basic and clinicalresearch on cryopreserved allograft, 3) application ofregenerative medicine to end-stage heart failure, 4)
mechanism analysis of right heart failure anddevelopment of effective pharmacological therapy, 5)

195development 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. Panthee N, Okada JI, Washio T, Mochizuki Y,
Suzuki R, Koyama H, Ono M, Hisada T, Sugiura S.
Tailor-made heart simulation predicts the effect ofcardiac resynchronization therapy in a canine
model of heart failure. Med Image Anal. 2016 July;
31: 46-62.
2. Fujino T, Kinugawa K, Nitta D, Imamura T, Maki
H, Amiya E, Hatano M, Kimura M, Kinoshita O,
Nawata K, Komuro I, Ono M.: Donor age is apredictor of early low output after heart transplantation. J Cardiol 2016 May；67(5): 477-482.
3. Kondo R, Itoda Y, Panthee N, Inui A, Ashiba H,
Ando T, Kobayashi E, Sakuma I, Ono M.: A New
Suturing Device for Small Arteries. Int Heart J.
2016 May; 57(3): 323-6.
4. Koyama S, Kitamura T, Itatani K, Yamamoto T,
Miyazaki S, Oka N, Nakashima K, Horai T, Ono M,
Miyaji K: Impact of top end anastomosis design on
patency and flow stability in coronary artery
bypass grafting. Heart Vessels 2016; 31(5): 643-8.
5. Nitta D, Kinugawa K, Imamura T, Endo M, Amiya
E, Hatano M, Takahashi Y, Iriyama T, Kinoshita O,
Nagamatsu T, Nawata K, Ono M, Komuro I.:
Successful Pregnancy and Delivery in a Heart
Transplantation Recipient. Int Heart J. 2016 May;
57(3): 383-5.
6. Takata M, Amiya E, Watanabe M, Shintani Y,
Sakuma K, Saito A, Fukayama M, Ono M, Komuro
I.: Phenotypic differences in aortic stenosis
according to calcification grade. Int J Cardiol. 2016
Aug; 216: 118-20.
7. Inafuku H, Kuniyoshi Y, Yamashiro S, Totsuka Y,
Ono M.: Successful left ventricular assist device
re-implantation with omental covering for MDRP
device infection. J Artif Organs 2016 Jun; 19(2):192-5.
8. Naito N, Mizuno T, Nishimura T, Kishimoto S,
Takewa Y, Eura Y, Kokame K, Miyata T, Date K,
Umeki A, Ando M, Ono M, Tatsumi E.: Influenceof a Rotational Speed Modulation System Used

With an Implantable Continuous-Flow Left
Ventricular Assist Device on von Willebrand
Factor Dynamics. Artif Organs. 2016 Sep; 40(9):877-83.
9. Date K, Kishimoto S, Fujii Y, Togo K, Kakuta Y,
Mizuno T, Tsukiya T, Takewa Y, Nishimura T,
Ono M, Tatsumi E. Effects of feeding state on
anticoagulation in adult goats treated with warfarin.
J Artif Organs. 2016 Sep; 19(3): 301-4.
10. Imamura T, Kinugawa K, Nitta D, Kinoshita O,
Nawata K, Ono M.: Is cardiopulmonary exercise
testing essential to indicate ventricular assist
device implantation in patients with INTERMACS
profile 4-7? J Artif Organs. 2016 Sep; 19(3): 22632.
11. Ono M, Sawa Y, Nakatani T, Tominaga R, Matsui
Y, Yamazaki K, Saiki Y, Niinami H, Matsumiya G,
Arai H; Japanese HeartMate II investigators.:
Japanese Multicenter Outcomes With theHeartMate II Left Ventricular Assist Device inPatients With Small Body Surface Area. Circ J.
2016 Aug 25; 80(9): 1931-6.
12. Imamura T, Kinugawa K, Nitta D, Kinoshita O,
Nawata K, Ono M.: Fontan-Like Hemodynamics
Complicated With Ventricular Fibrillation During
Left Ventricular Assist Device Support. Int Heart J.
2016 Jul 27; 57(4): 515-8.
13. Okamura K, Suematsu Y, Morizumi S, Kawata M,
Dai Y, Yamakawa M, Ono M.: Erdheim-Chester
Disease With Cardiovascular Involvement and
BRAF V600E Mutation. Circ J. 2016 Jun 24;80(7): 1657-9.
14. Date K, Nishimura T, Takewa Y, Kishimoto S,
Arakawa M, Umeki A, Ando M, Mizuno T,
Tsukiya T, Ono M, Tatsumi E.: Shifting thepulsatility by increasing the change in rotational
speed for a rotary LVAD using a native heart load
control system. J Artif Organs. 2016 Dec; 19(4):315-321.
15. Imamura T, Kinugawa K, Kinoshita O, Nawata K,
Ono M.: Reversible decline in pulmonary function
during left ventricular assist device therapy. J Artif
Organs. 2016 Dec; 19(4): 330-335
16. Yoshitake S, Itoda Y, Nawata K, Iwase T, HoshinoY, Kimura M, Kinoshita O, Yamauchi H, Ono M:
Successful management of apical abscess after
Nipro left ventricular assisted device explantation

196

by removal of apical cuff and omentopexy. J Artif
Organs. 2016 Dec; 19(4): 396-398.
17. Tanaka T, Panthee N, Itoda Y, Yamauchi N,
Fukayama M, Ono M: Negative pressure woundtherapy induces early wound healing by increased
and accelerated expression of vascular endothelial
growth factor receptors. Eur J Plast Surg. 2016; 39:
247-256.
18. Kitahara H, Nawata K, Kinoshita O, Itoda Y,
Kimura M, Yamauchi H, Ono M: A delayed
splenic rupture after transcatheter arterial
embolization required total splenectomy in apatient with an implantable left ventricular assist
device. J Artif Organs. 2016 Dec; 19(4): 392-395.
19. Tanaka S, Nawata K, Kitahara H, Yoshitake S,
Matsuoka T, Itoda Y, Kinoshita O, Kimura M, Ono
M: A successful management of infection of theleft ventricular assist device by pump exchange:
conversion from DuraHeart to Jarvik 2000. J Artif
Organs. 2016 Dec; 19(4): 387-391.
20. Amao R, Imamura T, Nakahara Y, Noguchi S,
Kinoshita O, Yamauchi H, Ono M, Haga N:
Reversible Motor Paralysis and Early Cardiac
Rehabilitation in Patients With Advanced Heart
Failure Receiving Left Ventricular Assist Device
Therapy. Int Heart J. 2016 Dec 2; 57(6): 766-768
21. Amao R, Imamura T, Sawada Y, Endo S, Ozaki S,
Okamura K, Masuzawa A, Takaoka T, Hirata Y,
Shindo T, Ono M, Haga N: Experiences With
Aggressive Cardiac Rehabilitation in PediatricPatients Receiving Mechanical Circulatory
Supports. Int Heart J. 2016 Dec 2; 57(6): 769-772.
22. Kikuchi R, Mizuta K, Urahashi T, Sanada Y,
Yamada N, Onuma E, Ono M, Endo M, Sato I,
Kamibeppu K.: Development of the Japanese
Version of the PedsQL™ Transplant Module.
Pediatr Int. 2017 Jan; 59(1): 80-88.
23. Naito N, Nishimura T, Takewa Y, Kishimoto S,
Date K, Umeki A, Ando M, Ono M, Tatsumi E.:
What Is the Optimal Setting for a Continuous-Flow
Left Ventricular Assist Device in Severe Mitral
Regurgitation? Artif Organs. 2016 Nov; 40(11):1039-1045.
24. Kitahara H, Nawata K, Kinoshita O, Itoda Y,
Shintani Y, Fukayama M, Ono M.: Implantation ofa Left Ventricular Assist Device for Danon

Cardiomyopathy Ann Thorac Surg. 2017 Jan;103(1): e39-e41.
25. Itoda Y, Nawata K, Yamauchi H, Kinoshita O,
Kimura M, Ono M: Central aortic valve closure
successfully treated aortic insufficiency of thepatient with Jarvik 2000 continuous flow left
ventricular assist device: a case report. J Artif
Organs. 2017 Mar; 20(1): 99-101.
26. Imamura T, Murasawa T, Kawasaki H, Kashiwa K,
Kinoshita O, Nawata K, Ono M: Correlation
between driveline features and driveline infectionin left ventricular assist device selection. J Artif
Organs. 2017 Mar; 20(1): 34-41.
27. Date K, Nishimura T, Arakawa M, Takewa Y,
Kishimoto S, Umeki A, Ando M, Mizuno T,
Tsukiya T, Ono M, Tatsumi E: Changing
pulsatility by delaying the rotational speed phasingof a rotary left ventricular assist device. J Artif
Organs 2017 Mar; 20(1): 18-25.
28. Fukushima N, Ono M, Saiki Y, Sawa Y, Nunoda S,
Isobe M.: Registry Report on Heart Transplantation in Japan (June 2016). Circ J. 2017 Feb
24; 81(3): 298-303.

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Department of
Gastrointestinal Surgery
Professor
Yasuyuki Seto M.D., Ph.D.

Associate Professor
Sachiyo Nomura M.D., Ph.D.

Lectuler
Hiroharu Yamashita M.D., Ph.D.

Associates
Masato Nishida M.D., Ph.D.

Susumu Aikou M.D., Ph.D.

Koichi Yagi M.D., Ph.D.

Takashi Mitsui M.D., Ph.D.

Raito Asaoka M.D.

Kotaro Sugawara M.D.

Yoshimi Yasukawa M.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 the elevation to a
department in the graduate school of medicine at ouruniversity. Our research activities in both departments
have been well organized and ultimately successful by
maintaining a close connection.
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
clinical and research activities have for the most partreceived the cooperation of members in the
Department of Metabolic Care and Endocrine Surgery
as well as those in other surgical departments at the
University of Tokyo.
Our fundamental principles of patient treatment arecomprehensive patient care which includes pre-, peri-,and postoperative management of the diseases as wellas patient care over long-term postoperative periods
which often extend to the terminal stage. We believethat patient care encompassing the entire lifespanprovides a wealth of valuable information concerning
the appropriateness of current treatment strategy, theestablishment of new surgical designs, the development of new basic research activities which can muchcontribute to clinical fields, and indications ofdesirable modes of terminal care.
Fostering good surgeons as well as scientists whomeet both clinical and academic needs has always
been the guiding principle of our Department.

Educational Activities:
The new system of clinical clerkship for medical
students has begun from 2013. During those periods,
the students are educated strictly and gently by staffs.
Clinical exercises, e.g., blood sampling, injection, andligation, etc, are performed. They can attend theoperations as an assistant.
They learn general patient care which encompasses
not only perioperative management of diseases but

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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.
Junior residents rotate every three months. Aftercompletion of their initial training program, they go
into a further clinical training program for several
consecutive years and become a chief resident. We
have also several postgraduate students who aremainly engaged in research work. Their researchworks are under supervision of the Professor.

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, nontransthoracic radical esophagectomy with extended
lymphadenectomy (NOVEL) has been applied, whichshows less pulmonary complications and good
respiratory functions after surgery. New methods ofendoscopic full-thickness resection (NEWS) has beendeveloped for some gastric tumor as a collaboration ofendoscopy and laparoscopy. The elimination of thepulmonary complications after esophagectomy and thedetection of minute metastasis for the establishment ofbetter 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 four 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 10-15 patients.
We have our own multidisciplinary diseaseevaluation systems for inpatients and outpatients, suchas endoscopy for upper and lower gastrointestinal
tracts, and barium roentgenogram. These multidisciplinary services provide good opportunities toevaluate the diseases systematically from thesurgeon's standpoint.
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. And, cancer board is held bi-weekly, where
the radiologists and endoscopists as well as surgeonsattend together and have discussions frankly.
Generally, elective surgery is scheduled on Tuesday，
Wednesday and Thursday. The statistics shows morethan 150 gastric and 50 esophageal cancer surgeries
performed a year, respectively. And, hernia surgery isusually perfomed, also. All residents and medical
personnel work many extra hours with highmotivation whenever it is necessary for the good of
the patients.

References
1. Zong L, Hattori N, Yoda Y, Yamashita S,
Takeshima H, Takahashi T, Maeda M, Katai H,
Nanjo S, Ando T, Seto Y, Ushijima T.
Establishment of a DNA methylation marker toevaluate cancer cell fraction in gastric cancer.
Gastric Cancer. 2016;19(2):361-9.
2. Mori K, Yamagata Y, Aikou S, Nishida M,

199

3.

4.

5.

6.

7.

8.

9.

Kiyokawa T, Yagi K, Yamashita H, Nomura S,
Seto Y. Short-term outcomes of robotic radical
esophagectomy for esophageal cancer by anontransthoracic approach compared withconventionaltransthoracic
surgery.
Dis
Esophagus. 2016;29(5):429-34.
Urabe M, Yamashita H, Seto Y. Pretreatment
Neutrophil to Lymphocyte Ratio Independently
Predicts Disease-specific Survival in Patients
With Resectable Gastroesophageal Junction and
Gastric Cancer. Ann Surg. 2016.
Higashizono K, Aikou S, Yagi K, Mori K,
Yamashita H, Nomura S, Seto Y. Early
endoscopic management for early bowel
obstruction after gastrectomy: a case report. Surg
Case Rep. 2016;2(1):35. doi: 10.1186/s40792016-0164-3.
Onoyama H, Kamiya M, Kuriki Y, Komatsu T,
Abe H, Tsuji Y, Yagi K, Yamagata Y, Aikou S,
Nishida M, Mori K, Yamashita H, Fujishiro M,
Nomura S, Shimizu N, Fukayama M, Koike K,
Urano Y, Seto Y. Rapid and sensitive detection ofearly esophageal squamous cell carcinoma withfluorescence probe targeting dipeptidylpeptidase
IV. Sci Rep. 2016;6:26399. doi: 10.1038/srep
26399.
Urabe M, Ushiku T, Seto Y, Fukayama M.
Pathologic Response of HER2-positive Gastric
Cancer to Trastuzumab-based Chemotherapy. Am
J Surg Pathol. 2016;40(10):1326-33.
Zong L, Abe M, Seto Y, Ji J. Randomized
Controlled Trial of Laparoscopic Versus Open D2Distal Gastrectomy for Advanced Gastric Cancer:
How Should We Define the Age of Included
Patents? J Clin Oncol. 2016. pii: JCO682500.
Kitani M, Yamagata Y, Tanabe A, Yagi K, Aikou
S, Kiyokawa T, Nishida M, Yamashita H, Mori K,
Nomura S, Seto Y. Radical esophagectomy for a
92-year-old
woman
with
granulocytecolony-stimulating factor-producing esophageal
squamous cell carcinoma: a case report. World J
Surg Oncol. 2016;14(1):264.
Mori K, Yoshimura S, Yamagata Y, Aikou S,
Seto Y. Preclinical study of transcervical upper
mediastinal dissection for esophageal malignancy
by robot-assisted surgery. Int J Med Robot.
2017;13(2). doi: 10.1002/rcs.1750.

10. Zong L, Abe M, Seto Y, Ji J. The challenge ofscreening for early gastric cancer in China. Lancet.
2016; 388(10060):2606. doi: 10.1016/S0140-6736(16)32226-7.
11. Yamashita H, Seto Y. Is the transthoracic
approach no longer a viable option for Siewert
type II esophagogastric junction carcinoma?
Transl Gastroenterol Hepatol. 2016;1:14. doi: 10.
21037/tgh.

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Hepato-biliary-Pancreatic Surgery
Division and Artificial Organ
and Transplantation Division
Professor and Chairman
Norihiro Kokudo, MD.

Associate Professor
Kiyoshi Hasegawa, MD.

Yoshihiro Sakamoto, MD.

Lecturers
Junichi Kaneko, MD.

Homepages

Nobuhisa Akamatsu, MD.

Junichi Arita, MD.

http://www.h.u-tokyo.ac.jp/patient/depts/hbps_md/index.html
http://www.h.u-tokyo.ac.jp/transplant/

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 120 years and has madetremendous contribution to the Japanese surgicaladvancement, such as the foundation of Japanese
Surgical Society. As departments in the style ofgraduate 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 perform about 170 hepatectomies
for HCC and colorectal mets, 80 Whipples, and 20
liver transplantations, mainly from living donors. The
overall number of operation is about 510/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
procedures, and postoperative managements. They

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also are expected to submit a report on a theme of
specific surgical topics.

Research
We have published papers on Hepato-BiliaryPancreatic Surgery and liver transplantations 50/year.
The ongoing topics involve clinical application of
ICG fluorescent images, especially for visualization ofbiliary trees, hepatic tumors, hepatic hemodynamics,
prospective clinical trials of adjuvant chemotherapy
for hepatocellular carcinoma, metastatic colorectal
cancer, neoadjuvant chemotherapy for borderline
resectable pancreatic cancer, utility of contrastenhanced intraoperative ultrasonography, and preoperative navigation for hepatic surgery.

Publications (2016)
1. Kawaguchi Y, Ishizawa T, Nagata R, Kaneko J,
Sakamoto Y, Aoki T, et al. Exclusion criteria forassuring safety of single-incision laparoscopiccholecystectomy. Bioscience trends. 2015;9(6):407-13.
2. Kawaguchi Y, Hasegawa K, Kokudo N. [II. Liver
resection for recurrence of metastatic liver tumor
following primary intervention with specialreference to colorectal liver metastasis]. Gan tokagaku ryoho Cancer & chemotherapy. 2015;
42(10):1169-72.
3. Maki H, Kaneko J, Akamatsu N, Arita J,
Sakamoto Y, Hasegawa K, et al. Interleukin-2
receptor antagonist immunosuppression andconsecutive viral management in living-donorliver transplantation for human immunodeficiency
virus/hepatitis C-co-infected patients: a report of2 cases. Clinical journal of gastroenterology.
2016;9(1):32-7.
4. Abe S, Akamatsu N, Hoshikawa M, Shirata C,
Sakamoto Y, Hasegawa K, et al. Ectopic Jejunal
Variceal Rupture in a Liver Transplant Recipient
Successfully Treated With Percutaneous Transhepatic Coil Embolization: A Case Report.
Medicine. 2015;94(47):e2151.
5. Sun Z, Tang W, Sakamoto Y, Hasegawa K,
Kokudo N. A systematic review and meta-analysisof feasibility, safety and efficacy of associating
liver partition and portal vein ligation for staged

hepatectomy (ALPPS) versus two-stage hepatectomy (TSH). Bioscience trends. 2015;9(5):284-8.
6. Sun Z, Zhu Y, Xia J, Sawakami T, Kokudo N,
Zhang N. Status of and prospects for cancer
vaccines against hepatocellular carcinoma inclinical trials. Bioscience trends. 2016;10(2):85-91.
7. Tanaka T, Akamatsu N, Kaneko J, Arita J, Tamura
S, Hasegawa K, et al. Daclatasvir and Asunaprevir
for Recurrent Hepatitis C following Living-Donor
Liver Transplantation with Human Immunodeficiency Virus Coinfection. Hepatology
research : the official journal of the Japan Societyof Hepatology. 2015.
8. Shindoh J, Makuuchi M, Matsuyama Y, Mise Y,
Arita J, Sakamoto Y, et al. Complete removal of
the tumor-bearing portal territory decreases local
tumor recurrence and improves disease-specificsurvival of patients with hepatocellular carcinoma.
Journal of hepatology. 2016;64(3):594-600.
9. Oba M, Hasegawa K, Shindoh J, Yamashita S,
Sakamoto Y, Makuuchi M, et al. Survival benefitof repeat resection of successive recurrences after
the initial hepatic resection for colorectal liver
metastases. Surgery. 2016;159(2):632-40.
10. Sakamoto Y, Kokudo N, Matsuyama Y, Sakamoto
M, Izumi N, Kadoya M, et al. Proposal of a newstaging system for intrahepatic cholangiocarcinoma: Analysis of surgical patients from anationwide survey of the Liver Cancer Study
Group of Japan. Cancer. 2016;122(1):61-70.
11. Akamatsu N, Sugawara Y, Kokudo N.
Asunaprevir (BMS-650032) for the treatment of
hepatitis C virus. Expert review of anti-infective
therapy. 2015;13(11):1307-17.
12. Kawaguchi Y, Velayutham V, Fuks D, Christidis C,
Kokudo N, Gayet B. Usefulness of Indocyanine
Green-Fluorescence Imaging for Visualization of
the Bile Duct During Laparoscopic Liver
Resection. Journal of the American College ofSurgeons. 2015;221(6):e113-7.
13. Kawaguchi Y, Hasegawa K, Tanaka N, Ishizawa T,
Kaneko J, Sakamoto Y, et al. Advances in
Assessment and Planning for Surgical Treatment
of Hepatocellular Carcinoma. Digestive diseases(Basel, Switzerland). 2015;33(5):683-90.

202

14. Kokudo N, Kawaguchi Y. Foreword. Digestive
diseases (Basel, Switzerland). 2015;33(5):633-4.
15. Kokudo N. How case reports have contributed tothe progress of surgery. Surgical case reports.
2015;1(1):1.
16. Mori K, Ishizawa T, Yamashita S, Kamiya M,
Urano Y, Kokudo N. Intraoperative visualizationof pancreatic juice leaking from the pancreatic
stump in a swine model. Gastroenterology. 2015;
149(6):1334-6.
17. Kawaguchi Y, Tanaka N, Nagai M, Nomura Y,
Fuks D, Gayet B, et al. Usefulness of Intraoperative Real-Time Tissue Elastography During
Laparoscopic Hepatectomy. Journal of theAmerican College of Surgeons. 2015;221(5):e103-11.
18. Omichi K, Shindoh J, Yamamoto S, Matsuyama Y,
Akamatsu N, Arita J, et al. Postoperative Outcomes for Patients with Non-B Non-C Hepatocellular Carcinoma: A Subgroup Analysis ofPatients with a History of Hepatitis B Infection.
Annals of surgical oncology. 2015;22 Suppl 3:
S1034-40.
19. Kawaguchi Y, Nagai M, Nomura Y, Kokudo N,
Tanaka N. Usefulness of indocyanine greenfluorescence imaging during laparoscopic hepatectomy to visualize subcapsular hard-to-identify
hepatic malignancy. Journal of surgical oncology.
2015;112(5):514-6.
20. Kawaguchi Y, Nomi T, Fuks D, Mal F, Kokudo N,
Gayet B. Hemorrhage control for laparoscopic
hepatectomy: technical details and predictive
factors for intraoperative blood loss. Surgicalendoscopy. 2016;30(6):2543-51.
21. Kawaguchi Y, Akamatsu N, Ishizawa T, Kaneko J,
Arita J, Sakamoto Y, et al. Evaluation of hepatic
perfusion in the liver graft using fluorescenceimaging with indocyanine green. International
journal of surgery case reports. 2015;14:149-51.
22. Miyata A, Ishizawa T, Tani K, Shimizu A, Kaneko
J, Aoki T, et al. Reappraisal of a Dye-Staining
Technique for Anatomic Hepatectomy by the
Concomitant Use of Indocyanine Green Fluorescence Imaging. Journal of the American Collegeof Surgeons. 2015;221(2):e27-36.

23. Ishizawa T, Lim C, Kokudo N. Reply to "Liver
Malignancies in Segment VII: The Role ofRobot-assisted Surgery". Annals of surgery. 2015.
24. Kono Y, Ishizawa T, Tani K, Harada N, Kaneko J,
Saiura A, et al. Techniques of Fluorescence
Cholangiography During Laparoscopic Cholecystectomy for Better Delineation of the Bile
Duct Anatomy. Medicine. 2015;94(25):e1005.
25. Nishioka Y, Akamatsu N, Sugawara Y, Kaneko J,
Arita J, Sakamoto Y, et al. Hereditary Hemorrhagic Telangiectasia with Hepatic Vascular Malformations. Case reports in medicine. 2015;2015:
917818.
26. Kokudo T, Hasegawa K, Uldry E, Matsuyama Y,
Kaneko J, Akamatsu N, et al. A new formula for
calculating standard liver volume for living donorliver transplantation without using body weight.
Journal of hepatology. 2015;63(4):848-54.
27. Abe H, Hayashi A, Kunita A, Sakamoto Y,
Hasegawa K, Shibahara J, et al. Alteredexpression of AT-rich interactive domain 1A in
hepatocellular carcinoma. International journal ofclinical and experimental pathology. 2015;8(3):2763-70.
28. Kawaguchi Y, Otsuka Y, Kaneko H, Nagai M,
Nomura Y, Yamamoto M, et al. Comparisons offinancial and short-term outcomes between
laparoscopic and open hepatectomy: benefits forpatients and hospitals. Surgery today. 2016;46(5):535-42.
29. Takahashi M, Hasegawa K, Oba M, Aoki T,
Sakamoto Y, Sugawara Y, et al. Repeat resection
leads to long-term survival: analysis of 10-year
follow-up of patients with colorectal liver metastases. American journal of surgery. 2015;210(5):904-10.
30. Song P, Inagaki Y, Wang Z, Hasegawa K,
Sakamoto Y, Arita J, et al. High Levels ofGamma-Glutamyl Transferase and Indocyanine
Green Retention Rate at 15 min as Preoperative
Predictors of Tumor Recurrence in Patients With
Hepatocellular Carcinoma. Medicine. 2015;
94(21):e810.
31. Inagaki Y, Song P, Tang W, Kokudo N.
Cancer-associated carbohydrate antigens forclinical diagnostic markers--its effectiveness and203limitations. Drug discoveries & therapeutics.
2015;9(2):129-32.
32. Nishioka Y, Shindoh J, Yoshioka R, Gonoi W, Abe
H, Okura N, et al. Radiological Morphology ofColorectal Liver Metastases after Preoperative
Chemotherapy Predicts Tumor Viability andPostoperative Outcomes. Journal of gastrointestinal surgery : official journal of the Society
for Surgery of the Alimentary Tract. 2015;19(9):1653-61.
33. Togashi J, Akamatsu N, Sugawara Y, Kaneko J,
Tamura S, Tanaka T, et al. One-year extended,monthly vaccination prophylaxis combined with
hepatitis B immune globulin for hepatitis B after
liver transplantation. Hepatology research : theofficial journal of the Japan Society of
Hepatology. 2016;46(3):E51-9.
34. Inagaki NF, Inagaki FF, Kokudo N, Miyajima A.
Cell-based therapy for preventing postoperativeadhesion and promoting regeneration after
hepatectomy. Journal of hepato-biliary-pancreaticsciences. 2015;22(7):524-30.
35. Yamaguchi T, Hasegawa K, Kokudo N. An
unusual cause of ascites. Gastroenterology. 2015;
148(5):e3-4.
36. Han G, Xia J, Gao J, Inagaki Y, Tang W, Kokudo
N. Anti-tumor effects and cellular mechanisms ofresveratrol. Drug discoveries & therapeutics.
2015;9(1):1-12.
37. Yamamoto S, Hasegawa K, Inoue Y, Shindoh J,
Aoki T, Sakamoto Y, et al. Bile duct preserving
surgery for hepatocellular carcinoma with bile
duct tumor thrombus. Annals of surgery. 2015;
261(5):e123-5.
38. Kokudo T, Bonard E, Gillet M, Kokudo N, Halkic
N. Reappraisal of shunt surgery for extrahepatic
portal vein obstruction in adults: Report of asingle-center case series. Hepatology research :the official journal of the Japan Society of
Hepatology. 2015;45(13):1307-11.
39. Tanaka T, Sugawara Y, Kokudo N. Livertransplantation and autoimmune hepatitis. Intractable & rare diseases research. 2015;4(1):33-8.
40. Akamatsu N, Sugawara Y, Kokudo N. BuddChiari syndrome and liver transplantation. Intractable & rare diseases research. 2015;4(1):24-32.

41. Omichi K, Inoue Y, Hasegawa K, Sakamoto Y,
Okinaga H, Aoki T, et al. Differential diagnosis ofliver tumours using intraoperative real-time tissue
elastography. The British journal of surgery.
2015;102(3):246-53.
42. Kokudo N. Is it a time to modify the BCLC
guidelines in terms of the role of surgery? World
journal of surgery. 2015;39(2):469-70.
43. Inagaki NF, Inagaki FF, Kokudo N, Miyajima A.
Use of mouse liver mesothelial cells to prevent
postoperative adhesion and promote liver
regeneration after hepatectomy. Journal ofhepatology. 2015;62(5):1141-7.
44. Yamashita S, Aoki T, Inoue Y, Kaneko J,
Sakamoto Y, Sugawara Y, et al. Outcome ofsalvage hepatic resection for recurrent hepatocellular carcinoma after radiofrequency ablation
therapy. Surgery. 2015;157(3):463-72.
45. Akamatsu N, Sugawara Y, Nakazawa A, Nishioka
Y, Kaneko J, Aoki T, et al. Hemostatic status inlivertransplantation:
association between
preoperative procoagulants/anticoagulants andpostoperative hemorrhaging/thrombosis. Livertransplantation : official publication of theAmerican Association for the Study of Liver
DiseasesandtheInternational
Liver
Transplantation Society. 2015;21(2):258-65.
46. Tanaka T, Sugawara Y, Akamatsu N, Kaneko J,
Tamura S, Aoki T, et al. Use of simeprevir
following pre-emptive pegylated interferon/ribavirin treatment for recurrent hepatitis C inliving donor liver transplant recipients: a 12-weekpilot study. Journal of hepato-biliary-pancreaticsciences. 2015;22(2):144-50.
47. Kokudo T, Hasegawa K, Kokudo N. Reply to:"ALPPS procedure for hepatocellular carcinoma
withmacrovascular thrombosis: a newopportunity?". Journal of hepatology. 2015;62(1):243.
48. Mise Y, Hasegawa K, Shindoh J, Ishizawa T, Aoki
T, Sakamoto Y, et al. The Feasibility of Third orMore Repeat Hepatectomy for Recurrent Hepatocellular Carcinoma. Annals of surgery. 2015;
262(2):347-57.
49. Yamashita S, Hasegawa K, Takahashi M, Arita J,
Sakamoto Y, Aoki T, et al. Hobson's choice
two-stage hepatectomy for multiple and bilobar

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colorectal liver metastases with portal vein
embolization: report of two cases. Surgery today.
2015;45(4):511-6.
50. Inoue Y, Arita J, Sakamoto T, Ono Y, Takahashi
M, Takahashi Y, et al. Anatomical Liver Resections Guided by 3-Dimensional Parenchymal
Staining Using Fusion Indocyanine Green
Fluorescence Imaging. Annals of surgery. 2015;
262(1):105-11.
51. Shindoh J, de Aretxabala X, Aloia TA, Roa JC,
Roa I, Zimmitti G, et al. Tumor location is astrong predictor of tumor progression and survival
in T2 gallbladder cancer: an international multicenter study. Annals of surgery. 2015;261(4):733-9.
52. Shindoh J, Hasegawa K, Kokudo N. Anatomic
resection of hepatocellular carcinoma: a step
forward for the precise resection of thetumor-bearing portal territory of the liver. Annalsof surgery. 2015;261(5):e145.
53. Ichida A, Sakamoto Y, Akahane M, Ishizawa T,
Kaneko J, Aoki T, et al. Successful case ofpancreaticoduodenectomy with resection of thehepatic arteries preserving a single aberrant
hepatic artery for a pancreatic neuroendocrine
tumor: report of a case. Surgery today. 2015;45(3):363-8.

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Department of Urology
Professor
Associate Professor
Hiroshi Fukuhara, M.D., Ph.D.,

Tetsuya Fujimura, M.D., Ph.D.

Assistant Professor
Akihiko Matsumoto, M.D., Ph.D., Sayuri Takahashi, M.D., Ph.D.,
Daisuke Yamada, M.D., Ph.D.

Associate
Taketo Kawai, M.D., Ph.D.,

Masaki Nakamura, M.D., Ph.D.,

Aya Niimi, M.D.,

Akira Nomiya, M.D.,

Yusuke Satoh, M.D., Ph.D.,

Shigekatsu Maekawa, M.D., Ph.D.,

Yoshiyuki Akiyama, M.D., Ph.D., Jun Kamei, M.D., Ph.D.,
Michio Shiozawa, M.D.,

Norihide Shirakawa, M.D.,

Masahiro Hikatsu, 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 1,100 from January 2016 to December 2016.
Elective operations are performed on Tuesday,

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Wednesday, Thursday and Friday. 1,538 operations
were performed in 2016. The numbers of main
operations are adrenalectomy 19, nephrectomy 33,
partial nephrectomy 38, nephroureterectomy 22,
radical cystectomy 28, radical prostatectomy 139,transurethral resection of the bladder tumor (TUR-Bt)
150, transurethral resection of the prostate (TUR-P)
16, laparoscopic surgery 79, and Robot assisted
surgery 163 (radical prostatectomy 139, partial
nephrectomy 24).
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 22,000 patientdays from January 2016 to December 2016.

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. Homma Y, Ueda T, Tomoe H, Lin AT, Kuo HC,
Lee MH, Oh SJ, Kim JC, Lee KS. Clinicalguidelines for interstitial cystitis and hypersensitive bladder updated in 2015. Int J Urol, 23,542-9, 2016.
2. Aizawa N, Fukuhara H, Fujimura T, Homma Y,
Igawa Y. Direct influence of systemic desensitization by resiniferatoxin on the activities of Aδand C-fibers in the rat primary bladder mechanosensitive afferent nerves. Int J Urol, 23, 952-6,
2016.
3. Aizawa N, Gandaglia G, Hedlund P, Fujimura T,
Fukuhara H, Montorsi F, Homma Y, Igawa Y.
URB937, a peripherally restricted inhibitor for
fatty acid amide hydrolase, reduces prostaglandin
E2 -induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres
in rats. BJU Int, 117, 821-8, 2016.
4. Aizawa N, Sugiyama R, Ichihara K, Fujimura T,
Fukuhara H, Homma Y, Igawa Y. Functional rolesof bladder alpha1-adrenoceptors in the activationof single-unit primary bladder afferent activity inrats. BJU Int, 117, 993-1001, 2016.
5. Akiyama Y, Morikawa T, Maeda D, Shintani Y,
Niimi A, Nomiya A, Nakayama A, Igawa Y,
Fukayama M, Homma Y. Increased CXCR3
expression of infiltrating plasma cells in Hunnertype interstitial cystitis. Sci Rep, 6, 28652, 2016.
6. Azuma T, Matayoshi Y, Sato Y, Sato Y, Nagase Y,
Oshi M. The safety and effect of chemotherapy
with short hydration for urothelial cancer onpatients' quality of life. Jpn J Clin Oncol, 46, 958963, 2016.
7. Fujimura T, Inoue S, Urano T, Takayama K,
Yamada Y, Ikeda K, Obinata D, Ashikari D,
Takahashi S, Homma Y. Increased expression of207

tripartite motif (TRIM) 47 is a negative
prognostic predictor in human prostate cancer.
Clin Genitourinary Cancer, 14, 298-303, 2016.
8. Fujimura T, Menon M, Fukuhara H, Kume H,
Suzuki M, Yamada Y, Niimi A, Nakagawa T,
Igawa Y, Homma Y. Validation of an educational
program balancing surgeon training and surgicalquality control during robot-assisted radical
prostatectomy. Int J Urol, 23, 160-6, 2016.
9. Ito H, Aizawa N, Sugiyama R, Watanabe S,
Takahashi N, Tajimi M, Fukuhara H, Homma Y,
Kubota Y, Andersson K E, Igawa Y. Functionalrole of the transient receptor potential melastatin 8(TRPM8) ion channel in the urinary bladderassessed by conscious cystometry and ex vivo
measurements of single-unit mechanosensitive
bladder afferent activities in the rat. BJU Int, 117,484-94, 2016.
10. Ito H, Kamei J, Aizawa N, Fujita Y, Suzuki M,
Fukuhara H, Fujimura T, Kojima T, Homma Y,
Kubota Y, Ito M, Andersson KE, Igawa Y.
Preventive effects of long-term caloric restriction
on aging related in vivo bladder dysfunction andmolecular biological changes in the bladder anddorsal root ganglia in rats. J Urol, 196, 1575-83,
2016.
11. Lim S, Hosaka K, Nakamura M, Cao Y. Co-optionof pre-existing vascular beds in adipose tissue
controls tumor growth rates and angiogenesis.
Oncotarget, 7, 38282-38291, 2016.
12. Makise N, Morikawa T, Nakagawa T, Ichimura T,
Kawai T, Matsushita H, Kakimi K, Kume H,
Homma Y, Fukayama M. MAGE-A expression,
immune microenvironment, and prognosis inupper urinary tract carcinoma. Hum Pathol, 50,
62-9, 2016.
13. Matsushita H, Sato Y, Karasaki T, Nakagawa T,
Kume H, Ogawa S, Homma Y, Kakimi K.
Neoantigen load, antigen presentation machinery,
and immune signatures determine prognosis inclear cell renal cell carcinoma. Cancer Immunol
Res, 4, 463-71, 2016.
14. Nakagawa T, Taguchi S, Uemura Y, Kanatani A,
Ikeda M, Matsumoto A, Yoshida K, Kawai T,
Nagata M, Yamada D, Komemushi Y, Suzuki M,
Enomoto Y, Nishimatsu H, Ishikawa A, Nagase Y,
Kondo Y, Tanaka Y, Okaneya T, Hirano Y,

Shinohara M, Miyazaki H, Fujimura T, Fukuhara
H, Kume H, Igawa Y, Homma Y. Nomogram forpredicting survival of post-cystectomy recurrent
urothelial carcinoma of the bladder. Urol Oncol,
in press.
15. Niimi A, Nomiya A, Yamada Y, Suzuki M,
Fujimura T, Fukuhara H, Kume H, Igawa Y,
Homma Y. Hydrodistension with or without
fulguration of hunner lesions for interstitial
cystitis: Long-term outcomes and prognostic
predictors. Neurourol Urodyn, 35, 965-9, 2016.
16. Niimi A, Suzuki M, Yamaguchi Y, Ishii M,
Fujimura T, Nakagawa T, Fukuhara H, Kume H,
Igawa Y, Akishita M, Homma Y. Sleep apnea andcircadian
extracellular
fluidchangeasindependent factors for nocturnal polyuria. J Urol,
196, 1183-9, 2016.
17. Nozaki K, Kamijo Y, Nakatsuka M, Azuma T,
Nakagawa T, Miyazaki H, Fujimura T, Fukuhara
H, Kume H, Ishibashi Y, Homma Y. Computed
tomography for the management of exit-site andtunnel infections in peritoneal dialysis patients.
Clin Nephrol, 86, 328-32, 2016.
18. Obinata D, Takada S, Takayama K, Urano T, Ito A,
Ashikari D, Fujiwara K, Yamada Y, Murata T,
Kumagai J, Fujimura T, Ikeda K, Horie-Inoue K,
Homma Y, Inoue S. ABHD2, an androgen target
gene, promotes prostate cancer cell proliferation
and resistant to chemotherapy. Eur J Cancer, 57,
39-49, 2016.
19. Obinata D, Takayama K, Urano T, Suzuki T,
Takahashi S, Fujimura T, Homma Y, Fujiwara K,
Fukuda N, Nagase H, Aburatani H, Tsutsumi S,
Inoue S. Targeting Oct1 genomic function inhibits
androgen receptor signaling and castrationresistant prostate cancer growth. Oncogene, 35,
6350-8, 2016.
20. Otsuka M, Taguchi S, Nakagawa T, Kawai T,
Morikawa T, Miyazaki H, Fujimura T, Fukuhara
H, Kume H, Homma Y. Lower ureteral lesion isan independent predictor of intravesical recurrence after radical nephroureterectomy for upper
tract urothelial carcinoma. Urol Oncol, 34, 59.e913, 2016.
21. Rosier PF, Kirschner-Hermanns R, Svihra J,
Homma Y, Wein AJ. ICS teaching module:
Analysis of voiding, pressure flow analysis (basic

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module). Neurourol Urodyn, 35, 36-8, 2016.
22. Seki T, Hosaka K, Lim S, Fischer C, Honek J,
Yang Y, Andersson P, Nakamura M, Näslund E,
Ylä-Herttuala S, Sun M, Iwamoto H, Li X, Liu Y,
Samani NJ, Cao Y. Endothelial PDGF-CC
regulates angiogenesis-dependent thermogenesis
in beige fat. Nat Commun, 7, 12152, 2016.
23. Sonpavde G, Pond GR, Choueiri TK, Mullane S,
Niegisch G, Albers P, Necchi A, Di Lorenzo G,
Buonerba C, Rozzi A, Matsumoto K, Lee JL,
Kitamura H, Kume H, Bellmunt J. Single-agent
taxane versus taxane-containing combination
chemotherapy as salvage therapy for advanced
urothelial carcinoma. Eur Urol, 69, 634-41, 2016.
24. Suzuki M, Iguchi Y, Igawa Y, Yoshida M, Sanada
H, Miyazaki H, Homma Y. Ultrasound-assisted
prompted voiding for management of urinary
incontinence of nursing home residents: Efficacy
and feasibility. Int J Urol, 23, 786-90, 2016.
25. Taguchi S, Akamatsu N, Nakagawa T, Gonoi W,
Kanatani A, Miyazaki H, Fujimura T, Fukuhara H,
Kume H, Homma Y. Sarcopenia evaluated using
the skeletal muscle index is a significant prognostic factor for metastatic urothelial carcinoma. Clin
Genitourin Cancer, 14, 237-43, 2016.
26. Taguchi S, Fukuhara H, Morikawa T, Matsumoto
A, Miyazaki H, Nakagawa T, Fujimura T, Kume
H, Igawa Y, Homma Y. Cessation of long-term
adjuvant androgen deprivation therapy afterradical prostatectomy: Is it feasible? Jpn J Clin
Oncol, 46, 1143-7, 2016.
27. Taguchi S, Kume H, Fukuhara H, Morikawa T,
Kakutani S, Takeshima Y, Miyazaki H, Fujimura T,
Nakagawa T, Ishikawa A, Igawa Y, Homma Y.
Symptoms at diagnosis as independent prognostic
factors in retroperitoneal liposarcoma. Mol Clin
Oncol, 4, 255-60, 2016.
28. Taguchi S, Nakagawa T, Uemura Y, Matsumoto A,
Nagase Y, Kawai T, Tanaka Y, Yoshida K,
Yamamoto S, Enomoto Y, Nose Y, Sato T,
Ishikawa A, Fujimura T, Fukuhara H, Kume H,
Homma Y. Validation of major prognostic models
for metastatic urothelial carcinoma using a
multi-institutional cohort of the real world. WorldJ Urol, 34, 163-71, 2016.
29. Taguchi S, Shiraishi K, Fukuhara H, Nakagawa K,
Morikawa T, Naito A, Kakutani S, Takeshima Y,

Miyazaki H, Nakagawa T, Fujimura T, Kume H,
Homma Y. Impact of Gleason pattern 5 including
tertiary pattern 5 on outcomes of salvage
treatment for biochemical recurrence in pT23N0M0 prostate cancer. Int J Clin Oncol, 21, 97580, 2016.
30. Taguchi S, Shiraishi K, Fukuhara H, Nakagawa K,
Morikawa T, Naito A, Kakutani S, Takeshima Y,
Miyazaki H, Nakagawa T, Fujimura T,Kume H,
Homma Y. Optimal timing of salvage radiotherapy for biochemical recurrence after radical
prostatectomy: is ultra-early salvage radiotherapy
beneficial? Radiat Oncol, 11, 102, 2016.
31. Yamada Y, Fujimura T, Fukuhara H, Miyagawa J,
Miyazaki H, Nakagawa T, Kume H, Homma Y.
Measuring contact pressure of lower extremities
in patients undergoing robot-assisted radical
prostatectomy. Urol Int, 96, 268-73, 2016.
32. Yamada Y, Nakagawa T, Sugihara T, Horiuchi T,
Yoshizaki U, Fujimura T, Fukuhara H, Urano T,
Takayama K, Inoue S, Kume H, Homma Y.
Prognostic value of CD66b positive tumorinfiltrating neutrophils in testicular germ celltumor. BMC Cancer, 16, 898, 2016.
33. Yang Y, Andersson P, Hosaka K, Zhang Y, Cao R,
Iwamoto H, Yang X, Nakamura M, Wang J,
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R, Samani N, Nakae S, Hams E, Dissing S, Fallon
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36. Zaitsu M, Nakamura F, Toyokawa S, Tonooka A,
Takeuchi T, Homma Y, Kobayashi Y. Risk of

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alcohol consumption in bladder cancer: Casecontrol study from a nationwide inpatient database in Japan. Tohoku J Exp Med,239,9-15,2016.

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Department of Surgical Oncology
Professor
Toshiaki Watanabe, M.D., Ph.D.

Lecturer
Soichiro Ishihara, M.D., Ph.D.

Hiroaki Nozawa, M.D., Ph.D.

Kazushige Kawai, M.D., Ph.D.

Assistant Professor
Keisuke Hata, M.D., Ph.D.

Tomomichi Kiyomatsu M.D., Ph.D.

Toshiaki Tanaka, M.D., Ph.D.

Takeshi Nishikawa, M.D., Ph.D.

Kensuke Otani, M.D., Ph.D.

Koji Yasuda, M.D.

Kazuhito Sasaki, H.D, Ph.D.

Manabu Kaneko, M.D. Ph.D.

Koji Murono, M.D., Ph.D.

Hirofumi Sonoda, M.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, three Lecturers and eleven
Assistant Professors. The outpatient office is locatedon the third floor of the Outpatient Building. The ward
is situated 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 Surgical
Oncology in clinical practice, education, and research
are summarized 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 590
surgically treated inpatients in the year of 2016. On
Monday, Wednesday and Friday mornings, pre- andpost-surgery conferences are held, and the Professor's
Round takes place after the conference every
Wednesday. Operating days are Monday, Tuesday andThursday. In addition to the clinical conferences,
research conferences are held every Monday morning.

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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 ulcerative colitis. In the
postgraduate education program, new residents aretrained to become qualified surgeons. In addition topre- and post-surgery clinical conferences, theresidents are expected to attend research conferences
and seminars, which are held periodically. They arealso asked to present cases at clinical meetings, which
are held locally such as the local meeting of theJapanese 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) The mechanism of liver metastasis of colorectal
cancer10) Dendritic cell Immunotherapy for advanced
cancer11) Cancer Immunotherapy targeting to the tumor
vessels12) Role of LPA S1P and productive enzymes intumor metastasis
13) Lipid metabolism in carcinogenesis and tumor
progression14) Role of peripheral nerve on the growth og
gastrointestinal cancer15) Genetic analysis on sensitivity to chemotherapeutic agents16) Hemostasis and fibrinolysis in Oncology17) Adiponectin and adiponectin receptors in Oncology18) Intraabdominal chemotherapy for peritoneal
metastasis of gastric cancer
19) Pharmacokinetics in intraperitoneal chemotherapy20) Fibroblast Growth Factor (FGF) in inflammatory
bowel disease21) Genetic analysis of undifferentiated colorectal
cancer22) High Frequency Ultrasonography (HIFU) for
solid cancer23) Quantitative analysis of intraperitoneal cancer
cells in peritonitis carcinomatosis24) Immunomodulation in chemoradiotherapy for
locally advanced rectal cancer25) Autophagy in Oncology
26) Robot assisted laparoscopic colorectal surgery (daVinci)

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27) Postoperative defecation function, urinary
function, and sexual function after rectal cancer
surgery

References
1. Ishikawa T, Abe S, Watanabe T, Nozawa Y, Sano
T, Iwanaga A, Seki K, Honma T, Yoshida T.
Improved survival with double platinum therapytranscatheter arterial infusion using cisplatin andtranscatheter arterial chemoembolization using
miriplatin for BCLC-B hepatocellular carcinoma.
Mol Clin Oncol. 5:511-516, 2016.
2. Nishikawa T, Hata K, Yoshida S, Murono K,
Yasuda K, Otani K, Tanaka T, Kiyomatsu T,
Kawai K, Nozawa H, Ishihara S, Koike K,
Watanabe T. Successful endoscopic treatment of
stapled J-pouch ileoanal canal anastomotic
hemorrhage by argon plasma coagulation: a casereport. J Med Case Rep. 10:309, 2016.
3. Kotaka M, Xu R, Muro K, Park YS, Morita S,
Iwasa S, Uetake H, Nishina T, Nozawa H,
Matsumoto H, Yamazaki K, Han SW, Wang W,
Ahn JB, Deng Y, Cho SH, Ba Y, Lee KW, Zhang T,
Satoh T, Buyse ME, Ryoo BY, Shen L, Sakamoto
J, Kim TW. Study protocol of the Asian XELIRI
ProjecT (AXEPT): a multinational, randomized,
non-inferiority, phase III trial of second-line
chemotherapy for metastatic colorectal cancer,
comparing the efficacy and safety of XELIRI withor without bevacizumab versus FOLFIRI with orwithout bevacizumab. Chin J Cancer. 35:102,
2016.
4. Watanabe T, Ajioka Y, Mitsuyama K, Watanabe K,
Hanai H, Nakase H, Kunisaki R, Matsuda K,
Iwakiri R, Hida N, Tanaka S, Takeuchi Y, Ohtsuka
K, Murakami K, Kobayashi K, Iwao Y, Nagahori
M, Iizuka B, Hata K, Igarashi M, Hirata I, Kudo
SE, Matsumoto T, Ueno F, Watanabe G, Ikegami
M, Ito Y, Oba K, Inoue E, Tomotsugu N,
Takebayashi T, Sugihara K, Suzuki Y, Watanabe
M, Hibi T. Comparison of Targeted vs Random
Biopsies for Surveillance of Ulcerative ColitisAssociated Colorectal Cancer. Gastroenterology.
151:1122-1130, 2016.
5. Tanaka T, Kawai K, Abe H, Murono K, Otani K,
Nishikawa T, Kiyomatsu T, Hata K, Nozawa H,

Yamaguchi H, Ishihara S, Fukayama M, Watanabe
T. Giant mucocele of the colon at the distal stump
due to low-grade mucinous neoplasia. Surg Case
Rep. 2:117, 2016.
6. Takiyama A, Nozawa H, Ishihara S, Takiyama H,
Murono K, Yasuda K, Otani K, Nishikawa T,
Tanaka T, Kiyomatsu T, Kawai K, Hata K,
Watanabe T. Secondary metastasis in the lymph
node of the bowel invaded by colon cancer: areport of three cases. World J Surg Oncol. 14:273,
2016.
7. Nishikawa T, Ishihara S, Hata K, Murono K,
Yasuda K, Otani K, Tanaka T, Kiyomatsu T,
Kawai K, Nozawa H, Yamaguchi H, Watanabe T.
Short-term outcomes of open versus laparoscopic
surgery in elderly patients with colorectal cancer.
Surg Endosc. 30:5550-5557, 2016.
8. Kawai K, Ishihara S, Nozawa H, Hata K,
Kiyomatsu T, Tanaka T, Nishikawa T, Otani K,
Yasuda K, Murono K, Sasaki K, Watanabe T.
Survival Impact of Extracolorectal Malignancies
in Colorectal Cancer Patients. Digestion. 94:92-99,
2016.
9. Nagai Y, Kazama S, Yamada D, Miyagawa T,
Murono K, Yasuda K, Nishikawa T, Tanaka T,
Kiyomatsu T, Hata K, Kawai K, Masui Y, Nozawa
H, Yamaguchi H, Ishihara S, Kadono T, Watanabe
T. Perianal and Vulvar Extramammary Paget
Disease: A Report of Six Cases and Mapping
Biopsy of the Anal Canal. Ann Dermatol. 28:
624-628, 2016.
10. Matsuzaki H, Ishihara S, Kawai K, Nishikawa T,
Tanaka T, Kiyomatsu T, Hata K, Nozawa H,
Yamada S, Watanabe T. Late sacral recurrence ofrectal cancer treated by heavy ion radiotherapy: acase report. Surg Case Rep. 2:109, 2016
11. Nishikawa T, Ishihara S, Ushiku T, Hata K, Sasaki
K, Murono K, Yasuda K, Otani K, Tanaka T,
Kiyomatsu T, Kawai K, Nozawa H, Watanabe T.
Anal metastasis from rectal adenocarcinoma. Clin
J Gastroenterol. 9:379-383, 2016.
12. Otani K, Ishihara S, Hata K, Murono K, Sasaki K,
Yasuda K, Nishikawa T, Tanaka T, Kiyomatsu T,
Kawai K, Nozawa H, Yamaguchi H, Watanabe T.
Colorectal cancer with venous tumor thrombosis.
Asian J Surg. 2016 Sep 29. pii:S1015-9584(16)30149-X.

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13. Abe S, Kawai K, Ishihara S, Nozawa H, Hata K,
Kiyomatsu T, Tanaka T, Watanabe T. Prognostic
impact of carcinoembryonic antigen and carbohydrate antigen 19-9 in stage IV colorectal cancer
patients after R0 resection. J Surg Res. 205:384392, 2016.
14. Zhang H, Nagaoka K, Usuda K, Nozawa K, TayaK, Yoshida M, Watanabe G. Estrogenic
Compounds Impair Primordial Follicle Formation
by Inhibiting the Expression of Proapoptotic Hrk
in Neonatal Rat Ovary. Biol Reprod. 95:78, 2016.
15. Murono K, Kawai K, Ishihara S, Otani K, Yasuda
K, Nishikawa T, Tanaka T, Kiyomatsu T, Hata K,
Nozawa H, Yamaguchi H, Watanabe T. Evaluationof the vascular anatomy of the right-sided colonusing three-dimensional computed tomography
angiography: a single-center study of 536 patientsand a review of the literature. Int J Colorectal Dis.
31:1633-638, 2016.
16. Arakawa K, Ishihara S, Kawai K, Shibata J, Otani
K, Yasuda K, Nishikawa T, Tanaka T, Kiyomatsu
T, Hata K, Nozawa H, Yamaguchi H, Sunami E,
Kitayama J, Watanabe T. Asynchronous bilateralanastomosis site sigmoid colon cancer after
ureteros gmoidostomy: a case report. World J
Surg Oncol. 14:180, 2016.
17. Nozawa H, Ishihara S, Kawai K, Murono K,
Yasuda K, Otani K, Nishikawa T, Tanaka T,
Kiyomatsu T, Hata K, Watanabe T. Paradoxical
Reductions in Serum Anti-p53 Autoantibody
Levels by Chemotherapy in Unresectable
Colorectal Cancer: An Observational Study.
Oncology. 91:127-134, 2016.
18. Anzai H, Hata K, Kishikawa J, Ishii H, Yasuda K,
Otani K, Nishikawa T, Tanaka T, Kiyomatsu T,
Kawai K, Nozawa H, Kazama S, Yamaguchi H,
Ishihara S, Sunami E, Watanabe T. Appendiceal
orifice inflammation is associated with proximal
extension of disease in patients with ulcerative
colitis. Colorectal Dis. 18:O278-O282, 2016.
19. Ishikawa T, Abe S, Watanabe T, Nozawa Y, Sano
T, Iwanaga A, Seki K, Honma T, Yoshida T.
Clinical efficacy of the highly sensitive hepatitis
C virus RNA quantitative assay in patients withrelapse following interferon-based therapy withsecond-generation
direct-acting
antivirals.
Biomed Rep. 4:664-666, 2016.

20. Arakawa K, Kiyomatsu T, Ishihara S, Ikemura M,
Hojo D, Takiyama H, Murono K, Otani K, Yasuda
K, Nishikawa T, Tanaka T, Kawai K, Hata K,
Nozawa H, Yamaguchi H, Watanabe T. A casereport of anorectal malignant melanoma withmucosal skipped lesion. Int J Surg Case Rep.
24:206-210, 2016.
21. Ozawa T, Ishihara S, Kawai K, Nozawa H,
Yamaguchi H, Kitayama J, Watanabe T.
Prognostic Significance of Preoperative Serum
Carbohydrate Antigen 19-9 in Patients With StageIV Colorectal Cancer. Clin Colorectal Cancer.
2016 Dec;15(4):e157-e163.
22. Ishihara S, Kanemitsu Y, Murono K, Otani K,
Yasuda K, Nishikawa T, Tanaka T, Tanaka J,
Kiyomatsu T, Kawai K, Hata K, Nozawa H,
Kazama S, Yamaguchi H, Sunami E, Sugihara K,
Watanabe T. Oncological benefit of lateral pelvic
lymph node dissection for rectal cancer treated
without preoperative chemoradiotherapy: amulticenter retrospective study using propensity
score analysis. Int J Colorectal Dis. 31:1315-1321,
2016.
23. Sato K, Tanaka T, Sato J, Shibata E, Nagai Y,
Murono K, Yasuda K, Otani K, Nishikawa T,
Tanaka J, Kiyomatsu T, Hata K, Kawai K,
Nozawa H, Kazama S, Yamaguchi H, Ishihara S,
Sunami E, Kitayama J, Ohtomo K, Watanabe T.
Usefulness of preoperative CT colonography forcolon cancer. Asian J Surg. 2016 May 20. pii:
S1015-9584(16)30037-9.
24. Nagai Y, Hata K, Kawai K, Murono K, Yasuda K,
Otani K, Nishikawa T, Tanaka T, Kiyomatsu T,
Nozawa H, Yamaguchi H, Ishihara S, Watanabe T.
Clinicopathological Features of Colorectal Cancer
Patients Under the Age of 50: Recent Experience
and Case-Control Study of Prognosis in a
Japanese Cohort. Digestion. 93:272-279, 2016.
25. Tachikawa Y, Nozawa H, Tanaka J, Nishikawa T,
Tanaka T, Kiyomatsu T, Hata K, Kawai K,
Kazama S, Yamaguchi H, Ishihara S, Sunami E,
Kitayama J, Fujisawa M, Takahashi K, Sakaguchi
Y, Ushiku T, Fukayama M, Watanabe T. Colonicperforation in a patient with systemic lupus
erythematosus accompanied by cytomegalovirus
infection: A case report. Int J Surg Case Rep. 23:
70-73, 2016.

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26. Okuno T, Yamaguchi H, Kitayama J, Ishigami H,
Nishikawa T, Tanaka J, Tanaka T, Kiyomatsu T,
Hata K, Nozawa H, Kawai K, Kazama S, Ishihara
S, Sunami E, Watanabe T. A case of disseminatedcarcinomatosis of the bone marrow originatingfrom gastric cancer 3 years after intraperitoneal
chemotherapy against peritoneal carcinomatosis.
World J Surg Oncol. 14:107, 2016.
27. Ota Y, Ishihara S, Otani K, Yasuda K, Nishikawa
T, Tanaka T, Tanaka J, Kiyomatsu T, Kawai K,
Hata K, Nozawa H, Kazama S, Yamaguchi H,
Sunami E, Kitayama J, Watanabe T. Effect ofnutrient starvation on proliferation and cytokine
secretion of peripheral blood lymphocytes. Mol
Clin Oncol. 4:607-610, 2016.
28. Nozawa H, Ishihara S, Murono K, Yasuda K,
Otani K, Nishikawa T, Tanaka T, Kiyomatsu T,
Hata K, Kawai K, Yamaguchi H, Watanabe T.
Laparoscopy-assisted versus open surgery for
multiple colorectal cancers with two anastomoses:a cohort study. Springerplus. 5:287, 2016.
29. Kawai K, Iida Y, Ishihara S, Yamaguchi H,
Nozawa H, Hata K, Kiyomatsu T, Tanaka T,
Nishikawa T, Yasuda K, Otani K, Murono K,
Watanabe T. Intraoperative colonoscopy inpatients with colorectal cancer: Review of recent
developments. Dig Endosc. 28:633-640, 2016.
30. Yasuda K, Kawai K, Ishihara S, Murono K, Otani
K, Nishikawa T, Tanaka T, Kiyomatsu T, Hata K,
Nozawa H, Yamaguchi H, Aoki S, Mishima H,
Maruyama T, Sako A, Watanabe T. Level ofarterial ligation in sigmoid colon and rectal cancer
surgery. World J Surg Oncol. 14:99, 2016.
31. Ishihara S, Otani K, Yasuda K, Nishikawa T,
Tanaka T, Tanaka J, Kiyomatsu T, Kawai K,
Hata K, Nozawa H, Kazama S, Yamaguchi H,
Sunami E, Kitayama J, Sugihara K, Watanabe T.
Prognostic impact of lymph node dissection isdifferent for male and female colon cancer
patients: a propensity score analysis in a multicenter retrospective study. Int J Colorectal Dis.
31:1149-1155, 2016.
32. Yoshioka Y, Nozawa H, Tanaka J, Nishikawa T,
Tanaka T, Kiyomatsu T, Kawai K, Hata K,
Kazama S, Yamaguchi H, Ishihara S, Sunami E,
Kitayama J, Watanabe T. Small bowel adenocarcinoma arising in a patient with hereditaryhemorrhagic telangiectasia: A case report. Oncol
Lett. 11:2137-2139, 2016.
33. Ishii H, Hata K, Kishikawa J, Anzai H, Otani K,
Yasuda K, Nishikawa T, Tanaka T, Tanaka J,
Kiyomatsu T, Kawai K, Nozawa H, Kazama S,
Yamaguchi H, Ishihara S, Sunami E, Kitayama J,
Watanabe T. Incidence of neoplasias andeffectiveness of postoperative surveillanceendoscopy for patients with ulcerative colitis:
comparison of ileorectal anastomosis and ileal
pouch-anal anastomosis. World J Surg Oncol.
14:75, 2016.
34. Kishikawa J, Kazama S, Oba K, Hasegawa K,
Anzai H, Harada Y, Abe H, Matsusaka K, Hongo
K, Oba M, Yasuda K, Otani K, Nishikawa T,
Tanaka T, Tanaka J, Kiyomatsu T, Hata K,
Kawai K, Nozawa H, Yamaguchi H, Ishihara S,
Sunami E, Ushiku T, Kitayama J, Fukayama M,
Kokudo N, Watanabe T. CD133 Expression at theMetastatic Site Predicts Patients' Outcome inColorectal Cancer with Synchronous Liver
Metastasis. Ann Surg Oncol. 23:1916-1923, 2016.
35. Yamaguchi H, Kitayama J, Ishigami H, Emoto S,
Nishikawa T, Tanaka J, Tanaka T, Kiyomatsu T,
Kawai K, Hata K, Nozawa H, Kazama S, Ishihara
S, Sunami E, Watanabe T. A patient with gastriccancer with peritoneal carcinomatosis treated withintraperitoneal chemotherapy who survived morethan 5 years receiving repeated laparoscopic
examinations: a case report. J Med Case Rep.
10:14, 2016.
36. Hata K, Yamamoto Y, Kiyomatsu T, Tanaka T,
Kazama S, Nozawa H, Kawai K, Tanaka J,
Nishikawa T, Otani K, Yasuda K, Kishikawa J,
Nagai Y, Anzai H, Shinagawa T, Arakawa K,
Yamaguchi H, Ishihara S, Sunami E, Kitayama J,
Watanabe T. Hereditary gastrointestinal cancer.
Surg Today. 46:1115-1122, 2016.
37. Anzai H, Hata K, Kishikawa J, Ishii H, Nishikawa
T, Tanaka T, Tanaka J, Kiyomatsu T, Kawai K,
Nozawa H, Kazama S, Yamaguchi H, Ishihara S,
Sunami E, Kitayama J, Watanabe T. Clinicalpattern and progression of ulcerative proctitis in
the Japanese population: a retrospective study ofincidence and risk factors influencing progression.
Colorectal Dis. 18:O97-O102, 2016.
38. Nozawa H, Ishihara S, Fujishiro M, Kodashima S,

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Ohtani K, Yasuda K, Nishikawa T, Tanaka T,
Tanaka J, Kiyomatsu T, Kawai K, Hata K,
Kazama S, Sunami E, Kitayama J, Watanabe T.
Outcome of salvage surgery for colorectal cancer
initially treated by upfront endoscopic therapy.
Surgery. 159:713-720, 2016.
39. Wurita A, Hasegawa K, Minakata K, Gonmori K,
Nozawa H, Yamagishi I, Suzuki O, Watanabe K.
Identification and quantification of metabolites of
AB-CHMINACA in a urine specimen of an
abuser. Leg Med (Tokyo). 19:113-118, 2016.
40. Hata K, Kishikawa J, Anzai H, Shinagawa T,
Kazama S, Ishii H, Nozawa H, Kawai K,
Kiyomatsu T, Tanaka J, Tanaka T, Nishikawa T,
Otani K, Yasuda K, Yamaguchi H, Ishihara S,
Sunami E, Kitayama J, Watanabe T. Surveillancecolonoscopy for colitis-associated dysplasia andcancer in ulcerative colitis patients. Digå Endosc.
28:260-265, 2016.

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Department of Vascular Surgery
Professor
Toshiaki Watanabe, M.D., Ph.D.

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

Assistant Professor
Takuya Miyahara, M.D., Ph.D., Kota Yamamoto, M.D., Ph.D., Daisuke Akagi, M.D., Ph.D.,
Atsushi Akai, M.D., 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 Vascular
Surgery and the Department of Surgical Oncology.
The staff of the Department of Vascular Surgery
consists of one Professor, one Lecturer, and four
Assistant Professors. The outpatient office is locatedon the third floor of the Outpatient Building. The ward
is situated 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 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

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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 noninvasive 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.

References
1. Taniguchi R, Miura Y, Koyama H, Chida T,
Anraku Y, Kishimura A, Shigematsu K, Kataoka
K, Watanabe T. Adequately-Sized Nanocarriers
Allow Sustained Targeted Drug Delivery to
Neointimal Lesions in Rat Arteries. Molecular
Pharmaceutics．13(6): 2108-16. 2016
2. Adachi K, Nemoto M(co-first authorship), Enatsu
K. A Bulky Posterior Mediastinal Tumor.
Gastroenterology. 150(4): e9-e11. 2016
3. Mochizuki Y, Hosaka A, Kamiuchi H, Nie JX,
Masamune K, Hoshina K, Miyata T, Watanabe T.
New simple image overlay system using a tablet
PC for pinpoint identification of the appropriate
site for anastomosis in peripheral arterial
reconstruction. Surgery Today. 46(2): 1387-93.
2016
4. Hoshina K, Yamamoto K, Miyata T, Watanabe T.
Outcomes of Critical Limb Ischemia in
Hemodialysis Patients After Distal Bypass
Surgery - Poor Limb Prognosis With Stage 4
Wound, Ischemia, and Foot Infection (WIfI). Circ
J. 80: 2382-87. 2016
5. Hashimoto T, Tsuneki M, Foster T, Santana J, Bai

218

H, Wang M, Hu H, Hanisch J, Dardik A.
Membrane-mediated regulation of vascular
identity. Birth Defects Research Part C: Embryo
Today: Review. 108(1): 65-84. 2016
6. Hashimoto T, Yamamoto K, Foster T, Bai H,
Shigematsu K, Dardik A. Intraluminal drugdelivery to the arteriovenous fistula endothelium.
Journal of Visualized Experiments. 109: e53905.
2016
7. Hashimoto T, Chen L, Kimura H, Endler A,
Koyama H, Miyata T, Shibasaki F, Watanabe T.
Silencing of eIF3e promotes blood perfusion
recovery after limb ischemia through stabilizationof hypoxia-inducible factor 2α activity. Journal of
Vascular Surgery. 64(1): 219-226.e.3. 2016
8. Gui L, Dash BC, Luo J, Qin L, Zhao L,
Yamamoto K, Hashimoto T, Wu H, Dardik A,
Tellides G, Niklason LE, Qyang Y. Implantabletissue-engineered blood vessels from humaninduced pluripotent stem cells. Biomaterials. 102:
120-9. 2016
9. Bai H, Wang M, Foster TR, Hu H, He H,
Hashimoto T, Hanisch JJ, Santana JM, Xing Y,
Dardik A. Pericardial patch venoplasty heals via
attraction of venous progenitor cells. Physiol
Reports. 4(12): pii: e12841. 2016
10. Wang M, Collins M, Foster T, Bai H, Hashimoto T,
Santana J, Shu C, Dardik A. Eph-B4 mediates
vein graft adaptation by regulation of eNOS.
Eph-B4 mediates vein graft adaptation by
regulation of eNOS. Journal of Vascular Surgery.
Epub ahead of print. pii: S0741-5214(15)02441-6.
2016
11. Bai H, Li X, Hashimoto T, Hu H, Foster T,
Hanisch J, Santata J, Dardik A. Patch angioplasty
in the rat aorta or inferior vena cava. Journal of
Visualized Experiments. In Press. e55253. 201612. Shirasu T, Hoshina K, Nishiyama A, Akagi D,
Miyahara T, Yamamoto K, Shigematsu K,
Watanabe T. Favorable outcomes of very elderly
patients with critical limb ischemia who undergo
distal bypass surgery. Journal of Vascular Surgery.
63(2): 377-84. 201613. Shirasu T, Koyama H, Miura Y, Hoshina K,
Kataoka K, Watanabe T. Nanoparticles Effectively
Target Rapamycin Delivery to Sites ofExperimental Aortic Aneurysm in Rats. PLoS One.

11(6): e0157813. 201614. Shirasu T, Hoshina K, Akagi D, Miyahara T,
Yamamoto K, Watanabe T. Pulse volume
recordings to identify falsely elevated ankle
brachial index. Asian Cardiovascular and Thorac
Annals. 24(6): 517-22. 201615. Shirasu T, Miyata T, Nishiyama A, Miyahara T,
Hoshina K, Shigematsu K, Watanabe T. Usefulpredictors for critical limb ischemia in severely
ischemic limbs. International Angiology. 35(5):460-8. 2016
16. Yamamoto K, Hoshina K, Akai A, Isaji T, Akagi
D, Miyahara T, Watanabe T. Results of surgicalinterventions for critical limb ischaemia due tovasculitis or collagen tissue related disease.
International Angiology. IN PRESS. 201617. Hosaka A, Miyata T, Nishiyama A, Miyahara T,
Hoshina K, Shigematsu K. Preservation of theaccessory renal arteries after endovascular repairof common iliac artery aneurysm using kissing
stent grafts. Journal of Vascular Surgery. 63:
523-6. 201618. Hosaka A, Kato M, Motoki M, Sugai H, Okubo N.
Quantified Aortic Luminal Irregularity as a
Predictor of Complications and Prognosis After
Endovascular Aneurysm Repair. Medicine(Baltimore). 95: e2863. 201619. Yamamoto S, Okamoto H, Haga M, Shigematsu K,
Miyata T, Watanabe T, Ogawa Y, Takagi Y,
Asakura T. Rapid endothelialization and thin
luminal layers in vascular grafts using silk fibroin.
Journal of Materials Chemistry B. 4(5): 938-46.
2016
20. Yamamoto S, Akai T, Chiyoda T, Goto H, Masaki
Y. Infected Iliac Artery Aneurysm Concomitantwith Liver Abscess Caused by Fusobacterium
nucleatum. Case Reports in Clinical Medicine. 5:
238-42. 2016
21. Yamamoto S, Yokomizo Y, Akai T, Chiyoda T,
Goto H, Masaki Y. Acute aortic occlusion in apatient with chronic paralysis due to spinal cord
injury: a case report. Surgical Case Reports. 2:121.
2016

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Department of Metabolic Careand Endocrine Surgery
Professor
Yasuyuki Seto M.D., Ph.D.

Associate Professor
Keiichiro Tada M.D., Ph.D.

Associates
Kotoe Nishioka M.D., Ph.D.

Yasuko Kikuchi M.D., Ph.D.

Takayoshi Niwa M.D., Ph.D.

Takako Wakeda M.D., Ph.D.

Homepage
Organization
Our section is staffed by one professor, one
associate professor, and four assistants. Official
activities of our sections are run by same schedule toDepartment of Gastrointestinal Surgery.

Clinical Activities
Endocrine Surgery is not familiar with Japanese yet,however, it has been a long time to be studied this area
by top level surgeons in western countries. We havestarted our activities for this area since 1987 and ourdepartment has been established with reconstructionof our hospital structure in 1997. This is a result of thegrowth of demand nationally and internationally and it
is caused by not only treatment for malignant disease
but also functional one or giving more attention toquality 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 surgicalprocedures for hyper-functional diseases. We co-workwith the department of endocrine internal medicine
and have about 250 surgical procedures annually intotal.

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
proceduresfor
endocrine
surgery
without
complications; 2) diagnosis and treatment of microbreast lesions under ultrasonographic guides; 3)preoperative diagnosis for thyroid neoplasmas andbreast tumors.

Research Acitivities
We investigate wide areas related to breast cancer,
thyroid disease, and parathyroid disease. Most of ourstudies are performed with other good instituteions.
1) Breast cancers originating from the axillary
region.

2202) Quantification of the hardness of breast cancer
using ultrasonography.
3) Clinical significance of Ki67 in the area of earlybreast cancer.
4) Clinical evaluation for the developing drugs inbreast cancer and thyroid cancer.
5) Studies in the area of sentinel node biopsy inbreast cancer.
6) Studies about management of the toxic effects ofchemotherapies.
7) Cover makeup studies for cancer patients.
8) Cancer epigenesist in thyroid cancer.
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

Publications
1. 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 andTFF3 but not TFF2 are higher in women withbreast cancer than in women without breast cancer.
Sci Rep. 2017 Jul 7;7(1):4846. doi: 10.1038/
s41598-017-05129-y.
2. Tada K, Nishioka K, Kikuchi Y, Niwa T, Seto Y.
Virtual Touch tissue quantification cannot assessbreast cancer lesions except for ductal carcinomas
in situ and small invasive cancers: a retrospective
study. World J Surg Oncol;13:147,2015.
3. Okubo M, Tada K, Niwa T, Nishioka K, Tsuji E,
Ogawa T, Seto Y. A case of breast cancer in theaxillary tail of Spence - enhanced magnetic
resonance imaging and positron emission
tomography for diagnostic differentiation andpreoperative treatment decision. World J Surg
Oncol;11:217,2013.
4. Kikuchi Y, Tsuji E, Yagi K, Matsusaka K, Tsuji S,
Kurebayashi J, Ogawa T, Aburatani H, Kaneda A.
Aberrantly methylated genes in human papillary
thyroid cancer and their association with
BRAF/RAS mutation. Front Genet;4:271,2013.
5. Yamashita H, Okuma K, Tada K, Shiraishi K,
Takahashi W, Shibata-Mobayashi S, Sakumi A,

Saotome N, Haga A, Onoe T, Ino K, Akahane M,
Ohtomo K, Nakagawa K. Four-dimensional
measurement of the displacement of internal
fiducial and skin markers during 320-multislice
computed tomography scanning of breast cancer.
Int J Radiat Oncol Biol Phys;84(2):331-5,2012.
6. Hinohara K, Kobayashi S, Kanauchi H, Shimizu S,
Nishioka K, Tsuji E, Tada K, Umezawa K, Mori
M, Ogawa T, Inoue J, Tojo A, Gotoh N. ErbB
receptor tyrosine kinase/NF-kappaB signaling
controls mammosphere formation in human breast
cancer. Proc Natl Acad Sci U S A;109(17):6584-9,2012.
7. Ogawa T, Tsuji E, Shirakawa K, Hayashibara N,
Kurabayashi R, Terada K, Kikuchi Y, Kanauchi H,
Sakatani T. Primary non-Hodgkin's lymphoma of
the breast treated nonsurgically: report of threecases. Breast Cancer;18(1):68-72,2011.

Surgical Sciences
2. Sensory and Motor System Medicine

222

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.

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

Masahiro Kamata, M.D., Ph.D.

Hospital Lecturer
Yuri Masui, M.D., Ph.D.

Kaname Akamata, M.D., Ph.D.

Associate
Daisuke Yamada, M.D., Ph.D.

Takashi Taniguchi, M.D., Ph.D.

Shinji Noda, M.D., Ph.D.

Yohei Ichimura, M.D., Ph.D.

Takehiro Takahashi, M.D., Ph.D.

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

Jun Omatsu, 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.

223

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. Ichimura Y, Sugaya M, Morimura S, Suga H,
Mori S, Takahashi H, Akutsu Y, Sato S. Twocases of CD8-positive hypopigmented mycosis
fungoides without TOX expression. Int J
Dermatol. 2016;55(3):e164-7.
2. Takahashi T, Asano Y, Oka T, Miyagaki T,
Tamaki Z, Nonaka S, Sato S. Scleroderma encoup de sabre with recurrent episodes of brain
hemorrhage. J Dematol. 2016;43(2):203-6.
3. Oka T, Sugaya M, Cury-Martins J, Berg RSV,
Suga H, Miyagaki T, Gansl R, Scheinberg P,
Fujita H, Izutsu K, Sato S, Sanches JA.
Hematopoietic stem cell transplantation for
cutaneous T-cell lymphoma: summary of elevencases from two facilities in Japan and Brazil. J
Dermatol. 2016;43(6):638-42.
4. Toyama T, Asano Y, Akamata K, Noda S,
Taniguchi T, Takahashi T, Ichimura Y, Shudo K,
Sato S, Kadono T. Tamibarotene ameliorates
bleomycin-induced dermal fibrosis by modulating
phenotypes of fibroblasts, endothelial cells, andimmune cells. J Invest Dermatol. 2016;136(2):387-98.

5. Takahashi N, Hirabayashi M, Hoashi T. A case of
double extramammary Paget’s disease of theumbilicus and the scrotum. Dermatol Surg. 2016;
42(3):436-8.
6. Saigusa R, Asano Y, Yamashita T, Taniguchi T,
Takahashi T, Ichimura Y, Toyama T, Yoshizaki A,
Miyagaki T, Sugaya M, Sato S. Fli1 deficiency
contributes to the downregulation of endothelial
protein C receptor in systemic sclerosis: apossible role in pro-thrombotic condition. Br J
Dermatol. 2016;174(2):338-47.
7. Yoshizaki A. B lymphocytes in systemicsclerosis: abnormalities and therapeutic targets. J
Dermatol. 2016 ;43(1):39-45.
8. Nakamura K, Yoshizaki A, Takahashi T, Saigusa
R, Taniguchi T, Asano Y, Gonoi W, Hinata M,
Sinozaki-Ushiku A, Sato S. The first case reportof fatal acute pulmonary dysfunction in asystemic sclerosis patient treated with rituximab
therapy. Scand J Rheumatol. 2016;45(3):249-50.
9. Nakamura K, Asano Y, Taniguchi T, Minatsuki S,
Inaba T, Maki H, Hatano M, Yamashita T,
Saigusa R, Ichimura Y, Takahashi T, Toyama T,
Yoshizaki A, Miyagaki T, Sugaya M, Sato S.
Serum levels of IL-18 binding protein isoform a;clinical association with inflammation andpulmonary hypertension in systemic sclerosis. J
Dermatol. 2016;43(8):912-8.
10. Nakamura K, Yoshizaki A, Saigusa R, Taniguchi
T, Asano Y, Sato S. The efficacy of dantrolene
sodium for muscle cramps in patients withlocalized scleroderma. J Eur Acad Dermatol
Venereol. 2016;30(12):e188-9.
11. Yoshizaki A, Taniguchi T, Saigusa R, Fukasawa
T, Ebata S, Numajiri H, Nakamura K, Yamashita
T, Takahashi T, Toyama T, Asano Y, Tedder TF,
Sato S. The Nucleosome in patients with systemicsclerosis: possible association with immunelogical abnormalities via abnormal activation of T
and B cells. Ann Rheum Dis. 2016;75(10):185865.
12. Kabasawa M, Sugaya M, Oka T, Takahashi N,
Kawaguchi M, Suga H, Miyagaki T, Takahashi T,
Shibata S, Fujita H, Asano Y, Tada Y, Kadono T,
Okochi H, Sato S. Decreased IL-21 expression inskin and blood in advanced mycosis fungoides. J
Dermatol. 2016;43(7):819-22.

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13. Saigusa R, Asano Y, Nakamura K, Yamashita T,
Ichimura Y, Takahashi T, Toyama T, Taniguchi T,
Yoshizaki A, Miyazaki M, Tamaki Z, Sato S. The
association of anti-RNA polymerase III antibody
and silicone breast implants in patients withsystemic sclerosis. J Dermatol. 2016;43(7):808-10.
14. Yamashita T, Asano Y, Taniguchi T, Nakamura K,
Saigusa R, Takahashi T, Ichimura Y, Toyama T,
Yoshizaki A, Miyagaki T, Sugaya M, Sato S. A
potential contribution of altered cathepsin L
expression to the development of dermal fibrosis
and vasculopathy in systemic sclerosis. Exp
Dermatol. 2016;25(4):287-92.
15. Asano Y. Recent advances in animal models ofsystemic sclerosis. J Dermatol. 2016;43(1):19-28.
16. Uratsuji H, Tada Y, Hau C, Shibata S, Kamata M,
Kawashima T, Asano Y, Sugaya M, Kadono T,
Asahina A, Sato S. Monosodium urate crystals
induce functional expression of P2Y14 receptor inhuman keratinocytes. J Invest Drmatol. 2016;
136(6):1293-6.
17. Morimura M, Oka T, Sugaya M, Sato S.
CX3CR1 deficiency attenuates imiquimodinduced psoriasis-like skin inflammation withdecreased M1 macrophages. J Dermatol Sci.
2016;82(3):175-88.
18. Nakao M, Asano Y, Nakamura K, Shida R,
Takahashi T, Yoshizaki A, Mitsui A, Shibata S,
Araki M, Watanabe R, Ikawa Y, Toyoda C, Oka
H, Sato S. The development of chronic
inflammatory demyelinating polyneuropathy
during adalimumab treatment in a patient withpsoriasis vulgaris. Eur J Dermatol. 2016;26(4):404-5.
19. Takahashi T, Asano Y, Hirakawa M, Nakamura K,
Saigusa R, Aozasa N, Sumida H, Fujita H, Sugaya
M, Ohmori A, Shimizu J, Sato S. Linear
scleroderma with prominent multiple lymphadenopathy followed by the development ofpolymyositis – a case report and review ofliterature. J Dermatol. 2016;43(10):1224-7.
20. Saigusa R, Asano Y, Sato S.A case ofdisseminated granuloma annulare with giant
plaques. J Dermatol. 2016;43812):1443-44.
21. Takahashi T, Asano Y, Nakamura K, Yamashita
T, Saigusa R, Ichimura Y, Toyama T, Taniguchi
T, Yoshizaki A, Tamaki Z, Tada Y, Sugaya M,

Kadono T, Sato S. A potential contribution of
antimicrobial peptide LL-37 to tissue fibrosis andvasculopathy in systemic sclerosis. Br J Dermatol.
2016;175(6):1195-1203.
22. Takahashi N, Sugaya M, Suga H, Oka T,
Kawaguchi M, Miyagaki T, Fujita H, Sato S.
Thymic stromal chemokine TSLP acts throughTh2 cytokine production to induce cutaneous T
cell lymphoma. Cancer Res. 2016;76(21):62416252.
23. Nakao M, Sugaya M, Takahashi N, Otobe S,
Nakajima R, Oka T, Kabasawa M, Suga H,
Morimura S, Miyagaki T, Fujita H, Asano Y, Sato
S． Increased syndecan-4 expression in sera andskin of patients with atopic dermatitis. Arch
Dermatol Res. 2016;308(9):655-660.

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Department of Plastic andReconstructive Surgery
Professor
Isao Koshima, M.D., Ph.D.

Lecturer
Takuya Iida, M.D., Ph.D.
Mitsunaga Narushima, M.D., Ph.D.

Project Lecturer
Shuji Yamashita, M.D., Ph.D.

Associate
Shuhei Yoshida, M.D.

Katsuya Takagi, M.D.

Yoko Tomioka, M.D.

Hidehiko Yoshimatsu, M.D.

Shinya Ogishima, M.D.

Homepage

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, 2lecturer, 1 project lecturer, 6 associates, 4 physicians,
and 6 residents. There are about 100 doctors in thedepartment, but most are serving in rotation ataffiliated 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 trauma, scars and keloids, facial paralysis,

hand, replantation, microsurgery, breasts, head andneck reconstruction, cleft lip and palate, craniofacial
malformation,congenital
anomalies,
vascularmalformations, lymphedema, and cosmetic surgery
including cosmetic dermatology. 1502 New patients
visited our department, including 648 patients inemergency. 1426 surgeries were performed. Eachweek, the professor goes the round of inpatients on
Tuesday evening. Preoperative and postoperative
conferences and seminar that all members of thedepartment should attend are held on Wednesday
evening.

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,

226

hand surgery, craniomaxillofacial surgery, burn andtrauma, cosmetic surgery, and regenerative medicine.
In the bed side practice the students have theopportunity of seeing various diseases and disorders in
the field of plastic surgery and attending outpatient
clinics, surgical operations and clinical lectures byfaculty members. For graduate school students,
microsurgical training program is undertaken in thelaboratory room. In the postgraduate course, after
completing the 6-year training program, a trainee cansit for the board examination of the Japan Society of
Plastic and Reconstructive Surgery. In addition, we
accepted 31 observers from foreign countries
including China, United Kingdom, United States,
Korea, Thailand, Spain, Belgium, Taiwan, Canada,
India and Australia.

Research Activities
Basic and clinical researches are performed ingroups. The major research subjects are as follows:
1) Studies on cell isolation from human tissue suchas adipose, amnion, and placenta.
2) Studies on mechanism of hypermelanogenesis of
the skin.
3) Studies on differentiation induction of humanadult stem cells from adipose, amnion, andplacenta4) Characterization of human adult stem cells anddermal papilla cells.
5) Studies on hair regrowth using epidermal stem
cells, dermal papilla cells and dermal sheath cells.
6) Clinical studies on fat regeneration using suctioned fat tissue and adipose stromal progenitor
cells.
7) Studies on biological function of extracellularmatrix taken from human adipose tissue.
8) Studies on angiogenesis using human adult stem
cells from adipose.
9) Studies on chondrogenesis and osteogenesis using
human fibrin and adipose stromal cells.
10) Studies on molecular mechanisms of vasculogenesis and angiogenesis in the mouse embryo.
11) Studies on molecular pathogenesis of holoprosencephaly using a mouse model.
12) Studies on MMPs and TIMPs expressed in keloid.

13) Studies on the cultured epidermal cells and thecell adhesive function.
14) Studies on clinical application and growth factor
extraction of a fluid from continuous suction
drainage.
15) Studies on mechanism of biological effects ofretinoids on epidermis and dermis.
16) Studies on regeneration of peripheral nerves.
17) Studies on monitoring tissue circulation using
flexible optical probe.

References (2016)
1: Iida T, Yoshimatsu H, Yamamoto T, Koshima I.A
pilot study demonstrating the feasibility of supermicrosurgical end-to-side anastomosis onto large
recipient vessels in head and neck reconstruction.J
Plast Reconstr Aesthet Surg. 2016 Dec;69(12):1662-1668. doi: 10.1016/j.bjps.2016.09.018. Epub
2016 Sep 28.PMID: 27789210
2: Yoshimatsu H, Yamamoto T, Hayashi A, Iida
T.Proximal-to-Distally
Elevated
Superficial
Circumflex Iliac Artery Perforator Flap Enabling
Hybrid Reconstruction.Plast Reconstr Surg. 2016
Oct;138(4):910-22. doi: 10.1097/PRS. PMID:
27673522
3: Hara H, Mihara M, Anan T, Fukumoto T,
Narushima M, Iida T, Koshima I.Pathological
Investigation of Acquired Lymphangiectasia
Accompanied by Lower Limb Lymphedema:
Lymphocyte Infiltration in the Dermis andEpidermis. Lymphat Res Biol. 2016 Sep;14(3):172-80. doi: 10.1089/lrb.2016.0016. Epub 2016
Sep 6. PMID: 27599121
4: Yamamoto T, Yoshimatsu H, Yamamoto N.
Complete lymph flow reconstruction: A freevascularized lymph node true perforator flap
transfer with efferent lymphaticolymphatic
anastomosis. J Plast Reconstr Aesthet Surg. 2016
Sep;69(9):1227-33. doi: 10.1016/j.bjps.2016.06.
028. Epub 2016 Jul 2.PMID: 27449876
5: Fujisawa K, Yamamoto T, Saito T, Ishiura R, Iida
T.
Inguinal seroma prevention by reverse
mapping using inodocyanine green lymphography.
Microsurgery. 2016 Sep;36(6):525-6. doi: 10.
1002/micr.22468. Epub 2015 Aug 25. No abstract
available. PMID: 26303783

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6: Tashiro K, Shibata T, Mito D, Ishiura R, Kato M,
Yamashita S, Narushima M, Iida T, Koshima I.
Indocyanine Green Lymphographic Signs ofLymphatic Collateral Formation in Lower
Extremity Lymphedema After Cancer Resection.
Ann Plast Surg. 2016 Aug;77(2):213-6. doi:
10.1097/SAP. PMID: 26418772
7: Mihara M, Hara H, Tange S, Zhou HP, Kawahara
M, Shimizu Y, Murai N. Multisite Lymphaticovenular Bypass Using Supermicrosurgery
Technique for Lymphedema Management in
Lower Lymphedema Cases. Plast Reconstr Surg.
2016 Jul;138(1):262-72. doi: 10.1097/PRS.
PMID: 27348659
8: Narushima M, Iida T, Kaji N, Yamamoto T,
Yoshimatsu H, Hara H, Kikuchi K, Araki J,
Yamashita S, Koshima I. Superficial circumflex
iliac artery pure skin perforator-based uperthin
flap for hand and finger reconstruction. J Plast
Reconstr Aesthet Surg. 2016 Jun;69(6):827-34.
doi: 10.1016/j.bjps.2016.03.005. Epub 2016 Mar
26.PMID: 27085610
9: Yamamoto N, Yamamoto T, Hayashi N, Hayashi
A, Iida T, Koshima I. Arm Volumetry Versus
Upper Extremity Lymphedema Index: Validity ofUpper Extremity Lymphedema Index for
Body-Type Corrected Arm Volume Evaluation.
Ann Plast Surg. 2016 Jun;76(6):697-9. doi:
10.1097/SAP. PMID: 25003442
10: Yamamoto T, Ishiura R, Hayashi A, Yoshimatsu H,
Iida T. Hands-free vein visualizer for preoperative
assessment of recipient veins. Microsurgery. 2016
May;36(4):351-2. doi: 10.1002/micr.22449. Epub2015 Jul 7. No abstract available. PMID:
26152884
11: Yamamoto T, Yamamoto N, Yamashita M, Furuya
M, Hayashi A, Koshima I.Efferent Lymphatic
Vessel Anastomosis: Supermicrosurgical Efferent
Lymphatic Vessel-to-Venous Anastomosis for theProphylactic
TreatmentofSubclinical
Lymphedema.Ann Plast Surg. 2016 Apr;76(4):424-7. doi: 10.1097/SAP.PMID: 25389716
12: Tashiro K, Yamashita S, Araki J, Narushima M,
Iida T, Koshima I.Preoperative color Doppler
ultrasonographic examination in the planning ofthoracodorsal artery perforator flap with capillary
perforators.J Plast Reconstr Aesthet Surg. 2016

Mar;69(3):346-50. doi: 10.1016/j.bjps.2015.10.
026. Epub 2015 Nov 14.PMID: 26732295
13: Yamamoto T, Yamamoto N, Yamashita M, Furuya
M, Hayashi A, Koshima I. Relationship Between
Lymphedema and Arteriosclerosis: Higher
Cardio-Ankle Vascular Index (CAVI) in
Lymphedematous Limbs. Ann Plast Surg. 2016
Mar;76(3):336-9. doi: 10.1097/SAP. PMID:
25695448
14: Tashiro K, Yamashita S, Saito T, Iida T, Koshima
I. Proximal and distal patterns: Different
spreading patterns of indocyanine green
lymphography in secondary lower extremity
lymphedema. J Plast Reconstr Aesthet Surg. 2016
Mar;69(3):368-75. doi: 10.1016/j.bjps.2015.10.
042. Epub 2015 Nov 5. PMID: 26644082
15: Iida T, Yamamoto T, Yoshimatsu H, Abe N,
Tsuchiya M, Nemoto N, Watanabe S. Supermicrosurgical free sensate superficial circumflex iliac
artery perforator flap for reconstruction of a soft
tissue defect of the ankle in a 1-year-old child.
Microsurgery. 2016 Mar;36(3):254-8. doi: 10.
1002/micr.22525. Epub 2015 Oct 29.PMID:
26510923
16: Yamamoto T, Yoshimatsu H, Hayashi A. A
method of continuous indirect aspiration for field
clearance in lymphatic supermicrosurgery. Microsurgery. 2016 Feb;36(2):175. doi: 10.1002/micr.
22426. Epub 2015 May 19. PMID: 25989528
17: Fuse Y, Yamamoto T, Saito T, Ishiura R, Iida T.
Near-infrared fluorescent swallow test for
detection of the alimentary tract anastomotic
leakage. J Plast Reconstr Aesthet Surg. 2016 Jan;69(1):141. doi: 10.1016/j.bjps.2015.09.019. Epub2015 Oct 9. PMID: 26481925
18: Narushima M, Yamamoto T, Ogata F, Yoshimatsu
H, Mihara M, Koshima I.Indocyanine Green
Lymphography Findings in Limb Lymphedema.J
Reconstr Microsurg. 2016 Jan;32(1):72-9. doi: 10.
1055/s-0035-1564608. Epub 2015 Sep 30. Review.
PMID: 26422172
19: Koshima I, Narushima M, Mihara M, Yamamoto
T, Hara H, Ohshima A, Kikuchi K, Todokoro K,
Seki Y, Iida T, Nakagawa M. Lymphadiposal
Flaps and Lymphaticovenular Anastomoses for
Severe Leg Edema: Functional Reconstruction for
Lymph Drainage System. J Reconstr Microsurg.

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2016 Jan;32(1):50-5. doi: 10.1055/s-00351554935. Epub 2015 Aug 10. Review. PMID:
26258914
20: Iida T, Yoshimatsu H, Tashiro K, Hara H,
Yamamoto T, Narushima M, Koshima I. Reconstruction of a full-thickness, complex nasal
defect that includes the nasal septum using a free,thin superficial inferior epigastric artery flap.
Microsurgery. 2016 Jan;36(1):66-9. doi: 10.1002/
micr.22363. Epub 2014 Dec 4.PMID: 25471263
21: Yamamoto T, Yamamoto N, Furuya M, Hayashi A,
Koshima I.Genital Lymphedema Score: Genital
Lymphedema Severity Scoring System Based on
Subjective Symptoms. Ann Plast Surg. 2016 Jan;77(1):119-21. doi: 10.1097/SAP.PMID: 27300039
22: Yamamoto T, Yamamoto N, Hayashi N, Hayashi
A, Koshima I. Practicality of the Lower Extremity
Lymphedema Index: Lymphedema Index Versus
Volumetry-Based Evaluations for Body-TypeCorrected Lower Extremity Volume Evaluation.
Ann Plast Surg. 2016 Jan;77(1):115-8. doi: 10.
1097/SAP.PMID: 26835820
23: Koshima I, Narushima M, Mihara M, Yamamoto
T, Hara H, Ohshima A, Kikuchi K, Todokoro K,
Seki Y, Iida T, Nakagawa M. Lymphadiposal
Flaps and Lymphaticovenular Anastomoses for
Severe Leg Edema: Functional Reconstruction for
Lymph Drainage System. J Reconstr Microsurg.
2016 Jan;32(1):50-5. doi: 10.1055/s-00351554935. Epub 2015 Aug 10. Review. PMID:
26258914
24: Ito T, Nakagawa R, Ishiura R, Yamamoto T,
Narushima M.Nerve reconstruction after sural
nerve biopsy with supermicrosurgical fascicularturnover flap.J Plast Reconstr Aesthet Surg. 2016
Jan;69(1):146. doi: 10.1016/j.bjps.2015.08.005.
Epub 2015 Aug 18. No abstract available. PMID:
26299828

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Department ofOral-Maxillofacial Surgery
Professor
Tsuyoshi Takato, M.D., Ph.D.

Associate Professor
Takafumi Susami, D.D.S., Ph.D.

Kazuto Hoshi, M.D., Ph.D.

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

Hideto Saijo, D.D.S., Ph.D.

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

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

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

Takahiro Abe, D.D.S., Ph.D.

Fujihara Yuko, D.D.S., Ph.D.

Madoka Sugiyama, D.D.S.

Yuki Kanno, D.D.S.

Takato Inokuchi, D.D.S., Ph.D.

Kazumichi Yonenaga, M.D., D.D.S.

Kosuke Kanke, D.D.S., Ph.D.

Homepage

http://plaza.umin.ac.jp/%7Eoralsurg/

Introduction and Organization
Department of Oral and Maxillofacial Surgery,commenced by Dr. Hisashi Ishihara in 1900, is one ofthe oldest departments in Graduate School of
Medicine, the University of Tokyo. This department
consists of wide variety of specialists, such as oral
surgeons, orthodontists and prosthodontists. We
handle all diseases in the oral-maxillofacial region,such as congenital anomalies, jaw deformities, benign
and malignant tumors, trauma and inflammation.
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 regener-

ative abilities of tissues such as bone, periosteum,
cartilage, perichondrium, vessels, nerve, and skin. At
present, we are focusing on tissue engineering inresearch works especially in bone, cartilage andvessels. Professor Takato had established Tissue
Engineering Division in the University of Tokyo
Hospital and our department has an endowment
department: Department of Cartilage and BoneRegeneration (FUJI SOFT Inc.). The department has 1
associate professor, 1 assistant professor, and several
graduate students. These staffs are focusing ontranslational research works in maxillofacial regions.

Clinical activities
In the outpatient clinic, we have 12 dental treatment
booths, one operation room and one speech therapy
room. Average number of patients treated at outpatient
clinic is approximately 100 per day.

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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 andgingivoplasty 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 byplastic 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 plateplasty 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 teamapproach that consists of oral and maxillofacial
surgeons, orthodontists and prosthodontists. In our
department, patients with congenital dento-facial
deformity are treated by utilizing several techniquessuch as distraction technique, autologous bone graft
technique, and the original artificial bone graft
technique in addition to orthognatic surgery. The
original bone graft is made from patient’s three
dimensional images of CT data and this technique is
now applied for patients.

Education
Teaching activities are divided into two parts; forundergraduate medical students and for postgraduate
dental students. For undergraduate students, we make5 systematic lectures in their second year of specialized course, and one lecture and one week bedsidelearning in final year. Through these curriculums, wedemonstrate the characteristics and treatments of thediseases in oral-maxillofacial region. Teaching isfocused on following points; congenital anomalies
such as cleft lip and palate and branchial arch
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 and orthodontists.
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.
Our aim 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

2316) 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 with craniomaxillofacial 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 tissueengineered 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

Publications(Original articles，Case reports)
1. Hoshi K, Fujihara Y, Saijo H, Asawa Y, Nishizawa S,
Kanazawa S, Uto S, Inaki R, Matsuyama M,
Sakamoto T, Watanabe M, Sugiyama M, Yonenaga
K, Hikita A, Takato T. Implant-type Tissueengineered Cartilage for Secondary Correction of
Cleft Lip-nose Patients: An Exploratory First-inhuman Trial. J Clin Trials. (in press)
2. Fujihara Y, Hikita A, Takato T, Hoshi K. Roles ofmacrophage migration inhibitory factor in cartilage
tissue engineering. J Cell Physiol. (in press)
3. Kanazawa S, Nishizawa S, Takato T, Hoshi K.
Biological roles of glial fibrillary acidic protein as abiomarker in cartilage regenerative medicine. J Cell
Physiol. (in press)
4. Ishibashi M, Hikita A, Fujihara Y, Takato T, Hoshi K.
Human auricular chondrocytes with high proliferation rate show high production of cartilage matrix.
Regenerative Therapy. (in press)
5. Yonenaga K, Nishizawa S, Nakagawa T, Fujihara Y,
Asawa Y, Hikita A, Takato T, Hoshi K. Optimal
conditions of collagenase treatment for isolation ofarticular chondrocytes from aged human tissues.
Regenerative Therapy. (in press)
6. Kubota K, Moriyama M, Furukawa S, Rafiul HASM,
Maruse Y, Jinno T, Tanaka A, Ohta M, Ishiguro N,
Yamauchi M, Sakamoto M, Maehara T, Hayashida
JN, Kawano S, Kiyoshima T, Nakamura S.
CD163(+)CD204(+) tumor-associated macrophages
contribute to T cell regulation via interleukin-10 and
PD-L1 production in oral squamous cell carcinoma.
Sci Rep. (in press)
7. Kawase-Koga Y, Mori Y, Fujii Y, Kanno Y, Chikazu
D, Susami T, Takato T. Complications after intraoral
vertical ramus osteotomy: relationship to the shapeof the osteotomy line. Int J Oral Maxillofac Surg.
2016 Feb; 45(2): 200-4.
8. Satake R, Komura M, Komura H, Kodaka T,
Terawaki K, Ikebukuro K, Komuro H, Yonekawa H,
Hoshi K, Takato T, Nakayama Y. Patch tracheoplasty
in body tissue engineering using collagenous
connetive tissue membranes (biosheets). J Pediatr
Surg. 2016 Feb; 51(2): 244-8.
9. Zong L, Abe M, Ji J, Zhu WG, Yu D. Tracking theCorrelation between CpG Island Methylator
Phenotype, and other Molecular Features andClinicopathological Features in Colorectal Cancers:
A Systematic Review and Meta-Analysis. Clin andTransl Gastroenteol. 2016 Mar; 7: e151.
10. Saijo H, Sugiyama M, Kanno Y, Ohkubo K, Hoshi K,
Takato T. A 2-Stage Reconstruction of the Jaw Using
Vascularized Bone and Secondary Alveolar Ridge
Augmentation With Particulate Cancellous Bone andMarrow. Implant Dent. 2016 Apr; 25(2): 302-6.
11. Chang SH, Yasui T, Taketomi S, Matsumoto T,
Kim-Kaneyama JR, Omiya T, Hosaka Y, Inui H,

232

Omata Y, Yamagami R, Mori D, Yano F, Chung UI,Tanaka S, Saito T. Comparison of mouse and humanankles and establishment of mouse ankle osteoarthritis models by surgically-induced instability.
Osteoarthritis Cartilage. 2016 Apr; 24(4):688-97.
12. Hori N, Abe T, Sato T, Kokabu S, Shimamura Y,
Sato T, Yoda T. Data in support of the bone analysis
of NOD-SCID mice treated with zoledronic acid andprednisolone. Data Brief. 2016 Apr; 7: 1486-90.
13. Fujihara Y, Nitta N, Misawa M, Hyodo K, Shirasaki
Y, Hayashi K, Kosaka R, Homma K, Numano T,
Kuribayashi S, Watanabe Y, Sato J, Ohtomo K,
Takato T, Hoshi K. T2 and Apparent Diffusion
Coefficient of MRI Reflect Maturation of TissueEngineered Auricular Cartilage Subcutaneously
Transplanted in Rats. Tissue Eng Part C Methods.
2016 May; 22(5): 429-38.
14. Sato T, Suenaga H, Sugiyama M, Hoshi K, Takato T.
Rare case report of huge Inflammatory Pseudotumorof the Mandible. J Oral Maxillofac Surg Med Pathol.
2016 May; 28(3): 222–227.
15. Abe M, Yamashita S, Mori Y, Abe T, Saijo H, Hoshi
K, Ushijima T, Takato T. High-risk oral leukoplakia is associated with aberrant promoter methylation of multiple genes. BMC Cancer. 2016 Jun;
16(1): 350
16. Suenaga H, Taniguchi A, Yonenaga K, Hoshi K,
Takato T. Computer-assisted preoperative simulation
for positioning of plate fixation in Lefort I
osteotomy: A case report. J Formos Med Assoc.
2016 Jun; 115(6): 470-4.
17. Abe T, Sato T, Kokabu S, Hori N, Shimamura Y,
Sato T, Yoda T. Zoledronic acid increases thecirculating soluble RANKL level in mice, with afurther increase in lymphocyte-derived soluble
RANKL in zoledronic acid- and glucocorticoidtreated mice stimulated with bacterial lipopolysaccharide. Cytokine. 2016 Jul; 83: 1-7.
18. Hoshi K, Fujihara Y, Mori Y, Asawa Y, Kanazawa S,
Nishizawa S, Misawa M, Numano T, Inoue H,
Sakamoto T, Watanabe M, Komura M, Takato T.
Production of three-dimensional tissue-engineered
cartilage through mutual fusion of chondrocyte
pellets. Int J Oral Maxillofac Surg. 2016 Sep; 45(9):1177-85.
19. Kashiwagi M, Hojo H, Kitaura Y, Maeda Y, Aini H,
Takato T, Chung UI, Ohba S. Local administrationof a hedgehog agonist accelerates fracture healing ina mouse model. Biochem Biophys Res Commun.
2016 Oct; 479(4): 772-778.
20. Suenaga H, Taniguchi A, Yonenaga K, Hoshi K,
Takato T. Computer-assisted preoperative simulation
for positioning and fixation of plate in 2-stage
procedure combining maxillary advancement by
distraction technique and mandibular setback
surgery. Int J Surg Case Rep. 2016 Oct; 28: 246-250.
21. Yonenaga K, Maita H, Yonehara Y, Namaki S,
Suenaga H, Takato T. Ossification of the anterior
longitudinal ligament found during upper endoscopy
for dysphagia. Oral Science International. 2016 Oct;13(2): 41-43
22. Kobayashi H, Chang SH, Mori D, Itoh S, Hirata M,
Hosaka Y, Taniguchi Y, Okada K, Mori Y, Yano F,
Chung UI, Akiyama H, Kawaguchi H, Tanaka S,
Saito T. Biphasic regulation of chondrocytes by Relathrough induction of anti-apoptotic and catabolic
target genes. Nat Commun. 2016 Nov; 7: 13336.
23. Kanno Y, Nakatsuka T, Saijo H, Fujihara Y, Hikita A,
Chung UI, Takato T, Hoshi K. Computed
tomographic evaluation of novel custom-madeartificial bones, “CT-bone”, applied for maxillofacialreconstruction. Regenerative Therapy. 2016 Dec; 5:
1-8.
24. Saijo H, Fujihara Y, Kanno Y, Hoshi K, Hikita A,
Chung U-I, Takato T. Clinical experience of
fullcustom-madeartificial
bones
for
the
maxillofacial region. Regenerative Therapy. 2016
Dec; 5: 72-8.
25. Abe M, Hoshi K, Shojima M, Ushiku T, Suenaga H,
Yonenaga K, Kobayashi K, Zong L, Abe T, andTakato T.
A large pyogenic granuloma withextensive maxillary bone resorption penetrating themaxillary sinus: a rare case report. Journal of Oral
Maxillofacial Surgery, Medicine, and Pathology. (inpress).
26. Kanazawa S, Nishizawa S, Takato T, Hoshi K.
Biological Roles of Glial Fibrillary Acidic Protein asa Biomarker in Cartilage Regenerative Medicine. J
Cell Physiol. (in press)
27. Horie N, Hikita A, Nishizawa S, Uto S, Takato T,
Hoshi K. Impairment of the transition fromproliferative stage to prehypertrophic stage inchondrogenic differentiation of human induced
pluripotent stem cells harboring the causative

233

mutation of achondroplasia in fibroblast growth
factor receptor 3. Regenerative Therapy. (in press)
28. Watanabe S, Ogasawara T, Tamura Y, Saito T, Ikeda
T, Suzuki N, Shimosawa T, Shibata S, Chung UI,Nangaku M, Uchida S.,Targeting gene expression to
specific cells of kidney tubules in vivo using
adenoviral promoter fragments. PLoS One. (inpress)
29. Wang J, Suenaga H, Yang L, Kobayashi E, Sakuma I.
Video See-Through Augmented Reality for Oral andMaxillofacial Surgery. Int J Med Robot. (in press)
30. Yonenaga K, Majima H, Oyama S, Ishibashi K,
Tanno H. Diagnosis and evaluation of 100 dysphagia
patients using videoendoscopy at a core hospital of a
local city in Japan. Odontology. (in press)
31. Yonenaga K, Nishizawa S, Nakagawa T, Fujihara Y,
Asawa Y, Hikita A, Takato T, Hoshi K. Protocol forcollagenase digestion of articular cartilage based on
differences in the biological characteristics ofarticular and auricular cartilage. Regenerative
Therapy (in press)
32. Taniguchi Y, Kawata M, Ho Chang S, Mori D,
Okada K, Kobayashi H, Sugita S, Hosaka Y, Inui H,
Taketomi S, Yano F, Ikeda T, Akiyama H, Mills AA,
Chung UI, Tanaka S, Kawaguchi H, Saito
T.Regulation of Chondrocyte Survival in Mouse
Articular Cartilage by p63. Arthritis Rheumatol. (inpress)(Review articles)
1. Hikita A, Chung UI, Hoshi K, Takato T. BoneRegenerative Medicine in Oral and Maxillofacial
Region Using a Three-Dimensional Printer. Tissue
Eng Part A. 2017 Jun; 23(11-12):515-521.
2. Takato T. Tissue Engineering in Bone: The
Contention of a Hundred Schools of Thought. Artif
Organs. 2016 Apr;40(4):331-3.
3. Zong L, Abe M, Seto Y, Ji J. A Randomized
Controlled Trial of Laparoscopic Versus Open D2Distal Gastrectomy for Advanced Gastric Cancer:
How Should We Define the Age of Included
Patents? J Clin Oncol 2016 Aug; 34(30): 3706.
4. Zong L, Abe M, Seto Y, Ji J. Challenge of China’s
diagnosis of early gastric cancer. Lancet 2016
Nov; 388(10060):2606.

234

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

Associate Professors
Hirotaka Chikuda, M.D., Ph.D.

Lecturers
Taku Saito, M.D., Ph.D.

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

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

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

Associates
Hiroshi Inui, M.D.

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.

Masashi Naito, M.D.

Yo Fujimoto, M.D.

Masato Anno, M.D.

Masachika Ikegami, M.D.

Ryoko Sawada, M.D.

Nobuyuki Shirakawa, M.D.

Taizo Kaneko, M.D.

Yoshihiko Tabira, 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

235(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, 4 lecturers, 15
associates, 9 medical staff members, 8 senior residents,
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 13 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 36,051 patients
visited the outpatient clinic in fiscal 2016.
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.
1,339 operations were performed in fiscal 2016.
These include 284 spine surgeries, 41 surgeries forrheumatoid arthritis patients, 137 hip surgeries, 267
knee surgeries (including 48 computer-assisted ACL
reconstructions, 80 computer-assisted TKA, 42 UKA),
244 hand surgeries, 62 foot and ankle surgeries, 38

236

pediatric surgeries, 112 surgeries for bone and soft
tissue tumor, and 162 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. Five
endowment departments take an active role inresearch activities in close collaboration with ourdepartment. Three were established in the 22nd
Century Medical Center. They deal with clinicalresearch, which houses the largest clinical database of
osteoarthritis patients in the world for the pursue ofgenomic and etiological research. One department isin the Division of Tissue Engineering, which seeks todevelop epochal bone and cartilage regenerative
medicine. In the collaboration of the departments, theROAD (research on osteoarthritis against disability)
study has been established as the biggest bone andjoint diseases project that covers from basic to clinicalresearches of the disease. The fourth is founded in the
Graduate School of Medicine and the researchers aredeveloping durable artificial joints in cooperation with
the Ishihara Laboratory of the Graduate School ofEngineering. Furthermore, we collaborate with theCenter for Disease Biology and Integrative Medicine(CDBIM), and are developing nonviral gene delivery
systems.
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 we have been getting achievement in the
new research topics such as “Osteoimmunology”, a
new research field studying on signaling cross-talk237

between bone metabolism and immunology, or“Epigenetics”, new research 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. Recently, weestablished mouse models for ankle osteoarthritis
and intervertebral disc degeneration. We further foundnovel roles of NF-κB signaling in articular cartilage.
We are also engaged in cartilage regenerative researchusing iPS cells with Dept. of Tissue Engineering.
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.

References
1. Tsuda Y, Yasunaga H, Horiguchi H, Fushimi K,
Kawano H, Tanaka S: Complications andPostoperative Mortality Rate After Surgery for
Pathological Femur Fracture Related to Bone
Metastasis: Analysis of a Nationwide Database.
Ann Surg Oncol 2016,23:801-810
2. Koyama T, Tanaka S: Mechanism of bone
destruction in rheumatoid arthritis and perspectives of the treatment. Clin Calcium 2016,26:
735-741
3. Iwata S, Uehara K, Ogura K, Akiyama T, Shinoda
Y, Yonemoto T, Kawai A: Reliability and Validityof a Japanese-language and Culturally Adapted
Version of the Musculoskeletal Tumor Society
Scoring System for the Lower Extremity. Clin
Orthop Relat Res 2016, 474:2044-2052
4. Kato S, Fehlings M: Degenerative cervicalmyelopathy. Curr Rev Musculoskelet Med 2016,
9:263-271
5. Matsumoto T, Shah R, Dave M, Shah N, Parekh
SG: Hallux Varus: An Under Reported Presentation of Rheumatoid Arthritis.Foot Ankle Spec
2016,9:169-173

6. Matsubayashi Y, Shimizu T, Chikuda H, Takeshita
K, Oshima Y, Tanaka S: Correlations of Cervical
Sagittal Alignment before and after Occipitocervical Fusion. Global Spine J 2016,6:362-369
7. Inui H, Taketomi S, Yamagami R, Sanada T,
Shirakawa N, Tanaka S: Impingement of the
Mobile Bearing on the Lateral Wall of the Tibial
Tray in Unicompartmental Knee Arthroplasty. J
Arthroplasty 2016,31:1459-1464
8. Nakajima K, Taketomi S, Inui H, Nakamura K,
Sanada T, Tanaka S: Missed Medial Malleolar
Fracture Associated With Achilles Tendon
Rupture: A Case Report and Literature Review. J
Foot Ankle Surg 2016,55:169-172
9. Miyamoto H, Serradori T, Mikami Y, Selber J,
Santelmo N, Facca S, Liverneaux P : Robotic
intercostal nerve harvest: a feasibility study in a
pig model. J Neurosurg 2016, 124: 264-268
10. Kato S, Debaud C, Zeller RD: Three-dimensional
EOS Analysis of Apical Vertebral Rotation in
Adolescent Idiopathic Scoliosis. J Pediatr Orthop
2016, Epub ahead of print
11. Taniguchi Y, Chikuda H, Oshima Y, Ohya J,
Matsubayashi Y, Morikawa T, Shirai H, Sasaki O,
Shibuya M, Fujio K, Yamamoto K, Tanaka S:
Thoracic intradural extramedullary lesions
causing progressive myelopathy as an initial
manifestation of granulomatosis with polyangiitis:
a case report and review of literature. J Spinal
Cord Med 2016, Epub 2016 Apr 22
12. Inui H, Taketomi S, Yamagami R, Sanada T,
Tanaka S : Twice cutting method reduces tibial
cutting error in unicompartmental knee arthroplasty. Knee 2016,23:173-176
13. Yamagami R, Taketomi S, Inui H, Sanada T,
Nakagawa T, Tanaka S: Myositis ossificans afternavigated knee surgery: A report of two cases andliterature review. Knee 2016,23:561-564
14. Inui H, Taketomi S, Yamagami R, Tahara K,
Tanaka S: Snapping Pes Syndrome after Unicompartmental Knee Arthroplasty. Knee Surg
Relat Res 2016,28:172-175
15. Inui H, Taketomi S, Tahara K, Yamagami R,
Sanada T, Tanaka S: A modified technique toreduce tibial keel cutting errors during an Oxford
unicompartmental knee arthroplasty. Knee SurgSports Traumatol Arthrosc 2016,e-pub

238

16. Kodama R, Muraki S, Oka H, Iidaka T, Teraguchi
M, Kagotani R, Asai Y, Yoshida M, Morizaki Y,
Tanaka S, Kawaguchi H, Nakamura K, Akune T,
Yoshimura N: Prevalence of hand osteoarthritis
and its relationship to hand pain and grip strength
in Japan: The third survey of the ROAD study.
Mod Rheumatol 2016,26:767-773
17. Yasui T, Nishino J, Shoda N, Koizumi Y, Ohashi S,
Kadono Y, Tanaka S, Tohma S: Prevalence of total
knee arthroplasty and its predictive factors inJapanese patients with rheumatoid arthritis:
Analysis using the NinJa cohort. Mod Rheumatol
2016,26:36-39
18. Ohya J, Oshima Y, Chikuda H, Oichi T, Matsui H,
Fushimi K, Tanaka S, Yasunaga H: Does the
microendoscopic technique reduce mortality andmajor complications in patients undergoing
lumbar discectomy? A propensity score-matchedanalysis using a nationwide administrative
database. Neurosurg Focus 2016,40:E5
19. Chang SH, Yasui T, Taketomi S, Matsumoto T,
Kim-Kaneyama JR, Omiya T, Hosaka Y, Inui H,
Omata Y, Yamagami R, Mori D, Yano F, Chung U,
Tanaka S, Saito T: Comparison of mouse andhuman ankles and establishment of mouse
ankleosteoarthritis models by surgically-induced
instability. Osteoarthritis Cartilage 2016,24:68897
20. Omata Y, Nakamura S, Koyama T, Yasui T, Hirose
J, Izawa N, Matsumoto T, Imai Y, Seo S,
Kurokawa M, Tsutsumi S, Kadono Y, Morimoto C,
Aburatani H, Miyamoto T, Tanaka S: Identification of Nedd9 as a TGF-ﾎｲ-Smad2/3 Target Gene
Involved in RANKL-Induced Osteoclastogenesis
by Comprehensive Analysis. PLoS One2016, 11:e0157992
21. Kato S, Lewis SJ: Temporary Iliac Fixation to
Salvage an Acute L4 Chance Fracture Following
Pedicle Screw Fixation for Adolescent Idiopathic
Scoliosis. Spine (Phila Pa 1976) 2016, Epubahead of print
22. Oshima Y, Takeshita K, Taniguchi Y,
Matsubayashi Y, Doi T, Ohya J, Soma K, Kato S,
Oka H, Chikuda H, Tanaka S: Effect ofPreoperative Sagittal Balance on CervicalLaminoplasty Outcomes. Spine (Phila Pa 1976)
2016, Epub ahead of print

23. Kato S, Chikuda H, Ohya J, Oichi T, Matsui H,
Fushimi K, Takeshita K, Tanaka S, Yasunaga H:
Risk of infectious complications associated withblood transfusion in elective spinal surgery-apropensity score matched analysis. Spine J 2016,
16:55-60
24. Miyamoto H, Morizaki Y, Kashiyama T, Tanaka
S: Grey-scale sonography and sonoelastography
for diagnosing carpal tunnel syndrome. World JRadiol 2016,8:281-28
25. Kato S, Shamji MF: My Crooked and Aching
Neck-SurgicalManagementofCervicalDeformity. World Neurosurg 2016,91:644-666
26. Kobahashi H, Chang SH, Mori D, Itoh S, Hirata
M, Hosaka Y, Taniguchi Y, Okada K, Mori Y,
Yano F, Chung UI, Akiyama H, Kawaguchi H,
TanakaS, and Saito T. Biphasic regulation ofchondrocytes by Rela through induction ofanti-apoptotic and catabolic target genes. Nat
Commun. 7:13336, 2016.
27. Aini H, Itaka K, Fujisawa A, Uchida H, Uchida S,
Fukushima S, Kataoka K, Saito T, Chung UI,
Ohba S. Messenger RNA delivery of a cartilageanabolic transcription factor as a diseasemodifying strategy for osteoarthritis treatment. Sci
Rep. 6:18743, 2016.

239

Department of Ophthalmology
Professor
Makoto Aihara, M.D., Ph.D.

Associate Professor
Satoshi Kato, M.D., Ph.D., Toshikatsu Kaburaki, M.D., Ph.D., Tomohiko Usui, M.D., Ph.D.

Lecturer
Megumi Honjyo, 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.,
Hiroshi Murata, M.D., Takashi Fujishiro, M.D., Ph.D.,
Tatsuya Inoue, M.D., Ph.D., Rei Sakata, M.D., Tetsuya Toyono, M.D., Ph.D.,
Fumiyuki Araki, M.D., Ph.D., Rie Tanaka, M.D., Rika Shirakawa, M.D., Ph.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 44
beds. Residents work in the ambulatory section andtake care of inpatients. Special services are provided
in units devoted to ophthalmic subspecialties such as

cornea, glaucoma, retina, uveitis, neuro-ophthalmology, orthoptics, diabetic retinopathy, and genetic
and color blindness problems. The staff members
supervise the ambulatory and special services
depending on each one’s specialty.
Most of the inpatients suffer from cataract, glaucoma,
corneal diseases, retinal detachment, diabetic
retinopathy, 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.

Teaching activities
As an undergraduate course, we give lectures on
corneal physiology, corneal diseases, and corneal

240transplantation. In addition, we are engaged inpractical 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.
2.

Research activities
Research 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. Analysis with laser-speckle method of vascularflow in retina and iris
3. Clinical investigation of normal tension glaucoma
4. Drug development in IOP reduction of glaucoma
5. Screening method of glaucoma
6. Tissue engineering of the cornea
7. Molecular analysis of corneal neovascularization
8. Gene therapy for corneal dystrophies
9. Analysis of Meibomian gland with Mibography
10. Analysis of safety of topical eye drops using
human corneal epithelial cell sheets
11. Molecular analysis of retinal degenerative diseases
12. Color blindness and visual function
13. Electrophysiological analysis of the effect ofdrugs on the retina
14. Pathophysiology of age-related macular degeneration
15. Molecular analysis of retinal neovascularization
16. Immuno-hereditary analysis of Harada’s disease
and Bechet’s disease
17. Immunosuppressive reagents on Bechet’s disease
18. Pathophysiology and molecular mechanisms of
diabetic retinopahty

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

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

Akinobu Kakigi, M.D., Ph.D.

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

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

Shotaro Karino, M.D., Ph.D．

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

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

Naoya Egami, M.D., Ph.D.

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

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

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

Sayaka Suzuki, M.D., Ph.D.

Chisato Fujimoto, M.D, Ph.D

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

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

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

Makoto Kinoshita, M.D., Ph.D.

Ken Akashi, M.D., Ph.D.

Osamu Fukuoka, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/orl /Introduction and Organization
The Department of Otorhinolaryngology was
founded in 1899 by Prof. Waichiro Okada who studiedin Germany. This is the first department ofotorhinolaryngology of the national university in Japan.
Our department covers all otorhinolaryngologicaldiseases and associated systemic diseases, and has
specialized clinics in middle ear and inner ear diseases,
hearing impaired infant and children, adult and elderly
patients, facial paresis, vertigo and balance disorders,olfactory disorders and paranasal diseases, voice andspeech disorders, taste and swallowing respiratory

disorders, aphasia, central auditory disorders and head& neck cancers.
A professor, associate professors, lecturers (assistantprofessors) and associates participate in surgery, outpatient and in-patient care as well as research andeducational activities. Moreover 12 Japanese graduate
students and one Chinese foreign graduate student
participate in basic research.
Weekly preoperative and postoperative conferences
are held to discuss surgical cases in detail. Special
lectures on leading research activities are presented byinvited guests on a regular basis. A weekly journal club246

is 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.
In the new inpatient hospital, 44 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 indevelopment 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.

24714) 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 conductedby staffs, residents, and graduate students as well as
doctors at affiliated hospitals.

References
1. Ando M, Kawazu M, Ueno T, Koinuma D, Ando
K, Koya J, Kataoka K, Yasuda T, Yamaguchi H,
Fukumura K, Yamato A, Soda M, Sai E,
Yamashita Y, Asakage T, Miyazaki Y, Kurokawa
M, Miyazono K, Nimer SD, Yamasoba T, Mano H.
Mutational Landscape and Antiproliferative
Functions of ELF Transcription Factors in Human
Cancer. Cancer Res 76(7): 1814-24, 2016
2. Anraku Y, Kishimura A, Kamiya M, Tanaka S,
Nomoto T, Toh K, Matsumoto Y, Fukushima S,
Sueyoshi D, Kano MR, Urano Y, Nishiyama N,
Kataoka K. Systemically Injectable EnzymeLoaded Polyion Complex Vesicles as In Vivo
Nanoreactors Functioning in Tumors. Angew
Chem Int Ed Engl 55(2): 560-5, 2016
3. Egami N, Kakigi A, Takeda T, Yamasoba T.
Dehydration effects of V2 antagonist on
endolymphatic hydrops in guinea pigs. Hearing
Research 332: 151-159, 2016
4. Fujimoto C, Kinoshita M, Kamogashira T, Egami
N, Sugasawa K, Yamasoba T, Iwasaki S.
Characteristics of vertigo and the affectedvestibular nerve systems in idiopathic bilateral
vestibulopathy. Acta Otolaryngol 136: 43-47, 2016
5. Fujimoto C, Yamamoto Y, Kamogashira T,
Kinoshita M, Egami N, Uemura Y, Togo F,
Yamasoba T, Iwasaki S. Noisy galvanic vestibular
stimulation induces a sustained improvement inbody balance in elderly adults. Sci Rep 6; 37575,
2016.
6. Hiraishi Y, Nambu A, Shibui A, Nakanishi W,
Yamaguchi S, Morita H, Iikura M, McKenzie AN,
Matsumoto K, Sudo K, Yamasoba T, Nagase T,
Nakae S. TIM-3 is not essential for development of

airway inflammation induced by house dust mite
antigens. Allergol Int 65(4): 459-465, 2016
7. Inoue A, Egami N, Fujimoto C, Kinoshita M,
Yamasoba T, Iwasaki S. Vestibular Evoked
Myogenic Potentials in Vestibular Migraine: Do
They Help Differentiating From Menière's
Disease? Ann Otol Rhinol Laryngol 125: 931937, 2016
8. Ishimaru M, Ono S, Suzuki S, Matsui H, Fushimi
K, Yasunaga H. Risk Factors for Free Flap Failure
in 2,846 Patients With Head and Neck Cancer: A
National Database Study in Japan. J Oral
Maxillofac Surg 74: 1265-70, 2016
9. Iwamura H, Kondo K, Sawamura H, Baba S,
Yasuhara K, Yamasoba T. Amblyopia Associatedwith Congenital Facial Nerve Paralysis. ORL J
Otorhinolaryngol Relat Spec 78(2): 105-10, 2016
10. Kamogashira T, Akamatsu Y, Kashio A, Ogata E,
Karino S, Kakigi A, Iwasaki S, Yamasoba T.
Development of auditory skills after cochlear implantation in children with inner ear malformations.
Acta Otolaryngol 136(1): 78-82, 2016
11. Karino S, Usami S, Kumakawa K, Takahashi H,
Tono T, Naito Y, Doi K, Ito K, Suzuki M, Sakata
H, Takumi Y, Iwasaki S, Kakigi A, Yamasoba T.
Discrimination of Japanese monosyllables inpatients with high-frequency hearing loss. Auris
Nasus Larynx 43(3): 269-80, 2016
12. Kashio A, Tejani VD, Scheperle RA, Brown CJ,
Abbas PJ.
Exploring the Source of Neural
Responses of Different Latencies Obtained fromDifferent Recording Electrodes in Cochlear
Implant Users. Audiol Neurootol 21: 141-9, 2016
13. Kikuta S, Matsumoto Y, Kuboki A, Nakayama T,
Asaka D, Otori N, Kojima H, Sakamoto T, Akinori
K, Kanaya K, Ueha R, Kagoya R, Nishijima H,
Toma-Hirano M, Kikkawa Y, Kondo K, Tsunoda
K, Miyaji T, Yamaguchi T, Kataoka K, Mori K,
Yamasoba T. Longer latency of sensory response
to intravenous odor injection predicts olfactory
neural disorder. Sci Rep. 13: 35361, 2016
14. Kitoh R, Nishio SY, Ogawa K, Okamoto M,
Kitamura K, Gyo K, Sato H, Nakashima T, Fukuda
S, Fukushima K, Hara A, Yamasoba T, Usami S.
SOD1
gene
polymorphisms
insuddensensorineural hearing loss. Acta Otolaryngol136(5): 465-9, 2016

248

15. Matsumoto Y, Nichols JW, Toh K, Nomoto T,
Cabral H, Miura Y, Christie RJ, Yamada N, Ogura
T, Kano MR, Matsumura Y, Nishiyama N,
Yamasoba T, Bae YH, Kataoka K. Vascular bursts
enhance permeability of tumour blood vessels andimprove nanoparticle delivery. Nat Nanotechnol
11(6): 533-8, 2016
16. Nakajima T, Yasuda T, Koide S, Yamasoba T, Obi
S, Toyoda S, Sato Y, Inoue T, Kano Y. Repetitive
restriction of muscle blood flow enhances mTOR
signaling pathways in a rat model. Heart Vessels
31(10): 1685-95, 201617. Nakanishi W, Hiraishi Y, Yamaguchi S, Takamori
A, Morita H, Matsumoto K, Saito H, Sudo K,
Yamasoba T, Nakae S. TSLP receptor is notessential for house dust mite-induced allergic
rhinitis in mice. Biochemistry and Biophysics
Reports 7: 119-123, 201618. Nishijima H, Kondo K, Toma-Hirano M, Iwasaki
S, Kikuta S, Fujimoto C, Ueha R, Kagoya R,
Yamasoba T. Denervation of nasal mucosa inducedby posterior nasal neurectomy suppresses nasal
secretion, not hypersensitivity, in an allergic
rhinitis rat model. Lab Invest 96(9): 981-93, 2016.
19. Ochi A, Yamasoba T, Furukawa S. Contributionsof Coding Efficiency of Temporal-Structure andLevel Information to Lateralization Performance inYoung and Early-Elderly Listeners. Adv Exp Med
Biol. 894: 19-28 2016
20. Oka M, Ueha R, Nito T, Yamasoba T. Giantfibrovascular polyp in the hypopharynx: a casereport and review of the literature. Springerplus
5(1): 1443, 2016
21. Omura G, Ando M, Saito Y, Kobayashi K,
Yamasoba T, Asakage T. Comorbidities aspredictor poor prognosis for advanced head andneck cancer Patients treated with major surgery.
Head Neck. 38: 364-369, 2016.
22. Omura G, Ando M, Saito Y, Kobayashi K, Yoshida
M, Ebihara Y, Kanaya K, Fujimoto C, Sakamoto T,
Kondo K, Asakage T, Yamasoba T. Association of
the upregulated expression of focal adhesion
kinase with poor prognosis and tumor
dissemination in hypopharyngeal cancer. Head
Neck 38(8): 1164-9, 2016
23. Omura S, Nakaya M, et al. A clinical review of 38
cases of cervical tuberculous lymphadenitis inJapan - The role of neck dissection. Auris Nasus
Larynx 43: 672-676, 201624. Saito Y, Ando M, Fujimoto C, Omura G,
Kobayashi K, Asakage T, Yamasoba T. Human
Papillomavirus 16 Physical Status and the TP53
Codon 72 Polymorphism in Japanese HPVPositive Oropharyngeal Cancer Patients. ORL J
Otorhinolaryngol Relat Spec 78: 46-54, 201625. Saito Y, Ando M, Omura G, Yasuhara K, Yoshida
M, Yamasoba T. Induction Chemotherapy for p16
Positive Oropharyngeal Squamous Cell Carcinoma.
Laryngoscope investigative otolaryngology 1: 2832, 201626. Shin M, Kondo K, Hanakita S, Hasegawa H,
Yoshino M, Teranishi Y, Kin T, Saito N.
Endoscopic transsphenoidal anterior petrosal
approach for locally aggressive tumors involving
the internal auditory canal, jugular fossa, andcavernous sinus. J Neurosurg 126: 212-221, 201627. Suzuki M, Sakamoto T, Kashio A, Yamasoba T.
Age-related morphological changes in thebasement membrane in the stria vascularis of
C57BL/6 mice. European Archives of Oto-RhinoLaryngology; 273:57-62,2016
28. Suzuki S, Yasunaga H, Matsui H, Fushimi K, Saito
Y, Yamasoba T. Factors Associated With Neck
Hematoma After Thyroidectomy: A Retrospective
Analysis Using a Japanese Inpatient Database.
Medicine (Baltimore) 95(7): e2812, 201629. Suzuki S, Yasunaga H, Matsui H, Fushimi K,
Yamasoba T. Factors associated with prolonged
duration of post-tympanoplasty local treatment in
adult chronic otitis media patients: A retrospective
observational study using a Japanese inpatient
database. Auris Nasus Larynx 43(4): 377-81, 201630. Suzuki S, Yasunaga H, Matsui H, Fushimi K, Saito
Y, Yamasoba T. Cerebral infarction after
intraarterial and intravenous chemoradiotherapy
for head and neck cancer: A retrospective analysis
using a Japanese inpatient database. Head Neck38(9): 1354-8, 201631. Suzuki S, Yasunaga H, Matsui H, Horiguchi H,
Fushimi K, Yamasoba T. Pharyngocutaneous
fistula and delay in free oral feeding after
pharyngolaryngectomy for hypopharyngeal cancer.
Head Neck Suppl 1: E625-30, 2016

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32. Ueha R, Ueha S, Sakamoto T, Kanaya K,
Suzukawa K, Nishijima H, Kikuta S, Kondo K,
Matsushima K, Yamasoba T. Cigarette Smoke
Delays Regeneration of the Olfactory Epitheliumin Mice. Neurotox Res 30(2): 213-24, 2016
33. Ueha R, Ueha S, Kondo K, Sakamoto T, Kikuta S,
Kanaya K, Nishijima H, Matsushima K, Yamasoba
T. Damage to Olfactory Progenitor Cells Is
Involved in Cigarette Smoke-Induced Olfactory
Dysfunction in Mice. Am J Pathol 186(3): 579-86,
2016
34. Ueha R, Nito T, Sakamoto T, Yamauchi A,
Tsunoda K, Yamasoba T. Post-operative
swallowing in multiple system atrophy. Eur J
Neurol 23(2): 393-400, 2016
35. Wang M, Miura Y, Tsuchihashi K, Miyano K,
Nagano O, Yoshikawa M, Tanabe A, Makino J,
Mochida Y, Nishiyama N, Saya H, Cabral H,
Kataoka K. Eradication of CD44-variant positive
population in head and neck tumors throughcontrolled intracellular navigation of cisplatinloaded nanomedicines. Journal of Controlled
Release 230: 26-33, 201636. Yamauchi A, Yokonishi H, Imagawa H,
Sakakibara K, Nito T, Tayama N, Yamasoba T.
Visualization and Estimation of Vibratory
Disturbance in Vocal Fold Scar Using High-Speed
Digital Imaging. J Voice 30(4): 493-500, 201637. Yamauchi A, Yokonishi H, Imagawa H,
Sakakibara K, Nito T, Tayama N, Yamasoba T.
Quantification of Vocal Fold Vibration in Various
Laryngeal Disorders Using High-Speed Digital
Imaging. J Voice 30(2): 205-14, 201638. Yamauchi A, Imagawa H, Sakakibara KI,
Yokonishi H, Nito T, Yamasoba T, Goto T,
Takano S, Tayama N. HSDI of the vocal foldvibrations in healthy young & elderly males andfemales. Normal Phonation. Volume II Application. Pacific Voice & Speech Foundation: 19-30,
2016
39. Yamauchi A, Imagawa H, Sakakibara KI,
Yokonishi H, Nito T, Yamasoba T, Tayama N.
Vibratory phase diference of phonation: HSDI
analyzed with laryngotopography. Normal
Phonation. Volume II Application. Pacific Voice &Speech Foundation: 31-40, 201640. Yokonishi H, Imagawa H, Sakakibara K,
Yamauchi A, Nito T, Yamasoba T, Tayama N.
Relationship of Various Open Quotients With
Acoustic Property, Phonation Types, Fundamental
Frequency, and Intensity. J Voice 30(2): 145-57,
2016

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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. Sixteen 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 4,000 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

251

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 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.

5.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with 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

6.

7.

8.

References
1. Amao R, Imamura T, Nakahara Y, Kinoshita O,
Yamauchi H, Ono M, Haga N: Reversible motor
paralysis and early cardiac rehabilitation in9.

patients with advanced heart failure receiving left
ventricular assist device therapy. Int Heart J 57(6):766-768, 2016
Amao R, Imamura T, Sawada Y, Endo S, Ozaki S,
Okamura K, Masuzawa A, Takaoka T, Hirata Y,
Shindo T, Ono M, Haga N: Experiences with
Aggressive Cardiac Rehabilitation in PediatricPatients Receiving Mechanical Circulatory
Supports. Int Heart J 57(6): 769-772, 2016
Goto M, Haga N, Yokota K,Takamizawa K,
Takedani H: A successful physiotherapy management case of a patient with acquired hemophilia A
prior to factor VIII inhibitor eradication.
Haemophilia 22(3): e228-231, 2016
Goto M, Takedani H, Yokota K, Haga N:
Strategies to encourage physical activity inpatients with hemophilia to improve quality of life.
J Blood Med 7: 85-98, 2016
Hasegawa S, Nishimura G, Victoria T, Zackai E,
Kayserili H, Haga N, Nakashima Y, Miyazaki O,
Kitoh H: Characteristic calcaneal ossification: an
additional early radiographic finding in infants
with fibrodysplasia ossificans progressiva.
Pediatric Radiology 46(11): 1568-1572, 2016
Iwashiro S, Koike S, Satomura Y, Suga M, Nagai
T, Natsubori T, Tada M, Gonoi W, Takizawa R,
Kunimatsu A, Yamasue H, Kasai K: Association
between impaired brain activity and volume at the
sub-region of Broca's area in ultra-high risk andfirst-episode schizophrenia: a multi-modal neuroimaging study. Schizophr Res 172(1-3): 9-15,
2016
Iwata S, Uehara K, Ogura K, Akiyama T, Shinoda
Y, Yonemoto T, Kawai A: Reliability and validityof a Japanese-language and culturally adapted
version of the Musculoskeletal Tumor Society
scoring system for the lower extremity. Clin
Orthop Relat Res 474(9): 2044-2052, 2016
Kaneoka A, Pisegna JM, Saito H, Lo M, Felling K,
Haga N, LaValley PM, Langmore SE: A
systematic review and meta-analysis ofpneumonia associated with thin liquid vs.
thickened liquid intake in patients who aspirate.
Clin Rehabil. Epub ahead of print. 2016
Kinoshita Y, Arai M, Ito N, Takashi Y, Makita N,
Nangaku M, Shinoda Y, Fukumoto S: High serum
ALP level is associated with increased risk of252

denosumab-related hypocalcemia in patients withbone metastases from solid tumors. Endocr J
63(5): 479-84, 2016
10. Nakahara Y, Yasunaga H, Inokuchi H, Ogata N,
Horiguchi H, Matsuda S, Fushimi K, Haga N:
Mortality-reducing effect of rehabilitation for
COPD: observational propensity-matched cohort
study using a Nationwide Database. Respir Care61(11): 1497-1504, 2016
11. Nishimura G, Nakajima M, Takikawa K, Haga N,
Ikegawa S: Distinctive skeletal phenotype in highbone mass osteogenesis imperfecta due to a
COL1A2 cleavage site mutation.Am J Med Genet
A 170(8): 2212-2214, 2016
12. Nishimura Y, Kawakubo Y, Suga M, Hashimoto K,
Takei Y, Takei K, Inoue H, Yumoto M, Takizawa
R, Kasai K: Familial influences on mismatch
negativity and its association with plasma
glutamate level: a magnetoencephalographic
study in twins. Mol Neuropsychiatry 2: 161–172,
2016
13. Ohki T, Ushiku T, Shinoda Y, Kobayashi H:
Necrotic lipoma at the posterior thigh mimicking
liposarcoma. BMJ Case Rep 2016 Jan 27, 201614. Suga M, Nishimura Y, Kawakubo Y, Yumoto M,
Kasai K: Magnetoencephalographic recording ofauditory mismatch negativity in response to
duration and frequency deviants in a single
session in patients with schizophrenia. Psychiatry
Clin Neurosci 70(7): 295-302, 2016

Surgical Sciences
3. Vital Care Medicine

254

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
Kyung-Ho Chang, M.D., Ph.D.

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

Takami Komatsu, M.D., Ph.D.

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

Associate
Yoshiteru Mori, M.D.,

Yoshie Suzuki, M.D.,

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

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

Miho Asahara, M.D., Ph.D.

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

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

Yuriko Tashiro, M.D.,

Yoko Hashimoto, M.D.,

Takuma Hiraiwa, M.D.,

Miki Shinokawa, M.D.,

Takuya Ohata, M.D.,
Ai Furuta, M.D.,

Kihoko Ichikawa,M.D.,

Emi Morinushi, M.D.,

Masaaki Asamoto, M.D.,
Michiko Ushio, M.D.,

Atsuko Kato, M.D.,

Yuko Araki, M.D.,

Yasuko Okagami, M.D.,

Seiichiro Kawashima, M.D.,

Toshiharu Tazawa, 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 30 faculty staffs, 12 graduate students and 11
residents. We introduce the activities about Teaching,
Research and 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 increasingin 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 adaily basis in all areas of diseases accompanied with

255

pain. From April 2016 to March 2017, 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. Wetake care 40 patients in our ward and approximately
100 in other wards annually, with multidisciplinary
approach in collaboration with neurologists,
psychiatrist, and orthopedists. Our palliative care teammanages varied somatic symptoms and psychologicaldistress of inpatients and outpatients with cancer.
Further, we manage the “cancer treatment-related
chronic pain management” outpatient clinic and also
the second opinion outpatient clinic for cancer pain
patients with advanced and terminal cancer stages.

Teaching activities
We give lectures for fourth year medical students
and provide clinical education (Clinical Clerkship) for
fifth and sixth year medical students on a man-to-man
basis with our faculty staff members. The lectures ofthe last year were the history of anesthesia, themechanisms of anesthesia, inhalational anesthesia,
intravenous anesthesia, anesthesia and respiratory/
circulatory system, the balance of body fluid, acidbase balance, muscle relaxants, management of thepatient during anesthesia, monitoring, resuscitation,
pain clinic and the physiology and the management ofpain.
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, andinteractive lectures on specific topics. During thepractice of anesthetic management, we teach students
how to evaluate patients in the perioperative period.
Through the practice of pain management, we teachstudents causes of intractable pain as well as treatmentof 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 andmedicine applied perioperatively. We discuss thecontents of the reports 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
mediated by 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 development of 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 general anesthesia
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 invivo17) Role of new plasma substitutes on hemorrhagicshock18) Mechanisms of chemotherapy-induced neuronal
dysfunction

256

Publications(1) Inoue R, Sumitani M, Yasuda T, Tsuji M, Nakamura
M, Shimomura I, Shibata M, Yamada Y.
Independent risk factors for positive and negative
symptoms in patients with diabetic polyneuropathy.
J Pain Palliat Care Pharmacother. 2016 Sep;30(3):178-83.
(2) Sumitani M, Ogata T, Natori A, Hozumi J, Shimojo
N, Kida K, Yamauchi H, Yamauchi T. Poor efficacyof the phosphorylated high-molecular-weightneurofilament heavy subunit, a biomarker of axonal
damage, as a marker of chemotherapy-induced
peripheral neuropathy. Biomed Rep. 2016 Jun;
4(6):758-760.
(3) Hozumi J, Sumitani M, Matsubayashi Y, Abe H,
Ohshima Y, Chikuda H, Takeshita K, Yamada Y.
Relationship between neuropathic pain andobesity .Pain Res Manag. 2016;2016:2487924. doi:
10.1155/2016/2487924.
(4) Sumitani M, Ueda H, Hozumi J, Inoue R, Kogure T,
Ogata T, Yamada Y. Minocycline does not decrease
intensity of neuropathic pain, but improves its affective dimension. J Pain Palliat Care Pharmacother.
2016; 30(1):31-5. doi: 10.3109/15360288.2014.
1003674.
(5) Kogure T, Sumitani M, Ikegami K, Abe H, Hozumi
J, Inoue R, Kawahara K, Yamada Y. Donepezil, anacetylcholinesterase inhibitor, can attenuate
gabapentinoid-induced somnolence in patients withneuropathic pain: a retrospective chart review.J Pain
Palliat Care Pharmacother. 2017 Mar;31(1):4-9. doi:
10.1080/15360288.2017.1279500.
(6) Ikeda T, Uchida K, Yamauchi Y, Nagase T, Oba K,
Yamada Y Relationship between pre-anesthetic andintra-anesthetic airway resistance in patients
undergoing general anesthesia: A prospective
observational study. PLoS ONE 12(2): e0172421.
https://doi.org/10.1371/journal.pone.0172421 2017
(7) Akasaka K, Tanaka T, Maruyama T, Kitamura N,
Hashimoto A, Ito Y, Watanabe H, Wakayama T,
Arai T, Hayashi M, Moriyama H, Uchida K,
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Nakata K. A mathematical model to predict protein
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Physiol Lung Cell Mol Physiol. 2015 Jan 15;308(2):L105-17.
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191-3

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Department of Emergency andCritical Care Medicine
Professor
Naoto Morimura, M.D.

Associate Professor
Susumu Nakajima, M.D.

Yoichi Kitsuta, M.D.

Lecturer
Masataka Gunshin, M.D. Kent Doi, M.D.
Takehiro Matsubara, M.D. Yoshihiro Ueda, M.D.

Associate
Takahiro Hiruma, M.D.
Ichiro Hirayama, M.D.
Ryohei Horie, M.D
Takuya Sato, M.D.

Rei Ito, M.D.
Kohei Yoshimoto, M.D.
Miyuki Yamamoto, M.D.
Shunsuke Tagami, M.D.

Tomoyasu Morita, M.D.
Shota Den, M.D.
Keisuke Nyuunoya, M.D.

Staff
Yusuke Katayama, M.D.

Yoriko Tsukamoto, M.D.

Homepage http://plaza.umin.ac.jp/todaiqq/
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.

258

Clinical activities
Our clinical activities are divided into four
categories as follows:
1) Emergency medicine
Our department is responsible for not only tertiary
emergency but also primary and secondary
emergency care on 24-hour-a-day basis. In 2016
fiscal year, we had about 5264 ambulance patientsout of total 17936 ER outpatients.
The new ER, four times the size of the previous
ER was built in November, 2006. The facility has 5
consultation rooms, 4 specialized consultation rooms
for dentistry, ophthalmology, otorhinolaryngology
and gynecology, 3 resuscitation bays, and 4
observation beds.
2) Intensive care
Staff members specialized in internal medicine,cardiovascular medicine, orthopedic surgery, surgery,neurosurgery or anesthesiology create “the semiclosed ICU” model. We are responsible for the entire
care of the critically ill patients (i.e. patients withrespiratory insufficiency such as ARDS, with sepsis,with MOF, with shock), post-operative patients, andtertiary emergency patients, placing an emphasis on
evidence-based medical therapy. We had 2,300
ICU/CCU patients in the 2016.
3) Bed management
The objective of bed management services is toprovide a timely and appropriate bed allocation for
all the patients. In our hospital, patients are allocatedto three types of wards, that is, general ward, ICU2
and ICU/CCU in accordance with their criticalcondition. The ICU2 undertakes the leading bed
management in the hospital to ensure maximum
performance as an acute hospital.
4) Risk management
It is split into two categories – in-hospital and outof hospital disasters. In regard to in-hospital risk
management, including “code blue emergency”, weare responsible for patient safety on 24-hour/365-day
basis. And in regard to out of hospital risk
management, our hospital has been authorized by the
Tokyo Metropolitan Government as a disaster basehospital, and also the Government has requested theformation of Disaster Medical Assistant Team(DMAT). We have oxygen and medical suction
equipment on the passageways in the ER in case oftreating the large number of disaster patients.

Teaching activities
The topics of lectures for the 2nd year medical
student include the prehospital emergency care, theinitial evaluation of emergency patients, disastermedicine, serious infections disease, and trauma. BasicLife Support. exercise is also mandatory for the 2ndyear medical student.
One month of elective clinical clerkship for the 3rdyear. Immediate Cardiac Life Support (ICLS) courseand 1 day Hospital MIMMS (Major Incident Medical
Management and Support) course are held for theparticipants in the clinical clerkship program, andsuccessful completion of each course will enable
students to be certified as providers.
Clinical integrated lecture for the 4th year students
includes diagnosis and treatment of serious patientsusing case studies of shock, conscious disorder, trauma,
intoxication, infections disease, burns, hypothermia,
and convulsion. Moreover, after exercise of Advanced
Life Support, students experience a real practice of
emergency medicine as fellow passengers in theambulances and as one day trainees in the emergency
centers of the affiliated hospitals.
In conformity with the guideline by Ministry of
Health, Labor and Welfare, all residents learn andpractice emergency medicine and primary care at every
level, primary, secondary and tertiary. The residents
attend the ICLS course during resident year to obtainthe knowledge and skills in CPR.
Junior residents are also assigned to ICU services togain the knowledge of intensive care from
pathophysiological and internal medicine’s point ofview.
According to the senior resident program in 2006, wetrain the senior residents to be skilled in advanced
critical care medicine including primary care trauma,
MOF, shock, and equipment support.

Research activities
Basic research by using the histone injection-induced
ARDS model and the ischemia reperfusion injury
models on several different organs including intestine259

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

References
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Ikari Y, Funakoshi H, Hayakawa K,Matsuzaki M,
Sakurai A, Tahara Y, Yonemoto N, Nagao K,
Yaguchi A, Morimura N;SOS-KANTO 2012 study
group. Does Antiarrhythmic Drug During
CardiopulmonaryResuscitation Improve the Onemonth Survival: The SOS-KANTO 2012 Study.
JCardiovasc Pharmacol. 2016 Jul;68(1):58-66."
2. Endo A, Shiraishi A, Otomo Y, Kushimoto S,
Saitoh D, Hayakawa M, Ogura H,Murata K,
Hagiwara A, Sasaki J, Matsuoka T, Uejima T,
Morimura N, Ishikura H,Takeda M, Kaneko N,
Kato H, Kudo D, Kanemura T, Shibusawa T,
Hagiwara Y, FurugoriS, Nakamura Y, Maekawa K,
Mayama G, Yaguchi A, Kim S, Takasu O,
Nishiyama K.Development of Novel Criteria of the""Lethal Triad"" as an Indicator of Decision
Making in Current Trauma Care: A Retrospective
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H, Matsuoka T, Uejima T,Hayakawa M, Takeda M,
Kaneko N, Saitoh D, Otomo Y, Yokota H,
Sakamoto T, TanakaH, Shiraishi A, Morimura N,
Ishikura H. Can Early Aggressive Administration
ofFresh Frozen Plasma Improve Outcomes inPatients with Severe Blunt Trauma?--AReport by
the Japanese Association for the Surgery of Trauma.
Shock. 2016 May;45(5):495-501.
4. Hayakawa M, Maekawa K, Kushimoto S, Kato H,
Sasaki J, Ogura H, Matauoka T,Uejima T,
Morimura N, Ishikura H, Hagiwara A, Takeda M,
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Shibusawa T, Furugori S, Nakamura Y, Shiraishi A,
Murata K, MayamaG, Yaguchi A, Kim S, Takasu
O, Nishiyama K. HIGH D-DIMER LEVELSPREDICT A POOROUTCOME IN PATIENTSWITH SEVERE TRAUMA, EVEN WITH HIGHFIBRINOGEN LEVELS ON ARRIVAL: A
MULTICENTER RETROSPECTIVE STUDY.
Shock. 2016 Mar;45(3):308-14.
5. Kashiura M, Hamabe Y, Akashi A, Sakurai A,
Tahara Y, Yonemoto N, Nagao K,Yaguchi A,
Morimura N; SOS-KANTO 2012 Study Group.
Applying the termination of resuscitation rules toout-of-hospital cardiac arrests of both cardiac andnon-cardiac etiologies: a prospective cohort study.
Crit Care. 2016 Mar 1;20:49.
6. Matsumura Y, Nakada TA, Shinozaki K, Tagami T,
Nomura T, Tahara Y, Sakurai A, Yonemoto N,
Nagao K, Yaguchi A, Morimura N; SOS-KANTO
2012 study group. Nighttime is associated withdecreased survival and resuscitation efforts for outof-hospital cardiac arrests: a prospective
observational study. Crit Care. 2016 May 10;20(1):141.
7. Tanaka C, Kuno M, Yokota H, Tagami T, Nakada
TA, Kitamura N, Tahara Y, Sakurai A, Yonemoto N,
Nagao K, Yaguchi A, Morimura N; SOS-KANTO
2012 Study Group. Changes in atropine use forout-of-hospital cardiac arrest patients with nonshockable rhythm between 2002 and 2012.
Resuscitation. 2016 Apr;101:e5-6.
8. Fukuda T, Ohashi-Fukuda N, Matsubara T, Doi K,
Kitsuta Y, Nakajima S, Yahagi N. Association of
initial rhythm with eurologically favorable
survival in non-shockable out-of-hospital cardiac
arrest without a bystander witness or bystandercardiopulmonary resuscitation. Eur J Intern Med.
2016 May;30:61-67.
9. Sonoo T, Iwai S, Inokuchi R, Gunshin M, Kitsuta
Y, Nakajima S. Embedded-structure template forelectronic records affects patient note quality andmanagement for emergency head injury patients:
An observational pre and post comparison quality
improvement study. Medicine (Baltimore). 2016
Oct;95(40):e5105.
10. Wada T, Yasunaga H, Horiguchi H, Fushimi K,
Matsubara T, Nakajima S, Yahagi N. Ozagrel for
Patients With Noncardioembolic Ischemic Stroke:
A Propensity Score-Matched Analysis. J Stroke
Cerebrovasc Dis. 2016 Dec;25(12):2828-2837.
11. Asada T, Aoki Y, Sugiyama T, Yamamoto M, Ishii
T, Kitsuta Y, Nakajima S, Yahagi N, Doi K. Organ
System Network Disruption in Nonsurvivors of

260

Critically Ill Patients. Crit Care Med. 2016
Jan;44(1):83-90.
12. Hirayama I, Hiruma T, Ueda Y, Doi K, Nakajima S.
Hamman syndrome: pneumomediastinum combined with hyperosmolar hyperglycemic state. Am
J Emerg Med.2016 Oct;34(10):2058.e1-2058.e2. "13. Maeda H, Uramatsu M, Nakajima S, Yoshida KI.
Lethal ventricular tachycardia triggered after
femoral fracture repair in an obese man withinsulin-resistant diabetes. Int J Legal Med. 2016
Nov;130(6):1587-1591.
14. Nakamura K, Inokuchi R, Hiruma T, Tokunaga K,
Doi K, Nakajima S. Switching therapy fromintravenous beta blocker to bisoprolol transdermal
patch for atrial fibrillation tachycardia. J Anesth.
2016 Oct;30(5):891-4.
15. Nakamura K, Inokuchi R, Hiruma T, Ohshima K,
Sonoo T, Tokunaga K, Doi K, Nakajima S.
Recombinant thrombomodulin for secondary
thrombotic thrombocytopenic purpura. Medicine(Baltimore). 2016 Jun;95(24):e3712.
16. Nakamura K, Inokuchi R, Hiruma T, Ohshima K,
Sonoo T, Tokunaga K, Doi K,Nakajima S.
Recombinant thrombomodulin for secondary
thrombotic thrombocytopenic purpura. Medicine(Baltimore). 2016 Jun;95(24):e3712.
17. Nakamura K, Qian K, Ando T, Inokuchi R, Doi K,
Kobayashi E, Sakuma I, Nakajima S, Yahagi N.
Cardiac Variation of Internal Jugular Vein for the
Evaluation of Hemodynamics. Ultrasound Med
Biol. 2016 Aug;42(8):1764-70.
18. Sonoo T, Iwai S, Inokuchi R, Gunshin M, Kitsuta
Y, Nakajima S. Embedded-structure template forelectronic records affects patient note quality andmanagement for emergency head injury patients:
An observational pre and post comparison quality
improvement study. Medicine (Baltimore). 2016
Oct;95(40):e5105.
19. Sonoo T, Iwai S, Inokuchi R, Gunshin M,
Nakajima S, Yahagi N. Quantitative analysis ofhigh plasma lactate concentration in ED patients
after alcohol intake. Am J Emerg Med. 2016 May;34(5):825-9.
20. Tagami S, Inokuchi R, Awaji K, Maehara H,
Yamaguchi Y, Nakajima S. Crowned dens
syndrome and interspinous ligament inflammation
due to calcium pyrophosphate deposition in anelderly man. Spine J. 2016 Jul;16(7):e453-4.
21. Wada T, Yasunaga H, Horiguchi H, Matsubara T,
Fushimi K, Nakajima S, Yahagi N. Outcomes ofArgatroban Treatment in Patients With Atherothrombotic Stroke:Observational Nationwide
Study in Japan. Stroke. 2016 Feb;47(2):471-6.
22. Arai S, Kitada K, Yamazaki T, Takai R, Zhang X,
Tsugawa Y, Sugisawa R,Matsumoto A, Mori M,
Yoshihara Y, Doi K, Maehara N, Kusunoki S,
Takahata A, Noiri E, Suzuki Y, Yahagi N,
Nishiyama A, Gunaratnam L, Takano T, Miyazaki
T. Apoptosis inhibitor of macrophage protein
enhances intraluminal debris clearance andameliorates acute kidney injury in mice. Nat Med.
2016 Feb;22(2):183-93.
23. Asada T, Isshiki R, Hayase N, Sumida M, Inokuchi
R, Noiri E, Nangaku M, Yahagi N, Doi K. Impact
of clinical context on acute kidney injury
biomarker performances: differences between
neutrophil gelatinase-associated lipocalin and Ltype fatty acid-binding protein. Sci Rep. 2016 Sep
8;6:33077.
24. Asada T, Doi K. The authors reply. Crit Care Med.
2016 May;44(5):e314.
25. Cutuli SL, Artigas A, Fumagalli R, Monti G,
Ranieri VM, Ronco C, Antonelli M; EUPHAS 2
Collaborative Group. Polymyxin-B hemoperfusion
in septic patients: analysis of a multicenter registry.
Ann Intensive Care. 2016 Dec;6(1):77.
26. Doi K, Rabb H. Impact of acute kidney injury on
distant organ function: recent findings andpotential therapeutic targets. Kidney Int. 2016
Mar;89(3):555-64.
27. Doi K, Noiri E. Mitochondrial Dysfunction in
Cardiorenal Syndrome. Antioxid Redox Signal.
2016 Aug 1;25(4):200-7.
28. Doi K. Kidney-Heart Interactions in Acute Kidney
Injury. Nephron. 2016;134(3):141-144. Epub 2016
Jun 16.
29. Doi K. Role of kidney injury in sepsis. J Intensive
Care. 2016 Mar 23;4:17.
30. Fukuda T, Ohashi-Fukuda N, Matsubara T, Doi K,
Kitsuta Y, Nakajima S, Yahagi N. Association of
initial rhythm with neurologically favorable
survival in non-shockable out-of-hospital cardiac
arrest without a bystander witness or bystandercardiopulmonary resuscitation. Eur J Intern Med.

261

2016 May;30:61-67.
31. Fukuda T, Ohashi-Fukuda N, Kondo Y, Sera T, Doi
K, Yahagi N. Epidemiology, Risk Factors, andOutcomes of Out-of-Hospital Cardiac Arrest
Caused by Stroke: A Population-Based Study.
Medicine (Baltimore). 2016 Apr;95(14):e3107.
32. Hayase N, Yamamoto M, Asada T, Isshiki R,
Yahagi N, Doi K. Association of Heart Rate with
N-Terminal Pro-B-Type Natriuretic Peptide in
Septic Patients: A Prospective Observational
Cohort Study. Shock. 2016 Dec;46(6):642-648.
33. Isshiki R, Asada T, Sato D, Sumida M, Hamasaki
Y, Inokuchi R, Matsubara T, Ishii T, Yahagi N,
Nangaku M, Noiri E, Doi K. Association of
Urinary
Neutrophil
Gelatinase-AssociatedLipocalin With Long-Term Renal Outcomes in
ICU Survivors: A Retrospective Observational
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34. Ito M, Doi K, Takahashi M, Koyama K, Myojo M,
Hosoya Y, Kiyosue A, Ando J, Noiri E, Yahagi N,
Hirata Y, Komuro I. Plasma neutrophil gelatinaseassociated lipocalin predicts major adverse
cardiovascular events after cardiac care unit
discharge. J Cardiol. 2016 Feb;67(2):184-91.
35. 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. 2016;
42(1):9-17.
36. 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. 2016 Feb;89(2):374-85.
37. Katagiri M, Takahashi M, Doi K, Myojo M,
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38. Komaru Y, Doi K. Early or delayed initiation ofrenal replacement therapy for critically ill patientsdo we know the right time? J Thorac Dis. 2016
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Nangaku M, Yahagi N, Doi K. IMPACT OF
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40. Nakamura K, Inokuchi R, Sonoo T, Hiruma T,
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42. Yamashita T, Noiri E, Hamasaki Y, Matsubara T,
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Health Sciences and Nursing
1. Health Sciences

263

Department of Mental HealthProfessor
Norito Kawakami, M.D., Ph.D.

Associate Professor
Akihito Shimazu, Ph.D.

Homepage

http://plaza.umin.ac.jp/heart/

Introduction and Organizationof Tokyo, and institutions within and outside Japan.

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 and Psychiatric Nursing. As the resultof the shift to the chair system of the Graduate Schoolof Medicine in 1996, two departments were
established, Department of Mental Health andDepartment of Psychiatric Nursing. Faculty, staff, andstudents of two departments have been working
cooperatively ever since. Since 2007, Department of
Mental Health became a part of School of Public
Health, with a perspective of “public mental health”.
The department currently has faculty members
introduced above, an associate professor, a project
associate professor, a project researcher, part-time
lecturers, a technical specialist, visiting research
fellows, 10 doctoral course students, 6 master course
students, research associates, and secretaries.
The department has two major objectives: one isto teach 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
conducted in collaboration with staff members in thedepartments, other departments within the University

Teaching activities
The department is responsible for giving lectures
on mental health; mental disorders; clinical and healthpsychology; and psychometry and behavior evaluation
to undergraduate students. Other than lectures, thedepartment provides students opportunities toexperience mental health activities in relevant mental
health settings.
The department provides graduate courses onmental health I and II, featuring epidemiology andpractice in mental health and occupational mental
health, respectively. The department also provided a
1.5 hour seminar every Wednesday evening for 20
weeks in each semester (40 weeks per year) for
graduate students and research students, withpresentations of research plans and progress, andliterature review by graduate students, as well as
presentation of and lectures by guest speakers.

Research activities
The department conducts research on mental
health and psychosocial support and provides
education/training of professionals in related fields
from global perspectives. The World Mental HealthJapan survey, which is part of a WHO international
collaboration, is a largest epidemiologic study ofcommon mental disorders in the community in Japan.
Assessment of health effects of job stressors andeffectiveness of interventions to reduce job stress arealso core research activities of the department.

264

Current issues around occupational mental health (e.g.,work engagement, workaholism, organizational justice,bullying, work-life balance, and the Civility, Respect
and Engagement at Work [CREW] program) are also
actively investigated. Furthermore, research in thedepartment includes various other topics, such assupporting rehabilitation and recovery of people withchronic mental illness, suicide prevention, social
disparity in mental health, disaster mental health, andglobal mental health. Most of the research has been
conducted in a close collaboration with researchers inother domestic and foreign institutions/universities.

References (Jan.-Dec., 2016)
1. Atwoli L, Stein DJ, King A, Petukhova M,
Aguilar-Gaxiola S, Alonso J, Bromet EJ, deGirolamo G, Demyttenaere K, Florescu S, Maria
Haro J, Karam EG, Kawakami N, Lee S, Lepine JP,
Navarro-Mateu F, O'Neill S, Pennell BE, Piazza
M, Posada-Villa J, Sampson NA, Ten Have M,
Zaslavsky AM, Kessler RC; WHO World Mental
Health Survey Collaborators. Posttraumatic stressdisorder associated with unexpected death of a
loved one: Cross-national findings from the world
mental health surveys. Depress Anxiety. 2016 Dec
6. [Epub ahead of print].
2. Benjet C, Bromet E, Karam EG, Kessler RC,
McLaughlin KA, Ruscio AM, Shahly V, Stein DJ,
Petukhova M, Hill E, Alonso J, Atwoli L, Bunting
B, Bruffaerts R, Caldas-de-Almeida JM, deGirolamo G, Florescu S, Gureje O, Huang Y,
Lepine JP, Kawakami N, Kovess-Masfety V,
Medina-Mora ME, Navarro-Mateu F, Piazza M,
Posada-Villa J, Scott KM, Shalev A, Slade T, ten
Have M, Torres Y, Viana MC, Zarkov Z, Koenen
KC. The epidemiology of traumatic event
exposure worldwide: results from the World
Mental Health Survey Consortium. Psychol Med.
2016 Jan;46(2):327-43.
3. Bromet EJ, Atwoli L, Kawakami N, NavarroMateu F, Piotrowski P, King AJ, Aguilar-Gaxiola
S, Alonso J, Bunting B, Demyttenaere K, Florescu
S, de Girolamo G, Gluzman S, Haro JM, de JongeP, Karam EG, Lee S, Kovess-Masfety V, MedinaMora ME, Mneimneh Z, Pennell BE, Posada-Villa
J, Salmerón D, Takeshima T, Kessler RC. Post-

traumatic stress disorder associated with naturaland human-made disasters in the World Mental
Health Surveys. Psychol Med. 2016 Aug 30:1-15.
[Epub ahead of print].
4. Chiba R, Umeda M, Goto K, Miyamoto Y,
Yamaguchi S, Kawakami N. Psychometricproperties of the Japanese version of the Recovery
Attitudes Questionnaire (RAQ) among mental
health providers: a questionnaire survey. BMC
Psychiatry. 2016 Feb 16;16:32.
5. Eguchi H*, Shimazu A*, Bakker AB, Tims M,
Kamiyama K, Hara Y, Namba K, Inoue A, Ono M,
Kawakami N. Validation of the Japanese versionof the Job Crafting Scale. J Occup Health 2016;
58: 231-240 (* Equal contribution).
6. Eguchi H, Shimazu A, Kawakami N, Inoue A,
Tsutsumi A. Source-specific workplace social
support and highsensitivity C-reactive protein
levels among Japanese workers: A 1-year
prospective cohort study. Am J Indl Med 2016
Aug;59(8):676-84.
7. Fujita S, Kawakami N, Ando E, Inoue A, Tsuno K,
Kurioka S, Kawachi I. The Association ofWorkplace Social Capital With Work Engagementof Employees in Health Care Settings: A
Multilevel Cross-Sectional Analysis. J Occup
Environ Med. 2016 Mar;58(3):265-71.
8. Fujiwara T, Shimazu A, Tokita M, Shimada K,
Takahashi M, Watai I, Iwata N, Kawakami N.
Association of parental workaholism and bodymass index of offspring: A prospective study
among Japanese dual workers. Frontiers in Public
Health. 2016; 4:41.
9. GBD 2015 Child Mortality Collaborators. Global,
regional, national, and selected subnational levelsof stillbirths, neonatal, infant, and under-5
mortality, 1980-2015: a systematic analysis for
the Global Burden of Disease Study 2015. Lancet.
2016 Oct 8;388(10053):1725-1774.
10. GBD 2015 DALYs and HALE Collaborators.
Global, regional, and national disability-adjusted
life-years (DALYs) for 315 diseases and injuries
and healthy life expectancy (HALE), 1990-2015:a systematic analysis for the Global Burden of
Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1603-1658.
11. GBD 2015 Disease and Injury Incidence and265

Prevalence Collaborators. Global, regional, andnational incidence, prevalence, and years lived
with disability for 310 diseases and injuries,
1990-2015: a systematic analysis for the Global
Burden of Disease Study 2015. Lancet. 2016 Oct
8;388(10053):1545-1602.
12. GBD 2015 HIV Collaborators. Estimates ofglobal, regional, and national incidence,prevalence, and mortality of HIV, 1980-2015: the
Global Burden of Disease Study 2015. Lancet
HIV. 2016 Aug;3(8):e361-87.
13. GBD 2015 HIV Collaborators., Wang H, Wolock
TM, et al. Estimates of global, regional, andnational incidence, prevalence, and mortality ofHIV, 1980-2015: the Global Burden of Disease
Study 2015. Lancet HIV. 2016 Aug;3(8):e361-87.
14. GBD 2015 Maternal Mortality Collaborators.
Global, regional, and national levels of maternalmortality, 1990-2015: a systematic analysis for
the Global Burden of Disease Study 2015. Lancet.
2016 Oct 8;388(10053):1775-1812.
15. GBD 2015 Mortality and Causes of Death
Collaborators. Global, regional, and national life
expectancy, all-cause mortality, and cause-specificmortality for 249 causes of death, 1980-2015: asystematic analysis for the Global Burden of
Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1459-1544.
16. GBD 2015 Risk Factors Collaborators. Global,
regional, and national comparative risk assessment of 79 behavioural, environmental andoccupational, and metabolic risks or clusters ofrisks, 1990-2015: a systematic analysis for the
Global Burden of Disease Study 2015. Lancet.
2016 Oct 8;388(10053):1659-1724.
17. GBD 2015 SDG Collaborators. Measuring thehealth-related Sustainable Development Goals in
188 countries: a baseline analysis from the Global
Burden of Disease Study 2015. Lancet. 2016 Oct
8;388(10053):1813-1850.
18. Hirokawa K, Miwa M, Taniguchi T, Tsuchiya M,
Kawakami N. Moderating effects of salivary
testosterone levels on associations between job
demand and psychological stress response inJapanese medical workers. Ind Health. 2016 Jun
10;54(3):194-203.
19. Horikoshi N, Iwasa H, Kawakami N, Suzuki Y,

Yasumura S. Residence-related factors andpsychological distress among evacuees after the
Fukushima Daiichi nuclear power plant accident:a cross-sectional study. BMC Psychiatry. 2016
Nov 24;16(1):420.
20. Imamura K, Kawakami N, Inoue A, Shimazu A,
Tsutsumi A, Takahashi M, Totsuzaki T. WorkEngagement as a Predictor of Onset of Major
Depressive Episode (MDE) among Workers,
Independent of Psychological Distress: A 3-Year
Prospective Cohort Study.PLoS One. 2016 Feb
3;11(2):e0148157.
21. Imamura K, Kawakami N, Tsuno K, Tsuchiya M,
Shimada K, Namba K, Shimazu A. Effects ofweb-based stress and depression literacy
intervention on improving work engagement
among workers with low work engagement: An
analysis of secondary outcome of a randomized
controlled trial. J Occup Health. 2016 Nov 22.
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22. Imamura K, Kawakami N, Tsuno K, Tsuchiya M,
Shimada K, Namba K. Effects of web-based stressand depression literacy intervention on improving
symptoms and knowledge of depression among
workers: A randomized controlled trial. J Affect
Disord. 2016; 203: 30–7.
23. Imamura K, Sekiya Y, Asai Y, Umeda M,
Horikoshi N, Yasumura S, Yabe H, Akiyama T,
Kawakami N. The effect of a behavioral
activation program on improving mental andphysical health complaints associated withradiation stress among mothers in Fukushima: arandomized controlled trial. BMC Public Health.
BMC Public Health. 2016;16(1):1144.
24. Inoue A, Kawakami N, Eguchi H, Tsutsumi A.
Buffering effect of workplace social capital on theassociation of job insecurity with psychologicaldistress in Japanese employees: a cross-sectional
study. J Occup Health. 2016 Sep 30;58(5):460469.
25. Inoue A, Kawakami N, Eguchi H, Tsutsumi A.
Modifying effect of cigarette smoking on theassociation of organizational justice with serious
psychological distress in Japanese employees: across-sectional study. Int Arch Occup Environ
Health. 2016 Aug;89(6):901-10.
26. Ishikawa H, Yasunaga H, Matsui H, Fushimi K,

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Kawakami N. Differences in cancer stage, treatment and in-hospital mortality between patientswith and without schizophrenia: retrospective
matched-pair cohort study. Br J Psychiatry. 2016
Mar;208(3):239-44.
27. Kachi Y, Abe A, Ando E, Kawada T. Socioeconomic disparities in psychological distress in anationally representative sample of Japaneseadolescents: A time trend study. Aust N Z J
Psychiatry. 2016 Sep 29. [Epub ahead of print].
28. Kato S, Itoh S, Yuasa M, Baba T, Miyashita C,
Sasaki S, Nakajima S, Uno A, Nakazawa H,
Iwasaki Y, Okada E, Kishi R. Association of
perfluorinated chemical exposure in utero withmaternal and infant thyroid hormone levels in the
Sapporo cohort of Hokkaido Study on theEnvironment and Children's Health. Environ
Health Prev Med. 2016 Sep;21(5):334-344.
29. Kovess-Masfety V, Evans-Lacko S, Williams D,
Andrade LH, Benjet C, Ten Have M, Wardenaar K,
Karam EG, Bruffaerts R, Abdumalik J, Haro Abad
JM, Florescu S, Wu B, De Jonge P, Altwaijri Y,
Hinkov H, Kawakami N, Caldas-de-Almeida JM,
Bromet E, de Girolamo G, Posada-Villa J,
Al-Hamzawi A, Huang Y, Hu C, Viana MC,
Fayyad J, Medina-Mora ME, Demyttenaere K,
Lepine JP, Murphy S, Xavier M, Takeshima T,
Gureje O. The role of religious advisors in mental
health care in the World Mental Health surveys.
Soc Psychiatry Psychiatr Epidemiol. 2016 Nov 2.
[Epub ahead of print]
30. Kubo T, Takahashi M, Xinxin LT, Ikeda H, Togo F,
Shimazu A, Tanaka K, Kamata N, Kubo Y, Uesugi
J. Fatigue and sleep among employees withprospective increase in work time control: A
1-year observational study with objective assessment. J Occup Environ Med. 2016 Nov;58(11):1066-1072.
31. Levine CS, Miyamoto Y, Markus HR, Rigotti A,
Boylan JM, Park J, Kitayama S, Karasawa M,
Kawakami N, Coe CL, Love GD, Ryff CD.
Culture and Healthy Eating: The Role ofIndependence and Interdependence in the UnitedStates and Japan. Pers Soc Psychol Bull. 2016
Oct;42(10):1335-48.
32. Miki T, Eguchi M, Kurotani K, Kochi T,
Kuwahara K, Ito R, Kimura Y, Tsuruoka H, Akter

S, Kashino I, Kabe I, Kawakami N, Mizoue T.
Dietary fiber intake and depressive symptoms inJapanese employees: The Furukawa Nutrition and
Health Study. Nutrition. 2016 May;32(5):584-9.
33. Otowa T, Kawamura Y, Tsutsumi A, Kawakami N,
Kan C, Shimada T, Umekage T, Kasai K,
Tokunaga K, Sasaki T. The First Pilot GenomeWide Gene-Environment Study of Depression in
the Japanese Population. PLoS One. 2016 Aug 16;
11(8):e0160823.
34. Peik SM, Mohan KM, Baba T, Donadel M,
Labruto A, Loh LC. Comparison of public healthand preventive medicine physician specialty
training in six countries: Identifying challenges
and opportunities. Med Teach. 2016 Nov;38(11):1146-1151. Epub 2016 Apr 19.
35. Purnawati S, Sutjana DP, Adiputra N, Shimazu A,
Kawakami N. Effects of an ergonomics-based job
stress management program on job strain,
psychological distress, and blood cortisol among
employees of a national private bank in Denpasar,
Bali. Ind Health. 2016 Aug 6. [Epub ahead ofprint].
36. Sakuraya A, Shimazu A, Imamura K, Namba K,
Kawakami N. Effects of a job crafting intervention program on work engagement among
Japanese employees: a pretest-posttest study.
BMC Psychol. 2016; 4: 49.
37. Scott KM, Lim C, Al-Hamzawi A, Alonso J,
Bruffaerts R, Caldas-de-Almeida JM, Florescu S,
de Girolamo G, Hu C, de Jonge P, Kawakami N,
Medina-Mora ME, Moskalewicz J, NavarroMateu F, O'Neill S, Piazza M, Posada-Villa J,
Torres Y, Kessler RC. Association of Mental
Disorders With Subsequent Chronic Physical
Conditions: World Mental Health Surveys From
17 Countries. JAMA Psychiatry. 2016 Feb;73(2):150-8.
38. Shimazu A, Matsudaira K, de Jonge J, Tosaka N,
Takahashi M. Psychological detachment fromwork during nonwork time: Linear or curvilinear
relations with mental health and work engagement.
Ind Health 2016;54: 282-292.
39. Suzuki Y, Yabe H, Horikoshi N, Yasumura S,
Kawakami N, Ohtsuru A, Mashiko H, Maeda M;
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40. 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. Behavioral activation for lateadolescents with subthreshold depression: arandomized controlled trial. Eur Child Adolesc
Psychiatry. 2016 Nov;25(11):1171-1182.
41. Takagaki K, Okamoto Y, Jinnin R, Mori A,
Nishiyama Y, Yamamura T, Yokoyama S, Shiota S,
Okamoto Y, Miyake Y, Ogata A, Shimoda H,
Kawakami N, Furukawa TA, Yamawaki S.
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symptoms from pre-treatment to post-treatment. J
Affect Disord. 2016 Nov 1;204:70-3.
42. Takano A, Miyamoto Y, Kawakami N, Matsumoto
T, Shinozaki T, Sugimoto T. Web-based cognitive
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protocol for a multicenter randomized controlled
trial in Japan. BMC Psychiatry. 2016, 16:87.
43. Takano A, Miyamoto Y, Kawakami N,
Matsumoto T. Web-based cognitive behavioral
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for people with methamphetamine and other drug
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JMIR Ment Heal. 2016;3(1):e1.
44. Tanaka E, Tsutsumi A, Kawakami N, Kameoka S,
Kato K, You Y-H. Long-term psychologicalconsequences among adolescent survivors of the
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48. Watanabe K, Imamura K, Kawakami N. Working
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49. Watanabe K, Kawakami N, Adachi H, Inoue S,
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Department of Biostatistics/
Epidemiology and Preventive
Health Sciences
Professor
Yutaka Matsuyama, Ph.D.

Associate Professor
Koji Oba, Ph.D.

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

Project Research Associate
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
researchandbiostatistics
toundergraduate students. We belong to Graduate
School of Medicine as Departments of Biostatistics/
Epidemiology and Preventive Health Sciences,providing education for undergraduate as well as
graduate-school students and consultation to clinicalresearchers.
Unfortunately, compared to the situation in the
US and European countries, education programs forbiostatistics and epidemiological methodology are notsufficient in Japanese universities and graduate
schools. Nevertheless the necessity for collaboration
between biostatisticians and clinical researchers/
epidemiologists has been to be claimed in recent years.
Hence, the central missions of our educational courses
are devoted to provide expert knowledge andextensive experience in biostatistics/epidemiology tostudents to take part in clinical/epidemiologicalresearch as biostatisticians or methodologists. We do
not only focus on practical aspects on statisticalanalysis in medical research but also place emphasison the methodological principles of biostatistics/
epidemiology.
Our main research area is the development ofmethodology for clinical/epidemiological research. Of
course, it requires keeping in touch with real clinical/
epidemiological problems. So, another indispensable
research area is a support for real-world clinical andepidemiological studies including clinical trials. To
achieve these requirements simultaneously, a nonprofit organization “The Japan Clinical Research
Support Unit” (current EP-CRSU, Co., Ltd.) wasestablished in 2001 by the former faculty members inour department. This organization J-CRSU hadprovided research support and coordination in design,
data management, and statistical analysis in many
projects inside/outside the university. Our experiencein J-CRSU is the basis of our supportive activities forclinical research that we work through today.

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Teaching activities
 Undergraduate Courses
1) Epidemiology and Biostatistics (2 credits) (thisclass will be separated into “Epidemiology” and“Biostatistics” [2 credits each] in new
curriculum from FY2017; the latter is named“Statistics” in medical doctor course)2) Applied Mathematics (2 credits)
3) Statistical Methods and Information Processing
Practice (2 credits) (“Biostatistics Practice” innew curriculum, 1 credits)4) Design and Analysis of EpidemiologicalResearch, and its Practice (2 and 1 credits)(“Practical Examples in Clinical andEpidemiologic Research” in new curriculum, 1
credits)
5) Medical Data Analysis, and its Practice (2credits each)6) (New curriculum) Theoretical Epidemiology
 School of Public Health (Graduate School)
1) Statistical Analysis of Medical Research(2 credits)
2) Practice of Biostatistics (2 credits)3) Design of Medical Research (2 credits) Doctoral Courses (Graduate School)
1) Biostatistics (4 credits)
2) Epidemiology and Preventive Health Sciences(4 credits)
3) Introduction to Medical Statistics(2 credits; for the School of Medicine)
The faculty of the department had provided
lectures in a series of educational courses organizedby “The Clinical Bioinformatics Research Unit” in
2002-2007.

Research activities
1. Methodology for designing and analyzing clinical
trials: Interim analysis
 Adaptive designs
 Multiplicity
 Data management of large-scale multicenter
clinical trials

2. Methodology of Biostatistics and theoreticalepidemiology:
 Analysis of longitudinal (time-to-event and/or
repeated measures) data
 Analysis of missing/incomplete data Causal inference Semiparametric modeling
3. International collaboration of individual-levelmeta-analysis on gastric cancer
4. Coordination and data analysis of collaborative
epidemiological/clinical research:
 Japan Arteriosclerosis Longitudinal Study Japan Diabetes Collaborative Study Chronic Kidney Disease Japan Cohort
5. Validity/reliability studies of QOL questionnaires
and other rating scales
6. Pharmacoeconomic assessment of medical technology
We had been supporting some of the above
collaborative clinical/epidemiologic studies throughtheaforementioned
J-CRSU(anon-profit
organization), which aims to support investigatorinitiated studies and to provide education toresearchers and support staffs. Currently, we are
officially conducting a consultation for design andanalysis of clinical trials assisted by the ClinicalResearch 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.

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Treatment of Metastatic Colorectal Cancer -The
PHOENiX Trial. Anticancer Res. 2016; 36:3437-43.
25. Matsumoto M, Kato M, Oba K, Abiko S, Tsuda M,
Miyamoto S, Mizushima T, Ono M, Omori S,
Takahashi M, Ono S, Mabe K, Nakagawa M,
Nakagawa S, Kudo T, Shimizu Y, Sakamoto N.
Multicenter randomized controlled study to assess
the effect of prophylactic clipping on
post-polypectomy delayed bleeding. Dig Endosc.
2016; 28: 570-6.
26. Moriya J, Matsuyama Y. Estimating treatment

272

effect of high hemoglobin using the principal
stratification approach. Jpn J Biometrics. 2016; 37:
7-22.
27. Nakamura M, Muramatsu T, Yokoi H, Okada H,
Ochiai M, Suwa S, Hozawa H, Kawai K, Awata M,
Mukawa H, Fujita H, Shiode N, Asano R,
Tsukamoto Y, Yamada T, Yasumura Y, Ohira H,
Miyamoto A, Takashima H, Ogawa T, Ito S,
Matsuyama Y, Nanto S; J-DESsERT investigators.
Three-year follow-up outcomes of SES and PES ina randomized controlled study stratified by thepresence of diabetes mellitus: J-DEsSERT trial.
International Journal of Cardiology. 2016; 208:
4-12.
28. Nakamura M, Aoyama T, Ishibashi K, Tsuji A,
Takinishi Y, Shindo Y, Sakamoto J, Oba K,
Mishima H. Randomized phase II study ofcetuximab versus irinotecan and cetuximab inpatients with chemo-refractory KRAS codon G13D
metastatic colorectal cancer (G13D-study). Cancer
Chemother Pharmacol. 2017; 79: 29-36.
29. Nishizaki Y, Shimada K, Tani S, Ogawa T, Ando J,
Takahashi M, Yamamoto M, Shinozaki T,
Miyazaki T, Miyauchi K, Nagao K, Hirayama A,
Yoshimura M, Komuro I, Nagai R, Daida H.
Association between the docosahexaenoic acid toarachidonic acid ratio and acute coronary
syndrome: a multicenter observational study. BMC
Cardiovasc Disord. 2016; 16: 143.
30. Noguchi K, Sakakibara M, Asakawa N, Tokuda Y,
Kamiya K, Yoshitani T, Oba K, Miyauchi K,
Nishizaki Y, Ogawa H, Yokoi H, Matsumoto M,
Kitakaze M, Kimura T, Matsubara T, Ikari Y,
Kimura K, Origasa H, Isshiki T, Morino Y, Daida
H, Tsutsui H; PACIFIC investigators. Higher
Hemoglobin A1c After Discharge Is an
Independent Predictor of Adverse Outcomes inPatients With Acute Coronary Syndrome - Findings
From the PACIFIC Registry. Circ J. 2016; 80:
1607-14.
31. Nomoto H, Miyoshi H, Furumoto T, Oba K,
Tsutsui H, Inoue A, Atsumi T, Manda N, Kurihara
Y, Aoki S; SAIS Study Group. A Randomized
Controlled Trial Comparing the Effects of
Sitagliptin and Glimepiride on Endothelial
Function and Metabolic Parameters: Sapporo
Athero-Incretin Study 1 (SAIS1). PLoS One. 2016;

11: e0164255.
32. Saitoh A, Saitoh A, Sato I, Shinozaki T, Kamiya H,
Nagata S. Effect of stepwise perinatal
immunization education: a cluster-randomized
controlled trial. Vaccine. 2017; 35: 1645-51.
33. Sakamoto Y, Kokudo N, Matsuyama Y, Sakamoto
M, Izumi N, Kadoya M, Kaneko S, Ku Y, Kudo M,
Takayama T, Nakashima O; Liver Cancer Study
Group of Japan. Proposal of a new staging system
for intrahepatic cholangiocarcinoma: analysis ofsurgical patients from a nationwide survey of theLiver Cancer Study Group of Japan. Cancer. 2016;
122: 61-70.
34. Shindoh J, Makuuchi M, Matsuyama Y, Mise Y,
Arita J, Sakamoto Y, Hasegawa K, Kokudo N.
Complete removal of the tumor-bearing portal
territory decreases local tumor recurrence andimproves disease-specific survival of patients with
hepatocellular carcinoma. Journal of Hepatology.
2016; 64: 594-600.
35. Shinozaki T, Hagiwara Y, Matsuyama Y. Re.
Biases in randomized trials: a conversation
between trialists and epidemiologists (Letter).
Epidemiology. 2017; 28: e40-e41.
36. Shiroiwa T, Fukuda T, Shimozuma K, Mouri M,
Hagiwara Y, Doihara H, Akabane H, Kashiwaba M,
Watanabe T, Ohashi Y, Mukai H. Long-term healthstatus as measured by EQ-5D among patients withmetastatic breast cancer: comparison of first-line
oral S-1 and taxane therapies in the randomized
phase III SELECT BC trial. Qual Life Res. 2017;
26: 445-53.
37. Tabuchi T, Goto A, Ito Y, Fukui K, Miyashiro I,
Shinozaki T. Smoking at the time of diagnosis andmortality in cancer patients: What benefit does thequitter gain? Int J Cancer. 2017; 140: 1789-95.
38. Takahashi M, Hasegawa K, Oba M, Saiura A, Arita
J, Sakamoto Y, Shinozaki E, Mizunuma N,
Matsuyama Y, Kokudo N. Phase 1 study on S-1
and oxaliplatin therapy as an adjuvant after
hepatectomy for colorectal liver metastases. Invest
New Drugs. 2016; 34: 468-73.
39. Takano A, Miyamoto Y, Kawakami N, Matsumoto
T, Shinozaki T, Sugimoto T. Web-based cognitive
behavioral relapse prevention program with
tailored
feedbackforpeoplewithmethamphetamine and other drug use problems:

273

protocol for a multicenter randomized controlled
trial in Japan. BMC Psychiatry. 2016; 16: 87.
40. Takao T, Suka M, Yanagisawa H, Matsuyama Y,
Iwamoto Y. Predictive ability of visit-to-visit
variability in HbA1c and systolic blood pressure
for the development of microalbuminuria andretinopathy in people with type 2 diabetes.
Diabetes Res Clin Pract. 2017; 128: 15-23.
41. Takeuchi Y, Bonkobara M. Receptor tyrosine
kinaseKIT:
Prognostic
andtherapeutic
involvement in canine mast cell tumours. Vet J.
2016; 210: 5-6.
42. Tani Y, Kondo N, Nagamine Y, Shinozaki T,
Kondo K, Kawachi I, Fujiwara T. Childhoodsocioeconomic disadvantage is associated withlower mortality in older Japanese men: the JAGES
cohort study. Int J Epidemiol. 2016; 45: 1226-35.
43. Taniguchi Y, Fujiwara Y, Murayama H, Yokota I,
Matsuo E, Seino S , Nofuji Y, Nishi M, Matsuyama
Y, Shinkai S. Prospective Study of Trajectories ofPhysical Performance and Mortality Among
Community-Dwelling Older Japanese. J Gerontol
Med Sci. 2016; 71: 1492-9.
44. Taniguchi Y, Kitamura A, Murayama H, Amano H,
Shinozaki T, Yokota I, Seino S, Nofuji Y, Nishi M,
Yokoyama Y, Matsuyama Y, Fujuwara Y, Shinkai S.
Mini-Mental State Examination Score Trajectories
and Incident Disabling Dementia Among
Community-Dwelling Older Japanese. Geriatr
Gerontol Int. 2016 [Epub ahead of print].
45. Taniguchi Y, Kitamura A, Seino S, Murayama H,
Amano H, Nofuji Y, Nishi M, Yokoyama Y,
Shinozaki T, Yokota I, Matsuyama Y, Fujiwara Y,
Shinkai S. Gait performance trajectories andincident disabling dementia among communitydwelling older Japanese. J Am Med Dir Assoc.
2017; 18: 192.e13-192.e20.
46. Watanabe T, Ajioka Y, Mitsuyama K, Watanabe K,
Hanai H, Nakase H, Kunisaki R, Matsuda K,
Iwakiri R, Hida N, Tanaka S, Takeuchi Y, Ohtsuka
K, Murakami K, Kobayashi K, Iwao Y, Nagahori
M, Iizuka B, Hata K, Igarashi M, Hirata I, Kudo
SE, Matsumoto T, Ueno F, Watanabe G, Ikegami M,
Ito Y, Oba K, Inoue E, Tomotsugu N, Takebayashi
T, Sugihara K, Suzuki Y, Watanabe M, Hibi T.
Comparison of targeted vs random biopsies forsurveillance of ulcerative colitis-associatedcolorectal cancer. Gastroenterology. 2016; 151:
1122-30.
47. Yamaue H, Shimizu A, Hagiwara Y, Sho M,
Yanagimoto H, Nakamori S, Ueno H, Ishii H,
Kitano M, Sugimori K, Maguchi H, Ohkawa S,
Imaoka H, Hashimoto D, Ueda K, Nebiki H,
Nagakawa T, Isayama H, Yokota I, Ohashi Y,
Shirasaka T. Multicenter, randomized, open-label
Phase II study comparing S-1 alternate-day oral
therapy with the standard daily regimen as afirst-line treatment in patients with unresectableadvanced pancreatic cancer. Cancer ChemotherPharmacol. 2017; 79: 813-23.
48. Yoshida M, Matsuyama Y. Interim analysis basedon the weighted log-rank test for delayed treatment
effects under staggered patient entry. J BiopharmStat. 2016; 26: 842-58.
49. Zhu Y, Chen CY, Matsuyama Y, Ohashi Y, Franklin
JM, Setoguchi S. Comparative validity of methods
to select appropriate cutoff weight for probabilistic
linkage without unique personal identifiers.
Pharmacoepidemiol Drug Saf. 2016; 25: 444-52.

274

Department of Biomedical Ethics &Department of Health Promotion
Sciences
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Jung Su Lee, Ph.D.
Yoshiyuki Takimoto, M.D., Ph.D.

Research Associate
Eisuke Nakazawa, 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.
Staff members of the two departments include a
professor, two associate professors, an associate, and atechnical specialist. All five members, seven undergraduate lecturers and ten graduate lecturers fromother organizations, and eight visiting researchers
contribute to department teaching and research
activities.
We have nine department graduate students. Six

275of 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. Sixteen bachelor theses, twenty-two mastertheses, and eleven doctoral dissertations werecompleted between April 2004 and March 2017. Our
departments’ staff members are also responsible forthe following undergraduate and graduate courses.
Undergraduate Courses
Required courses
1) Introduction to Biomedical Ethics (Lecture)2) Health Administration (2 credits, lecture)3) Biomedical Ethics (2 credits, lecture)4) Occupational Health and Law (1 credit, lecture)
Elective courses5) Health & Education (2 credits, lecture)6) Health Care & Welfare I & II (2 credits, lecture)7) Field Work for Health Administration (2 credits,
practicum)8) Health Promotion Sciences (1 credit, lecture)9) Health Policy & Administration (2 credits,
lecture)10) Integrated Lecture of Clinical Medicine,
Biomedical ethics (Lecture)
Graduate Courses
1) Biomedical Ethics I
2) Biomedical Ethics II3) Health Promotion Sciences I
4) Health Promotion Sciences II
In addition to these courses, each 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. Graduate courses in Health
Promotion Sciences focus on practical study using
theories and empirical models for planning, imple-

mentation, and evaluation of health promotion
programs for the prevention of lifestyle-relateddisease in the community and workplace.

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 theJapanese context

276

Department of Health Promotion Sciences
The main research activity of the Department of
Health Promotion Sciences is aimed at health policy
proposals concerning health promotion in thecommunity and workplace through experimental andsurvey research. The main research fields include
health behaviors and lifestyle-related disease and
QOL. The focus of health behaviors are physicalactivity, exercise, diet and nutrition, and obesity.

3.

4.
Specific research topics include:1) Development of effective health promotion
programs
2) Assessment of health promotion resources in thecommunity and at the workplace
3) Influence of health behavior change on medical
costs4) Cost-effectiveness analysis for health promotion
programs
5) Development of a physical activity questionnaire
for the Japanese
6) Studies of the social and physical environments
influence on health behaviors
7) Association between family structure and healthbehaviors in pre-school children
8) Influence of maternal health behavior on
children’s health behavior
9) Effects of health behavior modification on
lifestyle-related disease.
10) Life course epidemiology for women’s health11) Social and physical environmental influences on
the health behaviors of people with disease orpain12) Factors related to health check-ups13) Characteristics and determinants associated withthe uptake of influenza vaccination
14) Influence of employment status on self-rated
health5.

6.

7.

References
1. Alkebsi L, Ideno Y, Lee JS, Suzuki S, NakajimaShimada J, Ohnishi H, Sato Y, Hayashi K.
Gastroduodenal ulcers and ABO blood group: theJapan Nurses’ Health Study (JNHS). J Epidemiol
2017 (in press)
2. Etsuko Watanabe, Jung Su Lee, Katsumi Mori,

8.

9.

Kiyoshi Kawakubo. Clustering patterns ofobesity-related multiple lifestyle behaviours andtheir associations with overweight and family
environments: a cross-sectional study in Japanesepreschool children. BMJ Open 2016; 6:e012773.
doi:10.1136/bmjopen-2016-012773.
Fukushi T, Isobe T, Nakazawa E, Takimoto Y,
Akabayashi A, Sakura O. Neuroethics in Far East.
In Routledge Handbook of Neuroethics (in press)
Katanoda K, Noda M, Goto A, Mizunuma H, Lee
JS, and Hayashi K. Impact of birth weight on
adult-onset diabetes mellitus in relation to current
body mass index - Japan Nurses’ Health Study. J
Epidemiol 2017 (in press)
Mishra GD, Chung HF, Pandeya N, Dobson AJ,
Jones L, Nancy E. Avis NE, Crawford SL, GoldEB, Brown D, Sievert LL, Brunner E, Cade JE,
Burley VJ, Greenwood DC, Giles GG, Bruinsma F,
Goodman A, Hayashi K, Lee JS, Mizunuma H,
Kuh D, Cooper R, Hardy R, Obermeyer CM, Lee
KA, Simonsen MK, Yoshizawa T, Woods NF,
Mitchell ES, Hamer M, Demakakos P, Sandin S,
Hans-Olov Adami HO, Weiderpass E, Anderson D.
The InterLACE study: Design, data harmonizationand characterisitics across 20 studies on women’s
health. Maturitus 2016; 92: 176-185.
Mishra GD, Lee JS, Hayashi K, Watanabe E, MoriK, Kawakubo K. How do health behaviors relate
to dietary practice patterns among Japanese
adults? APJCN 2017; 26(2): 351-357.
Mishra GD, Pandeya N, Dobson AJ, Chung HF,
Anderson D, Kuh D, Sandin S, Giles GG,
Bruinsma F, Hayashi K, Lee JS, Mizunuma H,
Cade JE, Burley V, Greenwood DC, Goodman A,
Simonsen MK, Adami HO, Demakakos P,
Weiderpass E. Early Menarche Nulliparity, andthe Risk for Premature and Early Natural
Menopause: Results from Pooled Analysis of Data
from 51,126 Women. Human Reproduction 2017:
doi:10.1093/humrep/dew350
Nakazawa E, Yamamoto K, Tachibana K, Toda S,
Takimoto Y, Akabayashi A. Ethics of Decoded
Neurofeedback in Clinical Research, Treatment,
and Moral Enhancement. American Journal of
Bioethics Neuroscience 2016; 7(2): 110-117.
Takashima K, Takimoto Y, Nakazawa E, Hayashi
Y, Tsuchiya A, Fujita M, Akabayashi A. Discovery

277

and informing research participants of incidental
findings detected in brain magnetic resonanceimaging studies: Review and multi-institutional
study. Brain and Behavior (in press)
10. Yasumura A, Takimoto Y, Nakazawa E, Inagaki M.
Decision Making in Children with AttentionDeficit/Hyperactivity Disorder. Open Journal of
Pediatrics 6: 158-162.
11. Nakazawa E, Takimoto Y, Akabayashi A. Social
framework surrounding the development ofregenerative medicine in Japan. Cambridge
Quarterly of Healthcare Ethics 2016; 25(3): 466471.
12. Yumi Furusawa. Book Review: “Samuel J.M.M.
Alberti and Elizabeth Hallam (eds), Medical
Museums: Past, Present, Future (London: The
Royal College of Surgeons of England, 2013), pp.
vi, 250, £25.00, ISBN: 978-1-904096-21-4.”
Medical History 2017; 61(1): 130-132.

Health Sciences and Nursing
2. Preventive and Administrative Nursing

279

Department of
Nursing Administration/
Advanced Clinical Nursing
Associate Professor
Yukie Takemura, Ph.D., R.N., C.N.A.

Lecturer
Kimie Takehara, Ph.D., R.N.

Assistant Professor
Keiko Kunie, Ph.D., R.N.
Kazunori Komagata, M.S.N., R.N.

Project Assistant Professor
Naoko Ichikawa, Ph.D., R.N.

Homepage

http://nurs-adm.umin.jp/

Introduction and Organization
The Department of Nursing Administration/
Advanced Clinical Nursing has 60 years of history andtradition. It was first established 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.

Teaching Activities
Undergraduate Courses

In the undergraduate program, our department
oversees lectures and clinical practicums for
Introduction of Nursing Science, Fundamental Nursing
I, Fundamental Nursing II, Fundamental Nursing III,and Nursing Administration.
Introduction of Nursing Science (1 credit, lectures)
In this course, students learn nursing concepts,
functions, theories, targets, and the practical side ofnursing.
Fundamental Nursing 1 (2 credits, lectures)This course provides knowledge and nursing skills forunderstanding 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.

280

Fundamental Nursing 2 (2 credits, lectures)This course provides the basics for understanding
interpersonal relationships and assessing clients’ health.
Students will learn the following: 1) theories andpractices in communication and 2) physicalexamination skills essential for health assessments.
Fundamental Nursing 3(4 credits, lectures, and laboratory practicum)This course presents theories and practices infundamental nursing skills, which are essential for
providing nursing care with physiological andpsychosocial integrity. Students learn about the nursing
process and clients’ needs, with case discussions ingroups.
Clinical Practicum in Fundamental Nursing(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. In addition, they will observe
nurses working in outpatient clinics and learn the roleof nursing in healthcare teams.
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.
Nursing Administration Practicum(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 for Nursing Administration and Advance
Clinical Nursing.
Nursing Administration I, II (2 credits each)
These courses offer a critical analysis of theories innursing administration related to leadershipmanagement,
organizational
development/careerdevelopment, quality assurance/improvement, and costeffectiveness/efficient care delivery systems.
Advance Clinical Nursing I (2 credits)
This course offers an overview of the environment
surrounding nursing, political decision-making
processes, and public philosophy. Students develop
expertise and examine the potentialities of nurses andtheir legal responsibilities. The political andadministrative functional roles of nursing are discussed.
Seminar (4 credits)
We have a department seminar every week during
which members discuss plans and topics of their own
research studies.

Research Activities
Environment and Structures to Enable Nurse
Administrators to Fulfil their Potential
We have been examining administrative issues incontemporary nursing. Our main research topic is
developing
newmodelsfornursingadministration/organization development. We inquire
to clarify relationships among environmental/structural
factors, nurse administrators’ competencies/activities,
efficacies, and outcome indicators. We have also been
examining the methodology for nursing administrators’
development.
Environment and Structures to Enable Nurses toFulfil their Potentials
Another main research topic is contributing to theformation of an environment in which nurses/teams
mature and succeed. We are studying careerdevelopment, team/organizational development, teamcommunication, and diversity management.
Development of Nursing Care Technology
For more effective nursing care, we have beendeveloping innovative assessment technology using
ultrasound and preventive care technology for diabetic
foot.

References
1. Oe M, Takehara K, Noguchi H, Ohashi Y,
Watanabe A, Murayama R, Kadowaki T, Sanada H.

281

2.

Validation of a skin hardness meter for foot callus

depressive or anxiety disorders during thein patients with diabetes: Pilot study. Japaneseperinatal

Journal of Foot Care. 2016;14(4):141-143.

Healthcare. 2016;8:42-48.

Tsunemi Y, Takehara K, Miura Y, Nakagami G,

4.

5.

Sakka M, Sato I, Ikeda M, Hashzume H, Uemori
Appraisals of Caregiving by Employed Women

Strip can be used for direct microscopy. British

Caring for their Elderly Parents in Japan.

Journal of Dermatology, 2016. (Epub ahead ofIndustrial Health. 2016;54(3):272-281.
10. Nishigaki

K,

Ikeda

M,

Kamibeppu

K.

Amemiya A, Noguchi H, Oe M, Takehara K,

Preoccupation of mothers while caring for

Ohashi Y, Suzuki R, Yamauchi T, Kadowaki T,

technology-dependent children at home in Japan.

Sanada H, Mori T. Shear stress-normal stress

Asian Nursing Research. 2016. (in press)(pressure) ratio (SPR) decides forming callus in

11. Setoyama A, Ikeda M, Kamibeppu K. Objective

patients with diabetic neuropathy. Journal ofassessment of sleep status and its correlates among

Diabetes Research. 2016;vol.2016:Article ID

hospitalized children with cancer: An exploratory

3157123, 10 pages. doi:10.1155/2016/3157123.

study. Pediatrics International. 2016;58(9):842-

Oe M, Ohashi Y, Takehara K, Oba M, Doi M,

849.

Iizuka Y, Murayama R, Kadowaki T, Sanada H.

12. Takehara K, Amemiya A, Mugita Y, Tsunemi Y,

Foot complications in patients with diabetes

Seko Y, Ohashi Y, Ueki K, Kadowaki T, Oe M,

mellitus: Practical report of diabetic foot clinic in

Nagase T, Ikeda M, Sanada H. Association

Beijing. Japanese Journal of Foot Care. 2016;

between tinea pedis and feet washing behavior in

14(2):57-61.

diabetic

Kuraoka Y, Ibe T, Sasaki N, Kasamatsu Y,

Advances in Skin & Wound Care. 2016. (in press)

Sawabe A, Takemura Y, Yoshida C, Teshima M.

13. Takemura Y. Mission Management: development

Development and evaluation of a competency-of organization co-creating values with reliancebased management program for nurse managers

and dialog. Igaku-Shoin Ltd. 2016.

20(1): 26-37.
Hamatani M, Mori T, Oe M, Noguchi H, Takehara
K, Amemiya A, Ohashi Y, Ueki K, Kadowaki T,
Sanada H. Factors associated with callus indiabetic patients, focused on plantar shear stressduring gait. Journal of Diabetes Science andTechnology. 2016;10(6):1353-1359.
Furukawa K, Oe M, Hosaka Y, Ohashi Y,
Takehara K, Murayama R, Otomo E, Komiyama
C, Kato S, Sanada H. How to select shoes for footulcer prevention—the criteria of shoe selection indiabetic patients without foot ulcers. Japanese
Journal of Foot Care. 2016;14(1):11-15.
8.

Reproductivewith extraction solution of Dermatophyte Testof Nursing Administration and Policies. 2016;

7.

&

M, Kamibeppu K. Family-To-Work Spillover and(first report). The Journal of the Japan Academy

6.

SexualSanada H, Kawashima M. Specimens processed

print)
3.

9.

period.

Mizukoshi M, Ikeda M, Kamibeppu K. The
experiences of husbands of primiparas withpatients:

A

cross-sectional

study.

282

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 9 doctoral students, 6 master’s
students, 3 research 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)Nursing Consultation (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 Nursing (2)Clinical Immunology (1)3. Undergraduate Courses for Nursing Students in the
School of Integrated Health Sciences (credit hours)
Pediatric and Child Health Nursing (2)Clinical Practicum in Pediatric and Child HealthNursing (3)283with 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 was
conducted in 2016. We established a transition
outpatient clinic in the University of Tokyo Hospitalin June 2016, and provided a transitional care forpatients with congenital heart disease, epilepsy,
chromosomal abnormality, hematologic disease, andendocrine disease. We also develop the tool “My
Health Passport” in order for patients to summarize
the information about their disease and share theirexperiences with others (e.g., friends and coworkers).
Furthermore, we have been developing newly checklists to evaluate long-term follow ups in patients after
hematopoietic stem cell transplantation, and supports
for school reentry in pediatric cancer survivors. Thosestudies and activities have been ongoing ininterdisciplinary
collaboration
withhealthprofessionals 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. Kamibeppu K, Soejima T. Re‐integration to
School among Childhood Cancer Patients: “Aida”
which is expericnccd by children, bridged byfamilies, and connected interdisciplinacy team.
Qualitative Psychology Forum. 2016 Sep; 8:32-38.
2. Kita S, Haruna M, Matsuzaki M, Kamibeppu K.
Associations between intimate partner violence(IPV) during pregnancy, mother-to-infant bonding
failure, and postnatal depressive symptoms.
Archives of Women’s Mental Health. 2016 Aug;19(4): 623-34.
3. Takehara K, Dagvadorj A, Hikita N, Sumaya N,
Ganhuyag S, Bavuusuren B, et al. Maternal andchild health in Mongolia at 3 years afterchildbirth: A population-based cross-sectionaldescriptive study. Maternal and Child Health
Journal. 2016 May;20(5):1072-81.
4. Kageyama M, Solomon P, Kita S, Nagata S,
Yokoyma K, Nakamura Y, et al. Factors related tophysical violence experienced by parents ofpersons with schizophrenia in Japan. Psychiatry
Research. 2016 Jun; 243: 439-45.
5. Soejima T, Kamibeppu K. Are cancer survivors
well-performing workers?: A systematic review.
Asia Pacific Journal of Clinical Oncology. 2016
Dec; 12(4): e383-e397.
6. Sakka M, Sato I, Ikeda M, Hashizume H, Uemori
M, Kamibeppu K. Family-to-work spillover andappraisals of caregiving by employed womencaring for their elderly parents in Japan. Industrial
Health. 2016 Jun; 54(3): 272-81
7. Setoyama A, Ikeda M, Kamibeppu K. Objective
assessment of sleep status and its correlates
among hospitalized children with cancer.
Pediatrics International. 2016 Sep; 58(9); 842-9.
8. Sugishita K, Kamibeppu K, Matsuo H. The interrelationship of mental state between antepartum
and postpartum assessed by depression andbonding scales in mothers. Health. 2016 Sep;
8(12): 1234-43.
9. Nishigaki K, Kanamori Y, Ikeda M, Sugiyama M,
Minowa H, Kamibeppu K. Changes in Mother’s
psychosocial perceptions of technology-dependent
children and adolescents at home in Japan:

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acknowledgement of children’s autonomy. Asian
Nursing Research. 2016 Jun; 10(2): 100-5.
10. Komachi M, Kamibeppu K. Posttraumatic stresssymptoms in families of cancer patients admitted
to the intensive care unit: A longitudinal study.
Journal of Intensive Care. 2016 Jul; 4: 47.
11. Kasahara-Kiritani M, Kikuchi R, Ikeda M,
Kamibeppu K. Relationships in Families After a
Member’s Death: A Qualitative Metasynthesis.
Journal of Loss & Trauma. 2016 Apr; 22(5):396-411.
12. Mizukoshi M, Ikeda M, Kamibeppu K. The
experiences of husbands of primiparas withdepressive or anxiety disorders during theperinatal period. Sexual & Reproductive Healthcare. 2016 Jun; 8: 42-8.
13. Takanashi S, Sakka M, Sato I, Watanabe S,
Tanaka S, Ooshio A, et al. Factors influencing
mother–child communication about fathers withneurobehavioural sequelae after brain injury.
Brain Injury. 2016 Aug; 31(3): 312-8.
14. Yamamoto H, Nishigaki K, Miyazaki H, Fujishiro
F, Taya K, Kamibeppu K. The Confidence ofNurses in Health Care Activities at Nursery
Schools. The Journal of Child Health. 2016 Jan;75(1): 63-8.
15. Yamamoto H, Nishigaki K, Miyazaki H, Fujishiro
F, Taya K, Kamibeppu K. Needs for the Arrangement of Nursing Staff among Nursery School
Directors. The Journal of Child Health. 2016 Mar;75(2): 236-41.

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Department ofCommunity Health Nursing /Public Health Nursing
Associate Professor
Satoko Nagata, Ph.D., R.N., P.H.N.

Lecturer
Takashi Naruse, Ph.D., R.N., P.H.N.

Research Associate
Masako Kageyama, Ph.D., R.N., P.H.N.
Mahiro Fujisaki, 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
15 graduate course students (9 in master course, 6 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 homecare patients and the medical, health and welfare
system. Students learn the basics of care management, home health care service, and health caresystem.

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 thebasis of home nursing and understand the life ofhome care patients and their family at home-visit
nursing station and hospital’s department ofdischarge planning. Basic techniques and the roleof nursing through collaboration with otherprofession are mastered.
2. Graduate program, in the Graduate School of
Health Sciences and Nursing (* program for
public health 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 thecommunity organization.
2) Advanced Community Health Nursing II(2 credits, lectures)

286This program involves studying issues in homecare research and qualitative research methodology for community health nursing.
3) Advanced Community Health Nursing Seminar I,
II and Practice I, II (2 credits, practice)This seminar and practice includes 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 andskills that support the techniques required topromote the health of people living in thecommunity. Students will learn basic theory
regarding public health nursing.
5) Skills for Public Health Nursing II (2 credits,
lectures)*This program aims to provide knowledge andskills to support the techniques required topromote the health of people living in thecommunity. Students will learn the legal bases andsocial 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 andbasic theory of public health nursing, and provides
an understanding 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
care provision or activity, focusing on support for
the individual/family and a specific public healthissue. In addition, students will visit a clinicalsetting for school and occupational health nursing
practice.
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
public health nurses. Throughout their assessment,
students are expected to foster their ability to
manage and research public health nursing
practice.
We hold departmental meetings (journal reading
and introduction of research) every Tuesday andmonthly research seminars every third Friday toenhance research capacity.

Research
Our research focuses on the development andevaluation of health care programs, establishment ofcommunity health care systems, and standardizationof skills among public health nurses in response to thehealth care needs of individuals, families, aggregatesand communities. Our research is supported by aGrant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science andTechnology, Health Science research, as well as grants
from the Ministry of Health, Labour and Welfare, andother foundations.
Ongoing research projects in our department are listed
below.
1. Discharge planning
Discharge planning is an interdisciplinary process that
is ideally available to aid patients and their families indeveloping a feasible plan for the next step of care.
Demand for discharge planning is increasing. We areattempting to standardize discharge planning activities
and develop outcome indicators and an educational

287

program on discharge planning for ward nurses. We
are also conducting research on the discharge planningsystem, developing guidelines for multi-sectional andinter-agency cooperation among nurses, nurses’
support at outpatient settings.
2. Developing a community care system and fosteringcollaboration between home-care service providers
Fostering collaboration between home-care service
providers is an international concern in community
care, especially elderly health care. We are conducting
a study to measure the status of collaboration between
care providers in a community setting; it also aims todevelop efficient and feasible strategies to improve
this status.
3. Support for families with infants and children
Recently, custodial parents have faced manydifficulties and challenges. To address this, we areconducting research on children's injury prevention
and social environments for child-rearing parents.
4. Support for families of people with mental illness
Some mental health professionals have recognizedthat families of people with severe mental illness
should be easy to receive support from professionals
in the last few years.
5. 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).
6. Support for people with diseases or disabilities
Since the Great East Japan Earthquake on the 11th ofMarch, 2011, we have studied health conditions ofaffected individuals living in temporary housing inorder to improve their QOL in Otsuchi town, Iwate
prefecture. We aim to determine the relationshipbetween their health conditions and other related

factors.
7. Skills of public health nurses
Public health nurses use high-level support skills;
however, many of these skills have not been identified
through research. We aim to identify and standardize
the skills of public health nurses, focusing inparticular on skills regarding new community
diagnostic method (e.g., use of photo-voice, GIS) andgroup dynamics.

Publications(1) Takashi Naruse, Hiroshige Matsumoto, Natsuki
Yamamoto, Satoko Nagata. Association between
Geographic Accessibility of Home Care Clinics
and Hospitalization in Japan using Geographic
Information Systems and Insurance Claim Data.
Health, DOI:10.4236/health.2016.810102, 2016.
(2) Masako Kageyama, Phyllis Solomon, SachikoKita, Satoko Nagata, Keiko Yokoyama, Yukako
Nakamura, Sayaka Kobayashi, Chiyo Fujii.
Factors Related to Physical Violence Experienced
by Parents of Persons with Schizophrenia inJapan. Psychiatry Research, 243, 439-445, 2016.
(3) Masako Kageyama, Yukako Nakamura, Sayaka
Kobayashi, Keiko Yokoyama. Validity andreliability of the Family Empowerment Scale forcaregivers of adults with mental health issues.
Journal of Psychiatric and Mental Health Nursing,
DOI: 10.1111/jpm.12333, 2016.
(4) Mahiro Sakai, Takashi Naruse, Satoko Nagata.
Relational coordination among home healthcare
professions and goal attainment in nursing care.
Japan Journal of Nursing Sciences, 13(3), 402410, 2016.
(5) Mahiro Sakai, Takashi Naruse, Satoko Nagata.
Relational coordination between professionals
predicts satisfaction with home visit nursing care.
Clinical Nursing Studies, 4(1), 1-5, 2016.
(6) Natsuki Yamamoto, Takashi Naruse, Mahiro
Sakai, Satoko Nagata. The Relationship between
Maternal Mindfulness and Anxiety One Monthafter Childbirth in Japan. Japan Journal of
Nursing Science, DOI: 10.1111/jjns.12157, 2016.
(7) Natsuki Yamamoto, Chikako Honda, Satoko
Nagata. Current trends and age-based differences

288

of unintentional injury in Japanese children.
Bioscience trends, 10(2), 152-157, 2016.
(8) Chika Tanaka, Takashi Naruse, Atsuko Taguchi,
Satoko Nagata, Azusa Arimoto, Yuki Ohashi,
SachiyoMurashma.
onformitytotheneighborhood modifies the association between
recreational walking and social norms among
middle-aged Japanese people. Japan Journal of
Nursing Sciences, 13(4), 451-465, 2016.
(9) Takuma Kimura, Satoru Yoshie, Rumiko
Tsuchiya, Syohei Kawagoe, Satoshi Hirahara,
Katsuya Iijima, Toru Akahoshi, Tetsuo Tsuji.
Catheter replacement structure in home medicalcare settings and regional characteristics in Tokyoand three adjoining prefectures. Geriatrics &Gerontology International, DOI: 10.1111/ggi.
12769, 2016.
(10) Masako Kageyama, Yukako Nakamura, Sayaka
Kobayashi, Keiko Yokoyama. Validity andreliability of the Japanese version of the
Therapeutic Factors Inventory-19 (TFI-19J)‐A
study of family peer education self-help groups.
Japan Journal of Nursing Science, 13, 135-146,
2016.
(11) Masako Kageyama, Phyllis Solomon, Keiko
Yokoyama. Psychological distress and violence
towards parents of patients with schizophrenia.
Archives of Psychiatric Nursing, Epub ahead ofprint 19 FEV.2016, DOI: 10.1016/j.apnu.2016.
02.003.
(12) Takashi Naruse, Mahiro Sakai, Satoko Nagata.
The effects of perceived colleague nurse
relational coordination and span of control on
work engagement among home visiting nurses,
Japan Journal of Nursing Sciences, 13(2),240-246, 2016.
(13) Mahiro Sakai, Takashi Naruse, Satoko Nagata.
Relational coordination possibly enhance goal
attainment of nursing care among homehealthcare professions. Japan Journal of Nursing
Sciences, 13(3) 402-410, 2016.
(14) Masako Kageyama, Sayaka Kobayashi, Keiko
Yokoyama, Yukako Nakamura. Partnerships
between family caregivers and psychiatric social
workers
causedbyimplementationof"Omotenashi-Family
Experiences
Learning
Program" in psychiatric hospitals: Qualitativedescriptive analysis of interview data. Japanesejournal of psychiatric rehabilitation 20(2),177-183, 2016(15) Masako Kageyama, Keiko Yokoyama, Sayaka
Kobayashi, Yukako Nakamura. Exploring factors
related to adoption and continuation of a family
peer-education program on mental disorders in
psychiatric hospitals: A case study. Japanese
Journal of Public Health, 63(10)，627-636，2016．
(16) Mahiro Sakai, Takashi Naruse, Satoko Nagata.
Identifying work practice factors relate withinterprofessional relational coordination among
home visiting nurses. Hoken-iryo-fukushi-renkei，
9(2)，157-165，2016．
(17) Risa Nishikoori, Satoko Nagata, Midori Mizui,
Hikari Tomura. Difference of the characteristics
of hospital and activities for discharge planning
between hospital with and without nurses incharge of discharge planning in the ward. Japan
Academy of Community Health Nursing, 19(1)，72-79，2016．
(18) Naoko Noumi, Masako Kageyama. Experiencesof Middle-Aged Parents Whose Adult Children
Have Mental Illnesses: Strategies to Support for
Parents Based on Their Experiences throughParticipation in Family Peer Groups. Journal ofJapan Academy of Psychiatric and Mental HealthNursing 25(2), 41-50, 2016.
(19) Shiori Ninomiya, Yukako Nakamura, Masako
Kageyama, Keiko Yokoyama, Hajime Oketani,
Sayaka Kobayashi, Iwao Oshima. The Effect of"Omotenashi-Family
Experiences
Learning
Program" on the Empowerment of Family
Members: Comparison of family participants andfamily facilitators. Clinical psychiatry, 58(3)，199-207，2016．

Health Sciences and Nursing
3. Clinical Nursing

290

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.
Naoko Mikoshiba, Ph.D., R.N.
Aki Kawakami, Ph.D., R.N. (June, 2016～)

Project Assistant Professor
Training Program of Oncology Specialist, The University of Tokyo
Reiko Yamahana, CNS, 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.

291

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
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.

2925) Developing a clinical education program andeducational indicator to improve nurse’s clinicaljudgement competency
Education on clinical judgement is addressed inaccordance with the educational guidelines of bothbasic education and clinical education. However, there
are no references to concrete methods on acquiring
techniques in the guidelines. For this reason, various
teaching methods were looked at, but consistenteducation for basic education and clinical education
could not be found. It can be thought that education at
nursing school do not foster the competency of actual
practice. In this study, first, the current situation ofbasic nursing education and clinical education wasinvestigated. An attempt has been made at developing
a post-graduate physical assessment training programthat aims to strengthen the clinical judgmentcompetency of nurses.
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. Tsujimura M, Ishigaki K, Yamamoto- Mitani N,
Fujita J, Katakura N, Mochizuki Y, Okamoto Y,
Shinohara Y. Cultural characteristics of nursing
practice in Japan. International Journal of Nursing
Practice. 2016;22 Suppl 1:56-64. doi: 10. 1111/ijn.
12440.
2. Kawakami A, Tanaka M, Naganuma M, Maeda S,
Kunisaki R, Yamamoto-Mitani N. What strategies
do ulcerative colitis patients employ to facilitate
adherence? Patient Preference and Adherence.
2016 (11):157-163.
3. Kawakami A, Tanaka M, Ochiai R, Naganuma M,
Kunisaki R, Kazuma K. Difficulties in Performing
Mesalazine Enemas and Factors Related toDiscontinuation Among Patients With Ulcerative
Colitis. Gastroenterolgy Nursing. 2016. doi: 10.
1097/SGA.0000000 000000147.

4. Tanaka M, Kawakami A, Iwao Y, Fukushima T,
Yamamoto-Mitani N. Coping strategies forpossible flare-ups and their perceived effectiveness in patients with inflammatory bowel disease.
Gastroenterology Nursing. 2016; 39(2): 42-7.
5. Naoko Mikoshiba, Noriko Yamamoto- Mitani,
Takamasa Ohki, Yoshinari Asaoka, Hironori
Yamaguchi, Shuntaro Obi, Kazuki Sato, Kazuhiko
Koike, Mitsunori Miyashita. A simple homebased self- monitoring tool for early detection ofhand-foot syndrome in cancer patients. Japanjournal of clinical oncology. 2016. doi: 10.1093/
jjco/hyw112
6. Yamamoto-Mitani N, Fukahori N, NoguchiWatanabe M. Caring for Clients and Families
with Anxiety: Homecare Nurses’ PracticeNarratives. Global Qualitative Nursing Research.
2016 16;3:2333393616665503. doi: 10.1177/
2333393 616665503. eCollection 2016 Jan-Dec.
7. Yokoyama M, Suzuki M, Takai Y, Igarashi A,
Noguchi-Watanabe M, Yamamoto- Mitani N.
Workplace bullying among nurses and theirrelated factors in Japan: a cross-sectional survey. J
Clin Nurs. 2016 Sep;25(17-18):2478-88. doi:
10.1111/jocn.13270.
8. Noguchi-Watanabe M, Yamamoto-Mitani N,
Takai Y. How does collegial support increase
retention of registered nurses in homecare nursing
agencies? A qualitative study. BMC Nursing.
2016;15:35. doi: 10.1186/s12912- 016-0157-3.
eCollection 2016.
9. Igarashi A, Yamamoto-Mitani N, Yoshie S, Iijima
K. Patterns of long-term care services use in a
suburban municipality of Japan: A populationbased study. Geriatrics & Gerontology International. 2016;17(5):753-759. doi: 10.1111/ggi.
12781.

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Department ofMidwifery and Women's Health
Associate Professor
Megumi Haruna, Ph.D., R.N.M., P.H.N.

Lecturer
Masayo Matsuzaki, Ph.D., R.N.M., P.H.N.

Research Associate
Emi Sasagawa, Ph.D., M.P.H., R.N.M.

Project Research Associate
Kaori Yonezawa, Ph.D., R.N.M., P.H.N.

Homepage

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

Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
It has 4 faculty members introduced above, 15
graduate students (6 in master’s courses, 9 in doctoral
courses), and 2 visiting researchers.

Teaching activities
We have graduate and undergraduate courses.
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health I(2 credits, lectures)
2) Advanced Midwifery and Women’s Health II(2 credits, lectures)
2. Graduate Courses, School of Health Sciences andNursing for midwifery
1) Midwifery I (2 credits, lectures)
2) Midwifery II (2 credits, lectures)
3) Midwifery III (2 credits, lectures)
4) Midwifery IV (2 credits, lectures)
5) Midwifery V (2 credits, lectures)

6) Midwifery VI (1 credits, 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) Clinical Practicum in Maternal-Newborn
Nursing (2 credits, practices)

Research activities
Our research activities cover the field of maternal andchild health emphasizing on the promotion of
women’s health and quality of life at every stage oflife.
We conduct the following research projects:
1. Creating evidence of health guidance during
pregnancy
1) Adequate maternal nutrition and weight management

294This 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) The effect of exercise during pregnancy
This study investigates the effect of exercise on
mental and physical health among pregnant
women.
3) Lifestyle factors and oxidative stress markers
during pregnancy
This study investigates the potential relationships
between lifestyle factors and oxidative stressmarkers during pregnancy to establish optimal
oxidative stress markers for predicting a healthy
lifestyle for pregnant women.
4) 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) “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.

5) Sleep apnea syndrome during pregnancy
This study investigates the prevalence and risk
factors of obstructive sleep apnea (OSA) during
pregnancy using a portable device to evaluate sleepand effects of OSA on birth outcomes.

4) Fertility intention among working womenThis study investigates the factors related tofertility intention among working women.

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.

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).

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Publications
1. Haruna M, Shiraishi M, Matsuzaki M, Yatsuki Y,
Yeo S. Effect of tailored dietary guidance forpregnant women on nutritional status: adouble-cohort study. Matern Child Nutr. 2016
Nov 29.
2. Sasagawa E, Tung R, Horikosh Y, Takehara K,
Noguchi M, Egami Y, et al. Discrepancy between
the national protocol and healthcare providers’knowledge, attitude, and practice regarding
induction and augmentation of labor withoxytocin in Cambodia. J Int Health. 2016;31(4):289-298.
3. Kusaka M, Matsuzaki M, Shiraishi M, Haruna M.
Immadiate stress reduction effects of yoga during
pregnancy: One group pre-post test. Women andBirth. 2016;29(5):e82-e88.
4. Hayashi A, Matsuzaki M, Kusaka M, Shiraishi M,
Haruna M. Daily Walking Decreases Casual
Glucose Level Among Pregnant Women in theSecond Trimester. Drug Discov Ther. 2016;10(4):218-22.
5. Kita S, Haruna M, Matsuzaki M, Kamibeppu K.
Associations between intimate partner violence(IPV) during pregnancy, mother-to-infant bonding
failure, and postnatal depressive symptoms. Arch
Womens Ment Health. 2016;19(4):623-34.
6. Kita S, Haruna M, Hikita N, Matsuzaki M,
Kamibeppu K. Development of the Japaneseversion of the Woman Abuse Screening ToolShort. Nurs Health Sci. 2017;19(1):35-43. Epub
2016 Jul 18.
7. Takegata M, Haruna M, Matsuzaki M, Shiraishi
M, Okano T, Severinsson E. Aetiological relationships between factors associated with postnatal
traumatic symptoms among Japanese primiparasand multiparas: A longitudinal study. Midwifery.
2017;44:14-23. Epub 2016 Oct 28.
8. Dagvadorj A, Ota E, Shahrook S, Baljinnyam OP,
Takehara K, Hikita N, et al. Hospitalization risk
factors for children's lower respiratory tract infection: A population-based, cross-sectional study inMongolia. Sci Rep. 2016 Apr 19;6:24615.
9. Takehara K, Dagvadorj A, Hikita N, Sumya N,
Ganhuyag S, Bavuusuren B, et al. Maternal andChild Health in Mongolia at 3 Years After

Childbirth: A Population-Based Cross-Sectional
Descriptive Study. Matern Child Health J. 2016;20(5):1072-81.
10. Hirose N, Shiraishi M, Haruna M, Matsuzaki M,
Yoshida H. The impact of earthquake on
pregnancy outcomes: A systematic review. Journalof Japan Academy of Midwifery. 2016;30(2):342-349. In Japanese.
11. Suto M, Sasagawa E, Yoshiasa K, Matsuzaki Y,
Matsumoto A, Misago C. The effect of diaperlessparenting on the age at which toddlers stopneeding diapers. Japanese Journal of Health andHuman Ecology. 2016. In Japanese.

296

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.

Homepage

http:// plaza.umin.ac.jp/heart/

Introduction and Organization

Education

Our department was firstly established as Department of Fourth Clinical Medical Nursing in School of
Health Care and Nursing in 1957. When the School of
Health Care and Nursing was reorganized as the
School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two departments have been working cooperatively ever since.
Our department currently has two faculty
members introduced above, a project research
associate, part-time lecturers, visiting research fellows,
4 doctoral course students, 4 master course students,
and research associates.
Our department’s mission comprises twoelements. One is to provide education and researchtraining in mental health and psychiatric nursing toundergraduate and graduate students in order toprepare students to assume leadership roles in nursing
clinical practice, administration, teaching, andresearch in this field. The other is to conduct clinicalresearch in the fields of psychiatric nursing andadvance knowledge and theory through research.
All of the activities of our department are
conducted in collaboration with staff members in the
Department of Mental Health.

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.

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; disaster297

mental health nursing; and reducing the use of
seclusion and restraint. We are conducting studies incollaboration with researchers in other institutions anduniversities.

Publications
1. Nakanishi M, Miyamoto Y. Palliative care foradvanced dementia in Japan: knowledge andattitudes. Br J Nurs. 2016;25(3):146-55.
2. GBD 2015 Maternal Mortality Collaborators..
Global, regional, and national levels of maternalmortality, 1990-2015: a systematic analysis for the
Global Burden of Disease Study 2015. Lancet.
2016 Oct 8;388(10053):1775-1812.
3. GBD 2015 Child Mortality Collaborators.. Global,
regional, national, and selected subnational levelsof stillbirths, neonatal, infant, and under-5
mortality, 1980-2015: a systematic analysis for the
Global Burden of Disease Study 2015. Lancet.
2016 Oct 8;388(10053):1725-1774.
4. GBD 2015 Risk Factors Collaborators.. Global,
regional, and national comparative risk
assessment of 79 behavioural, environmental andoccupational, and metabolic risks or clusters ofrisks, 1990-2015: a systematic analysis for the
Global Burden of Disease Study 2015. Lancet.
2016 Oct 8;388(10053):1659-1724.
5. GBD 2015 DALYs and HALE Collaborators..
Global, regional, and national disability-adjusted
life-years (DALYs) for 315 diseases and injuries
and healthy life expectancy (HALE), 1990-2015:a systematic analysis for the Global Burden of
Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1603-1658.
6. GBD 2015 Disease and Injury Incidence andPrevalence Collaborators.. Global, regional, andnational incidence, prevalence, and years lived
with disability for 310 diseases and injuries,
1990-2015: a systematic analysis for the Global
Burden of Disease Study 2015. Lancet. 2016 Oct
8;388(10053):1545-1602.
7. GBD 2015 Mortality and Causes of Death
Collaborators.. Global, regional, and national life
expectancy, all-cause mortality, and cause-specificmortality for 249 causes of death, 1980-2015: asystematic analysis for the Global Burden of

Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1459-1544.
8. GBD 2015 SDG Collaborators.. Measuring thehealth-related Sustainable Development Goals in
188 countries: a baseline analysis from the Global
Burden of Disease Study 2015. Lancet. 2016 Oct
8;388(10053):1813-1850.
9. GBD 2015 HIV Collaborators., Wang H, Wolock
TM, et al. Estimates of global, regional, andnational incidence, prevalence, and mortality ofHIV, 1980-2015: the Global Burden of Disease
Study 2015. Lancet HIV. 2016 Aug;3(8):e361-87.
10. Horikoshi N, Iwasa H, Kawakami N, Suzuki Y,
Yasumura S. Residence-related factors andpsychological distress among evacuees after the
Fukushima Daiichi nuclear power plant accident:a cross-sectional study. BMC Psychiatry. 2016
Nov 24;16(1):420.
11. 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. Behavioral activation for lateadolescents with subthreshold depression: arandomized controlled trial. Eur Child Adolesc
Psychiatry. 2016 Nov;25(11):1171-1182.
12. Levine CS, Miyamoto Y, Markus HR, Rigotti A,
Boylan JM, Park J, Kitayama S, Karasawa M,
Kawakami N, Coe CL, Love GD, Ryff CD.
Culture and Healthy Eating: The Role ofIndependence and Interdependence in the UnitedStates and Japan. Pers Soc Psychol Bull. 2016
Oct;42(10):1335-48.
13. Inoue A, Kawakami N, Eguchi H, Tsutsumi A.
Buffering effect of workplace social capital on theassociation of job insecurity with psychologicaldistress in Japanese employees: a cross-sectional
study. J Occup Health. 2016 Sep 30;58(5):460-469.
14. GBD 2015 HIV Collaborators. Estimates of global,
regional, and national incidence, prevalence, andmortality of HIV, 1980-2015: the Global Burdenof Disease Study 2015. Lancet HIV. 2016 Aug;3(8):e361-87.
15. Takagaki K, Okamoto Y, Jinnin R, Mori A,
Nishiyama Y, Yamamura T, Yokoyama S, Shiota S,
Okamoto Y, Miyake Y, Ogata A, Shimoda H,

298

Kawakami N, Furukawa TA, Yamawaki S.
Mechanisms of behavioral activation for lateadolescents: Positive reinforcement mediate therelationship between activation and depressive
symptoms from pre-treatment to post-treatment. J
Affect Disord. 2016 Nov 1;204:70-3.
16. Inoue A, Kawakami N, Eguchi H, Tsutsumi A.
Modifying effect of cigarette smoking on theassociation of organizational justice with serious
psychological distress in Japanese employees: across-sectional study. Int Arch Occup Environ
Health. 2016 Aug;89(6):901-10.
17. Fujita S, Kawakami N, Ando E, Inoue A, Tsuno K,
Kurioka S, Kawachi I. The Association ofWorkplace Social Capital With Work Engagementof Employees in Health Care Settings: A
Multilevel Cross-Sectional Analysis. J Occup
Environ Med. 2016 Mar;58(3):265-71.
18. Chiba R, Umeda M, Goto K, Miyamoto Y,
Yamaguchi S, Kawakami N. Psychometricproperties of the Japanese version of the Recovery
Attitudes Questionnaire (RAQ) among mental
health providers: a questionnaire survey. BMC
Psychiatry. 2016 Feb 16;16:32.
19. Watanabe K, Otsuka Y, Shimazu A, Kawakami N.
The Moderating Effect of Health-Improving
Workplace Environment on Promoting Physical
Activity in White-Collar Employees: A Multi-Site
Longitudinal Study Using Multi-Level Structural
Equation Modeling. J Occup Environ Med. 2016
Feb;58(2):178-84.
20. Miki T, Eguchi M, Kurotani K, Kochi T,
Kuwahara K, Ito R, Kimura Y, Tsuruoka H, Akter
S, Kashino I, Kabe I, Kawakami N, Mizoue T.
Dietary fiber intake and depressive symptoms inJapanese employees: The Furukawa Nutrition and
Health Study. Nutrition. 2016 May;32(5):584-9.
21. Scott KM, Lim C, Al-Hamzawi A, Alonso J,
Bruffaerts R, Caldas-de-Almeida JM, Florescu S,
de Girolamo G, Hu C, de Jonge P, Kawakami N,
Medina-Mora ME, Moskalewicz J, NavarroMateu F, O'Neill S, Piazza M, Posada-Villa J,
Torres Y, Kessler RC. Association of Mental
Disorders With Subsequent Chronic Physical
Conditions: World Mental Health Surveys From
17 Countries. JAMA Psychiatry. 2016 Feb;73(2):150-8.

22. Hirokawa K, Miwa M, Taniguchi T, Tsuchiya M,
Kawakami N. Moderating effects of salivary
testosterone levels on associations between job
demand and psychological stress response inJapanese medical workers. Ind Health. 2016 Jun
10;54(3):194-203.
23. Ishikawa H, Yasunaga H, Matsui H, Fushimi K,
Kawakami N. Differences in cancer stage,
treatment and in-hospital mortality between
patients with and without schizophrenia: retrospective matched-pair cohort study. Br J
Psychiatry. 2016 Mar;208(3):239-44.
24. Benjet C, Bromet E, Karam EG, Kessler RC,
McLaughlin KA, Ruscio AM, Shahly V, Stein DJ,
Petukhova M, Hill E, Alonso J, Atwoli L, Bunting
B, Bruffaerts R, Caldas-de-Almeida JM, deGirolamo G, Florescu S, Gureje O, Huang Y,
Lepine JP, Kawakami N, Kovess-Masfety V,
Medina-Mora ME, Navarro-Mateu F, Piazza M,
Posada-Villa J, Scott KM, Shalev A, Slade T, ten
Have M, Torres Y, Viana MC, Zarkov Z, Koenen
KC. The epidemiology of traumatic event
exposure worldwide: results from the World
Mental Health Survey Consortium. Psychol Med.
2016 Jan;46(2):327-43.
25. Tanisho Y, Shigemura J, Kubota K, Tanigawa T,
Bromet EJ, Takahashi S, Matsuoka Y, Nishi D,
Nagamine M, Harada N, Tanichi M, Takahashi Y,
Shimizu K, Nomura S, Yoshino A; Fukushima
NEWS Project Collaborators. The longitudinalmental health impact of Fukushima nuclear
disaster exposures and public criticism among
power plant workers: the Fukushima NEWS
Project study. Psychol Med. 2016 46(15): 31173125.
26. Imamura K, Sekiya Y, Asai Y, Umeda M,
Horikoshi N, Yasumura S, Yabe H, Akiyama T,
Kawakami N. The effect of a behavioral
activation program on improving mental andphysical health complaints associated withradiation stress among mothers in Fukushima: arandomized controlled trial. BMC Public Health.
BMC Public Health. 2016;16(1):1144.
27. Sakuraya A, Shimazu A, Imamura K, Namba K,
Kawakami N. Effects of a job crafting
intervention program on work engagement among
Japanese employees: a pretest-posttest study.

299

BMC Psychol. 2016; 4: 49.
28. Watanabe K, Imamura K, Kawakami N. Working
hours and the onset of depressive disorder: asystematic review and meta-analysis. Occup
Environ Med. 2016 Dec;73(12):877-884.
29. Matsumoto T, Tachimori H, Takano A, Tanibuchi
Y, Funada D, Wada K. Recent changes in theclinical features of patients with new
psychoactive-substances-relateddisordersinJapan: Comparison of the Nationwide Mental
Hospital Surveys on Drug-related Psychiatric
Disorders undertaken in 2012 and 2014.
Psychiatry Clin Neurosci. 2016 Dec;70(12):560566.
30. Tsuno K, Kawakami N. The impact of workrelated physical assaults on mental health among
Japanese employees with different socioeconomic
status: The Japan Work Stress and Health Cohort
Study (JSTRESS). SSM Population Health 2016;
2: 572-579.
31. Otowa T, Kawamura Y, Tsutsumi A, Kawakami N,
Kan C, Shimada T, Umekage T, Kasai K,
Tokunaga K, Sasaki T. The First Pilot GenomeWide Gene-Environment Study of Depression in
the Japanese Population. PLoS One. 2016 Aug 16;
11(8):e0160823.
32. Tanaka E, Tsutsumi A, Kawakami N, Kameoka S,
Kato K, You Y-H. Long-term psychological consequences among adolescent survivors of the
Wenchuan earthquake in China: a cross-sectional
survey six years after the disaster. J Affect Dis
2016; 204: 255–261.
33. Purnawati S, Sutjana DP, Adiputra N, Shimazu A,
Kawakami N. Effects of an ergonomics-based job
stress management program on job strain,
psychological distress, and blood cortisol among
employees of a national private bank in Denpasar,
Bali. Ind Health. 2016 Aug 6. [Epub ahead ofprint]
34. Eguchi H*, Shimazu A*, Bakker AB, Tims M,
Kamiyama K, Hara Y, Namba K, Inoue A, Ono M,
Kawakami N. Validation of the Japanese versionof the Job Crafting Scale. J Occup Health
2016;58: 231-240 (* Equal contribution).
35. Eguchi H, Shimazu A, Kawakami N, Inoue A,
Tsutsumi A. Source-specific workplace social
support and highsensitivity C-reactive protein

levels among Japanese workers: A 1-year
prospective cohort study. Am J Indl Med 2016
Aug;59(8):676-84.
36. Imamura K, Kawakami N, Tsuno K, Tsuchiya M,
Shimada K, Namba K. Effects of web-based stressand depression literacy intervention on improving
symptoms and knowledge of depression among
workers: A randomized controlled trial. J Affect
Disord. 2016; 203: 30–7.
37. Arai K, Takano A, Nagata T, Hirabayashi N.
Predictive accuracy of the Historical-ClinicalRisk Managemant-20 for violence in forensic
psychiatric wards in Japan. Crim Behav Ment.
2016 Jun 13. [Epub ahead of print]
38. Fujiwara T, Shimazu A, Tokita M, Shimada K,
Takahashi M, Watai I, Iwata N, Kawakami N.
Association of parental workaholism and bodymass index of offspring: A prospective study
among Japanese dual workers. Frontiers in Public
Health. 2016; 4:41.
39. Takano A, Miyamoto Y, Kawakami N, Matsumoto
T. Web-based cognitive behavioral relapse
prevention program with tailored feedback forpeople with methamphetamine and other drug use
problems: development and usability study. JMIR
Ment Heal. 2016;3(1):e1.
40. Takano A, Miyamoto Y, Kawakami N, Matsumoto
T, Shinozaki T, Sugimoto T. Web-based cognitive
behavioral relapse prevention program with
tailored feedback for people with methamphetamine and other drug use problems: protocol
for a multicenter randomized controlled trial in
Japan. BMC Psychiatry. 2016, 16:87.
41. Imamura K, Kawakami N, Inoue A, Shimazu A,
Tsutsumi A, Takahashi M, Totsuzaki T. WorkEngagement as a Predictor of Onset of Major
Depressive Episode (MDE) among Workers,
Independent of Psychological Distress: A 3-Year
Prospective Cohort Study.PLoS One. 2016 Feb
3;11(2):e0148157.

300

Department ofGerontological Nursing /Wound Care Management
Professor
Hiromi Sanada, R.N., P.H.N., W.O.C.N., Ph.D.

Lecturer
Gojiro Nakagami, R.N., Ph.D.

Project Lecturer
Takeo Minematsu, Ph.D.

Research Associate
Nao Tamai, R.N., Ph.D., Mikako Yoshida, R.N.W., Ph.D.

Project Research Associate
Koichi Yabunaka, Ph.D.

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. These two departments are currently headed by 1
professor and assisted by 1 lecturer, 1 project lecturer, 2
research associates, 1 project research associate, 2 parttime lecturers for undergraduate courses, and 7 part-time
lecturers for graduate courses. The student body consistsof 6 doctoral course students and 9 master course students.
The goal of our department is to achieve “Evidence-based
practice and development of gerontological nursing andwound care management”.

Teaching activities
1. Undergraduate course
1) Health Support Practice(W in 2nd yr/ 1 credits)
Nursing is applied to various social situations, as well as

hospital, healthcare center or medical facilities. Nursing isa science of searching the necessary ways for healthsupport and achievement of self-actualization. The aim of
this practice is for students to understand the variety andwide potential of nursing, and to learn the methods andpractices for health support through experiential learning ofvarious types of nursing from the earliest stages of their
nursing course. The program in 2016 included a look into
how policies are shaped in order to solve problems
confronted in nursing, service for health support, hospitalmanagement based on nursing, and the generation of anursing body of knowledge based on nursing research.
2) Gerontological Nursing(A2 in 3rd yr/ S1 in 4th yr/ 4 credits)
The aim of the 3rd year course is for students to understandthe physical, psychological, and social characteristics of theelderly population, and to learn fundamental theories ofgerontological nursing. The main themes in the 2016
contents were as follows;a) Practical simulation for gerontological nursing

301b) Physical, psychological, and social characteristics ofthe elderly from a nursing standpointc) Gerontological nursing and its theoriesd) Geriatric syndrome and nursing (gait disorder,
incontinence malnutrition, infection, dementia andpressure ulcer)e) Future perspectives of gerontological nursing, such as
biological nursing, Mimamori engineering, and nursing
engineering.
f) Group work
The aim of the 4th year course is to promote anunderstanding of the ailments and conditions required toprovide proper care to the elderly. The main themes in the2016 contents were as follows;a) Age-related changes in the physiological systemb) Aging and dementiac) Aging and osteoporosisd) Aging and respiratory disorders.
e) Aging and cardiovascular disorders, renal function,
hypertension, and strokef) Pharmacological management of the elderlyg) Feeding and swallowing difficulty of the elderlyh) Nutritional management of the elderlyi) Relationship and communication skills with the elderly
The above lectures were provided through cooperationfrom the Department of Geriatric Medicine and otherdepartments at The University of Tokyo Hospital.

2) Gerontological Nursing II (A1/ 2 credits)
Gerontological Nursing II provided lectures regarding
recent topics around gerontological medicine and nursing
from broad viewpoints, including biological, individual,
and social aspects, by part-time lecturers and specialists
from each research field. The aim of this course was tounderstand and learn scientific ways of thinking forgerontological considerations of the future Japanesecommunity. The main themes in 2016 were as follows:a) Acute biomedical engineering and rehabilitation forhemiplegia patientb) Up-to-date information of sarcopeniac) Care for supporting persons with dementia, and theirfamilyd) The practice of home medical care —interprofessional
collaboration in health and social care and the application of information and communications technologiese) Treatment of pressure ulcers developed in chronic renal
disease patients, and nutrition management for patientsin perioperative and invasive phasesf) The aim of dysphagia rehabilitationg) Biological and medical research using the latest
technology for micro/nano devices2) Clinical Practice in Gerontological Nursing(S2 in 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 programin 2016 was supported by the long-term care facility owned
by Medical Corporation Tatsuoka.

3) Wound Care Management I (S2/ 2 credits)
The main topic of Wound Care Management I in 2016 waslearning basic knowledge (basic biology, clinical research,and engineering), which is necessary to understand wound
management studies. The topics were as follows:a) Basic knowledge of wounds and the nursing approachb) Basics of skinc) Basics of woundsd) Basics of molecular and cellular biological researche) Basics of clinical nursing researchf) Basics of engineering researchg) Molecular and cellular biological approach to nursing

2. Graduate course
1) Gerontological Nursing I(S1/ 2 credits)
The main theme of Gerontological Nursing I in 2016 wasto understand the latest research related to the care ofelderly persons and to discuss future perspectives ofgerontological nursing from three viewpoints: basic
biology, engineering, and clinical nursing research. Recent
research papers were selected from these three fields andcritically evaluated.

4) Wound Care Management II (A2/ 2 credits)
The main theme of Wound Care Management II in 2016
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) Basis and clinical application of ultrasonography innursingb) Basics of wound carec) Basics and application of wound care302d) Pressure redistribution for pressure ulcer preventione) Alteration of skin physiology caused by obesityf) Treatment and care of intractable ulcers
5) Master’s theses
The following were research themes in 2016:“Development of a plantar load estimation algorithm forevaluation of forefoot load of diabetic patients during daily
walks using a foot motion sensor”“Development of an automatic puncturing and samplingsystem for a self-monitoring blood glucose device”“Development of personalized fitting device with threedimensional solution for prevention of medical devicerelated pressure ulcers caused by non-invasive positive
pressure ventilation oral-nasal mask”“ Evaluation of comfort associated with the use of arobotic mattress with an interface pressure mapping system
and automatic inner air-cell pressure adjustment function”“Properties of pruritus and related factors among elderly
residents of Panti Werdha”
6) Doctoral theses
The followings were research themes in 2016:“Development of a nutritional monitoring method using
ultrasonography in the elderly: measuring temporal muscle
thickness as an estimate of energy adequacy”“Development of a pressure ulcer assessment method
based on peroxidase and alkaline phosphatase activity
detected by wound blotting”

Research activities
1. Activity policy
Our gerontological nursing research focuses on elderly
people suffering from geriatric syndromes, such as pressure
ulcers, incontinence, malnutrition, pain, dysphagia,
osteoporosis and dementia. Our wound care management
research focuses on pressure ulcers, diabetic foot ulcers,
ulcers with peripheral vascular diseases, and malignant
fungating wounds.
The majority of our clinical research has been conducted at
The University of Tokyo Hospital. We have been
participating with pressure ulcer multi-disciplinary teamrounds. We also attend the Foot Care Outpatient Clinic heldby the Department of Metabolic Diseases and the Stoma
Outpatient Clinic held by the Departments of Urology andColorectal Surgery. In addition, we support the Departmentof Advanced Nursing Technology which was established in
December 2012 as a social cooperation program to promoteteam nursing intervention and research involving the clinicaldivision, the nursing department, and the nursing
departments of Graduate School of Medicine. Through thisprogram, nurses can scientifically study the subject ofnursing, including research in epidemiological surveys andmolecular- and gene-level topics. Furthermore, thetechnology and medical equipment developed by companies
can be evaluated in the hospital, offering new nursing
technologies suitable for needs in clinical sites.
We further promoted a new research framework“Bioengineering Nursing” which consists of nursing biology(which investigates the detailed mechanism of the target
phenomenon), nursing engineering (which develops
technologies for the clarified target), and nursing
translational research (which evaluates the technologies in
the clinical filed and further explores new clinical problems).
For promoting this research framework to Japanese
researchers, we published a book “Bioengineering Nursing”
from University of Tokyo Press in 2015. We organized an
introductory seminar for bioengineering nursing research
involving many nursing researchers and clinical nurses. We
furthermore organized an advanced hands-on seminar of
bioengineering nursing research methodologies for those
who attended the introductory seminar and were interested
in this research framework.
In December 2016, we organized a seminar for advanced
wound care. We shared the latest and advanced knowledge
about skincare and wound care with clinical nurses
including wound, ostomy and continence nurses, andresearchers.
Regarding international activities, our department has beenpromoting collaborative research with researchers inuniversities around the world. Our counterparts include:
University of California, Los Angeles (CA), Florida
University (FL), Curtin University (Australia), and The
University of Nottingham (UK). Professor Sanada has beenworking as Secretary for World Union of Wound Healing
Societies and an International Board of Directors forInternational Lymphoedema Framework.
In February 2017, the Department of Skincare Science,
which aims to establish skincare practices to protect
vulnerable skin, was established. This department tries todevelop new nursing technologies to evaluate and improve
the physiological conditions of vulnerable skin due to aging
and disease.

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2. Research fields and themes in 2016
1) Basic experimental studies
・Development of a novel method for controlling wound
infection focusing on gene expression of bacteria andhosts
・Evaluation of wound condition using exudates
・Skin blotting for analyzing physiological status of theskin・Wound blotting for detecting wound biofilm
・Cutaneous wound healing and diabetes mellitus
・Mechanisms of skin maceration
・Research on scalp care science・Research on mechanism 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 ultrasonography and thermography
・Development of insole-type simultaneous measurement system of plantar pressure and shear force
during gait・ Development of fitting device for non-invasive
positive pressure ventilation oral-nasal mask using
three-dimensional solution3) Clinical studies
・Novel assessment technologies for pressure ulcers
・Objective evaluation method for wound pain
・Cross-sectional study of diabetic foot (ulcers, callus,
fissures, onychomycosis etc.) and its risk factors
・Cross-sectional study of malignant wounds in breast
cancer patients and its risk factors
・Survey and international comparison of lymphoedema(collaboration with International Lymphoedema
Framework)
・Methods for predicting skin tear development
・Establishment of a novel diagnosis method of latentdysphagia
・ Establishment of a novel assessment method of
malnutrition using ultrasonography
・ Establishment of a novel assessment method of
constipation using ultrasonography
・Cross-sectional study of the skin of elderly people in
the nursing home・Cross-sectional study of the skin of obese people
Several awards were given to our research as follows.
・Poster award from 46th Annual Congress of JapaneseSociety for Wound Healing.
Takehara K, Minematsu T, Makoto Oe, Noguchi H,
Tsunemi Y, Komagata K, Kunie K, Takemura Y, Sanada
H. Development of screening tool for tinea pedis byvisualization of keratinase for the prevention of diabetic
foot ulcers.
・Poster award from 4th Annual Congress of Nursing
Science and Engineering.
Shikama M, Nakagami G, Noguchi H, Mori T,
Sanada H. Examination of the position adjustment of
non-invasive positive pressure ventilation oral-nasal mask
on face using three-dimensional solution for thedevelopment of fitting device for prevention of medical
device-related pressure ulcers caused by face mask.
・President award from 25th Annual Congress of JapaneseSociety of Wound, Ostomy, and ContinenceManagement.
Nozawa K, Tamai N, Amachi H, Kitamura A,
Saegusa M, Minematsu T, Sanada H. Relationshipbetween morphological characteristics of pressure ulcer
and its occurrence in psychiatric patients.
・President award from 25th Annual Congress of JapaneseSociety of Wound, Ostomy, and ContinenceManagement.
Koyano Y, Nakagami G, Tamai N, Tabata K, Sugama
J, Sanada H. The dedebridement flowchart estimating
the causative external forces of skin tears from its
morphology.
・President award from 25th Annual Congress of JapaneseSociety of Wound, Ostomy, and Continence Management.
Saegusa M, Nakagami G, Noguchi H, Mori T, Sanada
H. Feasibility study of automatic inner air cell pressureadjustment algorithm based on peak interface pressure
measured by interface pressure sensor inside themattress.
・Incentive award from Nursing Science and Engineering
2016.
Nakagami G, Kubo T, Kawanami H, Iwasaki T,
Sanada H. Ceramide delivery to human skin by aceramide dressing repairs disrupted skin barrier function.
Journal of Nursing Science and Engineering. 2015;2(3):174-9.

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・Incentive award from Nursing Science and Engineering
2016.
Oe M, Nagai S, Ikeda M, Oya M, Ohashi Y, Otomo E,
Murayama R, Ueki K, Kadowaki T, Komiyama C,
Sanada H. Difficulties of the introduction of selfmonitoring of blood glucose in elderly diabetic patients.
Journal of Nursing Science and Engineering. 2015;2(3):164-73.
・Article award from Japanese Society of Wound, Ostomy,
and Continence Management 2016.
Noguchi H, Oe M, Takehara K, Mori T, Sanada H.
Reliability and validity of an on-site measurement andvisualization system to measure plantar pressure andshear force in footwear for the education of diabetic
patients. J Jpn WOCM. 2015;19(3):327-35.
・Best Teacher’s Award from Faculty of Medicine, The
University of Tokyo 2016.
Gojiro Nakagami

References
1. Yoshimura M, Iizaka S, Kohno M, Nagata O,
Yamasaki T, Mae T, Haruyama N, Sanada H. Risk
factors associated with intraoperatively acquiredpressure ulcers in the park-bench position: A
retrospective study. International Wound Journal.
2016;13(6):1206-13.
2. Kanazawa T, Kitamura A, Nakagami G, Goto T,
Miyagaki T, Hayashi A, Sasaki S, Mugita Y, Iizaka S,
Sanada H. Lower temperature at the wound edge
detected by thermography predicts undermining
development in pressure ulcers: a pilot study.
International Wound Journal. 2016;13(4):454-60.
3. Mori T, Komichi K, Noguchi H, Umeda-Kameyama Y,
Sanada H, Akishita M, Ohe K. Anomaly detection inhome monitoring system for the elderly using financial
theories. Journal of Nursing Science and Engineering.
2016;3(1):21-30.
4. Tanabe H, Takahashi T, Murayama R, Yabunaka K, Oe
M, Matsui Y, Arai UR, Komiyama C, Sanada H. Using
ultrasonography for vessel diameter assessment toprevent infiltration. Journal of Infusion Nursing.
2016;39(2):105-11.
5. Dai M, Sato A, Maeba H, Iuchi T, Matsumoto M,
Okuwa M, Nakatani T, Sanada H, Sugama J. Dermal
structure in lymphedema patients with history of acutedermatolymphangioadenitis evaluated by histogram

analysis of ultrasonography findings: a case-control
study. Lymphatic Research and Biology. 2016;14(1):2-7.
6. Nishijima Y, Ibuki A, Minematsu T, Sanada H.
Expression profiles of the antioxidant enzymes gene
(SOD1, CAT, GPX, and HMOX1) in the skin of UVirradiated and obese mice. Journal of Nursing Scienceand Engineering. 2016;3(1):13-20.
7. McCreath HE, Bates-Jensen BM, Nakagami G, Patlan
A, Booth H, Connolly D, Truong C, Woldai A. Use of
Munsell color charts to measure skin tone objectively
in nursing home residents at risk for pressure ulcer
development. Journal of Advanced Nursing. 2016;
72(9): 2077-85.
8. Kanazawa T, Nakagami G, Goto T, Noguchi H, Oe M,
Miyagaki T, Hayashi A, Sasaki S, Sanada H. Use ofsmartphone attached mobile thermography assessing
subclinical inflammation: a pilot study. Journal of
Wound Care. 2016;25(4):177-82.
9. Hamatani M, Mori T, Oe M, Noguchi H, Takehara K,
Amemiya A, Ohashi Y, Ueki K, Kadowaki T, Sanada
H. Factors associated with callus in diabetic patients,
focused on plantar shear stress during gait.. Journal of
Diabetes Science and Technology. 2016;10(6):1353-9.
10. Yabunaka K, Murayama TR, Takahashi T, Oe M, Oya
M, Fujioka M, Sanada H. Ultrasonographic
classification of subcutaneous edema caused byinfusion via peripheral intravenous catheters. Journalof Medical Ultrasound. 2016;24(2):60-5.
11. Huang L, Minematsu T, Kitamura A, Quinetti PC,
Nakagami G, Mugita Y, Oe M, Noguchi H, Mori T,
Sanada H. Topical administration of acylated
homoserine lactone improves epithelialization of
cutaneous wounds in hyperglycaemic rats. PLoS One.
2016;11(7):e0158647.
12. Arisandi D, Oe M, Roselyne RY, Matsumoto M, Ogai
K, Nakagami G, Tamaki T, Suriadi, Sanada H, Sugama
J. Evaluation of validity of the new diabetic foot ulcer
assessment scale in Indonesia. Wound Repair andRegeneration. 2016;24(5):876-84.
13. Miura Y, Nakagami G, Yabunaka K, Tohara H, Hara K,
Mori T, Sanada H. Detecting pharyngeal post-swallow
residue by ultrasound examination: a case series.
Medical Ultrasonography. 2016;18(3):288-93.
14. Yoshida M, Igawa Y, Higashimura S, Suzuki M, Niimi
A, Sanada H. Translation and reliability and validity
testing of a Japanese version of the Intermittent Self-

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Catheterization among disposable and reusable
catheter users. Neurourology and Urodynamics. 2016.
15. Kitamura A, Nakagami G, Minematsu T, Miyagaki T,
Sasaki S, Sanada H. Prediction of epithelialization
using the wound blotting method based on the
distribution of transforming growth factor β: a pilot
study. Journal of Japanese Society Wound, Ostomy,
and Continence Management. 2016;20(3):341-8.
16. Hori N, Tamai N, Noguchi H, Nakagami G, Sugama J,
Mori T, Sanada H. Development and assessment of air
mattress with independent air cell pressure control
responsive to interface pressure distribution. Journal ofJapanese Society Wound, Ostomy, and ContinenceManagement. 2016;20(3):300-9.
17. Goto T, Nakagami G, Tamai N, Kitamura A, Naito A,
Hirokawa M, Shimokawa C, Sanada H. Nerve growth
factor in exudate from venous leg ulcers is associatedwith inflammation alonalong temperature increace
assessed by infrared thermography. Journal ofJapanese Society Wound, Ostomy, and ContinenceManagement. 2016;20(3):310-8.
18. Sakai Y, Yokono T, Mizokami Y, Sanada H, Okkuwa
M, Nakatani T, Sugama J. Differences in the working
pattern among wound, ostomiy, and continence nurses
with and without conducting the specified medical act:a multicenter time and motion study. BMC Nursing.
2016;15(69):1-10.
19. Amemiya A, Noguchi H, Oe M, Takehara K, Ohashi
Y, Suzuki R, Yamauchi T, Kadowaki T, Sanada H,
Mori T. Shear stress-normal stress (Pressure) Ratio(SPR) decides forming callus in patients with diabetic
neuropathy. Journal of Diabetes Research. 2016; 2016:
1-10.
20. Goto T, Tamai N, Nakagami G, Kitamura A, Naito A,
Hirokawa M, Shimokawa C, Takahashi K, Umemoto
J, Sanada H. Can wound exudate from venous leg
ulcers measure wound pain status?: a pilot study. PLoS
One. 2016;11(12):e0167478.
21. Nakagami G, Schultz G, Gibson JD, Phillips P,
Kitamura A, Minematsu T, Miyagaki T, Hayashi A,
Sasaki S, Sugama J, Sanada H. Biofilm detection by
wound blotting can predict slough development inpressure ulcers: a prospective observational study.
Wound Repair and Regeneration. 2017;25(1):131-8.
22. Oya M, Takahashi T, Tanabe H, Oe M, Murayama R,
Yabunaka K, Matsui Y, Sanada H. Low-temperature
infiltration identified using infrared thermography inpatients with subcutaneous edema revealed ultrasonographically: a case report. Drug Discoveries &Therapeutics. 2016;10(2):117-22.
23. Oe M, Ohashi Y, Takehara K, Oba M, Doi M, Iizuka Y,
Murayama R, Kadowaki T, Sanada H. Foot
complications in patients with diabetes mellitus:
practical report of diabetic foot clinic in Beijing.
Japanese Journal of Foot Care. 2016;14(2):57-61.

International Health
1. International Social Medicine

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Department of
Global Health Policy
Professor
Kenji Shibuya, MD, DrPH

Project Professor
Manami Inoue, MD, PhD

Associate Professor
Stuart Gilmour, MPH, MStat, PhD

Assistant Professor
Sarah Abe, MSc, PhD
Shuhei Nomura, MSc

Project Assistant Professor
Eiko Saito, PhD
Md. Mizanur Rahman, 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 2014 the department,
headed by Professor Kenji Shibuya, included thefollowing staff complement: one project professor(Minami Inoue); one associate professor (Stuart
Gilmour); two assistant professors (Sarah Abe. Shuhei
Nomura; two project assistant professors (Eiko Saito,
Md. Mizanur Rahman); two post-doctoral fellows; 12
adjunct lecturers; 12 doctoral students; and ninemaster’s students.

The priority areas of research are:
- Health outcome research (mortality, morbidity anddisability; health service research; health technology assessment and cost-effectiveness; diseasemodeling; 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 G8 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.

308

Education
All lectures in the department are conducted in
English, in order to ensure that student writing andpresentation skills are held to an international standard.
Furthermore, through the Global Health Entrepreneurship Program (GHE) students are able to develop
skills and experience to become future leaders inglobal 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 completea minimum of 30 course credits and a master’s thesis.
Beyond the program and concentration requirements,
students are encouraged to consult with faculty
advisers to choose elective courses best suited to theirneeds.
PhD program
The PhD program is designed to train the next
generation of leaders in global health. PhD students
are required to complete a minimum of 24 course
credits and a doctoral thesis with which needs to be
published in a peer-reviewed journal. PhD students
without MPH degree should take the lectures toacquire fundamental public health skills such as healthpolicy, biostatistics and epidemiology.
Global Health Policy I and IIThis course introduces the principles and theories ofglobal health problems, as well as practical applications of 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 2014:- 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 healthComparative risk assessment
Health system performance assessment
Health service quality
Monitoring and evaluation
Financing health systems

GHP Monday seminar

Every Monday, 13:00-15:00 pm
1) Journal clubStudents present a brief summary of research articles
from the major medical, social science, economics
journals, which are relevant for global health policy.
The major objective is to share knowledge, evoke
debates and facilitate discussions.
2) Research seminar
A guest speaker or a master or doctoral student
presents his/her research. There is a 15-minutepresentation-followed by a 30-minute discussion.

Research
A comprehensive assessment of the burden of diseasein Japan. Ministry of Education, Culture, Sports,
Science and Technology, Grants-in-Aid for Scientific
Research (A). PI: Kenji Shibuya.
An evidence-based assessment of the Japanese healthsystem. Ministry of Health, Labour, and Welfare
Health and Labour Science Research Grants. PI: Kenji
Shibuya
Assessment of Japan's global health policy regarding
the 2016 G7 Ise-Shima Summit and its follow-up.
Ministry of Health, Labour, and Welfare Health andLabour Science Research Grants. PI: Kenji Shibuya
Global Health Entrepreneurship Program. PI: Kenji
Shibuya
AXA Chair on Health and Human Security, AXA
Research Fund309

Development and evaluation of cancer prevention
strategies in Japan. National Cancer Center, National
Cancer Center Research and Development Fund. CI:
Manami Inoue
Application of recipe-based dietary assessment inJapan. Ministry of Education, Culture, Sports, Scienceand Technology, Grants-in-Aid for Scientific Research(B). CI: Manami Inoue
Research to establish evidence to benefit healthmaintenance and improvement including cancer
prevention based on multipurpose cohort studies.
National Cancer Center Research and Development
Fund. CI: Manami Inoue.
Attributable burden of cancer in Japanese: latest
estimate and future prediction. Ministry of Education,
Culture, Sports, Science and Technology, Grantsin-Aid for Scientific Research (B). PI: Manami Inoue.
A retrospective cohort study to quickly elucidate risk
factors and protective factors in middle age dementia
patients. Ministry of Education, Culture, Sports,
Science and Technology, Grants-in-Aid for Scientific
Research (B). CI: Manami Inoue.
Study on establishing appropriate gastric cancer
screening provision system based on individual risk.
AMED (Project for Whole Implementation to Supportand Ensure the Female Life). CI: Manami Inoue.
Analysis of the time-dependent trend of internal
exposure examination after Fukushima Nuclear Power
Plant accident and factors related to consultation
behavior. Program of the network-type Joint Usage/
Research Center for Radiation Disaster Medical
Science of Hiroshima University, Nagasaki University,and Fukushima Medical University. PI: Shuhei
NomuraAssessment of the mid- to long-term health effects ofJapan's 2011 Fukushima nuclear disaster―towarddisaster-resilient health care systems. Toyota
Foundation Research Grant Program. PI: Shuhei
Nomura.

Publications
1. Liao Y, Ota E, Cheng K, Mori R. Alternative
prophylactic therapies (acupuncture and/or
moxibustion) for reducing blood loss in the third
stage of labour.. Cochrane Database of Systematic
Reviews. 2016; 6:CD012259. DOI: 10.1002/
14651858.CD012259
2. Svensson T, Yamaji T, Budhathoki S, Hidaka A,
Iwasaki M, Sawada N, et al. Alcohol consumption,
genetic variants in the alcohol- and folate
metabolic pathways and colorectal cancer risk: theJPHC Study.Scientific Reports. 2016;6:36607.
3. Saito I, Yamagishi K, Kokubo Y, Yatsuya H, Iso
H, Sawada N, et al. Association between mortality
and incidence rates of coronary heart disease andstroke: The Japan Public Health Center-based
prospective (JPHC) study. International Journalof Cardiology. 2016; 222:281-6.
4. Lin Y, Totsuka Y, Shan B, Wang C, Wei W, Qiao Y,
et al. Esophageal cancer in high-risk areas ofChina: research progress and challenges. Annalsof Epidemiology. Online first.
5. Khandaker G, Jung J, Britton PN, King C, Yin JK,
Jones CA. Long-term outcomes of infective
encephalitis in children: a systematic review andmeta-analysis. Developmental Medicine & Child
Neurology. 2016; 58(11): 1108-1115
6. GBD 2015 HIV Collaborators. Estimates of global,
regional, and national incidence, prevalence, andmortality of HIV, 1980–2015: the Global Burdenof Disease Study 2015. The Lancet HIV. 2016;
3(8): e361-e387.
7. GBD 2015 Maternal Mortality Collaborators.
Global, regional, and national levels of maternalmortality, 1990–2015: a systematic analysis for
the Global Burden of Disease Study 2015. The
Lancet. 2016;388(10053): 1775-1812.
8. GBD 2015 Child Mortality Collaborators. Global,
regional, national, and selected subnational levelsof stillbirths, neonatal, infant, and under-5
mortality, 1980–2015: a systematic analysis for
the Global Burden of Disease Study 2015. The
Lancet. 2016;388(10053): 1725-1774.
9. GBD 2015 Risk Factors Collaborators. Global,
regional, and national comparative risk assessment of 79 behavioural, environmental and310

occupational, and metabolic risks or clusters ofrisks, 1990–2015: a systematic analysis for the
Global Burden of Disease Study 2015. The Lancet.
2016;388(10053):1659-1724.
10. GBD 2015 DALYS and HALE Collaborators.
Global, regional, and national disability-adjusted
life-years (DALYs) for 315 diseases and injuries
and healthy life expectancy (HALE), 1990–2015:a systematic analysis for the Global Burden of
Disease Study 2015. The Lancet. 2016;388(10053):1603-1658.
11. GBD 2015 Disease and Injury Incidence andPrevalence Collaborators. Global, regional, andnational incidence, prevalence, and years lived
with disability for 310 diseases and injuries,
1990–2015: a systematic analysis for the Global
Burden of Disease Study 2015. The Lancet. 2016;
388(10053):1545-1602.
12. GBD 2015 Mortality and Causes of Death
Collaborators. Global, regional, and national life
expectancy, all-cause mortality, and cause-specificmortality for 249 causes of death, 1980–2015: asystematic analysis for the Global Burden of
Disease Study 2015. The Lancet. 2016; 388(10053): 1459-1544.
13. GBD 2015 SDG Collaborators. Measuring thehealth-related Sustainable Development Goals in
188 countries: a baseline analysis from the Global
Burden of Disease Study 2015. The Lancet. 2016;
388(10053): 1813-1850.
14. Chowdhury MRK, Rahman MS, Khan MMH.
Levels and determinants of complementary
feeding based on meal frequency among childrenof 6 to 23 months in Bangladesh. BMC Public
Health. 2016; 16:944.
15. Otsuki S, Nishiura H. Reduced Risk of Importing
Ebola Virus Disease because of Travel
Restrictions
in
2014:
A
Retrospective
EpidemiologicalModeling
Study.
PLOS
ONE2016;11(9): e0163418.
16. Kondo H, Soda M, Sawada N, Inoue M, Imaizumi
Y, Miyazaki Y, et al. Smoking is a risk factor for
development of adult T-cell leukemia/lymphoma
in Japanese human T-cell leukemia virus type-1
carriers. Cancer Causes and Control. 2016; 27(9):1059-1066.

17. Akter S, Kashino I, Mizoue T, Matsuo K, Ito H,
Wakai K, et al.Coffee drinking and colorectal
cancer risk: an evaluation based on a systematic
review and meta-analysis among the Japanese
population. Japanese Journal of ClinicalOncology. 2016;46(8):781-7.
18. Saito E, Gilmour S, Yoneoka D, Gautam GS,
Rahman MM, Shrestha PK, Shibuya K. Inequality
and inequity in healthcare utilization in urban
Nepal: a cross-sectional observational study.
Health Policy and Planning. 2016;31(7):817-24.
19. Nah K, Otsuki S, Chowell G, Nishiura H.
Predicting the international spread of Middle East
respiratory syndrome (MERS). BMC Infectious
Diseases. 2016; 16:356
20. Goto A, Noda M, Inoue M, Goto M, Charvat H.
Increasing Number of People with Diabetes inJapan: Is This Trend Real. Internal Medicine.
2016;55(14):1827-30.
21. Rahman MM, Rahman MM, Tareque MI, Ferdos J,
Jesmin SS. Maternal Pregnancy Intention andProfessional Antenatal Care Utilization in
Bangladesh: A Nationwide Population-Based
Survey. PLOS ONE. 2016; 11(6): e0157760.
22. Koyanagi Y, Matsuo K, Ito H, Wakai K, Nagata C,
Nakayama T, et al. Cigarette smoking and the riskof head and neck cancer in the Japanese
population: a systematic review and meta-analysis.
Japanese Journal of Clinical Oncology. 2016;46(6):580-95.
23. Yoshida H, Sakamoto H, Leslie A, Takahashi O,
Tsuboi S, Kitamura K. Contraception in Japan:
Current trends. Contraception. 2016; 93(6):475477.
24. Yoneoka D, Saito E, Nakaoka S. New algorithm
for constructing area-based index with geographical heterogeneities and variable selection:
An application to gastric cancer screening.
Scientific Reports. 2016; 6:26582.
25. Japan Global Health Working Group. Protecting
human security: proposals for the G7 Ise-Shima
Summit in Japan. The Lancet. 2016; 387 (10033):
2155-2162.
26. Shin S, Saito E, Inoue M, Sawada N, Ishihara J,
Takachi R, et al. Dietary pattern and breast cancer
risk in Japanese women: the Japan Public HealthCenter-based Prospective Study (JPHC Study).

311

British Journal of Nutrition. 2016;115(10):176979
27. Saito E, Charvat H, Goto A, Matsuda T, Noda M,
Sasazuki S, Inoue M. Burden of cancer associatedwith type 2 diabetes mellitus in Japan, 2010-2030.
Cancer Science. 2016;107(4):521-7.
28. Svensson T, Inoue M, Sawada N, Yamagishi K,
Charvat H, et al; the JPHC Study group. Coping
strategies and risk of cardiovascular disease
incidence and mortality: The Japan Public HealthCenter-based prospective study. European Heart
Journal. 2016;37:890-899.
29. Svensson T, Inoue M, Sawada N, Charvat H,
Iwasaki M, Sasazuki S, Shimazu T, Yamaji T,
Kawamura N, Shibuya K, Mimura M, Tsugane S;
JPHC Study group. Coping strategies and cancer
incidence and mortality: The Japan Public HealthCenter-based
prospective
study.
CancerEpidemiology. 2016;40:126-33.
30. Abe SK, Inoue M, Sawada N, Ishihara J, Iwasaki
M, Yamaji T, Shimazu T, Sasazuki S, Tsugane S.
Glycemic index and glycemic load and risk ofcolorectal cancer: a population-based cohort study(JPHC Study). Cancer Causes and Control. 2016;
27(4):583-93.
31. Takenoshita S, Nomura K, Ohde S, Deshpande G,
Sakamoto H et al. Having a Mentor or a Doctoral
Degree in helpful for mid-career physicians topublish papers in peer reviewed journals. The
Tohoku Journal of Experimental Medicine. 2016;
239(4): 325-331.
32. Liao Y, Gilmour S, Shibuya K. Health Insurance
Coverage and Hypertension Control in China:
Results from the China Health and Nutrition
Survey. PLOS ONE. 2016; 11(3): e0152091.
33. Masaoka H, Matsuo K, Ito H, Wakai K, Nagata C,
Nakayama T, et al. Cigarette smoking and bladdercancer risk: an evaluation based on a systematic
review of epidemiologic evidence in the Japanese
population. Jpn J Clin Oncol. 2016;46(3):273-83.
34. Muhit M, Wadud Z, Islam J, Khair Z, Shamanna
BR, Jung J, Khandaker G. Generating Evidence
for Program Planning: Rapid Assessment of
Avoidable Blindness in Bangladesh. Ophthalmic
epidemiology, 2016; 23 (3): 176-184.
35. Nomura S, Parsons AJQ, Hirabayashi M,
Kinoshita R, Liao Y, Hodgson S. Social

determinants of mid- to long-term disaster
impacts on health: A systematic review.
International Journal of Disaster Risk Reduction.
2016;16: 53-67.
36. Wada K, Gilmour S. Inequality in mortality byoccupation related to economic crisis from 1980
to 2010 among working-age Japanese males.
Scientific Reports. 2015; 6: 22255.
37. Nakaoka S, Iwami S, Sato K. Dynamics of HIV
infection in lymphoid tissue network. Journal of
Mathematical Biology. 2016; 72(4):909–938.
38. Nishiura H, Endo A, Saitoh M, Kinoshita R, Ueno
R, Nakaoka S, Miyamatsu Y, Dong Y, Chowell G,
Mizumoto K. Identifying determinants of heterogeneous transmission dynamics of the Middle
East respiratory syndrome (MERS) outbreak in
the Republic of Korea, 2015: A retrospective
epidemiological analysis. BMJ Open. 2016;6(2):e009936.
39. Abe SK, Inoue M, Sawada N, Iwasaki M,
Shimazu T, et al. Hepatitis B and C virus infection
and risk of pancreatic cancer: A population-based
cohort study (JPHC Study Cohort II). Cancer
Epidemiology, Biomarkers and Prevention. 2016;25(3):555-7.
40. Abe SK, Balogun OO, Ota E, Takahashi K, Mori
R. Supplementation with multiple micronutrientsfor breastfeeding women for improving outcomes
for the mother and baby. Cochrane Database of
Systematic Reviews. 2016, Issue 2. Art. No.:
CD010647. DOI: 10.1002/14651858.CD010647.
pub2
41. Chowdhury MRK, Rahman MS, Khan MMH,
Mondal MNI, Rahman MM, Billah B. Risk
Factors for Child Malnutrition in Bangladesh: A
Multilevel Analysis of a Nationwide PopulationBased Survey. The Journal of Pediatrics. 2016;
172:194-201.
42. Kinoshita R, Nishiura H. Assessing herd
immunity against rubella in Japan: a retrospective
seroepidemiological analysis of age-dependenttransmission dynamics. BMJ Open. 2016; 6(1):e009928.
43. Rahman MM, Abe SK, Rahman MS, Kanda M,
Narita S, Bilano V, Ota E, Gilmour S, Shibuya K.
Maternal anemia and risk of adverse birth andhealth outcomes in low- and middle-income

312

countries: systematic review and meta-analysis.
American Journal of Clinical Nutrition. 2016;
103(2):495-504.
44. Charvat H, Sasazuki S, Inoue M, Iwasaki M,
Sawada N, Shimazu T, Yamaji T, Tsugane S;
JPHC Study Group. Prediction of the 10-year
probability of gastric cancer occurrence in theJapanese population: the JPHC study cohort II.
International Journal of Cancer. 2016; 138(2):320-331. doi: 10.1002/ijc.29705.

313

Department of Community andGlobal HealthProfessor, Academic Leader
Masamine Jimba, MD, PhD, MPH

Assistant Professors
Junko Yasuoka, DSc, MPH
Keiko Nanishi, MD, PhD (until July 2016)
Akira Shibanuma, MID
Junko Kiriya, PhD (from November 2016)

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 inequalities
between and within nations on health and development
Our research focuses on how to promote
community-based activities and how to link abottom-up approach to national and international
policies. As of April 2016, the members of thedepartment include department chair and professor, 3assistant professors, 4 secretaries, 13 visiting lecturers,

14 doctoral students, 17 master's degree students, 4
research students, and 29 visiting scientists. Morethan half of the students in this department areinternational students.

International Cooperation
Activities
As one of our international cooperation activities
at the global level, a human security project was
conducted in collaboration with the Japan Center forInternational Exchange (JCIE) and PAHO. The‘health and human security’ guideline was publishedin 2016.
In addition, we contributed to a WHO conferenceon school health and played a key role to strengthenschool health at global level.
Furthermore, we carried out a research project onmaternal and child health in Ghana in collaboration
with JICA and the Ministry of Health, Ghana. To
disseminate the findings of the project, we hosted aninternational conference in collaboration with JICA.
Also, for enhancing human resources, we invitedhealth officers from Ghana, Myanmar, and Nepal to
Japan and held workshops on maternal, neonatal andchild health.

314

Education
The main objectives of our teaching activities are
the following two:1) To train researchers who understand and complement the wise activities of practitioners in thefield.
2) To train practitioners who can also wisely carryout research in the field.
The postgraduate curriculum is composed mainlyof community and global health advanced courses,
exercises and practical work. All curricula focus oncommunity health. Our main educational activities
other than the curriculum include technical 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 trainings run by JICA and lecturesin different universities to young leaders fromoverseas.

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 is 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 developing countries. We conduct research mainly
in developing countries, but we are also involved inresearch 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, andPeru.

Publications
1. Kanamori S, Castro MC, Sow S, Matsuno R,
Cissokho A, Jimba M. Impact of the Japanese 5S
management method on patients' and caretakers'
satisfaction: a quasi-experimental study in
Senegal. Glob Health Action. 2016 Nov 28;9:32852.
2. Shrestha RM, Miyaguchi M, Shibanuma A,
Khanal A, Yasuoka J, Jimba M. A School Health
Project Can Uplift the Health Status of SchoolChildren in Nepal. PLoS One. 2016 Nov 3;11(11):e0166001.
3. Kikuchi K, Okawa S, Zamawe CO, Shibanuma A,
Nanishi K, Iwamoto A, Saw YM, Jimba M.
Effectiveness of Continuum of Care-Linking
Pre-Pregnancy Care and Pregnancy Care to
Improve Neonatal and Perinatal Mortality: A
Systematic Review and Meta-Analysis. PLoS
One. 2016 Oct 27;11(10):e0164965.
4. Zamawe CO, Nakamura K, Shibanuma A, Jimba
M. The effectiveness of a nationwide universal
coverage campaign of insecticide-treated bed nets
on childhood malaria in Malawi. Malar J. 2016
Oct 18;15(1):505.
5. Shiratori S, Agyekum EO, Shibanuma A, Oduro
A, Okawa S, Enuameh Y, Yasuoka J, Kikuchi K,
Gyapong M, Owusu-Agyei S, Ansah E, Hodgson
A, Jimba M; EMBRACE Implementation
Research Team. Motivation and incentive
preferences of community health officers in
Ghana: an economic behavioral experimentapproach. Hum Resour Health. 2016 Aug 22;

315

14(1):53.
6. Shimizu M, Yi S, Tuot S, Suong S, Sron S,
Shibanuma A, Jimba M. The impact of alivelihood program on depressive symptoms
among people living with HIV in Cambodia. Glob
Health Action. 2016 Aug 9;9:31999.
7. Kanamori S, Shibanuma A, Jimba M.
Applicability of the 5S management method for
quality improvement in health-care facilities: areview. Trop Med Health. 2016 Jul 19;44:21.
8. Ayer R, Kikuchi K, Ghimire M, Shibanuma A,
Pant MR, Poudel KC, Jimba M. Clinic
Attendance for Antiretroviral Pills Pick-Up
among HIV-Positive People in Nepal: Roles ofPerceived Family Support and Associated Factors.
PLoS One. 2016 Jul 20;11(7):e0159382.
9. Ong KI, Araki H, Kano S, Jimba M. The potentialof positive deviance approach for the sustainable
control of neglected tropical diseases. (Letter)
Trop Med Health. 2016 Jul 13;44:20.
10. Withers M, Press D, Wipfli H, McCool J, Chan
CC, Jimba M, Tremewan C, Samet J. Training thenext generation of global health experts:
experiences and recommendations from Pacific
Rim universities. Global Health. 2016 Jun 23;12(1):34.
11. Korc M, Hubbard S, Suzuki T, Jimba M. Health,
Resilience, and Human Security: Moving Toward
Health for All. New York: Japan Center forInternational Exchange and Pan American HealthOrganization; 2016.
12. Sunguya BF, Munisamy M, Pongpanich S,
Yasuoka J, Jimba M. Ability of HIV Advocacy toModify Behavioral Norms and Treatment Impact:
A Systematic Review. Am J Public Health. 2016
Jun 16:e1-e8.
13. Pokhrel K, Nanishi K, Poudel KC, Pokhrel KG,
Tiwari K, Jimba M. Undernutrition Among
Infants and Children in Nepal: Maternal HealthServices and Their Roles to Prevent it. Matern
Child Health J. 2016 May 28.
14. Maulida R, Nanishi K, Green J, Shibanuma A,
Jimba M. Food-choice motives of adolescents in
Jakarta, Indonesia: the roles of gender and family
income. Public Health Nutr. 2016 May 16:1-9
15. Mlunde LB, Sunguya BF, Mbwambo JK,
Ubuguyu OS, Yasuoka J, Jimba M. Association of

opioid agonist therapy with the initiation of
antiretroviral therapy - a systematic review. Int J
Infect Dis. 2016 Mar 29.
16. Enuameh YA, Okawa S, Asante KP, Kikuchi K,
Mahama E, Ansah E, Tawiah C, Adjei K,
Shibanuma A, Nanishi K, Yeji F, Agyekum EO,
Yasuoka J, Gyapong M, Oduro AR, Quansah
Asare G, Hodgson A, Jimba M, Owusu-Agyei S;
Ghana EMBRACE Implementation Research
Project Team. Factors Influencing Health Facility
Delivery in Predominantly Rural Communities
across the Three Ecological Zones in Ghana: A
Cross-Sectional Study. PLoS One. 2016 Mar 31;
11(3):e0152235.
17. Mlunde LB, Sunguya BF, Mbwambo JK,
Ubuguyu OS, Shibanuma A, Yasuoka J, Jimba M.
A Mismatch between High-Risk Behaviors andScreening of Infectious Diseases among People
Who Inject Drugs in Dar es Salaam, Tanzania.
PLoS One. 2016 Feb 5;11(2):e0148598.

International Health
2. International Biomedical Sciences

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Department of Human Genetics
Professor
Katsushi Tokunaga, Ph.D.

Associate Professor
Akihiko Mabuchi, M.D., Ph.D.

Research Associate
Yuki Hitomi, Ph.D.,

Hiromi Sawai, Ph.D.

Project Research Associate
Hiromi Toyoda, Ph.D.

Homepage

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, 3 assistant professor,
4 research associates, 7 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.

318

References
1. Nakauchi A, Wong JH, Mahasirimongkol S, Yanai
H, Yuliwulandari R, Akihiko Mabuchi A, Liu X,
Mushiroda T, Wattanapokayakit S, Miyagawa T,
Keicho N, and Tokunaga K. Identification of ITPA
on Chromosome 20 as a susceptibility gene toyoung-onset Tuberculosis. Hum. Genome Var. 3:15067 Epub, 2016.
2. Shimada-Sugimoto M, Otowa T, Miyagawa T,
Khor S-S, Omae Y, Toyo-Oka L, Sugaya N,
Kawamura Y, Umekage T, Miyashita A, Kuwano
R, Kaiya H, Kasai K, Tanii H, Okazaki Y,
Tokunaga K, and Sasaki T. Polymorphisms in the
TMEM132D region are associated with panic
disorder in HLA-DRB1*13:02-negative individuals of a Japanese population. Hum. Genome Var.
3: 16001 Epub, 2016.
3. Yuliwulandari R, Susilowati RW, Wicaksono BD,
Viyati K, Prayuni K, Razari I, Kristin E, Syafrizal,
Subagyo, Diana ES, Setiawati S, Ariyani A,
Mahasirimongkol S, Yanai H, Mushiroda T, andTokunaga K. NAT2 variants are associated withdrug-induced liver injury caused by antituberculosis drugs in Indonesian patients withtuberculosis. J. Hum. Genet. 61(6): 533-537,
2016.
4. Mushiroda T, Yanai H, Yoshiyama T, Sasaki Y,
Okumura M, Ogata H, and Tokunaga K.
Development of a prediction system for antituberculosis drug-induced liver injury in Japanesepatients. Hum. Genome Var. 3: 16014 Epub, 2016.
5. Nishida N, Ohashi J, Khor S-S, Sugiyama M,
Tsuchiura T, Sawai H, Hino K, Honda M, Kaneko
S, Yatsuhashi H, Yokosuka O, Koike k, Kurosaki
M, Izumi N, Korenaga M, Kang J-H, Tanaka E,
Akinobu Taketomi A, Eguchi Y, Sakamoto N,
Yamamoto K, Tamori A, Sakaida I, Hige S, Itoh Y,
Mochida S, Mita E, Takikawa Y, Ide T, Hiasa Y,
Hiroto Kojima H, Yamamoto K, Nakamura M, Saji
H, Sasazuki T, Kanto T, Tokunaga K, andMizokami M. Understanding of HLA-conferred
susceptibility to chronic hepatitis B infection
requires HLA genotyping-based association
analysis. Sci. Rep. 6: e24767, 2016.
6. Yamasaki M, Miyagawa T, Toyoda H, Khor S-S,
Liu X, Kuwabara H, Kano Y, Shimada T,

Sugiyama T, Nishida H, Sugaya N, Tochigi M,
Otowa T, Okazaki Y, Kaiya H, Kawamura Y,
Miyashita A, Kuwano R, Kasai K, Tanii H, Honda
Y, Honda M, and Tokunaga K. Evaluation ofpolygenic risks for narcolepsy and essential
Hypersomnia. J. Hum. Genet. 61(10): 873-878,
2016.
7. Liu J, Ye Z, Mayer JG, Hoch BA, Green C, Rolak
L, Cold C, Khor SS, Zheng X, Miyagawa T,
Tokunaga K, Brilliant MH, and Hebbring SJ.
Phenome-wide association study maps new
diseases to the human major histocompatibility
complex region. J. Med. Genet. 53(10): 681-689,
2016.
8. Hoshino A, Saitoh M, Miyagawa T, Kubota M,
Takanashi J, Miyamoto A, Tokunaga K, Oka A,
and Mizuguchi M. Specific HLA genotypes confer
susceptibility to acute necrotizing encephalopathy.
Genes Immun. 17(6): 367-369, 2016.
9. Sun Y, Irowanto A, Toyo-Oka L, Hong M, Liu H,
Andiappan A, Choi H, Hitomi Y, Yu G, Yu Y,
Bao F, Wang C, Fu X, Yue Z, Wang H, Zhang H,
Kawashima M, Kojima K, Nagasaki M,
Nakamura M, Yang S-K, Ye BD, Denise Y,
Rotzschke O, Song K, Tokunaga K, Zhang F, and
Liu J. Fine-mapping analysis revealed complex
pleiotropic effect and tissue-specific regulatory
mechanism of TNFSF15 in primary biliary
cholangitis, Crohn's disease and leprosy. Sci. Rep.
6: e31429, 2016.
10. Otowa T, Kawamura Y, Tsutsumi A, Kawakami N,
Kan C, Shimada T, Umekage T, Kasai K,
Tokunaga K, and Sasaki T. The first pilot genomewide gene–environment study of depression in theJapanese population. PLoS One 11(8): e0160823,
2016.
11. Smittipat N, Juthayothin T, Billamas P, Jaitrong S,
Rukseree K, Dokladda K, Chaiyasirinroje B,
Disratthakit A, Chaiprasert A, Mahasirimongkol S,
Yanai
H,
YamadaN,
Tokunaga
K,
Palittapongarnpim P. Mutations in rrs, rpsL andgidB in streptomycin-resistant Mycobacterium
tuberculosis isolates from Thailand. J. Glob.
Antimicrob. Resist. 4: 5-10, 2016.
12. Matsunami K, Nishida N, Kaneko N, Ikeo K,
Toyo-oka L, Takeuchi H, Matsuura K, Tamori A,
Nomura H, Yoshiji H, Imamura M, Masaki N,

319

Hayakawa T, Ide T, Shimada N, Ikeda F, Hino K,
Nishiguchi S, Okuse C, Nojiri S, Sawamoto K,
Tokunaga K, Joh T, and Tanaka Y. Genome-wide
association study identifies ZNF354C variants
associated with depression by interferon-based
therapy for chronic hepatitis C. PLoS One 11(10):e0164418, 2016.
13. Wattanapokayakit S, Mushiroda T, Yanai H,
Wichukchinda N, Chuchottawon C, Nedsuwan S,
Rojanawiwat A, Denjanta S, Kantima T, Wongyai
J, Suwankesawong W, Rungapiromnan W,
Kidkeukarun R, Bamrungram W, Chaiwong A,
Suvichapanich S, Mahasirimongkol S, andTokunaga K. NAT2 slow acetylator associatedwith anti-tuberculosis drug-induced liver injury inThai patients. Int. J. Tuberc. Lung Dis. 20(10):1364-1369, 2016.
14. Thiri M, Honda K, Kashiwase K, Mabuchi A,
Suzuki H, Watanabe K, Nakayama M, Watanabe T,
Doi K, Tokunaga K, and Noiri E. High-density
association mapping and interaction analysis of
PLA2R1 and HLA regions with idiopathic
membranous nephropathy in Japanese. Sci. Rep.
6: 38189 Epub, 2016.

320

Department of Developmental
Medical Sciences
Professor
Masashi Mizuguchi, M.D., Ph.D.

Associate Professor
Teruyuki Tanaka, M.D., Ph.D.

Research Associate
Makiko Saitoh, M.D., Ph.D.

Sayaka Takanashi, M.D., Ph.D.

Project Research Associate
Ai Hoshino, M.D., Ph.D.

Homepage

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 andhealth promotion. In 2007, joined by new members,
the department has entered a new era, putting moreemphasis 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
project research associate, one assistant clerk, one
technical assistant, fifteen visiting lecturers, elevenvisiting researchers, and seven graduate students,
including three overseas students.

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, Italy, Greece, China, Taiwan,
Korea, Thailand, Viet Nam, Laos, Malaysia, Indonesia,
Bangladesh, Pakistan, Sri Lanka and Australia, inorder to promote the mothers’ and children’s health allover the world. We also have accepted many young
students from these countries, for the purpose ofbringing up professionals who either perform medical
research or lead local health policies.

Teaching activities
1. Undergraduate course, Faculty of Medicine, Schoolof Health Science and Nursing1) Human growth and development
2) Immunity and defense mechanism3) Infectious diseases
4) Topics in life and environmental sciences
5) Maternal and child health

3216) School health7) International health8) Seminar in life and environmental sciences
9) Introduction to general health science
2. Graduate course, the Graduate School of Medicine,
School of International Health Sciences
In 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, and acute encephalitis
with refractory, repetitive partial seizures.
(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 West syndrome and Rett syndrome, 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) Molecular genetics and biochemistry of inheritedmetabolic disorders, such as peroxisomal disorders, and of neurodegenerative diseases, suchas spinal muscular atrophy.
(7) Studies on the virulence and drug resistance ofherpesviruses and poxviruses.
(8) 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. Abe Y, Sakai T, Okumura A, Akaboshi S, Fukuda
M, Haginoya K, Hamano SI, Hirano K, Kikuchi K,
Kubota M, Lee S, Maegaki Y, Sanefuji M,
Shimozato S, Suzuki M, Suzuki Y, Takahashi M,
Watanabe K, Mizuguchi M, Yamanouchi H.
Manifestations and characteristics of congenital
adrenal hyperplasia-associated encephalopathy.
Brain and Development 2016; 38(7): 638-647.
2. Hoshino A, Saitoh M, Miyagawa T, Kubota M,
Takanashi JI, Miyamoto A, Tokunaga K, Oka A,
Mizuguchi M. Specific HLA genotypes confer
susceptibility to acute necrotizing encephalopathy.
Genes and Immunity 2016; 17(6): 367-369.
3. Nguyen TQ, Saitoh M, Trinh HT, Doan NM,
Mizuno Y, Seki M, Sato Y, Ogawa S, Mizuguchi
M. Truncation and microdeletion of EVC/EVC2
with missense mutation of EFCAB7 in Ellis-vanCreveld syndrome. Congenital Anomalies (Kyoto)
2016; 56(5): 209-216.
4. Nishimura N, Higuchi Y, Kimura N, Nozaki F,
Kumada T, Hoshino A, Saitoh M, Mizuguchi M.
Familial acute necrotizing encephalopathy
without RANBP2 mutation: Poor outcome.
Pediatrics International 2016; 58(11): 1215-1218.
5. Okitsu S, Khamrin P, Hanaoka N, Thongprachum
A, Takanashi S, Fujimoto T, Mizuguchi M,
Shimizu H, Hayakawa S, Maneekarn N, Ushijima
H. Cosavirus (family Picornaviridae) in pigs in
Thailand and Japan. Archives of Virology 2016;
161(1): 159-163.
6. Saitoh M, Kobayashi K, Ohmori I, Tanaka Y,
Tanaka K, Inoue T, Horino A, Ohmura K,
Kumakura A, Takei Y, Hirabayashi S, Kajimoto M,
Uchida T, Yamazaki S, Shiihara T, Kumagai T,
Kasai M, Terashima H, Kubota M, Mizuguchi M.
Cytokine-related and sodium channel polymorphism as candidate predisposing factors forchildhood
encephalopathy
FIRES/AERRPS.
Journal of the Neurological Sciences 2016; 368:272-276.
7. Tran DN, Trinh QD, Pham NT, Pham TM, Ha MT,
Nguyen TQ, Okitsu S, Shimizu H, Hayakawa S,
Mizuguchi M, Ushijima H. Human rhinovirus
infections in hospitalized children: clinical,
epidemiologicalandvirologicalfeatures.

322

Epidemiology and Infection 2016; 144(2): 346354.
8. Tran DN, Trinh QD, Pham NT, Vu MP, Ha MT,
Nguyen TQ, Okitsu S, Hayakawa S, Mizuguchi M,
Ushijima H. Clinical and epidemiologicalcharacteristics of acute respiratory virus infections
in Vietnamese children. Epidemiology and
Infection 2016; 144(3): 527-536.
9. Yamaguchi Y, Torisu H, Kira R, Ishizaki Y, Sakai
Y, Sanefuji M, Ichiyama T, Oka A, Kishi T,
Kimura S, Kubota M, Takanashi J, Takahashi Y,
Tamai H, Natsume J, Hamano S, Hirabayashi S,
Maegaki Y, Mizuguchi M, Minagawa K,
Yoshikawa H, Kira J, Kusunoki S, Hara T. A
nationwide survey of pediatric acquired
demyelinating syndromes in Japan. Neurology
2016; 87(19): 2006-2015.
10. Takeuchi H, Khan AF, Hasan MI, Hawlader MD,
Yunus M, Zaman K, Chowdhury HR, Takanashi S,
Wagatsuma Y, Iwata T. Comment on IgE
responses to Ascaris and mite tropomyosins arerisk factors for asthma. Clinical and Experimental
Allergy 2016;46(1):178-180.
11. Takeuchi H, Khan AF, Yunus M, Hasan MI,
Hawlader MD, Takanashi S, Kano H, Zaman K,
Chowdhury HR, Wagatsuma Y, Nakahara S,
Iwata T. Anti-Ascaris immunoglobulin E
associated with bronchial hyper-reactivity in 9year-old rural Bangladeshi children. Allergology
International 2016;65(2):141-146.

323

Department of Human Ecology
Professor
Chiho WATANABE, Ph.D.

Associate Professor
Masahiro UMEZAKI, Ph.D.

Research Associate
Satoko KOSAKA, Ph.D.
Shoko KONISHI, Ph.D.

Project Research Associate
Yosuke INOUE, Ph.D. (UEHAS program)
Mitsutoshi UMEMURA, Ph.D. (UEHAS program)

Homepage

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

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 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

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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.
We had six research/teaching faculties in FY2016,
two of them worked for “UEHAS” program in turn.
There are 11 extra-university lecturers delivering
lectures in either graduate or undergraduate course.
Professor Watanabe holds additional roles in the
Integrated Research System for Sustainability Science(IR3S) as well as in the Earth Observation Data
Integration&
FusionResearch
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”,“Environmental 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 were 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.
In addition to these “regular” courses, we have beencollaborating with the Graduate School of Engineeringof the University of Tokyo in operating the program,“Urban Engineering and Health in Asia (UEHAS)”,which been adopted as one of the MEXT-funding “Reinventing Japan” project (PI= Professor Takizawa,
Dept. of Urban Engineering). UEHAS is an
educational program at the graduate level entailing
credit exchange between the University of Tokyo andsix universities in ASEAN countries. Our department
has been in charge of coordinating the program from
SIH side.

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, and environment and sustainability. Experimental studies focusing on the effects of perinatal
exposures to heavy metals have been conducted,
emphasizing the factors that modify the effects.
Almost all the studies require “transdisciplinary”
approach, hence, we are collaborating with various
domestic and overseas research institutes. Whatfollows is a list of major activities conducted in thepast year.
In recent years we also use secondary data forresearch aiming to elucidate potential effects ofenvironmental exposure (such as air pollution) on
health.
1. Environmental contamination by metals and its
health impacts in South Asia
In the As-contaminated area in Myanmar, we
recruited pregnant others at clinics and collectedbiological specimens. We investigated potential
effect of arsenic and cadmium exposure on healthof mothers and newborns.

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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 men time, we also conducted astudy to categorize original strategies against aging
and depopulation that were used in each local
community.
4. Double-burden of malnutrition in Indonesia
To elucidate background and mechanisms of the
double-burden of malnutrition (coexistence ofundernutrition and overweight within the same
household), we conducted a survey in a rural and an
urban communities in West Java, Indonesia. The
prevalence of double-burden households was higher
in the urban than in the rural community. It was alsosuggested that differential nutrient intakes among
members of the same household may be one of thefactors
contributing
todouble-burdenofmalnutrition.
5. Study on Fecundity in Japan
Using an internet-based survey we estimatedage-pattern of time to pregnancy (duration between
discontinuing contraception and conception, used asa measure of fecundity). Additionally, to elucidate
which factors can explain the mechanisms of theage pattern of time to pregnancy, we conducted aprospective cohort study targeting pregnancy
planners.
6. Health effects of air pollution exposure
Usingmethodologies
ofenvironmental

epidemiology, we studied potential effect of air
pollution and airborne pollen on health (e.g.
mortality, number of clinical visits).

References
1. Igai K, Itakura M, Nishijima S, Tsurumaru H, Suda
W, Tsutaya T, Tomitsuka Eet al. (2016) Nitrogen
fixation and nifH diversity in human gut microbiota.
Scientific Reports, 6, 31942 doi:10.1038/srep31942
2. Inoue Y, Stickley A., Yazawa A., Fujiwara T, Kondo
K, Kondo N (2016) Month of birth is associatedwith mortality among older people in Japan:
Findings from the JAGES cohort. Chronobiol Int,
33:441-447.
3. Inoue Y, Stickley A, Yazawa A., Shirai K, AmemiyaA., Kondo N, Kondo K, Ojima T, Hanazato M,
Suzuki N, Fujiwara T (2016) Neighborhood
characteristics and cardiovascular risk among older
people in Japan: findings from the JAGES project.
PLoS one, 11(10), e0164525.
doi: 10.1371/journal.pone.0164525
4. Inoue Y, Umezaki M (2016) Medical pluralism andtraditional/complementary and alternative medicine
use among older people: a cross-sectional study in arural mountainous village in Japan. J Cross Cult
Gerontol, 31:57-72.
5. Inoue Y, Stickley A, Yazawa A, Li D, Du J, Jin Y,
Chen Y, Watanabe C (2016) The association
between economic development, lifestyle differentiation, and C-reactive protein concentration
within rural communities in Hainan Island, China.
Am J Hum Biol, 28:186-196.
6. Konishi S, Ng CFS, Stickley A, Watanabe C (2016)
Pollinosis and all-cause mortality among middleaged and elderly Japanese: a population-based
cohort study. Clin Exper Allergy, 46:1083-1089.
7. Konishi S, Tamaki E (2016) Pregnancy intention
and contraceptive use among married and unmarried
women in Japan. Jpn J Health Hum Ecol, 82:
110-124.
8. Konishi S, O’Connor, KA (2016) Salivary but not
blood cortisol excretion is associated with metabolic
biomarkers in healthy young women. Am J Hum
Biol, 28:539-544.
9. Morita A., Natsuhara K., Vengiau G, Chia‐Jung
Chen C, Odani S, Inaoka T, Tadokoro K, Suda K,

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Furusawa T, Phuanukoonnon S, Umezaki M (2016)
Reduced morning cortisol concentration in saliva
was associated with obesity: Evidence from
community‐dwelling adults in papua new guinea.
Am J Hum Biol. 28:587-590.
10. Ng CFS, Boeckmann M, Ueda K, Zeeb H, Nitta H,
Watanabe C, Honda Y (2016) Heat-related
mortality: Effect modification and adaptation in
Japan from 1972 to 2010. Global Environ Change,
39: 234-243.
11. Ng CFS, Stickley A, Konishi S, Watanabe C (2016)
Ambient air pollution and suicide in Tokyo, 2001–
2011. J Affect Disord, 201:194-202.
12. Nishihama Y, Yoshinaga J, Iida A, Konishi S, Imai H,
Yoneyama M., Nakajima, D. & Shiraishi, H. (2016).
Association between paraben exposure andmenstrual cycle in female university students inJapan. Reprod Toxicol, 63, 107-113.
13. Saw YM, Saw TN, Wai KM, Poudel KC, Win HH(2016) Correlates of sex trading among male noninjecting drug users in Myanmar: a cross-sectional
study, Harm Reduct J, 13:34
14. Stickley A, Ng CFS, Inoue Y, Yazawa A, Koyanagi
A, Kodaka M, DeVylder J E, Watanabe C (2016)
Birthdays are associated with an increased risk ofsuicide in Japan: Evidence from 27,007 deaths inTokyo in 2001–2010. J Affect Disord, 200:259-265.
15. Umezaki M, Naito YI, Tsutaya T, Baba J, Tadokoro
K, Odani S, Morita A, Natsuhara K, Phuanukoonnon
S, Vengiau G, Siba PM, Yoneda M (2016) Association between sex inequality in animal protein intake
and economic development in the Papua New
Guinea highlands: The carbon and nitrogen isotopic
composition of scalp hair and fingernail. Am J Phys
Anthropol, 159:164-173.
16. Yazawa A, Inoue Y, Fujiwara T, Stickley A, Shirai K,
Amemiya A, Kondo N, Watanabe C, Kondo K(2016) Association between social participation andhypertension among older people in Japan: the
JAGES Study. Hypertens Res, 39:818-824.

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Department of
Biomedical Chemistry
Professor
Tomoyoshi Nozaki, Ph.D., MD

Associate Professor
Yoh-ichi Watanabe, 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.

Teaching activities
Teaching activities in our department cover a broad
spectrum of biochemistry-oriented life sciences frompremise to frontiers and in either conceptual orexperimental point of view
Graduate Course: Biomedical Chemistry I, IIThis course is comprised of lectures and seminars toprovide basic concepts and newer vistas for understanding biomedical chemistry with special reference
to biochemistry and molecular biology. These include
the structure and function of biomolecules,
metabolism, its regulation, and underlying mechanism
at either molecular, cellular and systemic level.
Undergraduate

Course:Biochemistry,

Molecular

Biology, Laboratory Method in Health Science, BasicLife Science, Nutrition, Medical Chemistry, Practiceon Medical Chemistry, Parasitology, Life Science andGenome Science I & II, 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
andbiologicalanalysesofmetabolism and organelles unique to parasites
 Analysis of vesicular traffic, protein secretion, andphagocytosis/trogocytosis in parasites
 Genome wide analysis and comparison of parasite
strains Drug discovery and development against protozoan
infections such as malaria and amebiasis
 Elucidation of divergence of RNA maturation andtranslation

328

References
1. Drug selection using bleomycin for transfection of
the oyster-infecting parasite Perkinsus marinus.
Sakamoto, H., Kita, K., & Matsuzaki, M. (2016)
Parasitol. Int. 65, 563-566
2. Parasites resistant to the antimalarial atovaquone
fail to transmit by mosquitoes. Goodman, C.D.,
Siregar, J.E., Mollard, V., Vega-Rodríguez, J.,
Syafruddin, D., Matsuoka, H., Matsuzaki, M.,
Toyama, T., Sturm, A., Cozijnsen, A., JacobsLorena, M., Kita, K., Marzuki, S., & McFadden,
G.I. (2016) Science. 352, 349-353
3. Role of EhRab7A in phagocytosis of type 1
fimbriated E. coli by Entamoeba histolytica.
Verma, K., Nozaki, T., & Datta, S. (2016) Mol.
Microbiol. 102, 1043-1061
4. Heterogeneity of the serine synthetic pathway in
Entamoeba species. Chiba, Y., Makiuchi, T.,
Jeelani, G., & Nozaki, T. (2016) Mol. Biochem.
Parasitol. 207, 56-60
5. Immune Response of Amebiasis and Immune
Evasion by Entamoeba histolytica. NakadaTsukui, K., & Nozaki, T. (2016) Front. Immunol.
7, 175
6. Roles of acetyl-CoA synthetase (ADP-forming)and acetate kinase (PPi-forming) in ATP and PPi
supply in Entamoeba histolytica. Pineda, E.,
Vázquez, C., Encalada, R., Nozaki, T., Sato, E.,
Hanadate, Y., Néquiz, M., Olivos-García, A.,
Moreno-Sánchez, R., & Saavedra, E. (2016)
Biochim. Biophys. Acta 1860, 1163-1172
7. Endoplasmic reticulum-resident Rab8A GTPase isinvolved in phagocytosis in the protozoan parasite
Entamoeba histolytica. Hanadate, Y., SaitoNakano, Y., Nakada-Tsukui, K., & Nozaki, T.
(2016) Cell Microbiol. 18, 1358-1373
8. Screening and discovery of lineage-specificmitosomal membrane proteins in Entamoeba
histolytica. Santos, H.J., Imai, K., Hanadate, Y.,
Fukasawa, Y., Oda, T., Mi-Ichi, F., & Nozaki, T.
(2016) Mol. Biochem. Parasitol. 209, 10-17
9. Entamoeba thiol-based redox metabolism: A
potential target for drug development. Jeelani, G.,& Nozaki, T. (2016) Mol. Biochem. Parasitol. 206,
39-45

10. Crystal Structure Analysis of Wild Type and Fast
Hydrolyzing Mutant of EhRabX3, a Tandem Ras
Superfamily GTPase from Entamoeba histolytica.
Srivastava, V.K., Chandra, M., Saito-Nakano, Y.,
Nozaki, T., & Datta S. (2016) J. Mol. Biol. 428,
41-51
11. Genetic variants of Kudoa septempunctata(Myxozoa: Multivalvulida), a flounder parasite
causing foodborne disease. Takeuchi, F.,
Ogasawara, Y., Kato, K., Sekizuka, T., Nozaki, T.,
Sugita-Konishi, Y., Ohnishi, T., & Kuroda, M.
(2016) J. Fish. Dis. 39, 667-672.

School of Public Health
1. Epidemiology and Health Sciences

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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

331

with 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. Mori N, Asakura K, Sasaki S. Differential dietary
habits among 570 young underweight Japanesewomen with and without a desire for thinness: acomparison with normal weight counterparts. Asia
Pac J Clin Nutr 2016; 25: 97-107.
2. Balogun OO, Kobayashi S, Anigo KM, Ota E,
Asakura K, Sasaki S. Factors influencing
exclusive breastfeeding in early infancy: aprospective study in North Central Nigeria.
Matern Child Health J 2016; 20: 363-375.
3. Asakura K, Uechi K, Masayasu S, Sasaki S.
Sodium sources in the Japanese diet: difference
between generations and sexes. Public Health
Nutr 2016; 19: 2011-23.
4. Saido M, Asakura K, Masayasu S, Sasaki S.
Relationship between dietary sugar intake anddental caries among Japanese preschool children
with relatively low sugar intake (Japan Nursery
School SHOKUIKU Study): a nationwide crosssectional study. Matern Child Health J 2016; 20:556-66.
5. Uechi K, Asakura K, Ri Y, Masayasu S, Sasaki S.
Advantage of multiple spot urine collections for
estimating daily sodium excretion: comparison
with two 24-h urine collections as reference. J
Hypertens 2016; 34: 204-14.
6. Okuda M, Asakura K, Sasaki S, Shinozaki K.
Twenty-four-hour urinary sodium and potassium
excretion and associated factors in Japanese
secondary school students. Hypertens Res 2016;
39: 524-9.
7. Sugimoto M, Asakura K, Masayasu S, Sasaki S.
Relationship of nutrition knowledge and selfreported dietary behaviors with urinary excretionof sodium and potassium: comparison between
dietitians and non-dietitians. Nutr Res 2016; 36:
440-51.

8. Okubo H, Miyake Y, Sasaki S, Tanaka K, Hirota Y.
Feeding practices in early life and later intake offruit and vegetables among Japanese toddlers: theOsaka Maternal and Child Health Study. Public
Health Nutr 2016; 19: 650-7.
9. Aoki A, Inoue M, Nguyen E, Obata R,
Kadonosono K, Shinkai S, Hashimoto H, Sasaki S,
Yanagi Y. Dietary n-3 fatty acid, α-tocopherol,zinc, vitamin D, vitamin C, and β-carotene areassociated with age-related macular degenerationin Japan. Sci Rep 2016; 6: 20723.
10. Ogawa T, Uota M, Ikebe K, Notomi Y, Iwamoto Y,
Shirobayashi I, Kibi M, Masayasu S, Sasaki S,
Maeda Y. Taste detection ability of elderly nursing
home residents. J Oral Rehabil 2016; 43: 505-10.
11. Fujiwara A, Asakura K, Uechi K, Masayasu S,
Sasaki S. Dietary patterns extracted from thecurrent Japanese diet and their associations withsodium and potassium intakes estimated byrepeated 24 h urine collection. Public Health Nutr
2016; 19: 2580-91.
12. Okubo H, Miyake Y, Sasaki S, Tanaka K, Hirota Y.
Early sugar-sweetened beverage consumption
frequency is associated with poor quality of later
food and nutrient intake patterns among Japaneseyoung children: the Osaka Maternal and Child
Health Study. Nutr Res 2016; 36: 594-602.
13. Sugimoto M, Asakura K, Masayasu S, Sasaki S.
Relatively severe misreporting of sodium,
potassium, and protein intake among female
dietitians compared with nondietitians. Nutr Res
2016; 36: 818-26.
14. Miyake Y, Tanaka K, Okubo H, Sasaki S,
Furukawa S, Arakawa M. Milk intake during
pregnancy is inversely associated with the risk of
postpartum depressive symptoms in Japan: theKyushu Okinawa Maternal and Child HealthStudy. Nutr Res 2016; 36: 907-13.
15. Murakami K, Livingstone MBE, Okubo H, Sasaki
S. Younger and older ages and obesity areassociated with energy intake underreporting but
not overreporting in Japanese boys and girls aged
1-19 years: the National Health and Nutrition
Survey. Nutr Res 2016; 36: 1153-61.
16. Kohri T, Kaba N, Itoh T, Sasaki S. Effects of thenational school lunch program on bone growth inJapanese elementary school children. J Nutr Sci

332

Vitaminol 2016; 62: 303-9.
17. Katagiri R, Asakura K, Uechi K, Masayasu S,
Sasaki S. Iodine excretion in 24-hour urine
collection and its dietary determinants in healthy
Japanese adults. J Epidemiol 2016; 26: 613-21.
18. Sakurai M, Nakamura K, Miura K, Takamura T,
Yoshita K, Nagasawa SY, Morikawa Y, Ishizaki M,
Kido T, Naruse Y, Nakashima M, Nogawa K,
Suwazono Y, Sasaki S, Nakagawa H. Dietarycarbohydrate intake, presence of obesity and theincident risk of type 2 diabetes in Japanese men. J
Diabetes Investig 2016; 7: 343-51.

333

Department of Clinical
Epidemiology and
Health Economics
Professor
Hideo Yasunaga, MD, PhD.

Assistant Professor
Hiroki Matsui, MPH.

Homepage

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

Introduction and Organization
The Department of Clinical Epidemiology and Health
Economics was established in April 2007, as a part ofMaster of Public Health (MPH) program under the
new School of Public Health (SPH). The Department
is also affiliated with the Division of Social Medicine
for doctoral education.
The mission of the Department is two folds; to help
health professionals obtain scientifically sound basis
and skills for evidence-based practice, and toempirically evaluate the clinical practice, health caresystem/policy for further improvement of the qualityof health care. For this purpose, the Department puts aunique emphasis on quantitative analytic methods andinter-disciplinary theories across clinical epidemiology, health service research, health economics andhealth policy.

Teaching activities
Under the MPH program, the Department is responsible for 6 courses, one on introduction to clinicalmedicine for non-MD students, two on clinicalepidemiology, two on health economics, and one on
healthcare organization management.
The lecture course on clinical epidemiology provides
a quick review on elementary to intermediate levels of
epidemiology such as research design, bias and error,

and causal inference.
Health economics course provides an intermediatelevel of micro-economics and health economics
theories of consumer choice, insurance, and humancapital, and enhances discussion to apply these
theories to behaviors of providers and consumers. The
3-day intensive course offers students an opportunity
for hands-on training of actual cost-effectivenessanalysis of health care and technologies.
The 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 5 master students for the
fiscal years of 2016.

Research activities
Current activities in this Department cover a broad
range of health services research, including clinicalepidemiological studies, economic evaluation ofhealth technology and health policy, quality of life
research, and hospital administration and quality
assurance.

334

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.

References
1. Akiyama T, Saita K, Chikuda H, Horiguchi H,
Fushimi K, Yasunaga H. Mortality and Morbidity
following Surgery for Primary Malignant
Musculoskeletal Tumors in the Pelvis and Limbs:
A Retrospective Analysis Using the JapaneseDiagnosis Procedure Combination Database.
Journal of Cancer Therapy 2016;7:303-310
2. Akiyama T, Saita K, Chikuda H, Horiguchi H,
Fushimi K, Yasunaga H. Risk factors associatedwith in-hospital postchemotherapy mortality inpatients with malignant musculoskeletal tumors.
Journal of Cancer Therapy 2016;7:363-369
3. Aso S, Matsui H, Fushimi K, Yasunaga H. The
effect of intra-aortic balloon pumping undervenoarterial extracorporeal membrane oxygenation on mortality of cardiogenic patients: ananalysis using a nationwide inpatient database.
Crit Care Med 2016;44(11):1974-1979.
4. Aso S, Matsui H, Fushimi K, Yasunaga H.
In-hospital mortality and successful weaning fromvenoarterial extracorporeal membrane oxygenation: analysis of 5,263 patients using a national
inpatient database in Japan. Crit Care 2016;20(1):80
5. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Matsui H, Fushimi K, Koike K. Interstitial lungdisease associated with gemcitabine: A Japanese
retrospective cohort study. Respirology 2016;21(2):338-43.
6. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Matsui H, Fushimi K, Koike K. No Weekend
Effect on Outcomes of Severe Acute Pancreatitis
in Japan: Data from the Diagnosis Procedure
Combination Database. J Gastroenterol 2016;

51(11):1063-1072.
7. Hamada T, Nakai Y, Isayama H, Yasunaga H,
Matsui H, Takahara N, Mizuno S, Kogure H,
Matsubara S, Yamamoto N, Tada M, Koike K.
Progression-Free Survival as a Surrogate for
Overall Survival in First-Line Chemotherapy for
Advanced Pancreatic Cancer. European Journalof Cancer 2016;65:11-20.
8. Hirashima J, Yamana H, Matsui H, Fushimi K,
Yasunaga H. Effect of Intravenous Magnesium
Sulfate on Mortality in Patients with Severe Acute
Asthma. Respirology 2016;21(4):668-73
9. Ishikawa H, Yasunaga H, Matsui H, Fushimi K,
Kawakami N. Differences in cancer stage,
treatment and in-hospital mortality between
patients with and without schizophrenia:
retrospective matched-pair cohort study. British
Journal of Psychiatry 2016;208(3):239-44.
10. Ishimaru M, Ono S, Suzuki S, Matsui H, Fushimi
K, Yasunaga H. Risk factors for free flap failurein 2846 head and neck cancer patients: a national
database study in Japan. Journal of Oral andMaxillofacial Surgery 2016;74(6):1265-70
11. Ishimaru M, Ono S, Yasunaga H, Matsui H,
Koike S. Projected future distribution of dentists
in Japan. Journal of Public Health Dentistry2016;76(3):241-8.
12. Isogai T, Yasunaga H, Matsui H, Tanaka H,
Fushimi K. Relationship between hospital volume
and major cardiac complications of rotational
atherectomy: A nationwide retrospective cohort
study in Japan. Journal of Cardiology 2016;67(5):442-8
13. Isogai T, Yasunaga H Matsui H, Tanaka H,
Hisagi M, Fushimi K. Early β-blocker use andin-hospital mortality in patients with Takotsubo
cardiomyopathy. Heart 2016;102(13):1029-35
14. Isogai T, Matsui H,Tanaka H, Fushimi K,
Yasunaga H. Atrial natriuretic peptide therapy
and in-hospital mortality in acute myocardial
infarction patients undergoing percutaneous
coronary intervention. Int J Cardiol 2016;222:
163-70.
15. 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

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continuous renal replacement therapy: apropensity matched analysis. Blood Purification
2016;42(1):9-17
16. Japan Global Health Working Group. Protecting
human security: proposals for the G7 Ise-Shima
Summit in Japan. Lancet 2016;387:2155-62
17. Kato S, Chikuda H, Ohya J, Oichi T, Matsui H,
Fushimi K, Takeshita K, Tanaka S, Yasunaga H.
Risk of infectious complications associated withblood transfusion in elective spinal surgery – Apropensity score matched analysis. Spine J 2016;
16(1):55-60
18. Koike S, Shimizu A, Matsumoto M, Ide H,
Atarashi H, Yasunaga H. Career pathways ofboard-certified surgeons in Japan. Surgery Today
2016 ;46(6):661-7.
19. Koike S, Matsumoto M, Ide H, Kashima S,
Atarashi H, Yasunaga H. The effect ofconcentrating obstetrics services in fewer
hospitals on patient access: a simulation. International Journal of Health Geographics 2016;
15(1):4
20. Matsumoto T, Yasunaga H, Matsui H, Fushimi K,
Izawa N, Yasui T, Kadono Y, Tanaka S. Trends
and Risk Factors for Perioperative Complications
in Total Ankle Arthroplasty: Retrospective
Analysis using a National Database in Japan.
BMC Musculoskeletal Disorders 2016;17(1):450.
21. Michihata N, Matsui H, Fushimi K, Yasunaga H.
Hospital volume and mortality due to preterm
patent ductus arteriosus. Pediatrics International
2016;58(11):1171-1175.
22. Momosaki R, Yasunaga H, Matsui H, Abo M.
Predictive factors for oral intake after aspiration
pneumonia in older adults. Geriatrics &Gerontology International 2016;16(5):556-60
23. Momosaki R, Yasunaga H, Matsui H, Fushimi K,
Abo M. Proton Pump Inhibitors versus
Histamine-2 Receptor Antagonists and Risk ofPneumonia in Patients with Acute Stroke. Journalof Stroke and Cerebrovascular Diseases 2016;
25(5):1035-40
24. Momosaki R, Yasunaga H, Kakuda W, Matsui H,
Fushimi K, Abo M. Very early versus delayed
rehabilitation for acute ischemic stroke patientswith intravenous recombinant tissue plasminogenactivator: A nationwide retrospective cohort

study in Japan. Cerebrovascular Diseases 2016;
42(1-2):41-8
25. Naganuma M, Matsui H, Fushimi K, Yasunaga H.
Clinical Features of Isolated Dissections of
Abdominal Aortic Branches. Heart and Vessels
2016;31(6):1006-9
26. Nakahara Y, Yasunaga H, Inokuchi H, Ogata N,
Horiguchi H, Matsuda S, Fushimi K, Haga N.
Mortality-reducing effect of rehabilitation for
COPD: observational propensity-matched cohort
study using a Nationwide Database. Respiratory
Care 2016;61(11):1497-1504.
27. Niikura R, Yasunaga H, Yamada A, Matsui H,
Fushimi K, Hirata Y, Koike K. Factors associatedwith adverse events of therapeutic colonoscopy
for colorectal neoplasia: a retrospective nationwide study in Japan. Gastrointestinal Endoscopy
2016;84(6):971-982
28. Odagiri H, Iizuka T, Kikuchi D, Kaise M, Takeda
H, Ohashi K, Yasunaga H. Gastrointestinal
Endoscopy-Assisted Minimally Invasive Surgery
for Superficial Cancer of the Uvula. ClinicalEndoscopy 2016;49(3):289-93
29. Ohya J, Oshima Y, Chikuda H, Oichi T, Matsui H,
Fushimi K, Tanaka S, Yasunaga H. Does microendoscopic technique reduce mortality and majorcomplications in patients undergoing lumbar
discectomy? A propensity score-matched analysis
using a nationwide administrative database.
Neurosurgical Focus 2016;40(2):E5.
30. Ono S, Ishimaru M, Matsui H, Fushimi K,
Yasunaga H. Impact of body mass index on theoutcomes of open reduction for mandibular
fracture. Journal of Oral and Maxillofacial
Surgery 2016;74(5):1024.e1-5.
31. Ono S, Ono Y, Matsui H, Yasunaga H. Factors
associated with hospitalization for seasonal
influenza in a Japanese nonelderly cohort. BMC
Public Health 2016;16:922.
32. Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi K,
Tanaka Y. Factors associated with mortality ofthyroid storm: analysis using a national inpatient
database in Japan. Medicine 2016;95(7):e2848
33. Sasabuchi Y, Yasunaga H, Matsui H, Lefor AK,
Fushimi K. Prolonged propofol infusion formechanically ventilated children. Anaesthesia
2016;71(4):424-8.

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34. Sasabuchi Y, Kimura N, Shiotsuka J, Komuro T,
Mouri H, Ohnuma T, Asaka K, Lefor AT,
Yasunaga H, Yamaguchi A, Adachi H, Sanui M.
Long-term Survival in Patients with Acute Kidney
Injury After Surgery for Acute Type A Aortic
Dissection. Annals of Thoracic Surgery 2016;
102(6):2003-2009.
35. Sasabuchi Y, Matsui H, Lefor AK, Fushimi K,
Yasunaga H. Risks and benefits of stress ulcer
prophylaxis for patients with severe sepsis. Crit
Care Med 2016;44(7):e464-9.
36. Sasaki R, Yasunaga H, Matsui H, Michihata N,
Fushimi K. Hospital Volume and Mortality in
Mechanically Ventilated Children: Analysis of a
National Inpatient Database in Japan. Pediatric
Critical Care Medicine 2016;17(11):1041-1044.
37. Suzuki S, Yasunaga H, Matsui H, Fushimi K,
Yamasoba T. Pharyngocutaneous fistula and delay
in free oral feeding after pharyngolaryngectomy
for hypopharyngeal cancer. Head & Neck 2016;38
Suppl 1:E625-30
38. Suzuki S, Yasunaga H, Matsui H, Fushimi K,
Yamasoba T. Factors associated with prolonged
duration of post-tympanoplasty local treatment in
adult chronic otitis media patients: a retrospective
observational study using a Japanese inpatient
database. Auris Nasus Larynx 2016;43(4):377-81
39. Suzuki S, Yasunaga H, Matsui H, Fushimi K,
Yamasoba T. Factors associated with neckhematoma after thyroidectomy: a retrospective
analysis using a Japanese inpatient database.
Medicine 2016 ;95(7):e2812.
40. Suzuki S, Yasunaga H, Matsui H, Fushimi K,
Saito Y, Yamasoba T. Cerebral infarction after
intraarterial and intravenous chemoradiotherapy
for head and neck cancer: a retrospective analysis
using a Japanese inpatient database. Head & Neck
2016;38(9):1354-8.
41. Tagami T, Matsui H, Fushimi K, Yasunaga H.
Prophylactic antibiotics may improve outcome inpatients with severe burns requiring mechanicalventilation: propensity score analysis of aJapanese nationwide database. Clinical Infectious
Diseases 2016;62(1):60-6.
42. Tagami T, Matsui H, Fushimi K, Yasunaga H.
Changes in therapeutic hypothermia and coronary
intervention provision and in-hospital mortality ofpatients with out-of-hospital cardiac arrest: A
nationwide-database study. Crital Care Medicine
2016;44(3):488-95
43. Tagami T, Matsui H, Tanaka C, Kaneko J, Kuno
M, Ishinokami S, Unemoto K, FushimiK,
Yasunaga H. Amiodarone Compared with
Lidocaine for Out-of-hospital Cardiac Arrest with
Refractory Ventricular Fibrillation on Hospital
Arrival: A Nationwide Database Study.
Cardiovascular Drugs and Therapy 2016;30(5):485-491.
44. Tagami T, Matsui H, Kuno M, Moroe Y, Kaneko J,
Unemoto K, Fushimi K, Yasunaga H. Early
antibiotics
administration
duringtargeted
temperature management after out-of-hospital
cardiac arrest: a nationwide database study. BMC
Anesthesiology 2016;16(1):89.
45. Tagami T, Matsui H, Ishinokami S, Oyanagi M,
Kitahashi A, Fukuda R, Unemoto K, Fushimi K,
Yasunaga H. Amiodarone or nifekalant upon
hospital arrival for refractory ventricularfibrillation after out-of-hospital cardiac arrest.
Resuscitation 2016;109:127-132.
46. Tsuchiya A, Tsutsumi Y, Yasunaga H. Outcomes
after Helicopter versus Ground Emergency
Medical Services for Major Trauma--Propensity
Score and Instrumental Variable Analyses: A
retrospective
nationwide
cohortstudy.
Scandinavian Journal of Trauma, Resuscitationand Emergency Medicine 2016;24(1):140.
47. Tsuda Y, Yasunaga H, Horiguchi H, Fushimi K,
Kawano H, Tanaka S. Complications andpostoperative mortality rate after surgery forpathological femur fracture related to bone metastasis: Analysis of a nationwide database. Annalsof Surgical Oncology 2016;23(3):801-10
48. Wada T, Yasunaga H, Horiguchi H, Matsubara T,
Fushimi K, Nakajima S, Yahagi N. Outcomes ofArgatroban Treatment in Patients with Atherothrombotic Stroke: an Observational Nationwide
Study in Japan. Stroke 2016 ;47(2):471-6.
49. Wada T, Yasunaga H, Horiguchi H, Fushimi K,
Matsubara T, Nakajima S, Yahagi N. Ozagrel forpatients with noncardioembolic ischemic stroke: apropensity-score-matched analysis. Journal of
Stroke and Cerebrovascular Diseases 2016;25(12):2828-2837

337

50. Yagi M, Yasunaga H, Matsui H, Fushimi K,
Fujimoto M, Koyama T, Fujitani J. Effect of Early
Rehabilitation on Activities of Daily Living in
Patients with Aspiration Pneumonia. Geriatrics &Gerontology International 2016;16(11):11811187.
51. Yamada K, Yasunaga H, Kadono Y, Chikuda H,
MD, Ogata T, Horiguchi H, Tanaka S.
Postoperative outcomes of major lower extremity
amputations in patients with diabetes andperipheral artery disease: Analysis using the
Diagnosis Procedure Combination database inJapan. American Journal of Surgery 2016;212(3):446-50.
52. Yamaji Y, Yasunaga H, Hirata Y, Yamada A,
Yoshida S, Horiguchi H, Fushimi K, Koike K.
Association Between Colorectal Cancer andAtherosclerotic Diseases: a Study Using a
National Inpatient Database in Japan. Digestive
Diseases and Sciences 2016;61(6):1677-85.
53. Yamana H, Horiguchi H, Fushimi K, Yasunaga H.
Comparison of procedure-based and diagnosisbased identifications of severe sepsis anddisseminated intravascular coagulation in administrative data. J Epidemiol 2016;26(10):530-537.
54. Yamana H, Matsui H, Tagami T, Hirashima J,
Fushimi K, Yasunaga H. De-escalation versus
continuation of empirical antimicrobial treatment
in community-acquired pneumonia. J Infection2016 ;73(4):314-25
55. Yamauchi Y, Yasunaga H, Hasegawa W,
Sakamoto Y, Takeshima H, Jo T, Matsui H,
Fushimi K, Nagase T. Effect of outpatient therapy
with inhaled corticosteroids on decreasing
in-hospital mortality from pneumonia in patientswith COPD. International Journal of Chronic
Obstructive Pulmonary Disease 2016;11:1403-11.
56. Yamauchi Y, Yasunaga H, Sakamoto Y,
Hasegawa W, Takeshima H, Urushiyama H, Jo T,
Matsui H, Fushimi K, Nagase T. Mortality
associated with bone fractures in COPD patients.
International Journal of Chronic Obstructive
Pulmonary Disease 2016;11:2335-2340.

338

Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Hirono Ishikawa, 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 newly developed
professional graduate program that aims to foster thedevelopment of medical and public health professionals as well as researchers. We strive to make themost of our professional activities and experience at
UMIN Center. We provide lectures and practical
instruction in the program. The following is thecurrent curriculum:[Health Communication Lectures]
1. Introduction to health communication
2. Patient-provider communication (1): Patient perspective
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. Coaching
2. Manners in interpersonal relationship3. MBTI (Myers-Briggs Type Indicator) (1)(2)(3)4. Mass communication: Media doctor
5. Internet communication (1)(2)
We also provide lectures and practical instruction in
medical informatics / economics as part of the PhD
program of the Faculty of Medicine. In the undergraduate program, Professor Kiuchi presents a lecture

339

entitled “Medical Literature Informatics.”

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. In addition, we have a seminar to introduce
the Roter Interaction Analysis System (RIAS), one of
the most widely used tools of the analysis of medical
communication,(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 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.
(5) 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.
(6) 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.

340

References
1. Hosokawa C., Ishikawa H., Okada M., Kato M.,
Okuhara T., Kiuchi T. The relationship of genderrole orientation with health literacy andself-efficacy for healthy eating among Japanese
workers in early adulthood. Frontiers in Nutrition.
2016; 3: 17.
2. Kato M., Ishikawa H., Kiuchi T. Media Coverageof a Global Pandemic in Japan: Content Analysis
of A/H1N1 Influenza Newspaper Articles. Journalof Mass Communication & Journalism. 2016; 6:
293.
3. Ishikawa H., Kato M., Kiuchi T. Associations ofhealth literacy and information sources withhealth-risk anxiety and protective behaviors.
Journal of Communication in Healthcare. 2016;
9(1): 33-39.
4. Homma M., Yamazaki Y., Ishikawa H., Kiuchi T.
‘This really explains my case!’: biographicalreconstruction of Japanese people withfibromyalgia meeting peers. Health Sociology
Review. 2016; 25(1): 62-77.

School of Public Health
2. Behavioral Health Sciences

342

Departments ofHealth and Social Behavior &Health Education and HealthSociology
Professor in health and social behavior
Hideki Hashimoto, M.D., D.PH.

Associate Professor in health education and health sociology
Naoki Kondo, M.D., Ph.D.

Lecturer
Daisuke Takagi, Ph. D.

Associates

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 the Department of Health and Social
Behavior to apply a life-course perspective to a wider
range of social conditions and human wellbeing.
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 five courses in the master
degree program for public health, and seven courses in
the undergraduate program for the Integrated Health
Sciences track.
1. Graduate Courses, School of Public Health
1) Health and Society I & II: The course highlights
the significance of social determinants of health(SDH) as a key exposure causing social gradient343

of 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 invited lecturers
specialized in the field. The course is followedby course II which offers application of concepts
into practice through in-class discussion andgroup works.
2) Health Education; The course provides basic
knowledge on relevant behavioral theories forhealth promotion and behavioral modification,
followed by case method learning on healtheducational intervention in community, school,
and work places. The case discussion was
facilitated by invited lecturers to reach practicallessons for effective communication.
3) Health Sociology; Sociology in medicine andsociology applied to health issues are treated in
the systemic course of lectures, covering social
model of health, medical gaze and socializationof health professionals, phenomenology ofchronic ills, and culture and health.
4)
Hospital management practicum; usingcase-method and interactive teaching method,
the participant students were provided basic
knowledge/skills and real-world decision making
training for healthcare organization management
in financial accounting, strategic management,
and information/risk management.
2. Undergraduate Courses, School of Integrated
Health Sciences
1) Introduction to social survey and practice: The
course emphasizes that needs for specific knowledge and subsequent research question define themodes of survey. The course gives the students a
virtual situation where a social survey is required
to obtain data to support some decision making,e.g. market research situation. The students are
asked to define an inquired concept, refine a
research question, design the mode of survey,
and conduct a small pilot survey within the class.
The survey results were reported with some
practical implication, and were opened toin-class discussion.
2) Health sociology:3) Health education:4) Social security and welfare program: Lecture
series on the history and the current systems ofhealth care security and welfare policies in thiscountry.
5) Occupational health management; Lecture series
on risk/needs assessment, strategic managementof health resource, and health promotion intervention in work place.
FY2016 was the beginning of new curriculum thatprovides three majors in the School. For Public Health
Science track, a new lecture course “integrated
lectures of public health science” was offered for the
sophomore students expected to join the School. The
department was also responsible to offer a newlecture/practicum course on scientific writing, logic,
and rhetoric.” As such the department contributed toextend educational environment in the new frame of
School curriculum policy, and management ofeducational duties with limited resources became achallenge.

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), England Longitudinal Survey of Ageing (ELSA), and their global
sisters in Asian countries. The scope of JSTAR isdiverse; 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 environ-344

ments get to “under-skin” to cause social gradient ofhealth across socio-economic positions. In the year of
2011, the JSHINE conducted a supplemental survey torespondent’s spouse and children. Main and supplement surveys were followed in 2012 and 2013,
respectively. Obtained panel data are made open to abroader range of researchers under the data-control
committee, to share analytic scheme and to enhanceinter-disciplinary studies so as to better identify
common factors as well as unique factors affecting
health inequality in Japanese context. In 2015-2016,
third follow-up for children was conducted to
specifically evaluate child’s dietary habit change after
a policy intervention in one of participating
municipalities,
which
found
a
significant
improvement in vegetable intake among children in anintervention municipality compared to theircounterpart in other cities.
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 health inlater life. The team has been developing community
diagnosis tool using JAGES data to support
participating municipalities to effectively findleverage population for policy intervention, withsupport from AMED and other funding sources. The
developed tools are expected to be disseminated andstandardized for wider use in municipalities.

Publications
1. Shiba K, KondoN*, Kondo K. Informal andFormal Social Support and Caregiver Burden: The
AGES Caregiver Survey. J Epidemiol. 2016. 26(12), 622-628.
2. Haga C, Kondo N, Okamoto R. Factors Associatedwith Changes in Body Mass Trajectories during
Infancy: A Longitudinal Analysis in Japan. Health.
2016;8(14):1506-17
3. Matsuyama Y, Fujiwara T, Aida J, Watt RG,
Kondo N, Yamamoto T, Kondo K, Osaka K.
Experience of childhood abuse and later numberof remaining teeth in older Japanese: a life-course

study from Japan Gerontological Evaluation Study
project. Community Dent Oral Epidemiol. 2016 44(6), 531-539.
4. The Challenges of Japanese Community Medicine
from the Global Health Perspective JMAJ,
September 2016—Vol.59, No.2&3
5. Ishikawa Y*, Kondo N, Kondo K, Saito T,
Hayashi H, Kawachi I, for JAEGS Group. Social
participation and mortality: Does social position in
civic groups matter? J Epidemiol.
doi:
10.1186/s12889-016-3082-1
6. Tani Y, Kondo N, Nagamine-Takahashi Y, Kondo
K, Kawachi I, Fujiwara* T. Childhoodsocioeconomic disadvantage is associated withlower mortality in older Japanese men: the JAGES
cohortstudy.
Int
J
Epidemiol.
2016.
doi:10.1186/s12889-016-3082-1
7. Tani Y, Kondo N, Nagamine-Takahashi Y, Kondo
K, Kawachi I, Fujiwara* T. Childhoodsocioeconomic status and onset of depression
among Japanese older adults: The JAGES
prospective cohort study American Journal of
Geriatric Psychiatry 2016. 24 (9), 717-726.
8. Murakami K*, Kondo N, Ohkubo T, Hashimoto H.
The effect of Fathers' and mothers’ educational
level on adult oral health in Japan. Community
Dental Oral Epidemiol. 2016. DOI: 10.1111/
cdoe.12216
9. Ishikawa Y, Kondo N, Kawachi I, Viswanath K.
Are socioeconomic disparities in health behavior
mediated by differential media use? Test of thecommunication inequality theory. Patient EducCouns. 2016 99 (11), 1803-1807.
10. Ashida T, Kodo N*, Kondo K. Social participationand the onset of functional disability bysocioeconomic status and activity type: the AGES
cohort study. Preventive Medicine. 2016. 121-128.
11. Saito M*, Kondo N, Aida J, Kawachi I, Koyama S,
Ojima T, Kondo K. Development of an Instrument
for Community-Level Health Related Social
Capital among Japanese Older People: The
JAGES Study. Journal of Epidemiology. 201612. Matsuyama Y*, Kondo N, Osaka K. Experience ofchildhood abuse and later number of remaining
teeth in older Japanese: a life-course study fromJapan Gerontological Evaluation Study project"345

Community Dentistry and Oral Epidemiology.
DOI: 10.1111/cdoe.12246
13. Ota A*, Kondo N, Murayama N, Tanabe N,
Shobugawa Y, Kondo K. Serum Albumin Levels
and Economic Status in Japanese Older Adults.
PLoS One.. 11 (6), e0155022.
14. Yazawa A*, Inoue Y, Fujiwara T, Stickley A,
Shirai K, Amemiya A, Kondo N, et al. Association
between social participation and hypertension
among older people in Japan: the JAGES Study.
Hypertens Res. 2016. 39 (11), 818-824.
15. Ishikawa Y*, Kondo N, Kondo K, Saito T,
Hayashi H, Kawachi I, for the JAGES group.
Social participation and mortality: does social
position in civic groups matter? BMC Public
Health.2016, 16:394
16. Hayashi K*, Kawachi I, Ohira T, Kondo K, Shirai
K and Kondo N*. Laughter is the Best Medicine?
A Cross-Sectional Study of Cardiovascular
Disease Among Older Japanese Adults J
Epidemiol 2016 .26 (10), 546-552.
17. Takagi D*, Kondo N, Takada M, Hashimoto H.
Educational attainment, time preference, andhealth-related behaviors: A mediation analysis
from the J-SHINE survey. Soc Sci Med.
2016;153:116-22.
18. Koyama S*, Aida J, Saito M, Kondo N, Sato Y,
Matsuyama Y, et al. Community social capital andtooth loss in Japanese older people: a longitudinalcohort study. BMJ Open. 2016 April 1,
2016;6(4):e010768.
19. Takagi D*, Ikeda K, Kobayashi T, Harihara M,
Kawachi I. The impact of crime on social ties andcivic participation. Journal of Community &Applied Social Psychology. 2016. 26(2), 164-178.
20. Kato A, Fujimaki Y, Fujimori S, Isogawa A,
Onishi Y, Suzuki R, Yamauchi T, Ueki K,
Kadowaki T, Hashimoto H. Association between
self-stigma and self-care behaviors in patients with
type 2 diabetes: a cross-sectional study. BMJ Open
Diab
Res
Care
2016;4:e000156
doi:10.1136/bmjdrc-2015-000156.
21. Shibuya K, Nomura S, Okayasu H, et al. (HHashimoto as 61th out of 63 coauthors). Protecting
human security: proposals for the G7 Ise-Shima
SummitinJapan.
The
Lancet387(10033) · January 2016

22. Murakami K, Hashimoto H. Wealth-related versus
income-related inequalities in dental care use
under universal public coverage: a panel data
analysis of the Japanese Study of Aging andRetirement. BMC Public Health. 2016 Jan
12;16(1):24. doi: 10.1186/s12889-015-2646-9.
23. Aoki A, Inoue M, Nguyen E, Obata R,
Kadonosono K, Shinkai S, Hashimoto H, Sasaki S,
Yanagi Y. Dietary n-3 Fatty Acid, α-Tocopherol,
Zinc, vitamin D, vitamin C, and β-carotene are
Associatedwith
Age-Related
MacularDegeneration in Japan. Sci Rep. 2016 Feb
5;6:20723. doi: 10.1038/srep20723.
24. Kato A, Fujimaki Y, Fujimori S, Izumida Y,
Suzuki R, Ueki K, Kadowaki T, Hashimoto H. A
qualitative study on the impact of internalized
stigma on type 2 diabetes self-management.
Patient Educ Counselling 99(7):1233-39, 2016.
doi:10.1016/j.pec2016.02.002.
25. Hashimoto N, Hashimoto H. The Association
Between Maternal Employment and Prevalence ofAsthmainChildren.
Pediatric
Allergy,
Immunology,
andPulmonology.
2016,
doi:10.1089/ped.2016.0641.
26. Tokunaga M, Hashimoto H. The socioeconomic
within-gender gap in informal caregiving among
middle-aged women: Evidence from a Japanesenationwide survey. Soc Sci Med. 173. DOI:
10.1016/j.socscimed.2016.11.037
27. Ikari Y, Awata M, Mitsudo K, et al. (H Hashimotoas 13th of 16 coauthors). Efficient distal tip size ofprimary guidewire for antegrade percutaneous
coronary intervention in chronic total occlusion:
The G-FORCE study. Int J Cardiol 227, 2016.
DOI: 10.1016/j.ijcard.2016.11.076
28. Sakakibara E, Homae F, Kawasaki S, et al. (HHashimoto as 25th out of 27 coauthors). Detectionof resting state functional connectivity using
partial correlation analysis: A study using
multi-distance and whole-head probe near-infrared
spectroscopy. NeuroImage 142 · August 2016
DOI: 10.1016/j.neuroimage.2016.08.011

School of Public Health
3. Health Services Sciences

347

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Research Associate
Toki Saito, Ph.D.
Ayako Kohyama-Koganeya

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, the distribution of information became very easy and rapid,
not only within organizations, but also internationally.
In 2003, a high-quality, "finished" sequence of thehuman genome was completed. At the dawn of thetwenty-first century, bioinformatics appeared as a new
discipline, one that uses applied mathematics, informatics, statistics, computer science, and biochemistry
to solve biological problems. In medicine, advanced

information technologies have been applied to healthinformation infrastructures, electrical clinical guidelines, 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 an international level in order to apply advanced information
technologies to practical projects in clinical medicine
and the health sciences. It offers courses on
information system design, development methodology,
evaluation and project management in biomedicine,
health care and public health in the School of Public
Health, and data mining and virtual reality for clinicaldecision-making in social medicine.
Famous visiting lecturers and researchers from the
National Cancer Center and other universities havegiven lectures here, furthering our hope of becoming aworld leader in this field.
The education of graduate students is based on

348

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 combinationof information science, computer science, and clinicalscience designed to assist in the management andprocessing of data, information, and knowledge tosupport the practice and delivery of clinical care. Ourlaboratory is engaged in the following research
activities:(1) Medical Decision-making: We focus on how to
improve health outcomes by advancing systematic approaches to clinical decision-making andpolicy formation in health care using informationengineering methodology (IEM), especiallyelectrical clinical guidelines and encoded knowledge.
(2) Data Mining & Knowledge Discovery from
Databases: It is necessary to collate heterogeneous information, such as the clinicalindications for a drug, drug side effects,
pharmacokinetics, metabolic pathways, and drug
response genes for single nucleotide polymorphisms (SNPs). These data are distributed andmanaged in various clinical databases. We are
studying ways to integrate distributed biomedical
data and knowledge mining with virtualized
database technologies, such as auto-indexing andtechnical term identification algorithms.
(3) 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.
(4) 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. Ichikawa, D., Saito, T., Ujita, W., Oyama, H. How
can machine-learning methods assist in virtual
screening for hyperuricemia? A healthcare
machine- learning approach. Journal of Biomedical Informatics, 2016, 64:20-24. DOI: 10.
1016/j.jbi.2016.09.012.
2. Nakagawa D, Shojima M, Yoshino M, Kin T, Imai
H, Nomura S, Saito T, Nakatomi H, Oyama H,
Saito N. Wall-to-lumen ratio of intracranialarteries measured by indocyanine green angiography. Asian J Neurosurg. 2016 Oct-Dec;11(4):361-364. DOI: 10.4103/1793-5482.175637.
3. Yoshino M, Nakatomi H, Kin T, Saito T, Shono N,
Nomura S, Nakagawa D, Takayanagi S, Imai H,
Oyama H, Saito N. Usefulness of high-resolution
3D multifusion medical imaging for preoperativeplanning in patients with posterior fossa hemangioblastoma: technical note. J Neurosurg., 2016
Aug 26:1-9. DOI: 10.3171/2016.5.
4. Jiang J, Nakajima Y, Sohma Y, Saito T, Kin T,
Oyama H, Saito N. Marker-less tracking of brain
surface deformations by non-rigid registration
integrating surface and vessel/sulci features. Int J
Comput Assist Radiol Surg., 2016 Sep;11(9):1687-701. doi: 10.1007/s11548-016-1358-7.

Endowed Department

350

Department of Clinical
Epidemiology and Systems
Associate Professor
Daisuke Koide, R.Rh., HIM, Ph.D.

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

Researcher
Yoshiko Mizuno, M.D.,Ph.D.

Homepage

http://cbi.umin.ne.jp/dces/index_e.html

Introduction and Organization
The Department of Clinical Epidemiology and
Systems was established in 2007, supported by Banyu
pharmaceutical company (currently MSD K.K). Our
department took over and enhanced the function andinfrastructures of the Clinical Epidemiology Divisionin Clinical Bio-Informatics Research Unit (CBI)
which had been led by Professor Ryozo Nagai at the
Department of Cardiovascular Medicine (currently
President of Jichi Medical University), because theunit had been terminated its five-year programsupported by the Japan Science and Technology
Agency in 2007 as scheduled. At the time ofestablishment, the staffs were professor Yamazaki andassociate professor Koide.
Our objectives are to develop standards for thetransfer of clinical information and improve thequality of clinical epidemiologic researches in the areaof life-style related diseases and preventive medicine,
because large and longitudinal data are necessary.
Through these activities, we evaluate such standards
and establish academic foundations of “Clinical
Epidemiology and Systems” as well as contribute toprofessional training in this field which will be more
and more required in the future.
In order to facilitate our broad activities, ourorganization is subordinate to the Department of
Cardiovascular Medicine, and works with close

collaboration with the staffs in the Center for
Epidemiology and Preventive Medicine which wasestablished in 2007 because professor Yamazaki(currently director and professor of clinical researchsupport center) is also the head of the both sections.
The staffs of this center overlap with faculty membersin the Department of Ubiquitous Preventive Medicine
which also took over and enhanced the function andinfrastructures of the Genomic Science Division in
CBI. Furthermore, these departments work with the
Department of Clinical Trial Data Management in the
22nd Century Medical and Research Center, andprovide consultation on biostatistics and clinicalresearch. Since Dr. Koide has a background of
medical informatics, he develops and systemizes thestandards of information in the area of clinicalepidemiology in collaboration with the Department ofPlanning, Information and Management, theUniversity Hospital Medical Information Network(UMIN) Center, the Departments of Epidemiology
and Biostatistics, and the Department of Pharmacoepidemiology.
The first term for five-year passed in March 2012,
and the second term has been started since April 2012.
When it was renewed, professor Yamazaki moved to
the Clinical Research Support Center as director. Also,
this department has been supported by the department
of Diabetes and Metabolic Medicine (Professor

351

Takashi Kadowaki) since then. And associate
Takanashi and Researcher Yoshiko Mizuno became amember of this department and the Center for
Epidemiology and Preventive Medicine. In 2013, thedepartment of Cardiovascular Medicine (Professor
Issei Komuro) became the parental department again.
In addition to that, the Clinical Research Support
Center (Professor Tsutomu Yamazaki) joined as theparental department newly.
Through this cooperation with many departments
and centers, we have been conducting education andresearch. As before, Dr. Koide is an assistant managerof personal information that makes any data of studies
regarding human genome or gene anonymous. In thefiscal year of 2016, we received 51 requests and made3927 samples anonymous.
In addition, our department has been in collaboration with many institutions within and outside theuniversity, since the times of the CBI.

Teaching activities
On April 13 in 2016, Dr. Koide spoke about“Privacy protection and management in clinicalresearch” at ethical seminar for faculty members andstudents in the graduate school of medicine, theUniversity of Tokyo. It is mandatory for all
researchers in this graduate school to take this seminaronce in two years. But foreign researchers who unable
understand Japanese well can take alternative
e-learning on UMIN. The title of this e-learning is“Principles of Clinical Research and Design” which isprovided by MSD K.K. This e-learning is describedlater.
Also, Dr. Koide lectured to junior students ofIntegrated Health Sciences, Faculty of Medicine, theUniversity of Tokyo. The title of the lecture was“Drug life-cycle and survey” in the series of"pharmacology and toxicology" on December 20 in2016. And Dr. Koide gave a lecture which was entitled"Pharmacoepidemiology and Pharmacovigilance byusing database" in the series of “Epidemiologicalstudy, planning and analysis” for junior students ofIntegrated Health Sciences, Faculty of Medicine, theUniversity of Tokyo on November 4 in 2016. In
addition to that, the same lecture provided by Dr.
Koide took place as the series of medical common

lectures XXXIII on January 24 in 2017.
Furthermore, Dr. Takanashi has given a lecture on
lipid as a part of clinical training for the 5th and 6th
grade's students of Medicine, the University of Tokyo
since 2013.
And the basic lectures of Medical Writing took
place as an intensive course on August 25-26 in 2016,
hosted by the non-profit organization of Japan
Medical and Scientific Communicators Association,and supported by the three departments of Clinical
Epidemiology and Systems, Clinical Trial DataManagement, and Ubiquitous Preventive Medicine.
In addition, Dr. Koide gave lectures at the
department of Integrated Science and Engineering for
Sustainable Society, Faculty of Science andEngineering, Chuo University as “Pharmacovigilancewith database” on June 8 and as “Epidemiologicalresearch with database” on June 15 in 2016. And Dr.
Koide provided a lecture as “-Clinical Pharmacology-,
Evaluation of Drug Efficacy and Safety" (3)Pharmacoepidemiology”, which was given to thesixth-grade students at Tokyo University of pharmacy
and Sciences on July 7 in 2016. Also, Dr. Koide
lectured on “Research Question (RQ) andPharmacovigilance plan” and “Research Design andProtocol Writing” as Seminars for Regulatory Affairs
Professionals at the Pharmaceutical and Medical
Device Regulatory Science Society of Japan (PMRJ)
which is a non-profit foundation on June 21, 2016.
Moreover, Dr. Koide has lectured on ICT literacy as
15 series at faculty of International Liberal Arts,
Juntendo University, from October 5 in 2016 toJanuary 25 in 2017.
By the way of public subscription, Dr. Koide has
been selected as a research leader of the "collaborative
study with universities on development of thee-learning system for clinical research and trial
according to the level of skill and profession" for three
years since 2012. Although the grant was terminated,
this e-learning on UMIN has been continued since2015. Also, Prof. Matsuyama has obtained the fund by
the Agency for Medical Research and Development(AMED), and started to cultivate biostatistician since
October 2016. Dr. Koide also participates in thisproject.
Therefore, we expand our scope of human resource

352

development for not only clinical epidemiology, butalso clinical research and trial.

Research activities
1) Development of Medical Information Database forClinical Epidemiology and its validation study
The Ministry of Health, Labor and Welfare andPharmaceuticals and Medical Devices Agency(PMDA) in Japan started "10 Million patient's medical
data project" for improving safety measures, andselected 10 medical institutions including the
University of Tokyo. At first, the system development
has been launched in the University of Tokyo Hospital.
Dr. Koide is in charge of this system development andvalidation in 2014. In the future, this systeminfrastructure will be available with other medical
institutions for clinical epidemiology.
2) Improving Quality of Health Care
As a member of the quality improvement andassessment committee, clinical pathway committee,
and a vice-chair of the committee for quality care atour university hospital, Dr. Koide contributes to assess
our quality care and improvement.
3) Standardization
Epidemiology

ofInformationinClinical

As attending Health Level Seven (HL7) andClinical Data Interchange Standards Consortium(CDISC) which are the international standards
development organizations, we study on electronic
standards for the transfer pharmaceutical regulatory
information, especially focusing on electronic standards for reporting.

unprecedented roles of these lipases in diabetic
dyslipidemia, non-alcoholic steatohepatitis (NASH)
and atherosclerosis. In addition, we recently established an obesity-resistant mutant mouse strain which
may lead to the identification of new therapeutictargets to combat obesity-related disorders.
5) Preventive Medicine for Cardiovascular Disease
Cardiovascular disease is one of the main causes ofdeath in Japan and the related medical expenses arebigger than those for cancer. Preventive cardiology,
which was initiated by the Japanese medical society in
2000, is now regarded as a key solution to the problem.
In light of the need for novel approaches, Dr. Mizuno
sought to elucidate mechanisms of atherosclerosis byconducting comprehensive research in healthy
subjects. Firstly, we built a database with informationfrom medical check-up, thereafter conducted crosssectional and prospective studies. One of our recent
findings regarding oxidative stress suggests that
excessive state of serum iron levels in healthy patientsis associated with subclinical atherosclerosis. Dr.
Mizuno also elucidated the impact of infection on
early atherosclerosis, along with measuring oxidative
stress levels in stored blood samples.
6) Serological markers of malignant tumors
Serological markers of malignant tumors such as
Carcinoembryonic antigen (CEA) and carbohydrate
antigen 19-9 (CA19-9) are known to be associatedwith metabolic syndrome in several papers. Dr.
Mizuno sought to elucidate the relationship between
broad range of tumor markers and metabolic
syndrome as well as diabetes including impaired
glucose tolerance (IGT) by analyzing the data ofJapanese who underwent general health screening.

4) In Vivo Analysis on Lipid Metabolism
In order to elucidate the pathophysiological role ofneutral lipid accumulation in metabolic diseases, wetake advantage of mouse models of lipase deficiency
and genetic hyperlipidemia, such as hormone-sensitive
lipase (Lipe) deficient mice, neutral cholesterol esterhydrolase 1 (Nceh1) deficient mice, Ldlr/Apoe andApoa5 deficient mice.
Specifically, our recent findings suggest theReferences
1. Suzuki K, Koide D, Fujii K, Yamazaki T, Tsuji S,
Iwata A: Elevated Serum Uric Acid Levels Are
Related to Cognitive Deterioration in an Elderly
Japanese Population. Dement Geriatr Cogn Disord
Extra. 6(3): 580-8, 2016.
2. Lee SL, Daimon M, Di Tullio MR, Homma S,
Nakao T, Kawata T, Kimura K, Shinozaki T,353

Hirokawa M, Kato TS, Mizuno Y, Watanabe M,
Yatomi Y, Yamazaki T, Komuro I. Relationship ofleft ventricular diastolic function to obesity andoverweight in a japanese population with preserved
left ventricular ejection fraction. Circulation Journal
80(9):1951-1956.2016
3. Lee SL, Daimon M, Nakao T, Singer DE, Shinozaki
T, Kawata T, Kimura K, Hirokawa M, Kato TS,
Mizuno Y, Watanabe M, Yatomi Y, Yamazaki T,
Komuro I. Factors influencing left atrial volume in a
population with preserved ejection fraction: Leftventricular diastolic dysfunction or clinical factors?
Journal of Cardiology. 68(4):275-281.2016.
4. Hirokawa M, Daimon M, Lee SL, Nakao T, Kawata
T, Kimura K, Kato TS, Mizuno Y, Watanabe M,
Yatomi Y, Yamazaki T, Komuro I. Early menopause
does not influence left ventricular diastolic
dysfunction: A clinical observational study inhealthy subjects. Journal of Cardiology. 68:548553.2016.

354

Department of Ubiquitous
Preventive Medicine
Associate Professor
Yuichi Ikeda, M.D., Ph.D.

Assistant Professor
Kazutaka Ueda, M.D., Ph.D.

Introduction and Organization
As an official department in the Graduate School of
Medicine of the University of Tokyo, the Departmentof Ubiquitous Preventive Medicine was established inAugust 1st, 2007, with a donation from threepharmaceutical companies, Toa-Eiyo Ltd., Shionogi &Co., Ltd. and NEC Corporation to the University(since August 2010, from Shionogi & Co.). Its
predecessor is the Clinical Bio-Informatics Research
Unit, which was established in 2002 as a governmentfunded program (Bio-Informatics Training Programsupported by the Ministry of Education, Culture,
Sports, Science and Technology [MEXT] throughSpecial Coordination Funds for Promoting Scienceand Technology). When the Clinical Bio-Informatics
Research Unit completed its program tenure in 2007,
its academic services were succeeded by our department and the Department of Clinical Epidemiology
and Systems, both affiliated with the Department of
Cardiovascular Medicine in the Graduate School of
Medicine of the University of Tokyo.
Our department provides clinical as well as
academic support for the Department of Epidemiology
and Preventive Medicine, which was established in2007 within the University of Tokyo Hospital. In
collaboration with our department, the Department ofClinical Epidemiology and Systems also support the
management of the Department of Epidemiology andPreventive Medicine.

Research Activities
Our goal is to create diagnostic and 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 wasdevelopedincollaboration
withShimadzu
Corporation.
We have already confirmed andpublished its utility in clinical practice (Clin Chem, inpress), further, issued press-release from the
University of Tokyo Hospital.
In addition to the development of diagnostic
techniques, we have also established several screening
systems towards the discovery of bioactive substancesthat are involved in the pathogenesis of cardiovasculardiseases. Utilizing these newly developed systems,
we will screen tissue extracts and a small-moleculecompound library to identify novel bioactive
molecules.
In this way, Ubiquitous Preventive Medicine is anapplied science, based on which a comprehensive
system is to be developed in an effort to promote
preventive medicine for health promotion.

355

Clinical activities
The Department of Ubiquitous Preventive Medicine
is involved in the management of the Department of
Epidemiology and Preventive Medicine in the
University of Tokyo Hospital and provides clinical aswell as academic support for the department.

Teaching activities
The Department of Ubiquitous Preventive Medicine
offers education and research supervision to graduate
students and post-doctoral fellows in the affiliate
Department of Cardiovascular Medicine.

References
1. Izumi M, Ikeda Y, Yamashita H, Asaoka Y,
Fujishiro M, Shin M, Abo Y: Safety andeffectiveness of endovenous laser ablation
combined with ligation for severe saphenous
varicose veins in Japanese patients. Int Heart J.
57:87-90, 2016 (corresponding author)
2. Zempo H, Suzuki J, Watanabe R, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Isobe M: Cacao polyphenols ameliorate
autoimmune myocarditis in mice. Hypertens Res.
39:203-209, 2016
3. Watanabe R, Suzuki J, Wakayama K, Kumagai H,
Ikeda Y, Akazawa H, Komuro I, Isobe M:
Angiotensin II receptor blocker irbesartan
attenuates cardiac dysfunction induced bymyocardial infarction in the presence of renal
failure. Hypertens Res. 39:237-244, 2016
4. Kobayashi N, Suzuki J, Aoyama N, Sato H,
Akimoto S, Wakayama K, Kumagai H, Ikeda Y,
Akazawa H, Komuro I, Izumi Y, Isobe M:
Toll-like receptor 4 signaling plays a critical rolein Porphyromonas gingivalis accelerated neointimal formation after arterial injury in mice.
Hypertens Res. 39:717-722, 2016
5. Shiheido Y, Maejima Y, Suzuki JI, Aoyama N,
Kaneko M, Watanabe R, Sakamaki Y, Wakayama
K, Ikeda Y, Akazawa H, Ichinose S, Komuro I,
Izumi Y, Isobe M: Porphyromonas gingivalis, aperiodontal pathogen, enhances myocardial
vulnerability, thereby promoting post-infarct

cardiac rupture. J Mol Cell Cardiol. 99:123-137,
2016
6. Suzuki J, Imai Y, Aoki M, Fujita D, Takeda N,
Aoyama N, Wakayama K, Ikeda Y, Kumagai H,
Akazawa H, Izumi Y, Isobe M, Komuro I, Hirata
Y: Periodontitis may deteriorate sinus of valsalva
dilatation in marfan syndrome patients. Int Heart J.
57:456-460, 2016
7. Suzuki J, Shimamura M, Suda H, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Isobe M,
Komuro I, Morishita R: Current therapies andinvestigational drugs for peripheral arterial
disease. Hypertens Res. 39:183-191, 2016
8. Ikeda Y, Kumagai H, Motozawa Y, Suzuki J,
Akazawa H, Komuro I: Understanding vasculardiseases: Lessons from premature aging
syndromes. Can J Cardiol. 32:650-658, 2016
9. Ono S, Saito I, Ikeda Y, Fujishiro M, Komuro I,
Koike K: Current practices in the management ofantithrombotic therapy during the periendoscopic
period for patients with cardiovascular disease. Int
Heart J. 57:530-534, 201610. Suzuki J, Sato H, Kaneko M, Yoshida A, Aoyama N,
Akimoto S, Wakayama K, Kumagai H, Ikeda Y,
Akazawa H, Izumi Y, Isobe M, Komuro I:
Periodontitis
andmyocardial
hypertrophy.
Hypertens Res. 40:324-328, 2016
11. Ikeda Y, Kumagai H, Motozawa Y, Suzuki J:
Growth differentiation factor 15 (GDF15) as areliable biomarker for cardiovascular risk assessment. Int Heart J. 57:1-2, 2016 (corresponding
author)12. Fujishiro M, Ikeda Y: Re-bleeding after endoscopic hemostasis for peptic ulcer bleeding: Isenough said or are other factors important? Dig.
Dis. Sci. 61:1424-1425, 2016

356

Division of Chronic Kidney Disease(CKD) Pathophysiology
Division Chief (Associate Professor)
Reiko Inagi, Ph.D.

Assistant Professor
Tzu-Ming Jao, Ph.D.

Postdoctoral fellow
Kumi Shoji, M.D., Ph.D. (Division of Nephrology and Endocrinology)
Yu Ishimoto, M.D., Ph.D. (Division of Nephrology and Endocrinology)

PhD Students
Akira Okada, M.D. (Division of Nephrology and Endocrinology)
Hiroshi Maekawa, M.D. (Division of Nephrology and Endocrinology)

Visiting Researcher
Hiroaki Amano, M.D. (Saitama Medical University)
Rikardi Santosa, Msc.
(Faculty of Medicine, Andalas University, Padang, Indonesia)

Lab Technician
Ikumi Okuaki, B.S.
Rika Nakamura, Ph.D.

Homepage

http://www.todai-ckd.com

Introduction and Organization
In Japan, more than 13 million people suffer fromchronic kidney disease (CKD), or roughly one inevery eight adults. Why has the number of CKD
patients increased so remarkably? One major cause is
the sharp increase in the number of people withdiabetic nephropathy, which is a complication ofdiabetes; since 1998, this has been the most importantcause among diseases which require incipient dialysis
in Japan. Additional causes include the aging ofsociety and other social factors. The kidney is called asilent organ, and CKD progresses without subjective
symptoms. It is now evident, however, thatasymptomatic CKD which progresses over time
carries a number of risks.
One risk is the possible progression of CKD to
end-stage renal disease (ESRD), which requires renal
replacement therapy. A second risk is the development
and progression of lifestyle-related diseases, such asheart attack and arteriosclerosis. The kidneys work
closely with the heart and other organs, and a decrease
in renal function causes dysfunction of the heart andblood vessels. This adverse impact of the progressionof CKD on other organs underlines the importance of
the kidneys in maintaining general health. Further,357

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.

patients 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

Research Funds (PI)
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 in Japan Society for the Promotion of Science, Grantsin-Aid for Scientific Research
15KT0088 (to Reiko Inagi, Analysis of epigenetic
regulation of endoplasmic reticulum stress signals
on kidney aging),
16K15465 (to Reiko Inagi, Analysis of pathophysiological significance of D-amino acid in
kidney disease)
16K09604 (to Tzu-Ming Jao, Development of
Noveltherapeutic
approaches
targeting
ATF-6-mediated metabolic alteration)AwardsDr. Tzu-Ming Jao received the Investigators Awardof Nagoya Chronic Kidney Disease Frontier.
Dr. Yu Ishimoto received the Excellent Award of the
7th molecular Nephrology forum.
Dr. Yu Ishimoto received the Young InvestigatorAward Basic Science (Runner up) in the 15th Asian
Pacific Congress of Nephrology (Perth, Australia).
Dr. Yu Ishimoto received the Best Abstract Award in
the 7th Japanese Society of Pathophysiology in Kidney
DiseaseDr. Akira Okada received the High Score Abstract
Award in Kidney Summit 2016.

References
1. Tanaka S, Tanaka T, Kawakami T, Takano H,
Sugahara M, Saito H, Higashijima Y, Yamaguchi J,
Inagi R, Nangaku M. Vascular adhesion protein-1
enhances neutrophil infiltration by generation ofhydrogen peroxide in renal ischemia/reperfusion
injury. Kidney Int. 2017 Mar 16. pii: S0085-

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2.

3.

4.

5.
6.

7.

2538(17)30041-8. doi: 10.1016/j.kint.2017.01.014.
[Epub ahead of print]
Maekawa H, Inagi R. Stress Signal Network
between Hypoxia and ER Stress in Chronic
Kidney Disease. Front Physiol. 2017 Feb 8;8:74.
Hirakawa Y, Inagi R. Glycative Stress and Its
Defense Machinery Glyoxalase 1 in Renal
Pathogenesis. Int J Mol Sci. 2017 Jan 17;18(1).
pii: E174.
Yamaguchi J, Tanaka T, Inagi R. Effect of AST120 in Chronic Kidney Disease Treatment: Still aControversy. Nephron. 2017;135(3):201-206.
Inagi R. RAGE and glyoxalase in kidney disease.
Glycoconj J. 2016 Aug;33(4):619-26.
Nakatani Y, Inagi R. Epigenetic Regulation
Through SIRT1 in Podocytes. Curr Hypertens
Rev. 2016;12(2):89-94.
Ishimoto Y, Inagi R. Mitochondria: a therapeutictarget in acute kidney injury. Nephrol Dial
Transplant. 2016 Jul;31(7):1062-9.

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Department of Molecular Structure
and Dynamics
Project Professor
Nobutaka Hirokawa, M. D.

Project Associate
Tadayuki Ogawa, Ph. 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, cryoelectron 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. Tanaka, Y., S. Niwa, M. Dong, A. Farkhondeh,
Li. Wang, R. Zhou, and N. Hirokawa. The
molecular motor KIF1A transports the trkA
neurotrophin receptor and is essential for sensory
neuron survival and function. Neuron 90: 12151229, 2016
2. Wang, D., R. Nitta, M. Morikawa, H. Yajima, S.
Inoue, H. Shigematsu, M. Kikkawa, and N. Hirokawa.
Motility
andmicrotubule
deploymerization
mechanisms of the kinesin-8 motor, KIF19A. eLife
2016;5:e18101.doi:10.7554/eLife.18101
3. Niwa S., DM. Lipton, M. Morikawa, C. Zhao, N.
Hirokawa, H. Lu, and K. Shen. Autoinhibition of aneuronal kinesin UNC-104/KIF1A regulates the sizeand density of synapses. Cell Reports 16: 2129-2141,
2016.
4. Ogawa, T., S. Saijo, N. Shimizu, X. Jiang and N.
Hirokawa. Mechanism of Catalytic Microtubule
Depolymerization via KIF2-tubulin Transitional
Conformation. Cell Reports 20: 2626–2638, 2017.

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Department of Continence
Medicine
Professor
Yasuhiko Igawa, M.D.,Ph.D.

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

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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. Aizawa N. Editorial Comment from Dr Aizawa to
Propiverine increases urethral wall catecholaminelevels and bladder leak point pressure in rats. Int J
Urol. 2016 Jan;23(1):100-1.
2. Fujimura T, Menon M, Fukuhara H, Kume H,
Suzuki M, Yamada Y, Niimi A, NakagawaT,
Igawa Y, Homma Y. Validation of an educational
program balancing surgeon training and surgicalquality control during robot-assisted radicalprostatectomy. Int J Urol. 2016 Feb;23(2):160-6.
3. Taguchi S, Kume H, Fukuhara H, Morikawa T,
Kakutani S, Takeshima Y, Miyazaki H, Suzuki M,
Fujimura T, Nakagawa T, Ishikawa A, Igawa Y,
Homma Y. Symptoms at diagnosis as independent
prognostic factors in retroperitoneal liposarcoma.
Mol Clin Oncol. 2016 Feb;4(2):255-260.
4. Ito H, Aizawa N, Sugiyama R, Watanabe S,
Takahashi N, Tajimi M, Fukuhara H, Homma Y,
Kubota Y, Andersson KE, Igawa Y. Functionalrole of the transient receptor potential melastatin 8(TRPM8) ion channel in the urinary bladderassessed by conscious cystometry and ex vivo
measurements of single-unit mechanosensitive
bladder afferent activities in the rat. BJU Int. 2016
Mar; 117(3):484-94.
5. Aizawa N, Gandaglia G, Hedlund P, Fujimura T,
Fukuhara H, Montorsi F, Homma Y, Igawa Y.
URB937, a peripherally-restricted inhibitor for
fatty acid amide hydrolase, reduces prostaglandinE(2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibers
in rats. BJU Int. 2016 May;117(5):821-8.
6. Aizawa N, Sugiyama R, Ichihara K, Fujimura T,
Fukuhara H, Homma Y, Igawa Y. Functionalroles of bladder α1-adrenoceptors in the activationof single-unit primary bladder afferent activity inrats. BJU 2016 Jun; 117(6): 993-1001.
7. Akiyama Y, Morikawa T, Maeda D, Shintani Y,
Niimi A, Nomiya A, Nakayama A, Igawa Y,

Fukayama M, Homma Y. Increased CXCR3
Expression of Infiltrating Plasma Cells in HunnerType Interstitial Cystitis. Sci Rep. 2016 Jun
24;6:28652. doi:10.1038/srep28652.
8. Suzuki M, Iguchi Y, Igawa Y, Yoshida M, Sanada
H, Miyazaki H, Homma Y. Ultrasound-assisted
prompted voiding for management of urinary
incontinence of nursing home residents: Efficacy
and feasibility. Int J Urol. 2016 Sep; 23(9):786-90.
9. Niimi A, Suzuki M, Yamaguchi Y, Ishii M,
Fujimura T, Nakagawa T, Fukuhara H, Kume H,
Igawa Y, Akishita M, Homma Y. Sleep Apnea
and Circadian Extracellular Fluid Change as an
Independent Factor for Nocturnal Polyuria. J Urol.
2016 Oct; 196(4):1183-9.
10. Niimi A, Nomiya A, Yamada Y, Suzuki M,
Fujimura T, Fukuhara H, Kume H, Igawa Y,
Homma Y. Hydrodistension with or without
fulguration of hunner lesions for interstitial
cystitis: Long-term outcomes and prognostic
predictors. Neurourol Urodyn. 2016 Nov;35(8):965-969.
11. Ito H, Kamei J, Aizawa N, Fujita Y, Suzuki M,
Fukuhara H, Fujimura T, Kojima T, Homma Y,
Kubota Y, Ito M, Andersson KE, Igawa Y.
Preventive effects of long-term caloric restriction
on aging-related in vivo bladder dysfunctions andmolecular biological changes in the bladder anddorsal root ganglia in rats. J Urol. 2016 Nov;
196(5):1575-1583.
12. Aizawa N, Fukuhara H, Fujimura T, Homma Y,
Igawa Y. Direct influence of systemic
desensitization by resiniferatoxin on the activitiesof A- and C-fibers in the rat primary bladdermechanosensitive afferent nerves. Int J Urol. 2016
Nov; 23(11): 952-956.
13. Matos R, Cordeiro JM, Coelho A, Ferreira S,
Silva C, Igawa Y, Cruz F, Charrua A. Bladderpain induced by prolonged peripheral alpha 1A
adrenoceptor stimulation involves the enhance
ment of Transient Receptor Potential Vanilloid 1(TRPV1) activity and an increase of urothelial
Adenosine Triphosphate (ATP)-release. Acta
Physiol (Oxf). 2016 Dec; 218(4):265-275.
14. Taguchi S, Fukuhara H, Morikawa T, Matsumoto
A, Miyazaki H, Nakagawa T, Fujimura T, Kume

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H, Igawa Y, Homma Y. Cessation of long-term
adjuvant androgen deprivation therapy afterradical prostatectomy: is it feasible? Jpn J Clin
Oncol. 2016 Dec;46(12):1143-1147.

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Department of Medical Genomics
Associate Professor
Eirin Sai, M.D., Ph.D.

Lecturer
Masahito Kawazu, M.D., Ph.D.

Assistant Professor
Shinji Kohsaka, M.D., Ph.D.

Homepage

http://mano-lab.umin.jp/english/genome.html

Introduction and Organization

Teaching activities

Department of Medical Genomics was established in
September 2009 with the goal to identify essential
growth drivers in every cancer, by taking advantage ofour functional screening system coupled with the next
generation sequencing technologies. Department ofMedical Genomics had been settled by the tightsupport 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
has been run only by the donation from Astellas
Pharma Inc. Since April 2013, Department of Cellular
Signaling (Professor Hiroyuki Mano) co-supported
this Department. Starting from September 2014,
Department of Medical Genomics has entered thesecond 5-year-period by the support from Eisai Co.,
Ltd. In September 2014, Dr. Yoshihiro Yamashita waspromoted to become Associate Professor at Department of Cellular Signaling. In January 2015, Dr.
Shinji Kohsaka has jointed Department of Medical
Genomics as Assistant Professor.
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 Cellular Signaling.

We jointly take the responsibility for the lectures ofBiochemistry as wells as training of Biochemical
Experiments for the undergraduate students of the
School of Medicine. We also deliver training for
graduate students of the Graduate School of Medicine.

Research activities
Department of Medical Genomics tries to fulfill ourgoals mainly through two approaches.
(1) Functional screening with the use of retroviral
cDNA expression libraries.
The focus formation assay had been widely usedin 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 in recipient
cells. To make every gene expressed sufficiently inrecipient cells, we here developed a highly efficient
retrovirus–mediated cDNA expression library system.
Our system enables to make a library with highcomplexity (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

364

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 that those without it.
(2) Cancer genome resequencing
In addition to the functional screening shown
above, we also tried to search for somatically mutatedgenes 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 a cancer specimen even in private
laboratories, it is still a demanding task to conduct
full-genome sequencing for a large number of samples.
Therefore, many laboratories now purify exonic
fragments from a sample genome, and determine theirsequences. However, since gene fusions usually takeplace at intronic regions, such sequencing approachwith 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 the discovery 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.

References
1. Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F,
Kojima S, Ueno T, Imoto N, Kohsaka S, Kunita A,
Doi K, Sakura T, Yujiri T, Kondo E, Fujimaki K,
Ueda Y, Aoyama Y, Ohtake S, Takita J, Sai E,
Taniwaki M, Kurokawa M, Morishita S, Fukayama
M, Kiyoi H, Miyazaki Y, Naoe T and Mano H.
“Recurrent DUX4 fusions in B cell acutelymphoblastic leukemia of adolescents and young
adults” Nat Genet 48:569-574, 2016.
2. Katsura A, Suzuki HI, Ueno T, Mihira H, Yamazaki
T, Yasuda T, Watabe T, Mano H, Yamada Y and
Miyazono K. “MicroRNA-31 is a positive modulatorofendothelial-mesenchymaltransition
andassociated secretory phenotype induced by
TGF-beta” Genes Cells 21:99-116, 2016.
3. Fukumura K, Kawazu M, Kojima S, Ueno T, Sai E,
Soda M, Ueda H, Yasuda T, Yamaguchi H, Lee J,
Shishido-Hara Y, Sasaki A, Shirahata M, Mishima K,
Ichimura K, Mukasa A, Narita Y, Saito N, Aburatani
H, Nishikawa R, Nagane M and Mano H. “Genomic
characterization of primary central nervous systemlymphoma” Acta Neuropathol 131:865-875, 2016.
4. Ando M, Kawazu M, Ueno T, Koinuma D, Ando K,
Koya J, Kataoka K, Yasuda T, Yamaguchi H,
Fukumura K, Yamato A, Soda M, Sai E, Yamashita
Y, Asakage T, Miyazaki Y, Kurokawa M, Miyazono
K, Nimer SD, Yamasoba T and Mano H.
“Mutational Landscape and Antiproliferative
Functions of ELF Transcription Factors in Human
Cancer” Cancer Res 76:1814-1824, 2016.

365

Department of Life Support
Technology (Molten)
Project Professor
Taketoshi Mori, Ph.D.

Project Lecturer
Hiroshi Noguchi, Ph.D.

Project Assistant Professor
Mikako Yoshida, Ph.D, and Daichi Araki, 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.
Current members include a project professor, a project
lecturer and a project assistant professor. In addition,an academic support staff is belonging to ourdepartment from Global Leadership Initiative for an
Age-Friendly Society, Graduate Program in
Gerontology.
We accept students from Division of Health Scienceand Nursing. Accepted two master course students
were graduated at the end of 2013. The supportive
department is the Department of GerontologicalNursing / Wound Care Management. We also accept
foreign students. In 2013, we accepted a Ph.D. student
from Mexico.

366

Teaching activities
As for lectures, our department assisted the lectures ofthe supportive department, the Department ofGerontological Nursing/Wound Care Management. In
a part of Gerontological Nursing for undergraduate
course, Taketoshi Mori lectured monitoring system forelderly people. Hiroshi Noguchi also lectured nursing
engineering. In addition, Mikako Yoshida supported
Gerontological Practical for undergraduate course.
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 and other speakers related
to engineering to lecture for Gerontological Nursing II
for graduate course.
In a part of Gerontological Nursing I for graduate
course, the members in the department lectured thefeatures and reading method of journal papers ofengineering research based on typical publications.
As for the other education activity, our department
supported management of the forth seminar for
nursing science and engineering. The staffs in our
department had engineering-related lectures andintroduction of research using ultrasonography. In
addition, our departments hold advanced lecture
course about motion sensor.

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 andalgorithm for typical behavior pattern extraction
and transition estimation of human behavior
patternc) Three-dimensional leg movement measurement
and spatiotemporal 3D leg state measurement for
prevention of foot ulcerd) Clinical research and image processing technology
development for current status and management ofincontinencee) Human position measurement and behavior
estimation using laser range scannersf) Design and construction of human behavior
database
As for the clinical field, we attend the Foot Care
Outpatient Clinic held by Department of Metabolic
Diseases. Mikako Yoshida attended Outpatient Clinicof Urology.
We have been developing a new mattress for pressure
ulcer management collaborating with Department ofGerontological Nursing/Wound Care Management.
The mattress was called a robotic mattress, and wascommercialized from 2016. We developed an
automatic inner air-cell adjustment function as a new
function of the mattress. The mattress measures bodyinterface pressure continuously using pressure
distribution on the mattress and controls amount of
inner air-cell pressures. Due to this function, themattress can control optimal air-cell pressure whenmaximum interface pressure become lowest. The
function realizes automatic adjustment of inner air cellpressure whatever body types and postures people on
mattress are. This function leads to appropriatepressure ulcer management. A master course student,
who was belonging to Department of GerontologicalNursing/Wound Care Management developed andevaluated this function. In addition, she conducted367

case study using the mattress. She wrote master course
thesis “Evaluation of comfort associated with the useof a robotic mattress with an interface pressure
mapping system and automatic inner air-cell pressureadjustment function” and graduated.
2.

As for the research related to prevention of diabetic
foot ulcer, we supported the master course student,
who was belonging to Department of GerontologicalNursing/Wound Care Management. She developed a
new algorithm. The algorithm estimates perpendicularforce on forefoot using only motion sensor data oflegs and feet based on body kinematics. She also
compared estimated and reference values captured byplantar attached sensor. She also conducted pilot study
for two people with diabetes to confirm safety andcontinuous measurement of the motion sensors.
She wrote master course thesis “Development of aplantar load estimation algorithm for evaluation of
forefoot load of diabetic patients during daily walks
using a foot motion sensor” and graduated.
In this year, we started a new research theme. It is
known that a mask can cause medical device-relatedpressure ulcer on the nasal bridge under non-invasive
positive pressure ventilation therapy. We developed a
new device to prevent this pressure ulcer. The 3D
shape of face and mask were captured by portablescanner in advance. The gap between the face andmask was calculated. In order to fill this gap, the moldfor silicon was designed in 3D CG software, andprinted by a 3D printer. Finally, the device made ofsilicon was created by filling the silicon into theprinted mold. We call this device a personalized fitting
device. She evaluated the devices with healthy
participants. In addition, she conducted a case study
for one patient. She wrote the master thesis“Development of personalized fitting device withthree-dimensional solution for prevention of medical
device-related pressure ulcers caused by non-invasive
positive pressure ventilation oral-nasal mask”, andgraduated.

References
1.

Amemiya A, Noguchi H, Oe M, Takehara K, Ohashi
Y, Suzuki R, Yamauchi T, Kadowaki T, Sanada H,

3.

4.

5.

6.

Mori T. Shear stress-normal stress (Pressure) Ratio(SPR) decides forming callus in patients withdiabetic neuropathy. J Diabetes Res, vol. 2016,
Article ID 3157123, 10 pages, 2016. doi:10.1155/
2016/3157123.
Noriko Hori, Nao Tamai, Hiroshi Noguchi, Gojiro
Nakagami, Junko Sugama, Taketoshi Mori, andHiromi Sanada. Development and assessment of air
mattress with independent air cell pressure control
responsive to interface pressure distribution. Journalof Japanese Society Wound, Ostomy, and Continence Management. vol. 20, no. 3, pp. 300-309,
2016.
Miura Y, Nakagami G, Yabunaka K, Tohara H, Hara
K, Mori T, Sanada H. Detecting pharyngeal postswallow residue by ultrasound examination: a caseseries. Med Ultrason. 2016;18(3):288-93.
Huang L, Minematsu T, Kitamura A, Paes QC,
Nakagami G, Mugita Y, Oe M, Noguchi H, Mori T,
Sanada H. Topical Administration of Acylated
Homoserine Lactone Improves Epithelialization of
Cutaneous Wounds in Hyperglycaemic Rats. PLOS
one. 2016. http://dx.doi.org/10.1371/journal.pone.
0158647
Masako Hamatani, Taketoshi Mori, Makoto Oe,
Hiroshi Noguchi, Kimie Takehara, Ayumi
Amemiya, Yumiko Ohashi, Kohjiro Ueki, Takashi
Kadowaki, and Hiromi Sanada. Factors AssociatedWith Callus in Diabetic Patients, Focused on
Plantar Shear Stress During Gait. J Diabetes Sci
Technol 1932296816648164, first published on
May 8, 2016 as doi:10.1177/1932296816648164,
November 2016 10: 1353-1359.
Moriyoshi Fukuda, Keiko Tabata, Tomoe Nishizawa,
Misako Dai, Gojiro Nakagami, Hiroshi Noguchi,
Toshio Nakatani, Mayumi Okuwa, Hiromi Sanada,
Junko Sugama. Evaluation of the automaticbottoming-out releasing system in the automatic
self-regulating alternating pressure air-cell wheelchair cushion. Journal of Japanese Society of Wound,
Ostomy, and Continence. 2015;19(4):365-377.

368

Department of Youth Mental
HealthAssociate Professor
Tsuyoshi Araki, M.D., Ph.D.

Lecturer
Mio Masaoka, Ph.D.

Homepage

http:// plaza.umin.ac.jp/~youth-mh/

Introduction and Organization
The Department of Youth Mental health wasestablished May 2011. This department is supported
by Otsuka Pharmaceutical Co., Ltd. and keeps close
relationship with the department of neuropsychiatry.
Youth means the period of time when someone isyoung, especially the period when someone is ateenager. This period includes the period of puberty
and adolescence. This period is unique to human andis very important for developing the ego function. If
some critical event happens at this time, thedevelopment might be inhibited and this inhibition
may cause mental illness. In order to keep thisdevelopment safely, the close care for teenagers isvery useful. Although the importance of mental healthof children and adult is emphasized in the history ofneuropsychiatry, youth mental health did not attract a
lot of attention of psychiatrists and researchers. Fromthe late 20th century, psychiatrists began to notice theimportance of youth mental health.
This department has a focus on youth mental healthand combines the biological aspect and social aspectof psychiatry. We are trying to create the new conceptof the social psychiatry including early intervention
and education.

Clinical activities
We have outpatient clinics especially for the youth.
This clinic is a part of neuropsychiatry clinics but
treats young people especially suffering from earlystage of psychosis. We try to use cognitive and social
therapy for those patients and to minimize the use of
medication.
Psychiatrists and co medical staffs go to highschools and are engaged in educational activities.
School teachers often need some advises about mental
health problems happening in schools, we try to assist
those teachers as well.
Just after the Great East Japan Earthquake, staffs ofthe department of neuropsychiatry went to Miyagi
prefecture and support the staffs working at
Higashimatsushima City. This department also sends
staffs and meets the needs of staffs working at
Higashimatsushima City.

Educational activities
Staffs are participating in several kinds of lectureswith the staffs of the department of psychiatry. We
also manage the mental health research course which
is one of the courses of clinical research training
program in the University of Tokyo.

Research activities
Our research field covers Integrative neuroimaging
studies for schizophrenia targeting early intervention
and prevention (IN-STEP), Tokyo teen cohort study,
and the cohort-subsample brain imaging study.

369

References
1. Ando S, Kuwabara H, Araki T, Kanehara A,
Tanaka S, Morishima R, Kondo S, Kasai K:
Mental Health Problems in a Community Afterthe Great East Japan Earthquake in 2011: A
Systematic Review. Harv Rev Psychiatry 25(1):15-28, 2017
2. Kanehara A, Ando S, Araki T, Usami S,
Kuwabara H, Kano Y and Kasai K: Trends inpsychological distress and alcoholism after The
Great East Japan Earthquake of 2011. SSM –Population Health 2: 807-812, 2016
3. Sakakibara E, Homae F, Kawasaki S, Nishimura Y,Takizawa R, Koike S, Kinoshita A, Sakurada H,
Yamagishi M, Nishimura F, Yoshikawa A, Inai A,
Nishioka M, Eriguchi Y, Matsuoka J, Satomura Y,
Okada N, Kakiuchi C, Araki T, Kan C, Umeda M,
Shimazu A, Uga M, Dan I, Hashimoto H,
Kawakami N and Kasai K: Detection of restingstate functional connectivity using partial
correlation analysis: A study using multi-distanceand whole-head probe near-infrared spectroscopy.
Neuroimage 142: 590-601, 2016
4. Araki T, Kirihara K, Koshiyama D, Nagai T, Tada
M, Fukuda M and Kasai K: Intact neural activity
during a Go/No-go task is associated with highglobal functioning in schizophrenia. Psychiatry
Clin Neurosci 70(7): 278-285, 2016

370

Department of Immunotherapy
Management
Project Associate Professor
Hiroko Kanda, M.D., Ph.D.

Project Associate
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 the treatmentof rheumatoid arthritis, psoriasis, Behcet disease andinflammatory bowel diseases. These diseases are treatedin the Department of Allergy & Rheumatology,
Dermatology, Orthopedics Gastroenterology, Surgicaloncology & vascular surgery, and Ophthalmology. The
Department of Immunotherapy Management wasestablished in April 2013, and renewed throughdonations 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 in collaboration.
Biologics agents include infliximab, infliximab BS,
adalimumab, golimumab, certolizumab pegol, etanercept,
tocilizumab, abatacept, ustekinumab, secukinumab,
ixelizumb and brodulumab. The Jak kinase inhibitor
tofacitinib is only one small molecule. These molecularly
targeted drugs have been developed in succession.
However, it is difficult to predict the efficacy andtoxicity of these agents by the background characteristics
of patients with rheumatoid arthritis. The aims of thisdepartment are to propose an optimal treatment strategy

for each patient and to establish a platform to investigate
novel biologics through analyses of immunologicalchanges by molecularly targeted therapy and therelationship between 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 or
Behcet’s disease before molecularly targeted therapy
and judge whether these treatments can be used safely.
In every Friday afternoons, we evaluate for outpatientwith psoriatic arthritis including accurate diagnosis
and monitoring disease activity by clinical andimaging 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 provide
information of the agent for medical staffs. Moreover,
we are giving lectures about molecularly targeted
therapy for medical students at bed-side learning371

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. Nagafuchi Y, Shoda H, Sumitomo S, Nakachi S,
Kato R, Tsuchida Y, Tsuchiya H, Sakurai K,
Hanata N, Tateishi S, Kanda H, Ishigaki K, Okada
Y, Suzuki A, Kochi Y, Fujio K, Yamamoto K.
Immunophenotyping of rheumatoid arthritis
reveals a linkage between HLA-DRB1 genotype,CXCR4 expression on memory CD4(+) T cells,
and disease activity. Sci Rep. 2016 Jul 7; 6:29338.
2. Kubo K, Kanda H: evidences of non-drug therapy
for rheumatoid arthritis. Naika 117(5) 1173-6,
2016
3. Kanda H: Treatments and monitoring forrheumatoid arthritis with comorbidities. Medical
Practice 33(10) 1623-8, 2016

372

Department of medical researchand the management ofmusculoskeletal pain
Professor
Koh Matsudaira, M.D,Ph.D.

Associate Professor
Hiroyuki Oka, M.D,Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/undouki_toutu.html

Introduction and Organization
The department of medical research and the
management of musculoskeletal pain was establishedin 2014 at the 22nd Century Medical and ResearchCentre thanks to donations from Ono Pharmaceutical
Co. Ltd., Showa Yakuhin Kako Co., Ltd., and Nippon
Zoki Pharmaceutical Co., Ltd. The department is acollaboration among the Department of Orthopaedics,
the Department of Rehabilitation Medicine, and theDepartment of Anaesthesiology and Pain Medicine.
Currently, our aims are to design an algorithm fordiagnosing and treating most types of musculoskeletal
pain that do not have established treatment guidelines
and to elucidate evidence for the possibility ofdeveloping 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.

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:

3733) Evaluate the brain function of people who are on
administrative leave due to low back pain, since thisphenomenon is a major social problem.

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.

Specifically, we will conduct the following research:

References

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; and

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.

1. Matsudaira K, Oka H, Kikuchi N, Haga Y,
Sawada T, Tanaka S. The Japanese version of the
STarT Back Tool predicts 6-month clinicaloutcomes of low back pain. J Orthop Sci 22:
224-229, 2016
2. Katsuhira J, Matsudaira K, Oka H, Iijima S, Itou
A, Yasui T, Yozu A. Efficacy of a trunk orthosis
with joints providing resistive force on low backload during level walking in elderly persons. Clin
Interv Aging 11: 1589-1597, 2016
3. Tonosu J, Inanami H, Oka H, Katsuhira J, Takano
Y, Koga H, Yuzawa Y, Shiboi R, Oshima Y, Baba
S, Tanaka S, Matsudaira K. Diagnosing
Discogenic Low Back Pain Associated with
Degenerative Disc Disease Using a Medical
Interview. PLoS One 11: e0166031, 2016
4. Tsuji T, Matsudaira K, Sato H, Vietri J. The
impact of depression among chronic low backpain patients in Japan. BMC Musculoskelet
Disord 17: 447, 2016
5. Coggon D, Ntani G, Walker-Bone K, Palmer KT,
Felli VE, Harari R, Barrero LH, Felknor SA,
Gimeno D, Cattrell A, Vargas-Prada S, Bonzini M,
Solidaki E, Merisalu E, Habib RR, Sadeghian F,
Kadir MM, Warnakulasuriya SS, Matsudaira K,
Nyantumbu B, Sim MR, Harcombe H, Cox K,
Sarquis LM, Marziale MH, Harari F, Freire R,
Harari N, Monroy MV, Quintana LA, Rojas M,
Harris EC, Serra C, Martinez JM, Delclos G,
Benavides FG, Carugno M, Ferrario MM, Pesatori
AC, Chatzi L, Bitsios P, Kogevinas M, Oha K,
Freimann T, Sadeghian A, Peiris-John RJ,

374

Sathiakumar N, Wickremasinghe AR, Yoshimura
N, Kelsall HL, Hoe VC, Urquhart DM, Derrett S,
McBride D, Herbison P, Gray A, Salazar Vega EJ.:
Epidemiological differences between localised
and non-localised low back pain. Spine, 2016
Nov4.[ [Epub ahead of print]
6. Isomura T, Sumitani M, Matsudaira K,
Kawaguchi M, Inoue R, Hozumi J, Tanaka T,
Oshima H, Mori K, Taketomi S, Inui H, Tahara K,
Yamagami R, Hayakawa K. Development of theJapanese Version of the Leeds Assessment of the
Neuropathic Symptoms and Signs Pain Scale(LANSS-J): Diagnostic Utility in a ClinicalSetting. Pain Practice, 2016 Oct 22. [Epub aheadof print]
7. Taniguchi Y, Takahashi M, Matsudaira K, Oka H,
Momose T. Potential use of 18F-FDG-PET/CT tovisualize muscle pain in patients with adult spinal
deformity: A case report. Skeletal Radiol 45:
1577-81,2016
8. Hara N, Matsudaira K, Masuda K, Tohnosu J,
Takeshita K, Kobayashi A, Murakami M,
Kawamura N, Yamakawa K, Terayama S, Ogihara
S, Shiono H, Morii J, Hayakawa K, Kato S,
Nakamura K, Oka H, Sawada T, Inuzuka K,
Kikuchi N. Psychometric Assessment of theJapanese Version of the Zurich Claudication
Questionnaire (ZCQ): Reliability and Validity.
PLoS One 11:e0160183, 2016
9. Iwahashi H, Yoshimura N, Hashizume H, Yamada
H, Oka H, Matsudaira K, 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. The
Association between the Cross-Sectional Area of
the Dural Sac and Low Back Pain in a Large
Population: The Wakayama Spine Study. PLoS
One 11: e0160002, 2016
10. Yamada K, Matsudaira K, Imano H, Kitamura A,
Iso H. Influence of work-related psychosocial
factors on the prevalence of chronic pain andquality of life in chronic pain patients. BMJ Open6: e010365, 2016
11. Hayashi S, Katsuhira J, Matsudaira K, Maruyama
H: Effect of pelvic forward tilt on low backcompressive and shear forces during a manual
lifting task. J Phys Ther Sci 28: 802-6, 2016

12. Vargas-Prada S, Coggon D, Ntani G, Walker-BoneK, Palmer KT, Felli VE, Harari R, Barrero LH,
Felknor SA, Gimeno D, Cattrell A, Bonzini M,
Solidaki E, Merisalu E, Habib RR, Sadeghian F,
Kadir MM, Warnakulasuriya SS, Matsudaira K,
Nyantumbu B, Sim MR, Harcombe H, Cox K,
Sarquis LM, Marziale MH, Harari F, Freire R,
Harari N, Monroy MV, Quintana LA, Rojas M,
Harris EC, Serra C, Martinez JM, Delclos G,
Benavides FG, Carugno M, Ferrario MM, Pesatori
AC, Chatzi L, Bitsios P, Kogevinas M, Oha K,
Freimann T, Sadeghian A, Peiris-John RJ,
Sathiakumar N, Wickremasinghe AR, Yoshimura
N, Kelsall HL, Hoe VC, Urquhart DM, Derrett S,
McBride D, Herbison P, Gray A, Vega EJ.
Descriptive
EpidemiologyofSomatising
Tendency: Findings from the CUPID Study. PLoS
One 11 :e0153748, 2016
13. Tonosu J, Matsudaira K, Oka H, Okazaki H,
Oshio T, Hanaoka I, Muraoka Y, Midorikawa M,
Wakabayashi K, Tanaka S. A population approachto analyze the effectiveness of a back extension
exercise "One Stretch" in patients with low backpain: A replication study. J Orthop Sci 21:414-8,
2016
14. Matsudaira K, Oka H, Kikuchi N, Haga Y,
Sawada T, Tanaka S. Psychometric Properties of
the Japanese Version of the STarT Back Tool in
Patients with Low Back Pain. Plos One 11:
e0152019, 201615. Nomura T, Asada F, Takano K, Matsudaira K. The
current state along with outstanding issues related
to email-based guidance by physical therapists
aiming to prevent low back pain among workers.
JJOMT 64: 113-8, 2016
16. Matsudaira K, Hara N, Oka H, Kunogi J,
Yamazaki T, Takeshita K, Seichi S, Tanaka S.
Predictive factors for subjective improvement inlumbar spinal stenosis patients with nonsurgicaltreatment: a 3-year prospective cohort study. Plos
One 11:e0148584, 201617. Shimazu A, Matsudaira K, De Jonge J, Tosaka N,
Watanabe K, Takahashi M: Psychological
Detachment from Work during Nonwork Time:Linear or Curvilinear Relations with Mental
Health and Work Engagement? Ind Health 54:
282-92, 2016

375

18. Sawada T, Matsudaira K, Muto Y, Koga T,
Takahashi M: Potential risk factors for onset ofsevere neck and shoulder discomfort (Katakori) in
Urban Japanese workers. Ind Health 54: 230-6,
2016
19. Sarquis LM, Coggon D, Ntani G, Walker-Bone K,
Palmer KT, Felli VE, Harari R, Barrero LH,
Felknor SA, Gimeno D, Cattrell A, Vargas-Prada
S, Bonzini M, Solidaki E, Merisalu E, Habib RR,
Sadeghian F, Kadir MM, Warnakulasuriya SS,
Matsudaira K, Nyantumbu B, Sim MR, Harcombe
H, Cox K, Marziale MH, Harari F, Freire R,
Harari N, Monroy MV, Quintana LA, Rojas M,
Harris EC, Serra C, Martinez JM, Delclos G,
Benavides FG, Carugno M, Ferrario MM, Pesatori
AC, Chatzi L, Bitsios P, Kogevinas M, Oha K,
Freimann T, Sadeghian A, Peiris-John RJ,
Sathiakumar N, Wickremasinghe AR, Yoshimura
N, Kelsall HL, Hoe VC, Urquhart DM, Derrett S,
McBride D, Herbison P, Gray A, Salazar Vega EJ.:Classification of neck/shoulder pain in
epidemiological research a comparison of
personal and occupational characteristics,
disability and prognosis among 12,195 workers
from 18 countries. Pain 157: 1028-36, 2016

376

Department of Molecular Sciences
on Diabetes
Project Associate Professor
Hironori Waki, M.D.,Ph.D.

Project Research Associate
Masatoshi Kobayashi, 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 a new transcription factor that
controls brown-fat-specific gene program. This factor
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
identified another new factor that regulates PPARγ
expression through regulation of the cell cycle ofadipocytes. Suppression of this factor resulted ininhibition of adipocyte differentiation. Heterozygous
knockout mice exhibited smaller adipocytes and wereresistant to diet-induced obesity. We expect further
investigation on the pathophysiological roles of thesefactors will provide insights into better understandingof pathophysiology of obesity and development oftreatment for obesity.
Impact of inflammatory responses in adipose tissue on
obesity-induced insulin resistance
Inflammatory responses in adipose tissue caused byobesity change secretion of adipokines and metabolites, leading to systemic insulin resistance. To clarify
the mechanism of these changes, we have extensively
investigated expression of genes in human adipose
tissues taken from those with a wide range of BMI.
We have identified several adipokines, which may
initiate the inflammatory responses and subsequent
insulin resistance. We are now exploring the role ofthese adipokines using animal models.

377

Mechanisms regulating pancreatic β cell function andmass
Progressive decline in pancreatic β cell function andmass has been implicated in the development of type 2
diabetes. We have found that insulin signaling in β
cells plays a key role in maintaining β cell mass
through insulin receptor (IR)/insulin receptor
substrate-2 (IRS-2)/Phosphoinositide-3 kinase (PI3K)
by autocrine/paracrine mechanisms using knockout
animal models. More recently we have also shownthat this pathway contributes to maintaining normal
insulin secretion in response to glucose by controlling
intra islet communication and exocytotic machinery.
Thus, we propose that once insulin secretion isdecreased, reduced insulin signaling in b cells causes
decreased β cell mass and insulin secretion, leading todecreased β cell mass and subsequent further
hypoinsulinemia and hyperglycemia. We seek to
identify the strategies for correcting this vicious cycle
to cure type 2 diabetes.
Impact of cellular responses in liver to feeding andtheir disorders on insulin resistance
We have found that feeding transiently promotes
endoplasmic reticulum (ER) stress in liver underphysiologic condition, and in obesity the ER stress issustained, leading to inhibition of insulin signaling
and insulin resistance. We have also found that insulin
signaling suppresses ER stress after feeding and theinsulin resistant state decreases insulin signaling andup-regulates ER stress and subsequent further insulin
resistance. Recently, we have also shown that IRS-2 is
up-regulated in the fasted state to maintain fasting
glucose homeostasis and appropriate and prompt
metabolic responses to feeding. This is partly
regulated by insulin, but we have unraveled that
adiponectin contributes to this IRS-2 up-regulation
through communicating with adipose tissue-derived
substance.

References
1. Wang J, Rajbhandari P, Damianov A, Han A,
Sallam T, Waki H, Villanueva CJ, Lee SD, Nielsen
R, Mandrup S, Reue K, Young SG, Whitelegge J,
Saez E, Black DL, Tontonoz P. RNA-binding
protein PSPC1 promotes the differentiation-

2.

3.

4.

5.

dependent nuclear export of adipocyte RNAs. The
Journal of clinical investigation. Mar 2017;127(3):987-1004.
Shibuta T, Waki K, Tomizawa N, Igarashi A,
Yamamoto-Mitani N, Yamaguchi S, Fujita H,
Kimura S, Fujiu K, Waki H, Izumida Y, Sasako T,
Kobayashi M, Suzuki R, Yamauchi T, Kadowaki T,
Ohe K. Willingness of patients with diabetes touse an ICT-based self-management tool: a crosssectional study. BMJ open diabetes research &care. Feb 2017;5(1):e000322.
Okui R, Shiramizu M, Sugimoto T, Mase Y,
Nakahara S, Otomo K, Kitaura N, Waki H.
Experience of self-monitoring included structured
self-monitering of blood glucose among workers
with non insulin-treated type 2 diabetes Journal of
Kanagawa University of Human Services. Mar
2017;14(1):25-34.
Yamaguchi S, Waki K, Tomizawa N, Waki H,
Nannya Y, Nangaku M, Kadowaki T, Ohe K.
Previous dropout from diabetic care as a predictor
of patients' willingness to use mobile applications
for self-management: A cross-sectional study.
Journal of diabetes investigation. Dec 2016;8(4):542-549.
Song NJ, Kim S, Jang BH, Chang SH, Yun UJ,Park KM, Waki H, Li DY, Tontonoz P, Park KW.
Small Molecule-Induced Complement Factor D(Adipsin) Promotes Lipid Accumulation and
Adipocyte Differentiation. PloS one. Sep 2016;
11(9):e0162228.
.

378

Department of Integrated
Molecular Sciences on Metabolic
Diseases
Project Associate Professor
Masato Iwabu, M.D., Ph.D.

Project Lecturer
Miki Okada-Iwabu, Ph.D.

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.

Research activities
The DIMSMD Research Laboratory aims to elucidate
the molecular mechanisms of lifestyle-related diseases

379such 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.

380

Department of Osteoimmunology
Project Associate Professor
Kazuo Okamoto, Ph.D.

Project Assistant Professor
Asuka Terashima, Ph.D.

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 ofrheumatoid arthritis, the osteoimmunological insight
is now of growing importance in clinical applications.
It is necessary to comprehensively understand theinterplay between bone and immune systems for
elucidation of the molecular mechanisms underlying
the pathogenesis of various 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 osteoimmunology 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
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 osteo-

381

blasts 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.
These findings
suggest that osteoblasts are a potential target of thetreatment of systemic inflammatory diseases such as
sepsis.
Osteoclast differentiation and RANKL signaling
Bone is a dynamic organ that continuously undergoes
a process involving resorption and formation (boneremodeling), which are mediated by osteoclasts andosteoblasts, respectively. An imbalance of bone
resorption and formation is often central to metabolicbone diseases, including bone destruction inrheumatoid arthritis, postmenopausal osteoporosis,bone tumors 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. Recently, a fully

human anti-RANKL neutralizing antibody has been
introduced for the treatment of osteoporosis andskeletal-related events by bone tumors. However,certain reports have suggested that osteoclasts candifferentiate independently of RANKL. It has been
recently reported that lysyl oxidase (LOX), thecollagen cross-linking enzyme, promotes breast
cancer bone metastasis by potently inducing osteoclastdifferentiation in a RANKL-independent manner (Coxet al., Nature, 2015). However, it lacks sufficientexperimental evidence for the RANKL-independence.
By using RANKL-deficient mice, we demonstrated
that LOX alone fails to induce osteoclastogenesis, but
has the capacity to promote osteoclastogenesis
indirectly via induction of endogenous RANKL
expression on the mesenchymal cells (Tsukasaki et al.,J Bone Miner Res, 2016). These findings not only
deepened the understanding of the mechanisms
underlying bone metastasis, but also led to thereconsideration of the concept of RANKLindependent osteoclastogenesis.

References
1. Tsukasaki M*, Hamada K*, Okamoto K,
Nagashima K, Terashima A, Komatsu N, Win S,
Okamura T, Nitta T, Yasuda H, Penninger JM,
Takayanagi H. *equally contributed. LOX fails to
substitute for RANKL in osteoclastogenesis. J
Bone Miner Res, 32: 434-439, 2017
2. Terashima A, Okamoto K, Nakashima T, Akira S,
Ikuta K, Takayanagi H. Immunosuppression
caused by sepsis-induced osteoblast ablation.
Immunity, 44: 1434-1443, 2016

382

Health Economy and Society
PolicyProject Professor
Tomoyuki Takura, Ph.D, MEng.

Homepage http://plaza.umin.ac.jp/hehp/
Introduction and Organization

Research activities

Health Economy and Society policy is a donatedfund course established in 22nd Century Medical andResearch Center in February 2017, which is donatedby 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 dramaticchanges in the future. Our department was establishedto discuss future healthcare systems (medical practices
and systems, economy and industry), particularly interms of theory construction and validation studies
pertaining to the "evaluation of the value of thehealthcare field" and other topics. Concretely, we
promote theoretical and methodological research on
health technology assessment, cost effectivenessanalysis, and the healthcare industry structure, andaim to evaluate the value of healthcare technologies
and healthcare systems. We also promote manpower
training programs in health technology assessmentwith collaboration departments.

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 for end-stage renal failure and radiologicaldiagnostics.
2) A study of the socioeconomic impact of chronic
pain on the disease burden in Japan.
3) Testing and developing methods for evaluating
labor productivity (e.g., the productivity ofcardiology 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. Shiroiwa T, Fukuda T, Ikeda S, Takura T,
Moriwaki K. Development of an Official
Guideline for the Economic Evaluation ofDrugs/Medical Devices in Japan. Value Health.
2017;20(3):372-378.
2. Takura T. Regenerative medicine and Healthcare
economics. Regenerative Medicine. 2017;16(1):24-27.

383

Department of Biostatistics andBioinformatics
Project Professor
Daisuke Koide, R.Rh., HIM, 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, theJapanfunding agency, Agency for Medical Research andDevelopment (AMED), started the Support Programfor Biostatiscians from 2016. The aim of this programis as follows (http://www.amed.go.jp/en/program/list/
05/01/047.html):
This program, with the objective ofcultivating talent of excellent biostatisticians,
supports the efforts of training them throughcollaboration between graduate schools that
conduct school education, and hospitals that
conduct practical training.
Graduate schools/hospitals develop educational programs that train highly motivatedbiostatisticians with high expertise and ethics,
by enabling the graduate schools / hospitals
that properly practice PDCA in the program. In
FY2016, 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, whichfunction as core facilities, respectively. Eachgraduate school establishes a new biostatistics
course, forms a training center uponcollaboration with a hospital, and performs
on-the-job training.
This program improves the environment that
leads to higher quality in clinical research andtrials, with the collaboration of industry,
academia, and the government, based upon the
donations from drug companies and national
research funding. Collaborative projects ofindustry, academia, and the government
through the flow of funds in this program, arethe first of their kind in Japan. On March 1,
2017, the Deparment of Biostatistics andBioinformation was established in the Graduate
School of Medicine. In the Graduate School ofInterdisciplinary Information Studies in the
University of Tokyo, the Biostatistics andBioinformatics course will be established 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 researh,
programming, reporting) for conducting clinicalresearch. We will train biostatisticians withhigh communication skill and ethics that canpromote high quality research in collaboration
with health care professionals by teaching andon-the-job -training (OJT).

384

Teaching activities
1) Education in the Biostatistics and Bioinformatics course
In the Biostatistics and Bioinformatics course,
through the following teachings, we educate awide range of knowledge and skills required tobiostatisticians. Its curriculum is made up of 28
subjects including 42 credits. For students who
have taken over 38 credits, we will issue acertificate along with the Master degree.
Biostatistics
statistical inference, categorical data analysis,
survival analysis, longitudinal data analysis,
Bayesianstatistics,
multiplecomparison
prcedure, multivariate analysis, causal inference,
missing data analysis, stochastic process andtime 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 student receive the OJT at
University of Tokyo Hospital and the National
Cancer Center. The OJT programs are dvelopedby the biostatisticians of each institution. In thefirst year of master's program, the students learn
the basic practice of biostatistician through thetraining at the University of Tokyo Hospital. In
the second year, at the National Cancer
Research Center, students receive advanced
training in how to plan the design and analysisof clinical researches.
2) Seminars and symposiums for the healthcare
professionals and biostatisticiansWe
giveseminarsaboutclinicaltrial
methodologies and biostatistics for physician, nurse,
clinical research coordinator, monitor, and other
healthcare professionals. We also hold a symposiumu

for biostatisticians in academia and pharmaceuticalcompanies in order to share and discuss the“state-of-the-arts” of statistical methodolgies. On
February 28, 2017, we have implemented the first
seminar (Lecturer: Akihiro Hirakawa, Nagoya
University and Hajime Uno, Dana-Farber Cancer
Institute).
3) Symposium on establishment of Departmentof Biostatistics and Bioinformatics
Deparment of Biostatistics and Bioinformation
was established in the Graduate School of
Medicine on March 1, 2017, and the symposiumu
was held at the University of Tokyo on February
27, 2017. At the symposium, the AMED support
program was introduced and subsequently
necessity of nurturing biostatisticians was
disucssed as well as the introduction of faculty
members . A total of 165 people including
students were participated.

Research activities
The Department of Biostatistics and Bioinformatics consists of one project professor
and one project assistant professor. The mainreaeach areas are as follows:
1) Statistical methodology and design of clinical
trials and epidelimiology
We study on the statistical methodologies anddesign for streamlining clinical trial and estimating
treament effect precisely. The research area includes
Bayesian design in oncology, clinical trial designusing biomarkers, adaptive design, study on theuse of Bayesian statistics in clinical trials,
causal inference, and multiple comparison method.
2) Epidemiological methodology
Epidemilogy 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 rapidely in Japan. It is385

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, theimportance of clinical epidemiology has been
increasing.
5) Medical informatics
Medical informatics is a science of studying how to
use data, information and knowledge in the all
medical fields, such as clinical, medical studies,
education and government. Recently, the area of
medical informatics is much expanding because of the
progress of genomic studies or bioinformatics, andintroduction of new technologies, such as virtual
reality and artificial intelligence (AI).
6) Algebraic statistics
The focus of research is on developing and applying
methods of algebraic statistics to specific statisticalproblems. In statistical inference, the computation ofcomplicated integrals or summation sometimes makes
the problem intractable. When a statistical model
has algebraic structure, techniques from algebraic
statistics are useful. I currently work on the topics
related to Groebner basis theory and the holonomic
gradient method.

References
1. Suzuki K, Koide D, Fujii K, Yamazaki T, Tsuji S,
Iwata A: Elevated Serum Uric Acid Levels Are
Related to Cognitive Deterioration in an Elderly
Japanese Population. Dement Geriatr Cogn

2.

3.

4.

5.

Disord Extra. 6(3): 580-8, 2016
Ono S, Ishimaru M,Yamana H, Morita K, Ono Y,
Matsui H, Yasunaga H. Enhanced oral care andhealth outcomes among nursing facility residents:
analysis using the national long-term care
database in Japan. J Am Med Dir Assoc 18(3):277.
e1-5, 2017
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. Fam Pract 2017
epub
Ono S, Ishimaru M, Matsui H, Fushimi K,
Yasunaga H. Impact of body mass index on theoutcomes of open reduction for mandibular
fracture. J Oral Maxillofac Surg 2016;74(5):1024.
e1-5.
Ono S, Ono Y, Matsui H, Yasunaga H. Factors
associated with hospitalization for seasonal
influenza in a Japanese nonelderly cohort. BMC
Public Health 16:922, 2016

386

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 department of Preventive Medicine
for Locomotive Organ Disorders in 22nd Century
Medical and Research Center on March 1st, 2017,
which is an endowment 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 and in close
collaboration with departments of Orthopaedic
Surgery and Rehabilitation Medicin. Our department
has been established for the epidemiological study toclarify the frequencies and risk factors for locomotive
organ disorders including osteoarthritis (OA),
osteoporosis (OP) and sarcopenia (SP).

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 performed in
2008-2010, 2012-2013, and 2015-2016, respectively.
We will conduct further follow-up surveys.

Endowed Department(22nd Century Medical and Research Center)388

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
for basic 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 operatingprocedures. All these efforts allow us to reliably
perform cancer immunotherapy clinical trials incooperation with many 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.

389

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 ： UMIN000004130
active, recruiting. Intraperitoneal autologous γδ Tcell therapy for refractory gastric cancer withascites
4. UMIN registration number ： UMIN000008097
active, recruiting. Combination of chemotherapy
with docetaxel / cisplatin / fluorouracil (DCF) andautologous γδ T cell transfer therapy foresophageal cancer.
Dendritic cell therapy
1. UMIN registration number：UMIN000014703
active,recruiting.
Safety,efficacyandimmunogenicity of concomitant molecular target
drug or cytokine therapy and autologous tumor
lysate-pulsed dendritic cell therapy in patients withadvanced renal cell carcinoma
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. Makise N, Morikawa T, Nakagawa T, Ichimura T,
Kawai T, Matsushita H, Kakimi K, Kume H,
Homma Y, Fukayama M. MAGE-A expression,
immune microenvironment, and prognosis inupper urinary tract carcinoma. Hum Pathol. 2016
Apr;50:62-9.
2. Matsushita H, Sato Y, Karasaki T, Nakagawa T,
Kume H, Ogawa S, Homma Y, Kakimi K.
Neoantigen
Load,
AntigenPresentation

390

3.

4.

5.

6.

Machinery, and Immune Signatures Determine
Prognosis in Clear Cell Renal Cell Carcinoma.
Cancer Immunol Res. 2016 May;4(5):463-71.
Odaira K, Kimura SN, Fujieda N, Kobayashi Y,
Kambara K, Takahashi T, Izumi T, Matsushita H,
Kakimi K.CD27(-)CD45(+) γδ T cells can bedivided into two populations, CD27(-)CD45(int)and CD27(-)CD45(hi) with little proliferation
potential. Biochem Biophys Res Commun. 2016
Sep 23;478(3):1298-303.
Kakimi K, Karasaki T, Matsushita H, Sugie T.
Advances in personalized cancer immunotherapy.
Breast Cancer. 2017 Jan;24(1):16-24.
Aoki T, Matsushita H, Hoshikawa M, Hasegawa
K, Kokudo N, Kakimi K. Adjuvant combination
therapy with gemcitabine and autologous γδ T-celltransfer in patients with curatively resectedpancreaticcancer.
Cytotherapy.
2017
Apr;19(4):473-485.
Karasaki T, Nagayama K, Kuwano H, Nitadori JI,
Sato M, Anraku M, Hosoi A, Matsushita H,
Takazawa M, Ohara O, Nakajima J, Kakimi K.
Prediction and prioritization of neoantigens:
integration of RNA sequencing data withwhole-exome sequencing. Cancer Sci. 2017
Feb;108(2):170-177.

Presentation at International
conference
1. 2016/4/2, 2nd International Symposium of
Lymphedema Surgery and Breast Reconstruction,
Tokyo, Japan(Invited), Kazuhiro Kakimi, Cancer
Immunity Cycle
2. 2016/10/28, 2016 International Symposiumu for
Recent Advances in Cell Therapy and 3rd Annual
Meeting of Taiwan Association for Cell Therapy,
Taipei, Taiwan(Invited, Symposium), Kazuhiro
Kakimi, Personalized Cencer Immunotherapy
3. 2016/12/7, IASLC 17th World Conference on
Lung Cancer, Vienna, Austria, WCLC2016 Young
Investigators Travel Award 受, Takahiro Karasaki,
Kazuhiro Nagayama, Hideki Kuwano, Jun-ichi
Nitadori, Masaaki Sato, Masaki Anraku, Akihiro
Hosoi, Hirokazu Matsushita, Yasuyuki Morishita,
Kosuke Kashiwabara, Masaki Takazawa, Osamu
Ohara, Kazuhiro Kakimi, Jun Nakajima,

Immunogram for Cancer-Immunity Cycle towards
Personalized Immunotherapy of Lung Cancer
4. 2017/2/11, The 32nd Nagoya International Cancer
Treatment Symposium, Nagoya, Japan (Invited,
Symposium), Kazuhiro Kakimi, An Immunogram
for the Cancer Immunotherapy
5. 2017/2/23, ASCO-SITC Clinical ImmunoOncology Symposium, Orlando, Yasuyoshi Sato,
Hirokazu Matsushita, Kazuhiko Mori, Kazuhiro
Kakimi and Yasuyuki Seto, Safety, efficacy andimmunogenicity of autologous tumor lysatepulsed dendritic cell vaccination therapy after
resection of stage IIA (T2N0, T3N0) esophageal
cancer: A phase I trial

391

Department of Advanced Clinical
Science and Therapeutics
Project Associate Professor
Jun-ichi Suzuki, M.D., Ph.D.

Project Assistant Professor
Kouji Wakayama, M.D., Ph.D.
Hidetoshi Kumagai, 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.

392

References
1. Suzuki J, Imai Y, Aoki M, Fujita D, Takeda N,
Aoyama N, Wakayama K, Ikeda Y, Kumagai H,
Akazawa H, Izumi Y, Isobe M, Komuro I, Hirata
Y. Periodontitis may deteriorate sinus of Valsalva
dilatation in Marfan syndrome patients. Int HeartJ. 57(4):456-460, 2016.
2. Takamura C, Suzuki J, Ogawa M, Watanabe R,
Tada Y, Maejima Y, Akazawa H, Komuro I, Isobe
M. Suppression of murine autoimmune myocarditis achieved with direct renin inhibition. J
Cardiol. 68(3):253-260, 2016.
3. Zempo H, Suzuki J, Ogawa M, Watanabe R, Isobe
M. A Different Role of Angiotensin II Type 1a
Receptor in the Development and Hypertrophy ofPlantaris Muscle in Mice. J Applied Genet.
57(1): 91-97, 2016.
4. Zempo H, Suzuki J, Watanabe R, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Isobe M. Cacao polyphenols ameliorate autoimmune myocarditis in mice. Hypertens Res.
39(4): 203-209, 2016.
5. Zempo H, Suzuki J, Ogawa O, Watanabe R, Fujiu
K, Manabe I, Conway SJ, Taniyama Y, Morishita
R, Hirata Y, Isobe M, Nagai R. The influence of
periostin positive cell-specific Klf5 deletion on
aortic thickening in DOCA-salt hypertensive mice.
Hypertens Res. 39(11):764-768, 2016.
6. Watanabe R, Suzuki J, Wakayama K, Kumagai H,
Ikeda Y, Akazawa H, Komuro I, Isobe M.
Angiotensin II receptor blocker irbesartan
attenuates cardiac dysfunction induced bymyocardial infarction in the presence of renal
failure. Hypertens Res. 39(4): 237-244, 2016.
7. Kobayashi N, Suzuki J, Aoyama N, Sato H,
Akimoto S, Wakayama K, Kumagai H, Ikeda Y,
Akazawa H, Komuro I, Izumi Y, Isobe M. Toll-likereceptor 4 signaling plays a critical role inPorphyromonas gingivalis accelerated neointimal
formation after arterial injury in mice. Hypertens
Res. 39(10): 717-722, 2016.
8. Shiheido Y, Maejima Y, Suzuki J, Aoyama N,
Kaneko M, Watanabe R, Sakamaki Y, Wakayama
K, Ikeda Y, Akazawa H, Ichinose S, Komuro I,
Izumi Y, Isobe M. Porphyromonas gingivalis, aperiodontal pathogen, enhances myocardial

vulnerability, thereby promoting post-infarct
cardiac rupture. J Mol Cell Cardiol. 99:123-137,
2016.
9. Kaneko M, Suzuki J, Aoyama N, Watanabe R,
Yoshida A, Shiheido Y, Izumi Y, Isobe M.
Toll-like receptor-2 has a critical role inperiodontal pathogen-induced myocardial fibrosisin the pressure-overloaded murine hearts.
Hypertens Res. 2016 Sep 1. doi: 10.1038/hr.2016.
117. [Epub ahead of print]
10. Sato H, Suzuki J, Aoyama N, Watanabe R,
Kaneko M, Shiheido Y, Yoshida Y, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Isobe M, Izumi Y. A periodontal pathogen
Porphyromonas
gingivalis
deteriorates
isoproterenol-induced myocardial remodeling in
mice. Hypertens Res. 2016 Sep 8. doi: 10.1038/
hr.2016.114. [Epub ahead of print]
11. Oishi S, Shimizu Y, Hosomichi J, Kuma Y, Nagai
H, Maeda H, Usumi-Fujita R, Kaneko S, ShitanoC, Suzuki J, Yoshida K, Ono T. Intermittent
hypoxia induces disturbances in craniofacial
growth and defects in craniofacial morphology.
Ann Oral Biol. 61:115-124, 2016.
12. Oishi S, Shimizu Y, Hosomichi J, Kuma Y,
Maeda H, Nagai H, Usumi-Fujita R, Kaneko S,
Shibutani N, Suzuki J, Yoshida K, Ono T.
Intermittent hypoxia influences alveolar boneproper microstructure via hypoxia-inducible
factor and VEGF expression in periodontal
ligaments of growing rats. Front Physiol. 7: 416,
2016.
13. Kurinami H, Shimamura M, Nakagami H,
Shimizu H, Koriyama H, Kawano T, Wakayama
K, Mochizuki H, Rakugi H, Morishita R. A novel
therapeutic peptide as a partial agonist of RANKL
in ischemic stroke. Sci Rep. 6: 38062, 2016.
14. Ikeda Y, Kumagai H, Motozawa Y, Suzuki J.
Growth differentiation factor 15 (GDF15) as areliable biomarker for cardiovascular risk
assessment. Int Heart J. 57(1):1-2, 2016.
15. Hirose S, Ashikaga T, Hatano Y, Yoshikawa S,
Sasaoka T, Maejima Y, Isobe M. Treatment of
in-stent restenosis with excimer laser coronary
angioplasty: benefits over scoring balloon
angioplasty alone. Lasers Med Sci. 31(8):16911696, 2016.

393

16. Ito M, Maejima Y, Okazaki S, Isobe M, Saeki H.
Generalized pustular psoriasis associated with
Turner syndrome and dilated cardiomyopathy. J
Dermatol. 43(7):829-30, 2016.
17. Tamura N, Maejima Y, Tezuka D, Takamura C,
Yoshikawa S, Ashikaga T, Hirao K, Isobe M.
Profiles of serum cytokine levels in Takayasu
arteritis patients: Potential utility as biomarkers
for monitoring disease activity. J Cardiol. 2016
Dec 15. pii: S0914-5087(16)30291-X. doi: 10.
1016/j.jjcc.2016.10.016. [Epub ahead of print]
18. Ueshima D, Ashikaga T, Yoshikawa S, Sasaoka T,
Hatano Y, Kurihara K, Maejima Y, Isobe M.
Effect of over-2-year dual antiplatelet therapy on
the rate of major adverse cardiac and cerebral
events for everolimus-eluting stent implantation:
The landmark analysis from Tokyo-MD PCI
registry. J Cardiol. 2016 Sep 27. pii:
S0914-5087(16)30209-X. doi: 10.1016/j.jjcc.2016.
08.015. [Epub ahead of print]
19. Ohigashi H, Tamura N, Ebana Y, Harigai M,
Maejima Y, Ashikaga T, Isobe M. Effects ofimmunosuppressive and biological agents on
refractory Takayasu arteritis patients unresponsive
to glucocorticoid treatment. J Cardiol. 2016 Aug
23. pii: S0914-5087(16)30156-3. doi: 10.1016/j.
jjcc.2016.07.009. [Epub ahead of print]
20. Shirakabe A, Zhai P, Ikeda Y, Saito T, Maejima Y,
Nomura M, Egashira K, Levine B, Sadoshima J.
Drp1-dependent mitochondrial autophagy plays aprotective role against pressure-overload-induced
mitochondrial dysfunction and heart failure.
Circulation 133: 1249-1263, 2016.
21. Nakamura M, Zhai P, Del Re DP, Maejima Y,
Sadoshima J. Mst1-mediated phosphorylation of
Bcl-xL is required for myocardial reperfusion
injury. JCI Insight 1: e86217, 2016.
22. Matsumura T, Amiya E, Tamura N, Maejima Y,
Komuro I, Isobe M. A novel susceptibility locus
for Takayasu arteritis in the IL12B region can be a
genetic marker of disease severity. Heart Vessels
31: 1016-1009, 2016.
English Review
1. Suzuki J, Shimamura M, Suda H, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Isobe M,
Komuro I, Morishita R. Current therapies and

2.
3.

4.

5.

6.

investigational drugs for peripheral arterial
disease. Hypertens Res. 39(4): 183-191, 2016.
Tada Y, Suzuki J. Oxidative stress and myocarditis.
Curr Pharm Des. 22(4): 450-71, 2016.
Ikeda Y, Kumagai H, Motozawa Y, Suzuki J,
Akazawa H, Komuro I. Understanding vasculardiseases: Lessons from premature aging
syndromes. Can J Cardiol. 32(5): 650-658, 2016.
Kamo T, Akazawa H, Suzuki J, Komuro I. Rolesof renin-angiotensin system and Wnt pathway inaging-related phenotypes. Inflamm Regen. 36:12,
2016.
Maejima Y, Isobe M, Sadoshima J. Regulation of
autophagy by Beclin 1 in the heart. J Mol Cell
Cardiol. 95:19-25, 2016.
Suzuki J, Sato H, Kaneko M, Yoshida A, Aoyama
N, Akimoto S, Wakayama K, Kumagai H, Ikeda Y,
Akazawa H, Izumi Y, Isobe M, Komuro I.
Periodontitis andmyocardial hypertrophy.
Hypertens Res. 2016 Nov 10. doi: 10.1038/hr.
2016.146. [Epub ahead of print]

394

Department of Joint Disease
Research
Project Associate Professors
Noriko Yoshimura, M.D., Ph.D.
Shigeyuki Muraki, M.D., Ph.D.

Homepage

http:// www.h.u-tokyo.ac.jp/research/center22/index.html

Introduction and Organization
The department of Joint Disease Research wasestablished in 22nd Century Medical and ResearchCenter in 2005, which is an endowment department
supported by Chugai Pharmaceutical Co., Ltd. and inclose collaboration with departments of Orthopaedic
Surgery and Rehabilitation Medicin. Our department
has been established for the epidemipological study toclarify the frequencies and risk factors for bone andjoint system.

Research activities
Osteoarthritis (OA) and osteoporosis (OP) are two
major public health problems in the elderly that affectactivities of daily life (ADL) and quality of life (QOL),
leading to increased morbidity and mortality. As the
proportion of the aging population is expanding inJapan, there is an urgent need for a comprehensive andevidence-based prevention strategy for musculoskeletal diseases, including OA and OP. However, few
prospective, longitudinal studies have been undertaken, and little information is available regarding theprevalence and incidence of OA and OP as well as
pain and disability in the Japanese population. It isdifficiult to design rational clinical and public healthapproaches for the diagnosis, evaluation, andprevention of OA and OP without such epidemiological data.
We therefore established a large-scale nationwide
osteoarthritis/osteoporosis cohort study called ROAD
(Research on Osteoarthritis/osteoporosis Against

Disability) consisted of total 3,040 participants, ofwhich aims at the elucidation of an environmental andgenetic background for bone and joint diseases,
represented by OA and OP.
We have completed the baseline study in 2005-2007,
then 2nd, 3rd and 4th follow-ups were performed in
2008-2010, 2012-2013, and 2015-2016, respectively.

References
1. Iidaka T, Muraki S, Akune T, Oka H, Kodama R,
Tanaka S, Kawaguchi H, Nakamura K,
Yoshimura N: Prevalence of radiographic hip
osteoarthritis and its association with hip pain in
Japanese men and women: The ROAD study.
Osteoarthritis Cartilage 24:117-123, 2016
2. Teraguchi M, Yoshimura N, Hashizume H,
Muraki S, Yamada H, Oka H, Minimide A,
Nakagawa H, Ishimoto Y, Nagata K, Kagotani R,
Tanaka S, Kawaguchi H, Nakamura K, Akune T,
Yoshida M: Metabolic syndrome components areassociated with intervertebral disc degeneration:
the Wakayama Spine Study. PLoS One, 2016 Feb
3;11(2):e0147565.
3. Vargas-Prada S, Coggon D, Ntani G,
Walker-Bone K, Palmer KT, Felli VE, Harari R,
Barrero LH, Felknor SA, Gimeno D, Cattrell A,
Bonzini M, Solidaki E, Merisalu E, Habib RR,
Sadeghian F, Kadir MM, Warnakulasuriya SS,
Matsudaira K, Nyantumbu B, Sim MR,
Harcombe H, Cox K, Sarquis LM, Marziale MH,
Harari F, Freire R, Harari N, Monroy MV,
Quintana LA, Rojas M, Harris EC, Serra C,395

Martinez JM, Delclos G, Benavides FG, Carugno
M, Ferrario MM, Pesatori AC, Chatzi L, Bitsios
P, Kogevinas M, Oha K, Freimann T, SadeghianA,
Peiris-John
RJ,
Sathiakumar
N,
Wickremasinghe AR, Yoshimura N, Kelsall HL,
Hoe VC, Urquhart DM, Derrett S, McBride D,
Herbison P, Gray A, Vega EJ. CUPID Study:
Descriptive
epidemiologyofsomatisingtendency: Findings from the CUPID Study. PLoS
One, 2016 Apr 29;11(4):e0153748.
4. Sarquis LM, Coggon D, Ntani G, Walker-Bone K,
Palmer KT, Felli VE, Harari R, Barrero LH,
Felknor SA, Gimeno D, Cattrell A, Vargas-Prada
S, Bonzini M, Solidaki E, Merisalu E, Habib RR,
Sadeghian F, Kadir MM, Warnakulasuriya SS,
Matsudaira K, Nyantumbu B, Sim MR,
Harcombe H, Cox K, Marziale MH, Harari F,
Freire R, Harari N, Monroy MV, Quintana LA,
Rojas M, Harris EC, Serra C, Martinez JM,
Delclos G, Benavides FG, Carugno M, Ferrario
MM, Pesatori AC, Chatzi L, Bitsios P, Kogevinas
M, Oha K, Tiina, Freimann, Sadeghian A,
Peiris-John RJ, Sathiakumar N, Wickremasinghe
AR, Yoshimura N, Kelsall HL, Hoe VC,
Urquhart DM, Derrett S, McBride D, Herbison P,
Gray A, Salazar Vega EJ.: Classification ofneck/shoulder pain in epidemiologic research: A
comparison of personal and occupational
characteristics, disability and prognosis among
12,195 workers from 18 countries. Pain 157:
1028-1036, 2016
5. Silverman SL, Adachi JD, Dennison E;
International
Osteoporosis
Foundation
Epidemiology/Quality of Life Working Group(Abrahamsen B, Adachi J, Borgström F, Bruyère
O, Clark P, Cooper C, Dennison E, Diaz Curiel
M, Dimai HP, Harvey N, Hiligsmann M, Kanis
JA, Lau E, Lips P, Lewiecki ME, Lorenc E,
McCloskey E, Papaioannou A, Prieto Alhambra
D, Ortolani S, Silverman S, Sosa M, Szulc P,
Yoshimura N). Bisphosphonate drug holidays:
we reap what we sow. Osteoporos Int 27, 849852, 2016
6. Yoshimura N, Nakamura K: Epidemiology oflocomotive organ disorders and symptoms: An
estimation using the population-based cohorts inJapan. Clinical Reviews in Bone and Mineral

Metabolism 14: 68-73, 2016
7. Iwahashi H, Yoshimura N, Hashizume H,
Yamada H, Oka H, Matsudaira K, 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: The Association between the Cross-Sectional
Area of the Dural Sac and Low Back Pain in a
Large Population: The Wakayama Spine Study.
PLoS One. 2016 Aug 3;11(8):e0160002.
8. Kodama R, Muraki S, Oka H, Iidaka T,
Teraguchi M, Kagotani R, Asai Y, Hashizume H,
Yoshida M, Morizaki Y, Tanaka S, Kawaguchi H,
Nakamura K, Akune T, Yoshimura N: Prevalenceof hand osteoarthritis and its relationship to hand
pain and grip strength: The third survey of the
ROAD Study. Mod Rheumatol 26: 767-773,
2016
9. Teraguchi M, Samartzis D, Hashizume H,
Yamada H, Muraki S, Oka H, Cheung JPY,
Kagotani R, Iwahashi H, Tanaka S, Kawaguchi H,
Nakamura K, Akune T, Cheung KMC,
Yoshimura N, Yoshida M: Classification of highintensity zones of the lumbar spine and theirassociation with other spinal MRI phenotypes:
the Wakayama Spine Study. PLoS One 2016 Sep
20;11(9):e0160111.
10. Yoshimura N, Muraki S,Nakamura K, Tanaka S:
Epidemiology of the locomotive syndrome: The
Research on Osteoarthritis/Osteoporosis Against
Disability study 2005-2015. Mod Rheumatol
27(1):1-7, 2017
11. Yoshimura N, Muraki S, Oka H, Iidaka T,
Kodama R, Kawaguchi H, Nakamura K, Tanaka
S, Akune T: Is osteoporosis a predictor for futuresarcopenia, or vice-versa? Four-year observations between the second and third ROAD study
surveys. Osteoporos Int 28(1):189-199, 201712. Ishimoto Y, Yoshimura N, Muraki S, Yamada H,
Nagata K, Hashizume H, Takiguchi N, Minamide
A, Oka H, Tanaka S, Kawaguchi H, Nakamura K,
Akune T, Yoshida M: Association of lumbar
spondylotisthesis with back pain and symptomtic
lumbar spinal stenosis in the general population:
the Wakayama Spine Study. Spine (Phila Pa
1976), in press
13. Coggon D, Ntani G, Walker-Bone K, Palmer KT,

396

Felli VE, Harari R, Barrero LH, Felknor SA,
Gimeno D, Cattrell A, Vargas-Prada S, Bonzini
M, Solidaki E, Merisalu E, Habib RR, SadeghianF, Kadir MM, Warnakulasuriya SS, Matsudaira K,
Nyantumbu B, Sim MR, Harcombe H, Cox K,
Sarquis LM, Marziale MH, Harari F, Freire R,
Harari N, Monroy MV, Quintana LA, Rojas M,
Harris EC, Serra C, Martinez JM, Delclos G,
Benavides FG, Carugno M, Ferrario MM,
Pesatori AC, Chatzi L, Bitsios P, Kogevinas M,
Oha K, Freimann T, Sadeghian A, Peiris-John RJ,
Sathiakumar N, Wickremasinghe AR, Yoshimura
N, Kelsall HL, Hoe VC, Urquhart DM, Derrett S,
McBride D, Herbison P, Gray A, Vega EJ :Epidemiological differences between localised
and non-localised low back pain. Spine (Phila Pa
1976), in press
14. Teraguchi M, Yoshimura N, Hashizume H,
Yamada H, Oka H, Minamide A, Nagata K,
Ishimoto Y, Kagotani R, Kawaguchi H, Tanaka S,
Akune T, Nakamura K, Muraki S, Yoshida M:
Progression, incidence and risk factors forintervertebral disc degeneration in a longitudinal
population- based cohort: the Wakayama Spine
Study. Osteoarthritis Cartilage, in press
15. 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 metalloproteinase3, and autoantibodies related to rheumatoid
arthritis in general Japanese population and theirassociation with osteoporosis and osteoarthritis:
The ROAD study. J Bone Miner Metabol, inpress
16. Narumi K, Funaki Y, Yoshimura N, Muraki S,
Omori G, Nawata A, Seki R: Quadriceps muscle
strength reference value as index for functional
deterioration of locomotive 3 organs: Data from3617 men and women in Japan. J Orthop Sci, inpress
17. Nagata K, Yoshimura N, Hashizume H, IshimotoY, Muraki S, Yamada H, Oka H, Kawaguchi H,
Akune T, Tanaka S, Nakamura K, Yoshida M:
The prevalence of tandem spinal stenosis and its
characteristics in a population-based MRI study:
The Wakayama Spine Study. Eur Spine Journal,

in press
18. Asai Y, Tsutsui S, Oka H, Yoshimura N,
Hashizume H, Yamada H, Akune T, Muraki S,
Matsudaira K, Kawaguchi H, Nakamura K,
Tanaka S, Yoshida M. Sagittal spino-pelvicalignment in adults: The Wakayama Spine Study.
PLoS One, in press

397

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., Fumiko Mori, M.D.,Ph.D.

Project researcher
Mika Nagasaki, M.D.,Ph.D., Yukihiro Nomura, Ph.D., R.T., Mitsutaka Nemoto, Ph.D.,
Tomomi Takenaga, Ph.D., R.T.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/computer.html
Introduction and Organization

Clinical Activities

The Department of Computational Diagnostic
Radiology and Preventive Medicine (CDRPM) wasestablished in May 2005. It is under the supervision of
the Department of Radiology.
The aim of our research project is as follows: (1) tocreate 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.

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/X-ray computed
tomography (PET/CT), 3-tesla magnetic resonanceimaging (3T-MRI) system, ultrasound imaging system,and digital mammography.

Teaching Activities
At present, CDRPM does not accept students.
However, CDRPM participates in the education of
students and residents in the Department of Radiology.
CDRPM endeavors to help students whose research
themes include image analysis such as computerassisted detection, or epidemiologic studies employing
health-screening data.

398

Research Activities
1) Health screening database
We have developed a unique health screening
information system in order to facilitate daily
management of the health screening activities and to
input health screening data. This information systemis still under constant revision. The medical images
acquired in the health screenings are stored in thehospital picture archiving and communication system(PACS) for clinical use. Medical images used solely
for research purposes are stored in an independent
PACS installed inside the CDRPM department.
2) Image processing software development
We have structured an integrated software developing
system to facilitate the production of image processing
software. The system is divided into the clinical partand the research part, with the data in the latter being
anonymized. The clinical part consists of case entry
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) Akai H, Kiryu S, Shibata E, Maeda E, Sato J,
Tomizawa N, et al. Reducing CT radiation
exposure with organ effective modulation: A
retrospective clinical study. Eur J Radiol 2016;
85(9):1569-1573.
(2) Amemiya S, Takahashi K, Mima T, Yoshioka N,
Miki S, Ohtomo K. Reversible alterations of theneuronal activity in spontaneous intracranial
hypotension. Cephalalgia 2016 Feb;36(2):162171.
(3) Maeda E, Yamamoto K, Kanno S, Ino K,
Tomizawa N, Akahane M, et al. Diagnostic Phaseof Calcium Scoring Scan Applied as the Center ofAcquisition Window of Coronary Computed
Tomography Angiography Improves Image
Quality in Minimal Acquisition Window Scan
(Target CTA Mode) Using the Second Generation
320-Row CT. The Scientific World Journal 2016;
2016.
(4) Maeda E, Tomizawa N, Kanno S, Yasaka K,
Kubo T, Ino K, et al. The feasibility of Forwardprojected model-based Iterative Reconstruction
SoluTion (FIRST) for coronary 320-row
computed tomography angiography: A pilot study.
Journal of Cardiovascular Computed Tomography 2016.
(5) Maeda E, Tomizawa N, Kanno S, Yasaka K,
Kubo T, Ino K, et al. Subjective and objective
evaluation of 10–30% dose reduced coronary
artery phantom scans reconstructed with Forward
projected model-based Iterative Reconstruction
SoluTion (FIRST). Data in Brief 2016 Dec.3;
10:210-214.
(6) Miki S, Hayashi N, Masutani Y, Nomura Y,
Yoshikawa T, Hanaoka S, et al. ComputerAssisted Detection of Cerebral Aneurysms in MR
Angiography in a Routine Image-Reading
Environment: Effects on Diagnosis byRadiologists. AJNR Am J Neuroradiol 2016 Jun;
37(6):1038-1043.
(7) Nakashima R, Komori Y, Maeda E, Yoshikawa T,
Yokosawa K. Temporal Characteristics ofRadiologists' and Novices' Lesion Detection in
Viewing Medical Images Presented Rapidly and
Sequentially. Frontiers in psychology 2016;7.
(8) Nakayama A, Morita H, Hayashi N, Nomura Y,
Hoshina K, Shigematsu K, et al. Inverse
Correlation Between Calcium Accumulation andthe Expansion Rate of Abdominal Aortic
Aneurysms. Circ J 2016 Jan 25;80(2):332-339.
(9) Namiki Y, Maeda E, Gonoi W, Akamatsu N,
Ikemura M, Ohtomo K. Pancreatic lipoma with asolid nodule mimicking invasion from adjoining
intraductal papillary mucinous neoplasm.
Radiology case reports 2016;11(2):50-53.
(10) Tojo A, Asaba K, Kinugasa S, Ikeda Y, Shintani
Y, Fukayama M, et al. The reduced expression ofproximal tubular transporters in acquired Fanconi
syndrome with κ light chain deposition. Medical
molecular morphology 2016;49(1):48-52.

399(11) Yasaka K, Furuta T, Kubo T, Maeda E, Katsura
M, Sato J, et al. Full and hybrid iterative
reconstruction to reduce artifacts in abdominal
CT for patients scanned without arm elevation.
Acta Radiol 2016:0284185116684675.
(12) Yasaka K, Kamiya K, Irie R, Maeda E, Sato J,
Ohtomo K. Metal artefact reduction for patientswith metallic dental fillings in helical neckcomputed tomography: comparison of adaptive
iterative dose reduction 3D (AIDR 3D), forwardprojected model-based iterative reconstruction
solution (FIRST) and AIDR 3D with singleenergy metal artefact reduction (SEMAR).
Dentomaxillofacial
Radiology
2016;45(7):20160114.
(13) Yasaka K, Maeda E, Hanaoka S, Katsura M, SatoJ, Ohtomo K. Single-energy metal artifact
reduction for helical computed tomography of thepelvis in patients with metal hip prostheses.
Japanese journal of radiology 2016;34(9):625632.

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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, M.P.H.

Project Researcher
YukoYamabayashi, CSW.
Reiko Segawa, R.N., M.S. (-October 2016)

Project Academic Support Specialist
Yuriko Kobashi

Visiting Researcher
Tomoko Matsuura, M.S., Shinji Nagakawa, M.D., Ph.D.,
Reiko Segawa, R.N., M.S. (-October 2016)

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/iryou_anzen.html
http://hcsm.m.u-tokyo.ac.jp/
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
has kept increasing from the 1970s (about 100 new401cases 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 2009, with
733 new cases received and 952 cases resolved(preliminary figures).
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, making the best use of the experience of astate-of-the-art university hospital, we are establishing
an approach that promotes mutual understanding by
conversations between the patient and the health careprovider.

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 “Research on Patient Safety andPhysician Sanction Systems in the U.S.” as the joint
research under the Pfizer Health Research Foundation.
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, thisdepartment supports on-site measures at the place oftreatment; and together therewith promote research
related to topics transmitted from such sites andeducation for staff of the site.

*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
Domestic Meetings (in Japanese)
1. Masaki Anraku. Developing a new lung transplant
program in Tokyo. Lessons from the Toronto
Lung Transplant Program. Japan Society ofClinical Safety.(2016)
2. Masaki Anraku. Providing an option of lungtransplantation for patients with pulmonary
hypertension in Tokyo. Our challenge and goal.
Japanese Pulmonary Circulation and Pulmonary
Hypertension Society.(2016)
3. Masaki Anraku. Safety managements in the fieldof advanced medical therapy. Japanese Society for
Quality and Safety in Healthcare.(2016)

402

Department of Healthcare Quality
Assessment
Professor
Hiroaki Miyata, Ph.D.

Associate Professor
Shun Kosaka, M.D., Ph.D.

Lecturer
Hiraku Kumamaru, M.D., Sc.D.
Assistant Professor
Naoaki Ichihara, M.D., Ph.D., M.P.H.

Researcher
Hiroki Nogawa, M.D., Ph.D., Junichi Okubo,
Hiroyuki Yamamoto, M.D., Ph.D., M.P.H., Hideki Endo, M.D.,
Eriko Fukuchi, M.S.

Associate
Norimichi Hirahara, Ph.D., Arata Takanashi, M.S.

Clerical Staff
Chieko Fujimura, Naohiro Kato, Takayo Nakamura, Keita Otsugu,
Hitomi Okamoto

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 firstpriority in the field of medicine and healthcare.
“Quality improvement initiative,” therefore, needs toadjust the healthcare systems to accommodate thefee-for-service perspectives while improving theclinical environment for both patients and providers.

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

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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 approx.imately 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 4,500 hospitals and clinics are participatingin NCD with the accumulated data of 6.5 million cases(approximately 1.2 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 to different
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 numbers of clinical research output has
been coming out of the detailed analyses on NCD datain the collaboration of each specialty field. Besideprofessional societies, pharmaceutical companies aswell as medical device firms are now start operating
their post-marketing surveillance databases in relation
with NCD. Working in between NCD, the firms,
PMDA (Pharmaceuticals and Medical Devices
Agency), and the related medical societies, HQA helps
the project moving forward by giving academic
support. Furthermore, HQA has been involved withinternational research collaboration such as American
College of Surgeon’s NSQIP and Asian Cardiac
Database while contributing to the quality improvement activities in different regions of the world.

References
1. Maekawa Y, Miyata H, Ueda I, Ikemura N,
Fukuda K, Kohsaka S. Effect of Pre-Procedural
Beta-Blocker
inPatients
Undergoing
Percutaneous Coronary Intervention. JACC
Cardiovasc Interv 9(23):2458-2459, 2016

404

2. Yokoo H, Miyata H, Konno H, Taketomi A,
Kakisaka T, Hirahara N, Wakabayashi G, Gotoh M,
Mori M. Models predicting the risks of six
life-threatening morbidities and bile leakage in
14,970 hepatectomy patients registered in the
National Clinical Database of Japan. Medicine(Baltimore) 95(49) 2016
3. Takahara T, Wakabayashi G, Konno H, Gotoh M,
Yamaue H, Yanaga K, Fujimoto J, Kaneko H,
Unno M, Endo I, Seto Y, Miyata H, Miyazaki M,
Yamamoto M. Comparison of laparoscopic major
hepatectomy with propensity score matched open
cases from the National Clinical Database inJapan. J Hepatobiliary Pancreat Sci 2016
4. Ikemura N, Sawano M, Miyata H, Ueda I,
Numasawa Y, Noma S, Suzuki M, Momiyama Y,
Maekawa Y, Fukuda K, Kohsaka S. Use ofrenin-angiotensin system inhibitors after coronary
interventions in patients with the guideline-based
indications: A report from a Japanese multicenter
registry. Int J Cardiol 225:362-364 2016
5. Konno H, Kamiya K, Kikuchi H, Miyata H,
Hirahara N, Gotoh M, Wakabayashi G, Ohta T,
Kokudo N, Mori M, Seto Y. Association between
the participation of board-certified surgeons ingastroenterologicalsurgeryandoperative
mortality
after
eight
gastroenterologicalprocedures. Surg Today 2016
6. Kataoka A, Iwamoto T, Tokunaga E, Tomotaki A,
Kumamaru H, Miyata H, Niikura N, Kawai M,
Anan K, Hayashi N, Masuda S, Tsugawa K, Aogi
K, Ishida T, Masuoka H, Iijima K, Kinoshita T,
Nakamura S, Tokuda Y. Young adult breast cancer
patients have a poor prognosis independent ofprognostic clinicopathological factors: a study
from the Japanese Breast Cancer Registry. Breast
Cancer Res Treat 160(1):163-172 2016
7. Iino K, Miyata H, Motomura N, Watanabe G,
Tomita S, Takemura H, Takamoto S. Prolonged
Cross-Clamping During Aortic Valve Replacement Is an Independent Predictor of Postoperative
Morbidity and Mortality: Analysis of the Japan
Cardiovascular Surgery Database. Ann Thorac
Surg S0003-4975(16)30771-8 2016
8. Kunisaki C, Miyata H, Konno H, Saze Z, Hirahara
N, Kikuchi H, Wakabayashi G, Gotoh M, Mori M.
Modeling preoperative risk factors for potentiallylethal morbidities using a nationwide Japanese
web-based database of patients undergoing distal
gastrectomy for gastric cancer. Gastric Cancer
2016
9. Sakai Bizmark R, Kumamaru H, Nagata S.
Reduced Asthma susceptibility from earlychildhood exposure to residing in developing
country. Pediatr Allergy Immunol 2016
10. Endo S, Ikeda N, Kondo T, Nakajima J, Kondo H,
Yokoi K, Chida M, Sato M, Toyooka S, Yoshida K,
Okada Y, Sato Y, Okumura M, Masuda M,
Chihara K, Miyata H. Development of an annually
updated Japanese national clinical database forchest surgery in 2014. Gen Thorac Cardiovasc
Surg 201611. Sawano M, Kohsaka S, Okamura T, Inohara T,
Sugiyama D, Watanabe M, Nakamura Y,
Higashiyama A, Kadota A, Okud N, Murakami Y,
Ohkubo T, Fujiyoshi A, Miura K, Okayama A,
Ueshima H; National Integrated Project for
Prospective Observation of Non-Communicable
Disease and its Trends in the Aged (NIPPONDATA 80) Research Group. Validation of theeuropean SCORE risk chart in the healthy
middle-aged Japanese. Atherosclerosis 252:116121 201612. Ohira S, Miyata H, Doi K, Motomura N,
Takamoto S, Yaku H. Risk model of aortic valve
replacement after cardiovascular surgery based on
a National Japanese Database. Eur J Cardiothorac
Surg 201613. Sawano M, Kohsaka S, Okamura T, Inohara T,
Sugiyama D, Shiraishi Y, Watanabe M, Nakamura
Y, Higashiyama A, Kadota A, Okuda N,
Murakami Y, Ohkubo T, Fujiyoshi A, Miura K,Okayama A, Ueshima H; NIPPON DATA 80/90
Research Group. Independent Prognostic Value ofSingle and Multiple Non-Specific 12-Lead
Electrocardiographic Findings for Long-Term
Cardiovascular Outcomes: A Prospective Cohort
Study. PLoS One 11(6) 2016
14. Numasawa Y, Kohsaka S, Ueda I, Miyata H,
Sawano M, Kawamura A, Noma S, Suzuki M,
Nakagawa S, Momiyama Y, Fukuda K. Incidence
and predictors of bleeding complications after
percutaneous coronary intervention. J Cardiol
2016

405

15. Kodaira M, Miyata H, Numasawa Y, Ueda I,
Maekawa Y, Sueyoshi K, Ishikawa S, Ohki T,
Negishi K, Fukuda K, Kohsaka S. Effect of
Smoking Status on Clinical Outcome and Efficacy
of Clopidogrel in Acute Coronary Syndrome Circ
J 2016
16. Kumamaru KK, Kumamaru H, Bateman BT,
Gronsbell J, Cai T, Liu J, Higgins LD, Aoki S,
Ohtomo K, Rybicki FJ, Patorno E. Limited
Hospital Variation in the Use and Yield of CT for
Pulmonary Embolism in Patients Undergoing
Total Hip or Total Knee Replacement Surgery
Radiology 201617. Jalbert JJ, Nguyen LL, Gerhard-Herman MD,
Kumamaru H, Chen CY, Williams LA, Liu J,
Rothman AT, Jaff MR, Seeger JD, Benenati JF,
Schneider PA, Aronow HD, Johnston JA, Brott TG,
Tsai TT, White CJ, Setoguchi S. Comparative
Effectiveness of Carotid Artery Stenting Versus
Carotid Endarterectomy Among Medicare
Beneficiaries Circ Cardiovasc Qual Outcomes
9(3):275-85 201618. Sukegawa H, Maekawa Y, Yuasa S, Anzai A,
Kodaira M, Takei M, Sano F, Ueda I, Kawakami T,
Hayashida K, Kohno T, Kohsaka S, Abe T,
Fukuda K. Intensive statin therapy stabilizes
C-reactive protein, but not chemokine in stablecoronary artery disease treated with an
everolimus-eluting stent Coron Artery Dis 2016
19. Kondo M, Kohno T, Kohsaka S, Fukuoka R,
Shiraishi Y, Sawano M, Inohara T, Sano M,
Yoshikawa T, Fukuda K. Enhanced oxidative
stress is associated with sleep-disorderedbreathing and obesity in patients with heart failure
Int J Cardiol 209:133-5 2016
20. Inohara T, Kohsaka S, Miyata H, Ueda I,
Maekawa Y, Fukuda K, Cohen DJ, Kennedy KF,
Rumsfeld JS, Spertus JA. Performance andValidation of the US NCDR Acute Kidney Injury
Prediction Model in Japan J Am Coll Cardiol
67(14):1715-22 2016
21. Iwamoto T, Kumamaru H, Miyata H, Tomotaki A,
Niikura N, Kawai M, Anan K, Hayashi N, Masuda
S, Tsugawa K, Aogi K, Ishida T, Masuoka H,
Iijima K, Matsuoka J, Doihara H, Kinoshita T,
Nakamura S, Tokuda Y. Distinct breast cancer
characteristics between screen- and self-detected

breast cancers recorded in the Japanese Breast
Cancer Registry Breast Cancer Res Treat 156(3):485-94 2016
22. Kumamaru H, Schneeweiss S, Glynn RJ,
Setoguchi S, Gagne JJ. Dimension reduction andshrinkage methods for high dimensional diseaserisk scores in historical dataEmerg Themes
Epidemiol 201623. Miura F, Yamamoto M, Gotoh M, Konno H,
Fujimoto J, Yanaga K, Kokudo N, Yamaue H,
Wakabayashi G, Seto Y, Unno M, Miyata H,
Hirahara N, Miyazaki M. Validation of the board
certification system for expert surgeons(hepato-biliary-pancreatic field) using the data of
the National Clinical Database of Japan: part 2 –Pancreatoduodenectomy J Hepatobiliary Pancreat
Sci 2016
24. Miura F, Yamamoto M, Gotoh M, Konno H,
Fujimoto J, Yanaga K, Kokudo N, Yamaue H,
Wakabayashi G, Seto Y, Unno M, Miyata H,
Hirahara N, Miyazaki M. Validation of the board
certification system for expert surgeons(hepato-biliary-pancreatic field) using the data of
the National Clinical Database for Japan: part 1 Hepatectomy of more than one segment J
Hepatobiliary Pancreat Sci 2016
25. Kawai M, Tomotaki A, Miyata H, Iwamoto T,
Niikura N, Anan K, Hayashi N, Aogi K, Ishida T,
Masuoka H, Iijima K, Masuda S, Tsugawa K,
Kinoshita T, Nakamura S, Tokuda Y. Body massindex and survival after diagnosis of invasive
breast cancer: a study based on the Japanese
National Clinical Database-Breast Cancer
Registry Cancer Med 2016
26. Ueki C, Miyata H, Motomura N, Sakaguchi G,
Akimoto T, Takamoto S. Off-pump versus
on-pump coronary artery bypass grafting inpatients with left ventricular dysfunction J Thorac
Cardiovasc Surg 151(4):1092-8 201627. Sakai R, Fink G, Kumamaru H, Kawachi I. The
Impact of Pediatrician Supply on Child Health
Outcomes: Longitudinal Evidence from Japan
Health Serv Res 51(2):530-49 2016
28. Kumamaru H, Gagne JJ, Glynn RJ, Setoguchi S,
Schneeweiss S. Comparison of high-dimensional
confounder summary scores in comparative
studies of newly marketed medications J Clin

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Epidemiol 201629. Shiraishi Y, Sawano M, Kohno T, Nishiyama T,
Maekawa Y, Sano M, Fukuda K, Kohsaka S.
Validation of the Seattle Heart Failure Model inJapanese heart failure patients Int J Cardiol 203:
87-9 2016
30. Gotoh M, Miyata H, Hashimoto H, Wakabayashi
G, Konno H, Miyakawa S, Sugihara K, Mori M,
Satomi S, Kokudo N, Iwanaka T. National
Clinical Database feedback implementation for
quality improvement of cancer treatment in Japan:
from good to great through transparency Surg
Today 6(1):38-47 201631. Shiraishi Y, Kohsaka S, Abe T, Mizuno A, Goda A,
Izumi Y, Yagawa M, Akita K, Sawano M, Inohara
T, Takei M, Kohno T, Higuchi S, Yamazoe M,
Mahara K, Fukuda K, Yoshikawa T; West Tokyo
Heart Failure Registry Investigators. Validation of
the Get With The Guideline-Heart Failure risk
score in Japanese patients and the potential
improvement of its discrimination ability by the
inclusion of B-type natriuretic peptide level Am
Heart J 171(1):33-9 2016
32. Kohsaka S, Miyata H, Motomura N, Imanaka K,
Fukuda K, Kyo S, Takamoto S. Effects ofPreoperative β-Blocker Use on Clinical Outcomes
after Coronary Artery Bypass Grafting: A Reportfrom the Japanese Cardiovascular Surgery
Database Anesthesiology 124(1):45-55 2016
33. Mizuno M, Kajimoto K, Sato N, Yumino D,
Minami Y, Murai K, Munakata R, Asai K, Keida T,
Sakata Y, Hagiwara N, Takano T; ATTEND
Investigators. Clinical profile, management, andmortality in very-elderly patients hospitalizedwith acute decompensated heart failure: An
analysis from the ATTEND registry Eur J Intern
Med 27:80-5 2016

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Department of Clinical Trial DataManagement
Project Assistant Professor
Tempei Miyaji, M.S.

Project Researcher
Takuhiro Yamaguchi, Ph.D.

Registered Researcher

Satoru Fukimbara, Ph.D.
Hideki Suganami, Ph.D.

Project Academic Support Staff
Kimiyo Terada

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 carries out educationaland research activities on CDM in collaboration withThe Department of Biostatistics and The ClinicalResearch Support Center 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 activate researches on CDM
aimed at improving the quality of clinical trials. The
other is to produce data managers trained under 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
 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408

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 and developing ePRO in collaboration with other universities, pharmaceutical industries,
CRO and venders.
We are also supporting several clinical studies which
are conducted in the University of Tokyo Hospital. For
example, our department functions as a data center for“A clinical study of an oncolytic herpes simplex type
1 (HSV-1) G47delta for patients with castration
resistant prostate cancer” which are conducted at
Department of Urology in the University of Tokyo
Hospital. Moreover, we also have collaborative works
outside of University of Tokyo Hospital for several
clinical researches. For example, our department
support “Exploratory Clinical Trial on Methods andEffects of Tojisha-Kenkyu for Autism Spectrum
Disorder” which conducted at Research Center for
Advanced Science and Technology, The University ofTokyo and “Psychometric Property of Japaneseversion of Patient Reported Outcome - Common
Terminology Criteria for Adverse Event”, “Feasibility
study of collecting patient – generated health datausing mobile health” which conducted at Departmentof Pharmacy, Tokyo Medical University Hospital.
Finally, as the collaborative department of the ClinicalResearch Support Center (CresCent), we also involvedin their projects as biostatisticians and clinical datamangers.

References
1) Shiraya T, Kato S, Araki F, Ueta T, Yamaguchi T,
Miyaji T. Aqueous cytokine levels are associatedwith reduced macular thickness after intravitreal
ranibizumab for diabetic macular edema. PLOS
ONE 2017 Mar 27;12(3).

2) Ohnishi S, Watari H, Kanno M, Ohba Y, Takeuchi S,
Miyaji T, Oyamada S, Nomura E, Kato H, Sugiyama
T, Asaka M, Sakuragi N, Yamaguchi T, Uezono Y,
Iwase S. Additive effect of rikkunshito, an herbal
medicine, on chemotherapy-induced nausea,
vomiting, and anorexia in uterine cervical or corpus
cancer patients treated with cisplatin and paclitaxel:
results of a randomized phase II study (JORTC
KMP-02). J Gynecol Oncol 2017 Jan;28:e44..
3) Yoshida Y, Nitadori J, Shinozaki‑Ushiku A, Sato J,
Miyaji T, Yamaguchi T, Fukayama M, Nakajima J.
Micropapillary histological subtype in lungadenocarcinoma of 2 cm or less: impact onrecurrence and clinical predictors. Gen Thorac
Cardiovasc Surg. 2017 May;65(5):273-279.
4) Kikuta S, Matsumoto Y1, Kuboki A, Nakayama T,
Asaka D, Otori N, Kojima H, Sakamoto T, Akinori
K, Kanaya K, Ueha R, Kagoya R, Nishijima H,
Toma-Hirano M, Kikkawa Y, Kondo K, Tsunoda K,
Miyaji T, Yamaguchi T, Kataoka K, Mori K,
Yamasoba T. Longer latency of sensory response to
intravenous odor injection predicts olfactory neuraldisorder. Sci Rep. 2016 Oct 13;6:35361.
5) Yoshida H, Kobayashi N, Honda N, Matsuoka H,
Yamaguchi
T,
Homma
H,
TomitaH.
Post-traumatic growth of children affected by theGreat East Japan Earthquake and their attitudes tomemorial services and media coverage. Psychiatry
Clin Neurosci. 2016 May;70(5):193-201.
6) Kaneishi K, Nishimura K, Sakurai N, Imai K,
Matsuo N, Takahashi N, Okamoto K, Suga A, Sano
H, Maeda I, Nishina H, Yamaguchi T, Morita T,
Iwase S. Use of olanzapine for the relief of nausea
and vomiting in patients with advanced cancer: amulticenter survey in Japan. Support Care Cancer.
2016 Jun;24(6):2393-5.
7) Komatsu H, Yagasaki K, Yamaguchi T. Effects ofa nurse-led medication self-management programmein cancer patients: protocol for a mixed-method
randomised controlled trial. BMC Nurs. 2016 Feb
8;15:9.
8) Hata T, Ishida M, Motoi F, Yamaguchi T, Naitoh T,
Katayose Y, Egawa S, Unno M. Telomerase
activity in pancreatic juice differentiates pancreaticcancer from chronic pancreatitis: A meta-analysis.
Pancreatology. 2016 May-Jun;16(3):372-81.
9) Kurosawa S, Yamaguchi H, Yamaguchi T, Fukunaga

409

K, Yui S, Wakita S, Kanamori H, Usuki K, Uoshima
N, Yanada M, Shono K, Ueki T, Mizuno I, Yano S,
Takeuchi J, Kanda J, Okamura H, Inamoto Y,
Inokuchi K, Fukuda T. Decision Analysis of
Postremission
Therapyin
CytogeneticallyIntermediate-Risk Acute Myeloid Leukemia: The
Impact of FLT3 Internal Tandem Duplication,
Nucleophosmin, and CCAAT/Enhancer Binding
Protein Alpha. Biol Blood Marrow Transplant.
2016 Jun;22(6):1125-32.
10) Akizawa T, Kurita N, Mizobuchi M, Fukagawa M,
Onishi Y, Yamaguchi T, Ellis AR, Fukuma S, Alan
Brookhart M, Hasegawa T, Kurokawa K, Fukuhara
S. PTH-dependence of the effectiveness ofcinacalcet in hemodialysis patients with secondary
hyperparathyroidism. Sci Rep. 2016 Apr 13;6:
19612.
11) Ishiyama K, Sato T, Yamaguchi T, Taguma Y.
Efficacy of low-density lipoprotein apheresis
combined with corticosteroids for cholesterol crystal
embolism. Clin Exp Nephrol. 2016 Apr 21.
12) Ishiyama K, Yamaguchi T, Eto T, Ohashi K, Uchida
N, Kanamori H, Fukuda T, Miyamura K, Inoue Y,
Taguchi J, Mori T, Iwato K, Morishima Y,
Nagamura-Inoue T, Atsuta Y, Sakamaki H, Takami
A. Acute megakaryoblastic leukemia, unlike acuteerythroid leukemia, predicts an unfavorable outcome
after allogeneic HSCT. Leuk Res. 2016 May 12;
47:47-53.
13) Kurosawa D, Murakami E, Ozawa H, Koga H, Isu T,
Chiba Y, Abe E, Unoki E, Musha Y, Ito K, Katoh S,
Yamaguchi T. A Diagnostic Scoring System for
Sacroiliac Joint Pain Originating from the Posterior
Ligament. Pain Med. 2016 Jun 10.
14) Shiono M, Takahashi S, Takahashi M, Yamaguchi T,
Ishioka C. Current situation regarding central
venous port implantation procedures andcomplications: a questionnaire-based survey of 11,
693 implantations in Japan. Int J Clin Oncol. 2016
Jun 21.
15) Tanaka Y, Kanazawa M, Kano M, Morishita J,
Hamaguchi T, Van Oudenhove L, Ly HG, Dupont P,
Tack J, Yamaguchi T, Yanai K, Tashiro M, Fukudo S.
Differential Activation in Amygdala and Plasma
Noradrenaline during Colorectal Distention by
Administration of Corticotropin-Releasing Hormone
between Healthy Individuals and Patients with

Irritable Bowel Syndrome. PLoS One. 2016 Jul
22;11(7):e0157347.
16) Shiono M, Huang K, Downey RJ, Consul N,
Villanueva N, Beck K, Fenn K, Dietz D, Yamaguchi
T, Kato S, Divgi C, Kalinsky K, Wei Y, Zhang Y,
Borczuk AC, Inoue A, Halmos B, Acharyya S. An
analysis of the relationship between metastases andcachexia in lung cancer patients. Cancer Med.
2016 Aug 3.
17) Fuji S, Inoue Y, Utsunomiya A, Moriuchi Y,
Uchimaru K, Choi I, Otsuka E, Henzan H, Kato K,
Tomoyose T, Yamamoto H, Kurosawa S, Matsuoka
KI, Yamaguchi T, Fukuda T. Pretransplantation
Anti-CCR4 Antibody Mogamulizumab Against
Adult T-Cell Leukemia/Lymphoma Is AssociatedWith Significantly Increased Risks of Severe andCorticosteroid-Refractory
Graft-Versus-Host
Disease, Nonrelapse Mortality, and Overall
Mortality. J Clin Oncol. 2016 Aug 9.
18) Maeda I, Miyashita M, Yamagishi A, Kinoshita H,
Shirahige Y, Izumi N, Yamaguchi T, Igarashi M,
Kato M, Morita T.
Changes in Relatives'
Perspectives on Quality of Death, Quality of Care,
Pain Relief, and Caregiving Burden Before andAfter a Region-Based Palliative Care Intervention.
J Pain Symptom Manage. 2016 Sep 21.
19) Shinozaki T, Ebihara M, Iwase S, Yamaguchi T,
Hirakawa H, Shimbashi W, Kamijo T, Okamoto M,
Beppu T, Ohori J, Matsuura K, Suzuki M, Nishino H,
Sato Y, Ishiki H. Quality of life and functional
status of terminally ill head and neck cancer
patients: a nation-wide, prospective observational
study at tertiary cancer centers in Japan.Jpn J Clin
Oncol. 2016 Sep 27.
20) Kurokawa Y, Yamaguchi T, Sasako M, Sano T,
Mizusawa J, Nakamura K, Fukuda H. Institutionalvariation in short- and long-term outcomes after
surgery for gastric or esophagogastric junction
adenocarcinoma: correlative study of two
randomized phase III trials (JCOG9501 andJCOG9502).Gastric Cancer. 2016 Aug 27.

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Pharmacology andPharmacokinetics
Project Associate Professor
Masashi Honma, Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/yakuri.html
Introduction and Organization

Education and clinical activities

The research of our laboratory, Pharmacology
and Pharmacokinetics, targets quantitative kinetic
analysis of efficacy and safety of drugs by applying
techniques of modeling and simulation, which havebeen developed systematically in the field of
Pharmacokinetics (PK). It includes some topics inseveral relating fields such as system pharmacology,
quantitative pharmacology, and pharmacometrics.
We will survey various issues need to be solved in thecurrent hospital pharmacotherapy and perform various
assays of biomarkers and drug concentrations inbiological specimens kindly provided from patients.
Personalized medicine is one of our important goals toimprove current pharmacotherapies by stabilizing
efficacy without accompanying unpleasant adverse
effects.
The staffs are involved not only in the researchand the education in this university, but also in theactivity of hospital pharmacy, and are even experienced experts of new drug development in thepharmaceutical industry. Pharmacology and Pharmacokinetics is supported by the Department ofPharmacy in the Tokyo University Hospital.
Pharmacology and Pharmacokinetics received kind
donations from seven pharmaceutical companies(Takeda Pharma Co Ltd, MSD Co Ltd, Towa
Pharmaceutical Co Ltd, Daiichi Sanko Co Ltd, Eisai
Co Ltd, Chugai Pharmaceutical Co Ltd, Kyowa Hakko
Kirin Co Ltd, Mitsubishi Tanabe Pharma
Corporation).

Although Pharmacology and Pharmacokinetics is notoriented to education and clinical activities in thehospital, the staffs are hospital pharmacists and are
involved in the education of graduates and undergraduates in the faculties of medicine andpharmaceutical sciences. Please refer to the annual
report of the Department of Pharmacy.

Research activities
Selected research topics ongoing in Pharmacology andPharmacokinetics are overviewed in the following.
Systematic analysis and prediction of drug-druginteraction
In Japan, more than two thousand drugs are usedin pharmacotherapy in hospital. Among them, somecombinations would cause unpleasant adverse effects
due to pharmacokinetic drug-drug interaction (DDI).
We surveyed DDIs caused by inhibition or inductionof drug metabolizing enzyme in the literature, anddeveloped a new framework for prediction of various
pharmacokinetic DDIs (Hisaka A et al. Pharmacol.
Ther., 2010; 125: 230-48. Hisaka A et al. Clin.
Pharmacokinet., 2009: 48: 653-66).
By applying this theory, we have been annually
making a comprehensive list of drugs which are
involved in significant pharmacokinetic DDI incollaboration with the faculty of pharmaceuticalsciences. It lists more than 300 drugs which areclassified by both clearance pathway and degree of
DDI, and is published in a journal which is distributed

411

to all pharmacies and relating facilities in Japan forfree. The list is used for inspection of prescriptions
in pharmacies, and in addition, for various purposes in
the industry and regulation.
Establishment of disease progression models using
AD as a model disease
For evaluation of the pathology of Alzheimer's
disease (AD), several biomarkers including amyloidbeta peptide (Aβ), tau protein (Tau), and phosphorylated tau protein (pTau) in cerebrospinal fluid, as
well as volume of hippocampus, and cerebral
FDG-PET have been widely utilized in addition to thescore of recognition tests such as ADAS-cog. In
ADNI activity, information of these biomarkers wascollected extensively to define the progression of AD.
However, available information of biomarker isfragmented because of practical restrictions of aperiod of observation; typically 1~4 years.
Incontrast, 10~20 years elapse for most patients to beconverted from normal to AD. For this reason,
relationships among chronological changes ofbiomarkers and their significance to the disease state
have not been fully understood yet. In this study, weapplied a new mathematical method, so called SReFT,
for estimation of the entire chronological changes ofmultiple biomarkers from numerous fragmented
observations to solve this problem.
Establishment of the evaluation method for acompound property to induce immune-mediateddrug adverse reactions
Drug adverse reactions are generally classified
into two groups.
One is an extension of thepharmacological effect, and the other is idiosyncratic
drug reaction. The former is dose-dependent andbasically predictable based on animal experiments.
The latter is not always predictable, including
Stevens-Johnson syndrome (SJS), toxic epidermal
necrolysis (TEN), and a drug hypersensitivity. Largepart of idiosyncratic drug toxicity is thought to be
immune-mediated, and previous reports haveindicated the relationships between the developmentof the idiosyncratic drug adverse reaction and patienthuman leucocyte antigen (HLA) genotype.
In
addition, recent reports have revealed that abacavir,
which is known to induce severe drug hypersensitivity

to patients with HLA-B*57:01 genotype, can binddirectly to HLA-B*57:01 protein, leading to thechange in peptide repertoire presented by HLA-B*
57:01 protein.
The project goal is to establish the method todetermine whether a compound interacts with HLA
protein and changes presented peptide repertoire ornot. To achieve this, construction of HLA protein
expression library is necessary. Using the constructed library, differences of peptide repertoire presented
by HLA proteins in the presence or absence of acompound can be analyzed.
Detection of thedifference means that the compound can interact with
the HLA protein and possibly induce idiosyncratic
adverse reactions.
Activities in our laboratory during two terms (10years) were finished in fiscal year 2016. Research
projects will be continued in Department of Pharmacy.

412

Department of
Therapeutic Strategy forHeart Failure
Research Associate Professor
Masaru Hatano, M.D.

Research Assistant Professor
Seitaro Nomura, M.D

Project Researcher
Naoko Kato

Research AssistantMotoko Oshima

Homepage

http: http://plaza.umin.ac.jp/~heart-f/

Introduction and Organization

Clinical Activities

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 thirteen 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.

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 myocardial biopsy once a month in the firstyear and once a year afterwards. When some symptom
or findings which suggest rejection are detected,
patients will undergo in-hospital treatment.
2. Ventricular Assist Device (VAD) Therapy
We recently implant not only extracorporeal
pulsatile but also implantable ventricular assist device(VAD). All candidates fell into end-stage heart failure
before VAD implantation, and a significant number ofthem were rescued with heart transplantation or bridge
to recovery. We implant centrifugal VAD (EVAHEART
and DuraHeart) or axial VAD (HeartMate II and Jarvik
2000) considering patients’ physics and clinical status).
We also assisted VAD implantation in affiliate orcooperative hospital in 2012 to establish VAD networkin Shinsyu University Hospital, Saku General Hospital,
Shinsyu University Hospital, Akita University Hospital,

413

Gunma Prefectural Cardiovascular Center, and Nagoya
Tokusyukai Hospital.
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) development of Compact CP externalcounterpulsation, 3) basic and clinical research on
regenerative therapy, 4) establishment of social support
system for patients with implantable LVAD. We haveorganized 4series of clinical trial of implantable rotary
blood pump LVAD, EVAHEART, DuraHeart, Jarvik
2000, and HeartMate II since 2007.

References
1. Kimura M, Nawata K, Kinoshita O, Yamauchi H,
Hoshino Y, Hatano M, Amiya E, Kashiwa K, Endo
M, Kagami Y, Nemoto M, Ono M. Readmissions
after continuous flow left ventricular assist device
implantation. J Artif Organs. 2017 (In Press)
2. Tamura Y, Kumamaru H, Satoh T, Miyata H,
Ogawa A, Tanabe N, Hatano M, Yao A, Abe K,
Tsujino I, Fukuda K, Kimura H, Kuwana M,
Matsubara H, Tatsumi K; Japan PH Registry(JAPHR) Network. Effectiveness and Outcome of
Pulmonary Arterial Hypertension-Specific Therapy in Japanese Patients With Pulmonary Arterial
Hypertension. Circ J. 2017 (In Press)
3. Kiriyama H, Amiya E, Hatano M, Hosoya Y, Maki
H, Nitta D, Saito A, Shiraishi Y, Minatsuki S, SatoT, Murakami H, Uehara M, Manaka K, Makita N,
Watanabe M, Komuro I. Rapid Improvement of
thyroid storm-related hemodynamic collapse by
aggressive anti-thyroid therapy including steroid
pulse: A case report. Medicine (Baltimore). 2017.
4. Hara H, Takeda N, Morita H, Hatano M, Amiya E,
Maki H, Minatsuki S, Taki M, Shiraishi Y,
Fujiwara T, Maemura S, Komuro I. Three novel

414

BMPR2 mutations associated with advanced
pulmonary arterial hypertension. Hum Genome Var.
2017.
5. Tanabe N, Ikeda S, Tahara N, Fukuda K, Hatano M,
Ito H, Nakayama T, Anzai T, Hashimoto A, Inoue
T, Kajinami K, Kihara Y, Kinoshita H, Kuwahara
K, Murohara T, Okazaki O, Sakai S, Satoh T,
Takeda Y, Takeishi Y, Taniguchi M, Watanabe H,
Yamamoto T, Yamauchi-Takihara K, Yoshioka K,
Sasayama S. Efficacy and Safety of an Orally
Administered Selective Prostacyclin Receptor
Agonist, Selexipag, in Japanese Patients With
Pulmonary Arterial Hypertension. Circ J. 2017 (InPress)
6. Yamaguchi J, Tanaka T, Saito H, Nomura S,
Aburatani H, Waki H, Kadowaki T, Nangaku M.
Echinomycin inhibits adipogenesis in 3T3-L1 cells
in a HIF-independent manner. Sci Rep. 7: 6516.
2017.
7. Higo T, Naito AT, Sumida T, Shibamoto M, Okada
K, Nomura S, Nakagawa A, Yamaguchi T, Sakai T,
Hashimoto A, Kuramoto Y, Ito M, Hikoso S,
Akazawa H, Lee JK, Shiojima I, McKinnon PJ,
Sakata Y, Komuro I. DNA single-strand breakinduced DNA damage response causes heart failure.
Nat Commun. 8: 15104.
8. Kamo T, Akazawa H, Suda W, Saga-Kamo A,
Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT,
Takeda N, Harada M, Toko H, Kumagai H, Ikeda
Y, Takimoto E, Suzuki JI, Honda K, Morita H,
Hattori M, Komuro I. Dysbiosis and compositional
alterations with aging in the gut microbiota ofpatients with heart failure. PLoS One. 2017.
9. Kushida N, Nomura S, Mimura I, Fujita T,
Yamamoto S, Nangaku M, Aburatani H. HypoxiaInducible Factor-1α Activates the Transforming
Growth Factor-β/SMAD3 Pathway in Kidney
Tubular Epithelial Cells. Am J Nephrol. 44: 276285. 2016.
10. Nakagawa A, Naito AT, Sumida T, Nomura S,
Shibamoto M, Higo T, Okada K, Sakai T,
Hashimoto A, Kuramoto Y, Oka T, Lee JK, Harada
M, Ueda K, Shiojima I, Limbourg FP, Adams RH,
Noda T, Sakata Y, Akazawa H, Komuro I.
Activation of endothelial β-catenin signaling
induces heart failure. Sci Rep.
11. Fukada I, Araki K, Kobayashi K, Shibayama T,

Hatano M, Takahashi S, Iwase T, Ohno S, Ito Y.
Imatinib could be a new strategy for pulmonary
hypertension caused by pulmonary tumor
thrombotic microangiopathy in metastatic breast
cancer. Springerplus. 2016.
12. Amiya E, Morita H, Hatano M, Nitta D, Hosoya Y,
Maki H, Motozawa Y, Sato N, Ishiura H,
Numakura S, Shintani Y, Kinugawa K, Takeda N,
Shimizu J, Tsuji S, Komuro I. Fukutin genemutations that cause left ventricular noncompaction. Int J Cardiol. 222: 727-729. 2016.
13. Maemura S, Amiya E, Seki H, Ueda K, Nitta D,
Imamura T, Uehara M, Kawata T, Watanabe M,
Hatano M, Kinugawa K, Komuro I. Endomyocardial Fibrosis Associated With ApicalCalcification and High Uptake on Myocardial
Gallium-67 Scintigraphy. Circ J. 80: 2053-2055.
2016.
14. Tahara N, Dobashi H, Fukuda K, Funauchi M,
Hatano M, Ikeda S, Joho S, Kihara Y, Kimura T,
Kondo T, Matsushita M, Minamino T, Nakanishi N,
Ozaki Y, Saji T, Sakai S, Tanabe N, Watanabe H,
Yamada H, Yoshioka K, Sasayama S. Efficacy and
Safety of a Novel Endothelin Receptor Antagonist,
Macitentan, in Japanese Patients With Pulmonary
Arterial Hypertension. Circ J. 80: 1478-1483. 2016.
15. Nitta D, Kinugawa K, Imamura T, Endo M, Amiya
E, Hatano M, Takahashi Y, Iriyama T, Kinoshita O,
Nagamatsu T, Nawata K, Ono M, Komuro I.
Successful Pregnancy and Delivery in a Heart
Transplantation Recipient. Int Heart J. 57: 383-385.
2016.
16. Hatano M. Potential of Receptor for Advanced
Glycation End-Products (RAGE) as an Eligible
Biomarker for Therapy Evaluation in Patients With
Pulmonary Hypertension. Int Heart J. 57: 132-133.
2016
17. Nakamura K, Asano Y, Taniguchi T, Minatsuki S,
Inaba T, Maki H, Hatano M, Yamashita T, Saigusa
R, Ichimura Y, Takahashi T, Toyama T, Yoshizaki
A, Miyagaki T, Sugaya M, Sato S. Serum levels ofinterleukin-18-binding protein isoform a: Clinicalassociation with inflammation and pulmonary
hypertension in systemic sclerosis. J Dermatol. 43:
912-918. 2016.
18. Niwa R, Hasumi E, Fujiu K, Uehara M, Nitta D,
Hatano M, Akazawa H, Watanabe M, Komuro I. A

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Case of Multiple Coronary Artery-Left Ventricular
Micro Fistulae Complicated With Hepatic
Arteriovenous Fistulae. Int Heart J. 57: 123-126.
2016.
19. Nitta D, Kinugawa K, Imamura T, Endo M, Inaba
T, Maki H, Amiya E, Hatano M, Kinoshita O,
Nawata K, Kyo S, Ono M. Novel Scoring System
to Predict Ineligibility for Bridge to Implantable
Left Ventricular Assist Device as Destination
Therapy Before Extracorporeal Ventricular Assist
Device Implantation - For the Coming Era of
Destination Therapy in Japan. Circ J. 80: 387-394.
2016.
20. Matsubara TJ, Fujiu K, Asada K, Kojima T, Hisaki
M, Yamagata K, Shimizu Y, Hasumi E, Masaru H,
Akazawa H, Komuro I. Direct left atrial ICE
imaging guided ablation for atrial fibrillation
without employing contrast medium. Int J Cardiol.
203: 733-739. 2016.
21. Nitta D, Kinugawa K, Imamura T, Hatano M, Ono
M, Nakamura F, Kurokawa M, Komuro I. How
Should We Treat Early Post-Transplant Lymphoproliferative Disease After Heart Transplantation?
Int Heart J. 56: 676-678. 2016.

Social Cooperation Program417

Department of Lipidomics
Professor
Takao Shimizu, M.D., 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

Introduction and Organization
The Department of Lipidomics was established in
April 2011, funded by Shimadzu Corp. and Ono
Pharmaceutical Co., Ltd. The objective of the laboratory is to establish and improve mass spectrometrybased lipidomics methodologies, and its application tobiomedical studies including basic lipid biology as
well as clinical research.
The laboratory was started with three staff scientists,
Takao Shimizu (Professor), Yoshihiro Kita (Associate
Professor. He moved to Life Science Core Facility in
Dec. 2013), and Suzumi Tokuoka (Assistant Professor). In April, 2014, Fuyuki Tokumasu joined as an
Associate Professor. In 2014, we had another assistant professor, two guest researchers and two technicalassistants.

Teaching activities
The department staffs gave several lectures forundergraduate and graduate students. For undergraduate students, Drs. Shimizu and Kita delivered
several lectures on biochemistry. Dr. Kita gave
lectures on “Proteome and metabolome” for master’s
students and “Principles and Applications of Mass
Spectrometry” for doctoral students.

Research activities
Our research interests cover following topics.

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
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, and418

tissue 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. 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.
2. 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)
3. 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)
4. 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)
5. 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)
6. Hayakawa EH, Tokumasu F, Usukura J, Matsuoka
H, Tsuboi T, Wellems TE. Imaging of thesubsurface structures of "unroofed" plasmodium

419

falciparum-infected erythrocytes. Exp. Parasitol.,
153, 174-179 (2015)
7. 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)
8. 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)
9. 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)
10. Yoshioka W, Kawaguchi T, Fujisawa N,
Aida-Yasuoka K, Shimizu T, Matsumura F,
Tohyama C. Predominant role of cytosolic
phospholipase A2α in dioxin-induced neonatalhydronephrosis in mice. Sci. Rep., 4, 4042 (2014)
11. 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)12. 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)
13. 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)
14. 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)15. Sumida H, Yanagida K, Kita Y, Abe J,
Matsushima K, Nakamura M, Ishii S, Sato S,
Shimizu T. Interplay between CXCR2 and BLT1
facilitates neutrophil infiltration and resultant
keratinocyte activation in a murine model of
imiquimod-induced psoriasis. J. Immunol. 192,
4361-4369 (2014)
16. Eto M, Shindou H, Shimizu T. A Novel
Lysophosphatidic Acid Acyltransferase Enzyme(LPAAT4) with a Possible Role for Incorporating
Docosahexaenoic Acid into Brain Glycerophospholipids. Biochem. Biophys. Res. Commun.,
443, 718-724 (2014)17. Sugatani J, Sadamitsu S, Yamaguchi M, Yamazaki
Y, Higa R, Hattori Y, Uchida T, Ikari A, Sugiyama
W, Watanabe T, Ishii S, Miwa M, Shimizu T.
Antiobese function of platelet-activating factor:
increased adiposity in platelet-activating factor
receptor-deficient mice with age. FASEB J., 28,
440-452 (2014)18. Hikiji H, Endo D, Horie K, Harayama T,
Akahoshi N, Igarashi H, Kihara Y, Yanagida K,
Takeda J, Koji T, Shimizu T, Ishii S. TDAG8
activation inhibits osteoclastic bone resorption.
FASEB J., 28, 871-879 (2014)

420

Verbal Analysis of Pathophysiology
Project Associate Professor
Shinichi TOKUNO, M.D.,Ph.D.

Project Lecturer
Shunji MITSUYOSHI, Ph.D.

Websitehttp://www.univ.tokyo/

Introduction and Organization

Teaching activities

Department of Verbal 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.
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, Shunji MITSUYOSHI,
Ph.D., Project Lecture and three project researchers.
Additionally, four guest researchers will attend ourdepartment.

Shunji MITSUYOSHI, Project Lecturer isperforming 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.
Tokuno Shinichi Project Associate Professor, taking
advantage of his expertise, supports the lecture ofdisaster medicine in emergency medicine.

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

421

2)

3)

4)

5)



1)

2)

3)



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.
A study on the monitoring of health status byvoice using a smartphone
As a pre-stage of society implementation, aprospective study of long-term use by volunteers
scheduled to start in 2015 summer.
Use in industrial hygiene field of stress check byvoice
As research for social implementation, we arepreparing 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 preparing 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, joint research in the multi-center isplanned.
Application of the verbal analysis ofpathophysiology technology to other than the
stress-depression
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.
Cerebral infarction
We are conducting research to capture thechange of voice due to cerebral infarction.
OthersWe are preparing for research for several
disease such as mental disorders (PTSD ·schizophrenia),
neurologicaldisorders(Parkinson's disease), dementia (including;Alzheimer's disease), cardiovascular disease(ischemic heart disease) respiratory disease(COPD · asthma), metabolic diseases (diabetes,gout), for such as otolaryngology disease (tongue
adhesion disease, vocal cord polyp), I'm
preparing for research.
A study for the effects of driving a car on thehealth of maindWe perform the joint research with Mazda Co.,
Ltd., which our investment company.
The development of medical devices for voice
acquisition and construction of multicenter
research infrastructure
We perform the joint research with MKI Co.,
Ltd., which our investment company.

References
1. Voice disability index using pitch rate. In
Biomedical Engineering and Sciences (IECBES),
Shinohara S, Nakamura M, Mitsuyoshi S, Tokuno
S, Omiya Y, Hagiwara N. (2016, December). 2016
IEEE EMBS Conference on (pp. 557-560). IEEE.
2. Validity of the Mind Monitoring System as a
Mental Health Indicator, Hagiwara N, Omiya Y,
Shinohara S, Nakamura M, Yasunaga H,
Mitsuyoshi S, Tokuno S. 16th International Conference on BioInformatics and BioEngineering(IEEE BIBE2016), 2016. 262-265.
3. 音 声 病 態 分 析 学 , 徳 野 慎 一 , 細 胞 48(14),9-12, 2016
4. 音声感情認識 ST と音声病態分析技術 PST, 光
吉俊二, 心と社会 47(3), 10-15, 2016
5. 音声病態分析技術の医学的検証, 徳野慎一,
心と社会 47(3), 16-21, 2016
6. スマートフォンを用いた音声による健康状態のモニタリングシステム(MIMOSYS)の開発,
大宮康宏, 心と社会 47(3), 22-25, 2016
7. 企業版ストレスレジリエンスプログラムとその効 果, 宮 崎賢 治, 心 と社 会 47(3), 26-31,
2016
8. 音声病態分析技術の自動車への応用, 岡崎俊実, 心と社会 47(3), 32-37, 2016
9. 医療と人工知能の未来, 光吉俊二, 心と社会
47(3), 70-75, 201610. 心を持った機械. 光吉俊二. 建築雑誌 116(6),2016, 18-19

422

Department ofAdvanced Nursing Technology
Project Associate Professor
Ryoko Murayama, Ph.D., R.N.M.

Project Lecturer
Makoto Oe, Ph.D., R.N.

Collaborative 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, seeking to develop
new academic fields for creating advanced nursing
technology based on clinical evidence. Our primary
belief is that “Never let patients endure in healthcare.” and we hope that through our activities, we canassist patients to live longer, healthier lives.
Till date, significant difficulties regarding thecreation of an advanced nursing technology havecreated a gap between academic research and clinicalneeds of the clinical setting. Thus, the strategies ofadvanced nursing technology could not be applied tohospitals because of their unsuitability to this clinicalsetting, despite being useful to academic nursing
researchers at universities. In contrast, new nursing
technologies are often developed because of nurses’
experiences in clinical settings with limitations suchas the unavailability of scientific processes. Furthermore, systems to promote and support nurses whowish to undertake research in the clinical setting are
insufficient.
The Department of Advanced Nursing Technology
was established at the University of Tokyo Hospital,
supported by Terumo Co., Tokyo, Japan, as a social
cooperation program. The United Cooperation
Program, established to develop solutions for theabovementioned difficulties and to further thedevelopment of nursing technology, comprise thefollowing departments at the University of Tokyo:
Department of Gerontological Nursing/Wound CareManagement, Department of Nursing, and Department
of Diabetes and Metabolic Diseases. We aim todevelop a new research model through collaborative
research with Tokyo Hospital’s Departments ofNursing and Medical examination and School of
Health Science at the university. In addition, we aim
to disseminate advances in nursing technology basedon the needs of clinical practices worldwide. We
promote our collaborative research with additional
investment from Paramount Bed Corporation since
December 2015.
The following are the members from various
departments at the University of Tokyo: Ryoko
Murayama (Project Associate Professor) and Makoto
Oe (Project Lecturer) as well as Hidenori Tanabe(Collaborative Researcher; from Terumo Co.).

Teaching activities
We advised Master’s and PhD course students fromthe Department of Gerontological Nursing/Wound
Care management on matters concerning researchplanning and practical work. We were involved inproviding lectures such as Gerontological Nursing andGerontological Nursing I, for undergraduates, mastercourse students, or PhD course students with the423

Department of Gerontological Nursing/Wound Caremanagement.
The followings were Master’s themes in 2016;“Development of an automatic puncturing andsampling system for a self-monitoring blood glucose
device.”Research activities
1. Activity policy
We will develop a new nursing research scheme aimed
at identifying clinical needs (i.e., “Never let patientsendure in health care.”). An interview survey of nurses
at the University of Tokyo hospital were therefore
conducted to identify clinical needs in the clinicalsetting. This survey was conducted as a collaborative
research with the Department of nursing (Universityof Tokyo hospital), and is ongoing.
Several research projects are ongoing in our
department. These include development of a nursing
device for early ambulation and development of aself-monitoring blood glucose device for the elderly.
In addition, we are conducting a cross-sectional studyof extravasation at our laboratory. These researches
are conducted in collaboration with nurses at the
University of Tokyo hospital.
We provided nurses with information as the career
ladder system in the Department of nursing at the
University of Tokyo Hospital. The risk factors fordevelopment of diabetic foot disorders andvenipuncture are all components of this system.
We offer consultations on research matters andprovide guidance on article writing in order topromote nursing research in the clinical setting. A
study meeting was planned with the graduate schoolof the University of Tokyo to educate nurses regarding
research. In addition, cross-sectional studies of pelvic
floor disorders and diabetic foot were conducted as
per the researcher’s area of expertise.
2. Research fields and themes in 2016
• Investigation of clinical needs in the clinicalsetting.
• Early ambulation: the management of infusion
systems, drains, and catheters for early ambulation and early discharge from the hospital.
• Determining the mechanism of extravasation anddevelopment of an indwelling needle for prevention of extravasation.
• Development of a blood glucose self-monitoring
device for the elderly.
• Risk assessment for pelvic floor disorders during
the postpartum period.
• The diabetic foot and associated risk factors.
Several awards were given to our research as
follows.
•Research Award from 4th Conference of Nursing
Science and Engineering (Oct.2016)“Difficulties of the introduction of self-monitoring ofblood glucose in elderly diabetic patients.”
・Research Award from 25th Conference of JapaneseSociety of Wound, Ostomy, and ContinenceManagement (Jun.2016)“Reliability and validity of an on-site measurement
and visualization system to measure plantar pressure
and shear force in footwear for the education ofdiabetic patients.”

References
1. Oya M, Murayama R, Oe M, Yabunaka K, Tanabe
H, Takahashi T, Matsui Y, Otomo E, Komiyama C,
Sanada H. Continuous thermographic observation
may predict extravasation in chemotherapy-treatedpatients. European Journal of Oncology Nursing.
2017; 28: 56-61.
2. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Availability of two self-administered
diet history questionnaires for pregnant Japanesewomen: A validation study using 24-hour urinary
markers. Journal of Epidemiology Available online
30 January 2017.
3. Oe M, Takehara K, Noguchi H, Ohashi Y,
Watanabe A, Murayama R, Kadowaki T, Sanada H.
Validation of a skin hardness meter for foot callus
in patients with diabetes: pilot study. Japanese
Journal of Foot Care. 2016; 14(4): 141-143.
4. Amemiya A, Noguchi H, Oe M, Takehara K,
Ohashi Y, Suzuki R, Yamauchi T, Kadowaki T,
Sanada H, Mori T. Shear stress-normal stress(Pressure) Ratio (SPR) decides forming callus inpatients with diabetic neuropathy. Journal of
Diabetes Research, vol. 2016, Article ID 3157123,
10 pages, 2016. doi:10.1155/2016/3157123.

424

5. Tanabe H, Murayama R, Yabunaka K, Oe M,
Takahashi T, Komiyama C, Sanada H. Low-angled
peripheral intravenous catheter tip placement
decreases phlebitis. The Journal of VascularAccess. 2016; 17(6): 542-547.
6. Oe M, Ohashi Y, Takehara K, Oba M, Doi M,
Iizuka Y, Murayama R, Kadowaki T, Sanada H.
Foot complications in patients with diabetes
mellitus: practical report of diabetic foot clinic in
Beijing. Japanese Journal of Foot Care. 2016;
14(2); 57-61.
7. 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. 2016;
3(2):86-92.
8. Arisandi D, Oe M, Roselyne Yotsu R, Matsumoto
M, Ogai K, Nakagami G, Tamaki T, Suriadi,
Sanada H, Sugama J. Evaluation of validity of the
new diabetic foot ulcer assessment scale inIndonesia. Wound Repair Regen. 2016 Jul 11. doi:
10.1111/wrr.12464.
9. Huang L, Minematsu T, Kitamura A, Quinetti PC,
Nakagami G, Mugita Y, Oe M, Noguchi H, Mori T,
Sanada H. Topical administration of acylated
homoserine lactone improves epithelialization of
cutaneous wounds in hyperglycaemic rats. PLoS
One. 2016 Jul 12;11(7):e0158647.
10. Yabunaka K, Murayama R, Tanabe H, Takahashi T,
Oe M, Oya M, Fujioka M, Sanada H.
Ultrasonographic classification of subcutaneousedema caused by infusion via peripheral
intravenous catheter. Journal of medical ultrasound.
doi.org/10.1016/j.jmu.2016.02.001
11. Oya M, Takahashi T, Tanabe H, Oe M, Murayama
R, Yabunaka K, Matsui Y, Sanada H.
Low-temperature infiltration identified using
infraredthermographyinpatients
with
subcutaneous edema revealed ultrasonographically:
A case report. Drug Discoveries & Therapeutics.
2016; 10(2):117-122.
12. Hamatani M, Mori T, Oe M, Noguchi H, Takehara
K, Amemiya A, Ohashi Y, Ueki K, Kadowaki T,
Sanada H. Factors associated with callus indiabetic patients, focused on plantar shear stressduring gait. Journal of Diabetes Science andTechnology. doi:10.1177/1932296816648164
13. Kanazawa T, Nakagami G, Goto T, Noguchi H, Oe
M, Miyagaki T, Sasaki S, Sanada H. Use ofsmartphone attached mobile thermography
assessing subclinical inflammation: a pilot study.
Journal of Wound Care. 2016; 25(4):177-82.

425

Department of Health Services
Research
Project Associate Professor
Taisuke Jo, M.D.,Ph.D.

Project Assistant Professor
Nobuaki Michihata, M.D., MPH.
Yusuke Sasabuchi, M.D., MPH.

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 staffs were Taisuke Jo (Project
Associate Professor), Nobuaki Michihata (Project
Assistant Professor) and Yusuke Sasabuchi (Project
Assistant Professor).

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) participatedin 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
conducted in 2016.
1) Increase in avoidable hospital admissions after theGreat East Japan Earthquake.
The Great East Japan Earthquake and subsequent426

tsunami and nuclear disaster on 11 March 2011 had ashort-term influence on the increase in emergency
department visits and hospital admissions due tovarious diseases. However, it remains unclear whether
the earthquake and tsunami disaster affected thelong-term health conditions of people in the affectedareas.
Therefore, using a national inpatient database inJapan, people’s ambulatory care sensitive conditions(ACSCs), which are defined as conditions for which
effective management and treatment should prevent
admission to a hospital was investigated. We
compared the number of admissions for ACSCs
before-quake (July 2010 to February 2011) withafter-quake (July 2012 to February 2013) periods inthe disaster area compared with other areas using a
difference-in-differences design. To estimate theimpact of the earthquake on admissions for ACSCs,
linear regression models with the interaction between
periods and areas were used.
No significant difference in difference was seen inpreventable ACSCs (where immunization and otherinterventions can prevent illness) nor chronic ACSCs(where effective care can prevent flare-ups), whereasin acute ACSCs (where early intervention can prevent
more serious progression) significant increase wasobserved (3.3 admissions per 100 000 population;
95% CI 0.4 to 6.3; p=0.028).
Preventable and chronic ACSCs may haveincreased transiently after the earthquake. However,avoidable admissions due to acute ACSCs were
sustained high after the earthquake and tsunami
disaster.
2) Association between Dementia and Discharge toHome in Patients Hospitalized for Pneumonia.
Pneumonia is the most common cause of death indementia, whilst the outcomes of hospitalized
pneumonia patients with dementia has been poorly
investigated. The objective of this study was to clarify
the association of dementia with in-hospital mortalityand discharge status in patients hospitalized forpneumonia.
Using the Diagnosis Procedure Combination
database, which is a national inpatient database, we
retrospectively identified patients who were aged ≥ 60
years and admitted to hospital for pneumonia fromMay 1 2010 to March 31 2014. We extracted data onsex, age, body mass index, severity of pneumonia,
comorbidities including dementia. The outcomes werein-hospital mortality and discharge to home. Cox
regression analysis was performed to analyze factors
affecting discharge to home.
We identified 397,453 pneumonia patients,
including those with dementia (n=38,083) and without
dementia (n=359,369). In-hospital mortality was
12.8% and 13.0% in patients with and without
dementia, respectively. The proportions of patientsdischarged to home were 53.6% and 72.2% in patientswith and without dementia, respectively. The hazard
ratio to return to their home for patients with dementia
was 0.69 (95% confidence interval, 0.68-0.70;
P<0.001).
In-hospital mortality of pneumonia were identicalbetween patients with and without dementia; however,pneumonia patients with dementia were less likely toreturn home than those without dementia.
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. Yamauchi Y, Yasunaga H, Sakamoto Y, Hasegawa
W, Takeshima H, Urushiyama H, Jo T, Matsui H,
Fushimi K, Nagase T. Mortality associated withbone fractures in COPD patients. Int J Chron
Obstruct Pulmon Dis. 2016;11:2335-40.
2. Yamauchi Y, Yasunaga H, Hasegawa W, Sakamoto
Y, Takeshima H, Jo T, Matsui H, Fushimi K,
Nagase T. Effect of outpatient therapy withinhaled corticosteroids on decreasing in-hospitalmortality from pneumonia in patients with COPD.
Int J Chron Obstruct Pulmon Dis. 2016;11:1403-11.
3. Sasaki R, Yasunaga H, Matsui H, Michihata N,
Fushimi K. Hospital Volume and Mortality in
Mechanically Ventilated Children: Analysis of a
National Inpatient Database in Japan. Pediatr Crit
Care Med. 2016;17(11):1041-4.
4. Sasabuchi Y, Yasunaga H, Matsui H, Lefor AK,
Fushimi K. Prolonged propofol infusion formechanically ventilated children. Anaesthesia.

427

5.

6.

7.

8.

2016;71(4):424-8.
Sasabuchi Y, Yasunaga H, Lefor AK. Propofol
infusion in children - a reply. Anaesthesia. 2016;
71(8):987.
Sasabuchi Y, Matsui H, Lefor AK, Fushimi K,
Yasunaga H. Risks and Benefits of Stress Ulcer
Prophylaxis for Patients With Severe Sepsis. Crit
Care Med. 2016;44(7):e464-9.
Sasabuchi Y, Kimura N, Shiotsuka J, Komuro T,
Mouri H, Ohnuma T, Asaka K, Lefor AK,
Yasunaga H, Yamaguchi A, Adachi H, Sanui M.
Long-Term Survival in Patients With Acute
Kidney Injury After Acute Type A Aortic
Dissection Repair. Ann Thorac Surg. 2016;102(6):2003-9.
Michihata N, Matsui H, Fushimi K, Yasunaga H.
Hospital volume and mortality due to preterm
patent ductus arteriosus. Pediatr Int. 2016;58(11):1171-5.

Social Cooperation Program(22nd Century Medical and Research Center)429

Department of Ubiquitous Health
Informatics
Associate Professor
Waki Kayo, M.D., M.P.H., Ph.D.

Assistant Professor
Fujiu Katsuhito, M.D., Ph.D. Satoko Yamaguchi, M.D., Ph.D., Aki Hayashi, M.D., Ph.D.

Homepage

http://uhi.umin.jp

Introduction and Organization
Our mission is to promote research and developmentof a novel integration system in which pieces ofpatients’ healthcare information are virtuallycombined and stored separately in diverse medical/
healthcare facilities. Recently developed mobile
information communication technologies (ICT)—in
conjunction with cloud computing—provide a sturdy
environment in which to build a “virtual ubiquitous
health information space.” We particularly 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 tothe integral components of diabetes care. Selfmanagement is the core of diabetes treatment because
it ties the components of diabetes therapy together,enabling patients to assess and control the interplay ofnutrition, physical activity, emotional/physical stress,and medications that are critical with diabetes. There
had long been a need for an effective self-management
tool that could automate and standardize much of thecounseling process, facilitating self-monitoring ofblood glucose, blood pressure, body weight andlifestyle, and particularly diet and exercise.

Accordingly, we developed just such a real-time,
partially automated interactive system to interpretpatients’ data—biological information, exercise, anddiet content calculated from a message sent by
patients—and respond with appropriate actionablefindings, helping the patients achieve diabetes
self-management. In addition, the safety and clinicaleffectiveness of the system had to be examined. A
one-month,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-month clinical trial for type 2
diabetes patients using DialBetics in Pavia, Italy.
Thirty-six patients completed the trial and theirglycemic control was significantly improved. The
effectiveness of this system was also confirmed in
Italy. We also devised automatically evaluate systemby meal photograph which is healthy food or
non-healthy food. It was investigated that healthy foodlevel is able to evaluate with one meal photographusing the system. In addition, we supported theresearch
projectofadoctor’s
degreecandidate—“Intention of using an ICT-based
self-management tool among patients with diabetes: A
cross sectional study”—from the department of Adult
Health/Palliative Care Nursing. We plan to conduct afurther study to apply the use of the system in clinicalenvironments.

430

 GlucoNote: Self-management and recording
application for the type 2 diabetes and diabetes
spare group
We started a clinical study of a smartphone application we call "GlucoNote" for type 2 diabetes andimpaired glucose tolerance using ResearchKit byApple Inc. This application continuously collects
data about blood sugar level, blood pressure, weight,
active mass and lifestyle including diet, exercise andsleep. This is the first such clinical study in Japan.
About 400 patients tried to use GlucoNote during
4-month research. It has potentials for betterself-management like decreasing body weight ifpatients have continued their vital record.
 HearTily: Self-management and recording
application 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 7,000
participants used Heartily during last one year, a newarrhythmia people were detected in 1.9% of them.
 Self-management and Recording System for
Dialysis (SMART-D)
The proper intake of water, potassium and phosphorus
impacts the survival of dialysis patients, andadherence to fluid-intake restrictions is one of themost difficult aspects of the hemodialysis regimen. So
the “Self-management and Recording System for
Dialysis” (SMART-D) was developed. It featured theessential indicators for dialysis patients, and its
performance was verified. A two-week, non-blinded,
non-randomized observational study was conducted.
Although there was no change in clinical outcomes
after two weeks of using SMART-D, most of theparticipants reported that using SMART-D helped to
improve their lifestyle and self-management. Our
study was accepted in this year2).
 Health support study using in Singapore
For the purpose of preventing development oflifestyle-related diseases in Singapore, a clinical study
was performed using a smartphone application to
support better self-management of lifestyle. We werebrought into this study by NTT Resonant, Inc., which

was tasked with it by the Ministry of Internal Affairs
and Communications. Our department was asked tosupervise the study and analysis the results. We
conducted the evaluation of the support application ina clinical trial.
 Inspection of the correlation of blood sugar leveland expiration acetone measurements
Current practice makes it necessary to perform
urinalysis with a blood test in order to diagnose the
ketoacidosis of diabetes. We plan a clinical study todetermine whether clinicians can instead use portable
expiration acetone measuring equipment which could
measure acetone levels for a diagnosis. The clinical
trial was conducted with 120 diabetics, and weinvestigated the variation of within same participants.
 Multi-institutional joint prospective study onarrhythmia detection efficiency by wearable heart
rate monitor
Cardiogenic cerebral infarction has a poor prognosis
in that it leaves big sequelae, and its early detection isimportant. In order to investigate whether it is possible
to capture pulse irregularities simply and conveniently,
we planned research to monitor long-term heart rateusing a wearable heart rate monitor that is on themarket. We conducted clinical research for 100
workers who are at risk of developing cerebral
infarction if they have atrial fibrillation, such as highblood pressure, diabetes, cerebral infarction, heart
failure etc. New atrial fibrillation were confirmed in
two participants. It was suggested that atrial
fibrillation can be detected by long-term
electrocardiogram monitoring.
 Study of specific health guidance for workers to
reduce the risk of diabetes mellitus.
For the purpose of reducing the risk of diseases
mellitus, a clinical study was performed using ICT
system (smile data vision) to support betterself-management of lifestyle. We were brought into
this study by Meiji Yasuda Life Health Insurance
Association. Our department was asked to supervise
the study and analysis the results. Currently, theparticipants are measuring their blood glucose level,
blood pressure, body weight and dietary intakes athome and will continue to analyze at the University of431Tokyo to promote the improvement of the subject's
lifestyle habits.
 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 management of PHR. We
surveyed 5,000 people and got responses from about
2,500 people, and analyzing the result.
Future directions
To fulfill our mission, we plan to generalize thefindings made in the several clinical studies, andpromote ongoing and growing telemedicine service
with the use of ICT in the future.

Publications in English(Original article)
1) Yamaguchi S, Waki K, Tomizawa N, Waki H,
Nannya Y, Nangaku M, Kadowaki T, Ohe K.
Previous dropout from diabetic care as a predictor
of patients' willingness to use mobile applications
for self-management: A cross-sectional study. J
Diabetes Investig. 2017 Jul;8(4):542-549. doi: 10.
1111/jdi.12613
2) Hayashi A, Yamaguchi S, Waki K, Fujiu K,
Hanafusa N, Nishi T, Tomita H, Kobayashi H,
Fujita H, Kadowaki T, Nangaku M, Ohe K.
Testing the feasibility and usability of a novelsmartphone-based
self-management
supportsystem for dialysis patients: A pilot study. JMIRRes Protoc. 2017 Apr; 6(4):e63. doi:10.2196/
resprot.7105
3) Shibuta T, Waki K, Tomizawa N, Igarashi A,
Yamamoto-Mitani N, Yamaguchi S, Fujita H,
Kimura S, Fujiu K, Waki H, Izumida Y, Sasako T,
Kobayashi M, Suzuki R, Yamauchi T, Kadowaki
T, Ohe K. Willingness of patients with diabetes touse an ICT-based self-management tool: a crosssectional study. BMJ Open Diabetes Res Care.
2017 Feb 7;5(1):e000322. doi: 10.1136/bmjdrc2016-000322.
4) Tan X, Fujiu K, Manabe I, Nishida J, Yamagishi R,
Terashima Y, Matsushima K, Kaburaki T, Nagai R,
Yanagi Y, Choroidal Neovascularization Is
Inhibitedin
Splenic-Denervatedor

Splenectomized Mice with a Concomitant
Decrease in Intraocular Macrophage. PLoS One,11(8):e0160985, 20165) Zempo H, Suzuki J, Ogawa O, Watanabe R, Fujiu
K, Manabe I, Conway SJ, Taniyama Y, Morishita
R, Hirata Y, Isobe M, Nagai R. The influence of
periostin positive cell-specific Klf5 deletion on
aortic thickening in DOCA-salt hypertensive mice.
Hypertens Res. 39: 764-768, 2016.
6) Yokota J, Fujiu K, Kojima T, Komuro I,
Pseudo-Reentry of Atrial Tachycardia after
Surgical Repair of Congenital Heart Disease, J
Cardiovasc Electrophysiol, 27: 876-877, 2016,
doi: 10.1111/jce.12932

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

434

Department of Clinical Laboratory
Professor
Yutaka Yatomi, M.D.

Associate Professor
Hitoshi Ikeda, M.D.

Lecturer
Masao Daimon, M.D., Tatsuo Shimosawa, M.D.
Daiya Takai, M.D., Masato Yumoto, M.D.,

Associate
Tomoko Nakao, M.D., Akiko Masuda, M.D
Makoto Kurano, M.D., Atsushi Yasumoto, M.D.

Chief Technologist
Shinji Sone, M.T.

Homepage

http://lab-tky.umin.jp/

Introduction and Organization
Clinical Laboratory Center consists of 12 doctors, achief technologist, and 80 technicians, and is divided
into the following sections. The second - 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 and blood and urine sampling. In
2016, 232,532 outpatient blood sampling were
performed in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2016, over 5,335,679

serum enzyme tests (such as AST and ALT), and594,535 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, gene analysis tests and urinalysis.
In 2016, 1,259,635 samples were examined for complete blood cell counts, cell surface marker analysis,
prothrombin time, fibrinogen, glucose, and HbA1C
tests, and 247,789 urine samples were examined.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2016, 47,399 ECG, 25,490
pulmonary function tests, 11,384 echocardiography
tests, 17,544 abdominal echography tests, and 10,258
EEG were performed.
The Hospital Ward Section
This section has been recently founded and is incharge of laboratory tests, mainly ECG, for seriouslyill, hospitalized patients. In the future, this section isgoing to be further expanded since there is so much435

demand from clinical doctors.

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.
The reversed CPC program is presented to the sixth
grade students. Laboratory practice teaching isprovided for the sixth year medical students, in small
groups of 6-7 students for one-week duration. In thiscourse, students learn clinical and practical knowledge
and techniques 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) the clinical significance of reticulated
platelets and immature platelet fraction, iv) novel
biomarker in liver diseases, v) genetic testing, vi)
bioactive peptides, especially adrenomedullin, vii)
oxidative stress and organ injury, viii) analysis ofcardiac functions using ultrasound, ix) elucidation ofabnormality in epigenetics in cancer and its clinicalapplication, and x) analysis of brain function using
magnetoencephalography and near-infrared spectroscopy.

References
Original article:
1. Akaishi, M., Asanuma, T., Izumi, C., Iwanaga, S.,
Kawai, H., Daimon, M., Toide, H., Hashimoto, S.,
Hayashida, A., Yamada, H.,and Nakatani, S.
Guidelines for conducting transesophageal echocardiography (TEE) : Task force for guidelines for
conducting TEE: November 15, 2015. J.
Echocardiogr. 14:47-48, 2016.

2. Altinel K., Hashimoto K., Wei Y., Neuveut C.,
Gupta I., Suzuki AM., Dos Santos A., Moreau P.,
Xia T., Kojima S., Kato S., Takikawa Y., Hidaka
I., Shimizu M., Matsuura T., Tsubota A., Ikeda H.,
Nagoshi S., Suzuki H., Michel ML., Samuel D.,
Buendia MA., Faivre J., and Carninci P. SingleNucleotide Resolution Mapping of Hepatitis B
Virus Promoters in Infected Human Livers andHepatocellular Carcinoma. J Virol. 90:1081110822, 2016.
3. Chiang, SJ., Daimon, M., Miyazaki, S., Kawata,T., Ichikawa-Morimoto, R., Maruyama, M.,
Ohmura, H., Miyauchi, K., Lee, SL., Daida, H.
When and how aortic stenosis is first diagnosed: asingle-center observational study. J. Cardiol. 68:
324–328, 2016.
4. Daikoku, T., Yatomi, Y., and Yumoto, M.
Pitch-class distribution modulates the statisticallearning of atonal chord sequences. Brain Cogn.
108: 1-10, 2016.
5. Enooku, K., Uranbileg, B., Ikeda, H., Kurano, M.,
Sato, M., Kudo, H., Maki, H., Koike, K.,
Hasegawa, K., Kokudo, N., and Yatomi, Y.
Higher LPA2 and LPA6 mRNA levels inhepatocellular carcinoma are associated withpoorer differentiation, microvascular invasion andearlier recurrence with higher serum autotaxin
levels. PLoS One. 11: e0161825, 2016.
6. Hirohama, D., Kawakami-Mori, F., Ogura, S., Mu,
S., Jimbo, R., Uetake, U., Yatomi, Y., Nangaku,M., Fujita, T., and Shimosawa, T. Renal
Denervation
Improves
Cardiac
DiastolicDysfunction by Restoring Serca2a Transcriptionin Uninephrectomized Rats. J. Hypertens. (LosAngel) 5:225., 2016.
7. Hirokawa, M., Daimon, M., Lee, S.L., Nakao, T.,
Kawata, T., Kimura, K., Kato, T.S., Mizuno, Y.,
Watanabe, M., Yatomi, Y., Yamazaki, T., andKomuro, I. Early menopause does not influenceleft ventricular diastolic dysfunction: A clinicalobservational study in healthy subjects. J. Cardiol.
68:548–553, 2016.
8. Ishikawa, R., Amano, Y., Kawakami, M.,
Sunohara, M., Watanabe, K., Kage, H., Ohishi, N.,
Yatomi, Y., Nakajima, J., Fukayama, M., Nagase,T., and Takai, D. The chimeric transcript
RUNX1-GLRX5: a biomarker for good436

postoperative prognosis in stage IA non-small celllung cancer. Jpn. J. Clin. Oncol. 46:185-189,
2016.
9. Kimura, K., Morita, H., Daimon, M., Horio, M.,
Kawata, T., Nakao, T., Hirokawa, M., Kitao, R.,
Watanabe, D., Komori, T., Nagata, T., Takeda, S.,
Komaki, H., Segawa, K., Nakajima, T., Takenaka,K., and Komuro, I. Utility of Cystatin C for
Estimating Glomerular Filtration Rate in Patients
With Muscular Dystrophy. Int. Heart J. 57:
386-388, 2016.
10. Kurano, M., Hara, M., Nojiri, T., Ikeda, H.,
Tsukamoto, K., and Yatomi, Y. Resveratrol exerts
a biphasic effect on apolipoprotein M. Br. J.
Pharmacol. 173:222-233, 2016.
11. Kurano, M., Tsukamoto, K., Kamitsuji, S.,
Kamatani, N., Hara, M., Ishikawa, T., Kim B.J.,
Moon S., Kim Y.J., and Teramoto, T.
Genome-wide association study of serum lipids
confirms previously reported, associations as well
as new associations of common SNPs within
PCSK7 gene with triglyceride. J. Hum. Genet.
61:427-433, 2016.
12. Lee, SL., Daimon, M., Nakao, T., Singer, DE.,
Shinozaki, T., Kawata, T., Kimura, K., Hirokawa,
M., Kato, TS., Mizuno, Y., Watanabe, M., Yatomi,
Y., Yamazaki, .T, and Komuro, I. Factors
Influencing Left Atrial Volume in a Population
with Preserved Ejection Fraction: Left Ventricular
Diastolic Dysfunction or Clinical Factors? J.
Cardiol. 68:275–281, 2016.
13. Lee, SL., Daimon, M., Di, Tullio, MR., Homma,
S., Nakao, T., Kawata, T., Kimura, K., Shinozaki,T., Hirokawa, M., Kato, T.S., Mizuno, Y.,
Watanabe, M., Yatomi, Y., Yamazaki, T., andKomuro, I. Relationship of Left Ventricular
Diastolic Function to Obesity and Overweight in a
Japanese Population With Preserved Left
Ventricular Ejection Fraction. Circ. J. 80:19511956, 2016.
14. Morita, K., Nakamura, F., Taoka, K., Satoh, Y.,
Iizuka, H., Masuda, A., Seo, S., Nannya, Y.,
Yatomi, Y., and Kurokawa M. Incidentallydetected t(9;22)(q34;q11) /BCR-ABL1-positive
clone developing into chronic phase chronic
myeloid leukaemia after four years of dormancy.
Br. J. Haematol. 174: 815-817, 2016.

15. Nagura, Y., Tsuno, NH., Kano, K., Inoue, A.,
Aoki, J., Hirowatari, Y., Kaneko, M., Kurano, M.,
Matsuhashi, M., Ohkawa, R., Tozuka, M., Yatomi,
Y., and Okazaki, H. Regulation of thelysophosphatidylserine
andsphingosine
1-phosphate levels in autologous whole blood by
the pre-storage leukocyte reduction. Transfus
Med. 26: 365-372, 2016.
16. Otsuka, A., Yumoto, M., Kuriki, S., Hotehama, T.,
and Nakagawa, S. Frequency characteristics ofneuromagnetic auditory steady-state responses tosinusoidally amplitude-modulated sweep tones.
Clin. Neurophysiol. 127:790-802, 2016.
17. Sato M, Ikeda H, Uranbileg B, Kurano M, Saigusa
D, Aoki J, Maki H, Kudo H, Hasegawa K,
Kokudo N, Yatomi Y. Sphingosine kinase-1, S1Ptransporter spinster homolog 2 and S1P2 mRNA
expressions are increased in liver with advanced
fibrosis in human. Sci. Rep. 6: 32119. , 2016.
18. Sato, M., Ohkawa, R., Yoshimoto, A., Yano, K.,
Ichimura, N, Nishimori, M., Okubo, S., Yatomi,
Y., and Tozuka, M. Effects of serum amyloid A
on the structure and antioxidant ability ofhigh-density lipoprotein. Biosci. Rep. 36:e00369,
2016.
19. Shimizu, M., Furuichi, K., Toyama, T., Yamahana,J., Ohkawa, R., Igarashi, K., Aoki, J., Kaneko, S.,
Yatomi, Y., and Wada, T. Serum autotaxin levels
are associated with proteinuria and kidney lesions
in Japanese type 2 diabetic patients withbiopsy-proven diabetic nephropathy. Internal
Medicine 55:215-221, 2016.
20. Shinohara, K., Hamasaki, N., Takagi, Y., Yatomi,Y., Kikuchi, H., Hosogaya, S., Kawai, Y.,
Miyachi, H., Kaneko, K., Miyajima, Y.,
Matsumoto, H., Yamamoto, Y., Iwagami, M.,
Osawa, S., Umeda, M., Koide, H., Yoshimura, D.,
and Kato, H. Multi-analyte conventional referencematerial (MacRM): a useful tool for nationwide
standardization of laboratory measurements for
medical care (a model study in Japan). Clin.
Chem. 62:392-406, 2016.
21. Shukuya, K., Ogura, S., Tokuhara, Y., Okubo, S.,
Yatomi, Y., Tozuka, M., and Shimosawa, T.
Novel Round Cells in Urine Sediment and Their
Clinical Implications Clin. Chim. Acta. 457:
142-149, 2016.

437

22. Soroida, Y., Sato, M., Hikita, H., Hagiwara, S.,
Sato, M., Gotoh, H., Kato, S., Iwai, T., Yamazaki,T., Yatomi, Y., Sasano, T., and Ikeda, H.
Pancreatic cysts in general population on
ultrasonography: Prevalence and development ofrisk score. J. Gastroenterol. 51:1133-1140, 2016.
23. Suga, M., Nishimura, Y., Kawakubo, Y., Yumoto,M., and Kasai, K. MEG recording of auditory
mismatch negativity in response to duration andfrequency deviants in a single session in patientswith schizophrenia. Psychiatry Clin. Neurosci.
70:295-302, 2016.
24. Tanaka, M., Shukuya, K., Morita, Y., Kagaeyama,Y., Okubo. S., Shimosawa, T., and Yatomi, Y.
Performance Evaluation of the XN-550
Automated Hematology Analyzer Body Fluid
Mode – Considerations for Operational
Conditions for Cell Counting With Cerebrospinal
andSynovial
Fluids.
SysmexJournalInternational 26(1): 1-9, 2016.
25. Tokushige, S., Terao, Y., Uchio, N., Tsuji, S., andYumoto, M. Adult onset ictal aphasia withepileptic discharges in Broca's and Wernicke's
areas. Clin. Neurophysiol. 127:1754-1756, 2016.
26. Uranbileg, B., Ikeda, H., Kurano, M., Enooku, K.,
Sato, M., Saigusa, D., Aoki, J., Ishizawa, T.,
Hasegawa, K., Kokudo, N., and Yatomi, Y.
Increased mRNA Levels of Sphingosine Kinases
and S1P Lyase and Reduced Levels of S1P Were
Observed in Hepatocellular Carcinoma in
Association with Poorer Differentiation andEarlier Recurrence. PLoS One. 11:e0149462,
2016.
27. Yoshikawa, N., Masuda, A., Jona, M., Okubo, S.,
Nannya, Y., Yokota, H., Kurokawa, M., andYatomi, Y. Evaluation of Immature Platelet
Fraction Measurements Using a AutomatedHematology Analyzer, Sysmex XN. Rinsho Byori(The official journal of Japanese Society ofLaboratory Medicine)64: 1220-1228, 2016.
Review article, Book:
1. Nakao, T., Morita, H. Neuromuscular Electrical
Stimulation in Patients With Acute Myocardial
Infarction. Int Heart J. 57:659-660, 2016.
2. Ogura,S., Latapati, R., Shimosawa, T. andNakayama, T. Vascular Inflammation andHypertension. Austin J. Cardiovasc. Dis.
Atherosclerosis 3:1017, 2016.
3. Uetake, U., Akabayashi, A., and Yatomi, Y.
Environment for Research Ethics in Japan.
Clinical Case Reports, Research & Trials 1:1-4,
2016.
4. Xu, B., Daimon, M. Cardiac aging phenomenon
and its clinical features by echocardiography. J.
Echocardiogr. 14: 139–145, 2016.
5. Yumoto, M., and Daikoku, T. Auditory System
Basic Function. Clinical Applications ofMagnetoencephalography (eds., Tobimatsu, S.,
and Kakigi, R.) pp. 97-112, Springer Japan, Tokyo.
2016

438

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
Kazuhiro Fukatsu. M.D., Ph.D.

Lecturer
Takami Komatsu, M.D., Ph.D.
Ryoji Fukushima, M.D., Ph.D.

Associate
Saito Yuhei, M.S.
Satoshi Murakoshi, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/syujutsu/index.html

Introduction and Organization
Uniform management of operating rooms (OR) firstbegan at the University of Tokyo Hospital in July
1955. The office, so called the surgical center, waslocated in the Old Central Building till December
1987. The center moved to the new Central Clinical
Service Building 1 on 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 number of ORs andnurses.
In July 2001, the branch hospital in Mejiro area wasmerged with the University of Tokyo Hospital in
Hongo area, which opened a new Ward 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, werenovated an OR into a hybrid OR that 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 theyear 2006, the Central Clinical Service Building 2,
which had 11 ORs, was completed to solve theshortage of the number of ORs. As a result, the total
number of ORs became 23, and then the number ofoperations 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 and 11,161
operations were performed in 2006, 2007, 2008, 20092010, 2011, 2012, 2013, 2014, 2015 and 2016 fiscal
year, respectively. The number of operations in 2016
fiscal year counts for approximately 1.8 times
comparing to that in 2001.

439

These days more and more patients undergo theoperation, using endoscopic technique, 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 withpositive test for 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 (HAI) are criticalissues in the surgical center. It is mandatory to educate
how to prevent HAI and occupational infections. As
the number of operation of the patients withemergence and re-emergence infectious diseases suchas HIV and tuberculosis has increased, all health carestaff in the surgical center are required to adhere to theprinciples of standard precautions and transmissionbased 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

440

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,
preventionofperioperative
infections,andmaintenance of reusable surgical instruments such as
forceps, scissors and clamps. These subjects are
summarized and stated in the manual. Lectures arealso given to the senior technical officers andtemporary employees to promote their technicalknowledge and skills.

Research Activities
1) Safe surgery and risk management in the OR2) Improvement of cost-effectiveness in the surgicaltreatment
3) Development of central monitoring system using
IT technology
4) Introduction of robot-assisted operation
5) Efficient use of human resources6) Introduction of advanced operation assisted by the
microscopy and/or laparoscopy
7) Proper
managementof
equipmentofendoscopy-assisted 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（2016）
1. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Novel concept of cleanlinessof instruments for robotic surgery. J Hosp Infect2016; 93: 360-361.
2. Furuya Y, Hiroshima K, Wakahara T, Akimoto H,
Yanagie H, Harigaya K, Yasuhara H. Undifferentiated carcinoma of the gallbladder with endothelial differentiation: A case report and literature review. Molecular and Clinical Oncology 2016;
5(6): 773-776.
3. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Safety management in OR
utilizing perioperative nursing documentation.
Japanese Journal of Operative Medicine 2016;37(3): 175-178 (in Japanese)

441

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, 73 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 one hundred and fifty 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 four 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,442

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, C-11,
N-13 and O-15. Whole body FDG-PET for staging of
malignancy plays an important role in the clinicalmanagement of the patients. These nuclear imaging
procedures are performed and reported by radiologists
and cardiologists.
3) Radiation Oncology:
The radiation therapy is performed 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.

443

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Lecturer
Tappei Takada, Ph.D.

Research Associate
Takahiro Amemiya, Ph.D.,

Yuki Ikebuchi, Ph.D.,

Yoshiyuki Ohno, Ph.D.,

Yoshiaki Kariya, Ph.D.,

Kazuo Takayama,

Tomoko Mayuzumi,

Yoshihide Yamanashi, Ph.D.,

Homepage

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

Introduction and Organization
We have 9 faculty members, 72 pharmacy staffs,
and 10 graduate students and 2 undergraduate students
from the faculty of pharmaceutical sciences (as ofJanuary 1st, 2017). In addition, project associate
professor (Masashi Honma, Ph.D.) is involved in ourwork.

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 of444

every information of drug affairs. Drug management section takes care of supplying and safekeeping of all the in-hospital medicines (2,461
items), out-patient medicines, anesthetics, muscle
relaxation drugs, psychotropic drugs, poison
medicines.
5) Narcotic section
Under the supervision of authorized manager fornarcotics (the director of the department ofpharmacy), narcotics are properly managed,
recorded, reported, inspected and directed.
Narcotics are properly arranged and managed at
the dispensing section and each medical caresection.
6) Ward section
They contribute to the team medical care byproviding specialized drug information andsharing them with all the staffs involved in thetreatment as follows;① Supporting the proper use of medication bypharmacists stationed at ICU sections.
② Arrangement and mixing of injections forpatients at the staff station of Hematology andOncology.
③ Investigation of carrying medicines and theadverse effect histories, allergy histories etc. at
the time of hospitalization. Participation for
conferences. Procurement and appraisal ofpatients’ basic information about the disease,compilation of the medicine history. Monitoringof medication guidance and the adverse effectfor patients, and compilation of guidance record.
Offering the doctor with drug information,prescription design support and detailed
contents of medication guidance to each patient.
④ Investigation and management of ward stock
medicine.
⑤ Nutrient support of the patients as a member of
NST.
⑥ Management of proper use of narcotics as amember of palliative care team.
⑦ Management of proper use of antibiotics,
rounds of a hospital ward, and training of thestaffs as a member of ICT.
Statistical Data (fiscal year 2016)
Number of items on in-hospital formulary: 2,461

Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
416,282 ps.
(outside :347,579 ps.)(inside :68,703 ps.)out-patient chemotherapy:
12,478 ps.
in-patients :238,190 ps.
injection drugs:
209,470 ps.
IVH:
3,948 ps.
chemotherapy:
10,208 pp.
TDM consultations (annual) :16,128 pp.
Numbers of hospital pharmaceutical cares (annual):
18,186 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

445

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 thehospital is one of the most important curriculums. In
2016, 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 andeducated them for 2.5 months. In addition, we have
had an original one-year post-graduate training course
for pharmacists 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
continued by shortening the period to half a year. In
2016, 11 pharmacists finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

2.

3.

4.

5.

uric acid, and establishment of new therapy forlife-style related diseases based on those
integrated understanding.
Elucidation of the dynamic regulatory mechanismof bone resorption / bone formation, and establishment of new therapy for bone metabolic disease
based on those integrated understanding.
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.
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.
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) Higashino T, Matsuo H, Sakiyama M, Nakayama A,
Nakamura T, Takada T, Ogata H, Kawamura Y,
Kawaguchi M, Naito M, Kawai S, Takada Y,
Ooyama H, Suzuki H, Shinomiya N. Common
variant of pdz domain containing 1 (PDZK1) geneis associated with gout susceptibility: A replication
study and meta-analysis in Japanese population.
Drug Metab Pharmacokinet. 2016;31:464-66.
(2) Matsuo H, Tsunoda T, Ooyama K, Sakiyama M,
Sogo T, Takada T, Nakashima A, Nakayama A,
Kawaguchi M, Higashino T, Wakai K, Ooyama H,
Hokari R, Suzuki H, Ichida K, Inui A, Fujimori S,
Shinomiya N. Hyperuricemia in acute gastroenteritis is caused by decreased urate excretion via
ABCG2. Sci Rep. 2016;6:31003.
(3) Matsuo H, Yamamoto K, Nakaoka H, Nakayama A,
Sakiyama M, Chiba T, Takahashi A, Nakamura T,
Nakashima H, Takada Y, Danjoh I, Shimizu S, Abe
J, Kawamura Y, Terashige S, Ogata H, Tatsukawa S,
Yin G, Okada R, Morita E, Naito M, Tokumasu A,
Onoue H, Iwaya K, Ito T, Takada T, Inoue K, Kato
Y, Nakamura Y, Sakurai Y, Suzuki H, Kanai Y,

1. Elucidation of the molecular mechanism which
controls in vivo disposition of lipids / bile acids /446

Hosoya T, Hamajima N, Inoue I, Kubo M, Ichida K,
Ooyama H, Shimizu T, Shinomiya N. Genome-wide
association study of clinically defined gout
identifies multiple risk loci and its association withclinical subtypes. Ann Rheum Dis. 2016;75:652-9.
(4) Miyata H, Takada T, Toyoda Y, Matsuo H, Ichida K,
Suzuki H. Identification of febuxostat as a newstrong ABCG2 inhibitor: Potential applications andrisks in clinical situations. Front Pharmacol. 2016;
7:518.
(5) Miyata Y, Akamatsu N, Sugawara Y, Kaneko J,
Yamamoto T, Suzuki H, Arita J, Sakamoto Y,
Hasegawa K, Tamura S, Kokudo N. Pharmacokinetics of a once-daily dose of tacrolimus early
after liver transplantation: With special reference to
CYP3A5 and ABCB1 single nucleotide polymorphisms. Ann Transplant. 2016;21:491-9.
(6) Sakiyama M, Matsuo H, Shimizu S, Nakashima H,
Nakamura T, Nakayama A, Higashino T, Naito M,
Suma S, Hishida A, Satoh T, Sakurai Y, Takada T,
Ichida K, Ooyama H, Shimizu T, Shinomiya N. The
effects of URAT1/SLC22A12 nonfunctionalvariants, R90H and W258X, on serum uric acidlevels and gout/hyperuricemia progression. Sci Rep.
2016;6:20148.
(7) Stiburkova B, Miyata H, Zavada J, Tomcik M,
Pavelka K, Storkanova G, Toyoda Y, Takada T,
Suzuki H. Novel dysfunctional variant in ABCG2
as a cause of severe tophaceous gout: Biochemical,
molecular genetics and functional analysis.
Rheumatology (Oxford). 2016;55:191-4.
(8) Sugamori Y, Mise-Omata S, Maeda C, Aoki S,
Tabata Y, Murali R, Yasuda H, Udagawa N, Suzuki
H, Honma M, Aoki K. Peptide drugs accelerate
BMP-2-induced calvarial bone regeneration andstimulate osteoblast differentiation throughmTORC1 signaling. Bioessays. 2016;38:717-25.
(9) Takaki J, Ohno Y, Yamada M, Yamaguchi R, Hisaka
A, Suzuki H. Assessment of drug-drug interaction
between warfarin and aprepitant and its effects on
PT-INR of patients receiving anticancer chemotherapy. Biol Pharm Bull. 2016;39:863-8.
(10) Tomioka NH, Tamura Y, Takada T, Shibata S,
Suzuki H, Uchida S, Hosoyamada M. Immunohistochemical and in situ hybridization study ofurate transporters glut9/uratv1, abcg2, and urat1 in
the murine brain. Fluids Barriers CNS. 2016;13:22.

(11) Toyoda Y, Gomi T, Nakagawa H, Nagakura M,
Ishikawa T. Diagnosis of human axillary osmidrosis
by genotyping of the human ABCC11 gene:
Clinical practice and basic scientific evidence.
Biomed Res Int. 2016;2016:7670483.
(12) Toyoda Y, Takada T, Miyata H, Ishikawa T,
Suzuki H. Regulation of the axillary osmidrosisassociated ABCC11 protein stability by N-linked
glycosylation: Effect of glucose condition. PLoS
One. 2016;11:e0157172.
(13) Toyoda Y, Takada T, Suzuki H. Halogenatedhydrocarbon solvent-related cholangiocarcinoma
risk: Biliary excretion of glutathione conjugates of
1,2-dichloropropane evidenced by untargeted
metabolomics analysis. Sci Rep. 2016;6:24586.

447

Delivery Unit
Professor
Tomoyuki Fujii

Associate Professor
Takeshi Nagamatsu

Homepage

http://www.iiosan.umin.jp/index.html

Organization
The Delivery Unit of the University of Tokyo
Hospital is organized by one professor, one associate
professor and about 10 fellows. All the staff members
are taking part in research activities of reproductive
endocrinology, gynecologic oncology, or perinatal
medicine, as well as being engaged with in-patient andout-patient care for pregnant women including theactivities in the delivery units.

Activities
Total number of delivery cases was 1065 (22 weeks
later) in 2016.
Recently, cases of obstetrical emergencies like
abruptio placentae, eclampsia and uterine rupturestransported from neighboring hospitals have been
increasing. Three doctors and three midwives are on
duty every night. Our service is an important part ofTokyo Metropolitan Service System for Maternal
Welfare and Perinatal Medicine.

References[See Department of Perinatal Medicine.]

448

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Lecturer

Yusuke Shinoda, M.D.

Research Associate
Yauo Nakahara, 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 the present time our department consists of four
sections. Rehabilitation physicians’ section includes
five full-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. Eighteen
physical therapists are working in the physical therapy
section. In the occupational therapy section, five
occupational therapists work for the generalrehabilitation service and the other four therapists
work for the psychiatric rehabilitation. Four acupuncture therapists perform acupuncture and moxbustion.

In the Day-care Unit, clinical psychologists and nurses
also work. In 2006, speech therapists who had
belonged to other departments in the University ofTokyo Hospital were included in our department.
From 2009, a speech therapist added to ourdepartment, and now three therapists perform therapy
for patients with aphasia, dysarthria, and dysphagia.

Clinical activities
The professor serves as a director of Rehabilitation
Center, the University of Tokyo Hospital. The Rehabilitation Center and the Department of Rehabilitation
Medicine are united and engage in clinical practice.
We have at present no charged ward, and treat about
4,000 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
medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such as449

cerebrovascular 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 year students from Wednesday to
Friday every week. They experience a few patientsand learn how to take a patients’ history, physicalfindings, functional evaluation, and how to plan
rehabilitation programs. We have introduced a few ofelective students for elective clinical clerkship to ourcollaborating hospitals with specialized rehabilitationward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

2.

3.

4.

5.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with other departments in our hospital, other faculties in our university,and institutions outside the University of Tokyo. The
ongoing and scheduled projects are as follows.
1) 3D Motion analysis of patients with musculoskeletal disorders
2) Study on the relationship between sensory deficit
and motor control
3) Rehabilitation and long-term outcome in patientswith skeletal dysplasias
4) Pathology and treatment for patients withcongenital limb deficiencies
5) Analysis of rehabilitation outcome using DPC
data

6.

7.

8.

References
1. Amao R, Imamura T, Nakahara Y, Kinoshita O,
Yamauchi H, Ono M, Haga N: Reversible motor
paralysis and early cardiac rehabilitation in9.

patients with advanced heart failure receiving left
ventricular assist device therapy. Int Heart J 57(6):766-768, 2016
Amao R, Imamura T, Sawada Y, Endo S, Ozaki S,
Okamura K, Masuzawa A, Takaoka T, Hirata Y,
Shindo T, Ono M, Haga N: Experiences with
Aggressive Cardiac Rehabilitation in PediatricPatients Receiving Mechanical Circulatory
Supports. Int Heart J 57(6): 769-772, 2016
Goto M, Haga N, Yokota K,Takamizawa K,
Takedani H: A successful physiotherapy
management case of a patient with acquired
hemophilia A prior to factor VIII inhibitor
eradication. Haemophilia 22(3): e228-231, 2016
Goto M, Takedani H, Yokota K, Haga N:
Strategies to encourage physical activity inpatients with hemophilia to improve quality of life.
J Blood Med 7: 85-98, 2016
Hasegawa S, Nishimura G, Victoria T, Zackai E,
Kayserili H, Haga N, Nakashima Y, Miyazaki O,
Kitoh H: Characteristic calcaneal ossification: an
additional early radiographic finding in infants
with fibrodysplasia ossificans progressiva.
Pediatric Radiology 46(11): 1568-1572, 2016
Iwashiro S, Koike S, Satomura Y, Suga M, Nagai
T, Natsubori T, Tada M, Gonoi W, Takizawa R,
Kunimatsu A, Yamasue H, Kasai K: Association
between impaired brain activity and volume at the
sub-region of Broca's area in ultra-high risk andfirst-episode schizophrenia: a multi-modal neuroimaging study. Schizophr Res 172(1-3): 9-15,
2016
Iwata S, Uehara K, Ogura K, Akiyama T, Shinoda
Y, Yonemoto T, Kawai A: Reliability and validityof a Japanese-language and culturally adapted
version of the Musculoskeletal Tumor Society
scoring system for the lower extremity. Clin
Orthop Relat Res 474(9): 2044-2052, 2016
Kaneoka A, Pisegna JM, Saito H, Lo M, Felling K,
Haga N, LaValley PM, Langmore SE: A
systematic review and meta-analysis ofpneumonia associated with thin liquid vs.
thickened liquid intake in patients who aspirate.
Clin Rehabil. Epub ahead of print. 2016
Kinoshita Y, Arai M, Ito N, Takashi Y, Makita N,
Nangaku M, Shinoda Y, Fukumoto S: High serum
ALP level is associated with increased risk of450

denosumab-related hypocalcemia in patients withbone metastases from solid tumors. Endocr J
63(5): 479-84, 2016
10. Nakahara Y, Yasunaga H, Inokuchi H, Ogata N,
Horiguchi H, Matsuda S, Fushimi K, Haga N:
Mortality-reducing effect of rehabilitation for
COPD: observational propensity-matched cohort
study using a Nationwide Database. Respir Care61(11): 1497-1504, 2016
11. Nishimura G, Nakajima M, Takikawa K, Haga N,
Ikegawa S: Distinctive skeletal phenotype in highbone mass osteogenesis imperfecta due to a
COL1A2 cleavage site mutation.Am J Med Genet
A 170(8): 2212-2214, 2016
12. Nishimura Y, Kawakubo Y, Suga M, Hashimoto K,
Takei Y, Takei K, Inoue H, Yumoto M, Takizawa
R, Kasai K: Familial influences on mismatch
negativity and its association with plasma
glutamate level: a magnetoencephalographic
study in twins. Mol Neuropsychiatry 2: 161–172,
2016
13. Ohki T, Ushiku T, Shinoda Y, Kobayashi H:
Necrotic lipoma at the posterior thigh mimicking
liposarcoma. BMJ Case Rep 2016 Jan 27, 201614. Suga M, Nishimura Y, Kawakubo Y, Yumoto M,
Kasai K: Magnetoencephalographic recording ofauditory mismatch negativity in response to
duration and frequency deviants in a single
session in patients with schizophrenia. Psychiatry
Clin Neurosci 70(7): 295-302, 2016

451

Central Supply Service
Associate Professor
Kazuhiko Fukatsu, M.D., Ph.D.

Associate
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 instructor, one
nurse, 10 staff members, and 26 members fromexternal staff sources are the main members of thisdivision.

Facilities
The following facilities are located in an area of
1,077 square meters :Cleaning equipment : 7 washer disinfectors (WDs), 1
vacuum-ultrasonic cleaning unit.
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: 30435 for surgical center,
14201for wards and outpatient clinics in 2015).
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 6651 in 2015.

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. Shimizu N, Hatao F, Fukatsu K, Aikou S,
Yamagata Y, Mori K, Yamashita H, Nomura S,
Seto Y. Results of a nationwide questionnairebased survey on nutrition management following
gastric cancer resection in Japan. Surg Today.

4522017 Jun 9. doi: 10.1007/s00595-017-1552-4.
[Epub ahead of print]
2. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Priority of Patient Safety
Associated With Robotic Surgical InstrumentsResponse to Landenberg et al. Infect Control
Hosp Epidemiol. 2017 Jul;38(7):879-880.
3. Hatao F, Chen KY, Wu JM, Wang MY, Aikou S,
Onoyama H, Shimizu N, Fukatsu K, Seto Y, Lin
MT. Randomized controlled clinical trial
assessing the effects of oral nutritional supplements in postoperative gastric cancer patients.
Langenbecks Arch Surg. 2017 Mar;402(2):203211.
4. Ri M, Fukatsu K, Miyakuni T, Yanagawa M,
Murakoshi S, Yasuhara H, Seto Y. Influences of
Vagotomy on Gut Ischemia-Reperfusion Injury inMice. Shock. 2017 May;47(5):646-652.
5. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Challenging Residual
Contamination of Instruments for Robotic Surgery
in Japan. Infect Control Hosp Epidemiol. 2017
Feb;38(2):143-146.
6. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Novel concept ofcleanliness of instruments for robotic surgery. J
Hosp Infect. 2016 Aug;93(4):360-1.
7. Moriya T, Fukatsu K, Iwaya K, Ikezawa F, Saitoh
D, Hase K, Yamamoto J. The effect of dietary
restriction on hepatic mononuclear cell number
and function in mice. J Surg Res.2015.
8. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Time-dependent influenceon assessment of contaminated environmental
surfaces in operating rooms. Am J Infect Control.
2015 Jun 3. pii: S0196-6553(15)00462-9. doi: 10.
1016/j.ajic.2015.04.196. [Epub ahead of print]
9. Moriya T, Fukatsu K, Noguchi M, Okamoto K,
Murakoshi S, Saitoh D, Miyazaki M, Hase K,
Yamamoto J. Intravenous administration of highdose Paclitaxel reduces gut-associated lymphoidtissue cell number and respiratory immunoglobulin A concentrations in mice. Surg Infect(Larchmt). 2014 Feb;15(1):50-7.
10. Fukatsu K. Impact of the feeding route on gut
mucosal immunity. Curr Opin Clin Nutr Metab
Care. 2014 Mar;17(2):164-70

11. Moriya T, Fukatsu K, Iwaya K, Noguchi M,
Murakoshi S, Okamoto K, Kubo T, Saitoh D,
Hase K, Yamamoto J. Influence of fish to soybean
oil ratio on hepatic mononuclear cell function andsurvival after intraportal bacterial challenge inparenterally fed mice. Surgery. 2014 Apr;155(4):711-8.
12. Yasuhara H, Fukatsu K, Komatsu T, Murakoshi S,
Saito Y, Uetera Y. Occult Risk of Broken
Instruments for Endoscopy-assisted Surgery.
World J Surg. 2014 Jun 21. [Epub ahead of print]
13. Yanagawa M, Fukatsu K, Mitsui T, Murakoshi S,
Noguchi M, Yasuhara H, Nishimura R. Effects ofa New Immune-Modulating Diet Enriched with
Whey-Hydrolyzed Peptide, Fermented Milk, andIsomaltulose on Gut Associated Lymphoid Tissue
in Mice. eSPEN. 2013
14. Mitsui T, Fukatsu K, Yanagawa M, Amenomori S,
Ogawa E, Fukuda T, Murakoshi S, Moriya T,
Yasuhara H, Seto Y. Truncal vagotomy causes
temporal decreas of pro- and anti-inflammatory
cytokine levels in small intestine. Surg Today.
2014 Jun;44(6):1123-7.
15. Okamoto K, Fukatsu K, Hashiguchi Y, Ueno H,
Shinto E, Moriya T, Saitoh D, Yamamoto J, Hase
K. Lack of Preoperative Enteral Nutrition
Reduces Gut-Associated Lymphoid Cell Numbersin Colon Cancer Patients: A Possible Mechanism
Underlying Increased Postoperative Infectious
Complications During Parenteral Nutrition. Ann
Surg. 2013 Dec;258(6):1059-64.
16. Fukatsu K. The long road to optimizing theparenteral provision of nutrients. JPEN J Parenter
Enteral Nutr. 2012 Mar;36(2):157-8.
17. Moriya T, Fukatsu K, Maeshima Y, Ikezawa F,
Hashiguchi Y, Saitoh D, Miyazaki M, Hase K,
Yamamoto J. The effect of adding fish oil toparenteral nutrition on hepatic mononuclear cellfunction and survival after intraportal bacterial
challenge in mice. Surgery. 2012 May;151(5):745-55.
18. Yasuhara H, Fukatsu K, Komatsu T, Obayashi T,
Saito Y, Uetera Y.Prevention of medical accidents
caused by defective surgical instruments. Surgery.
2012 Feb;151(2):153-61.

453

19. Fukatsu K. Friend or foe? Linkage between
hormonal response and innate immunity. J Surg
Res. 2012 Jan;172(1):83-4.
20. Fukatsu K, Moriya T, Murakoshi S, Yasuhara H.
Interleukin-7 treatment reverses parenteralnutrition-induced impairment of resistance tobacterial pneumonia with increased secretory
immunoglobulin A levels. J Surg Res. 2012 May
15;174(2):334-8.

454

Division of Diagnostic Pathology
Professor (Director)
Masashi Fukayama, M.D., Ph.D.*

Associate Professor (Deputy Director)
Tetsuo Ushiku, M.D., Ph.D.*
Takeshi Sasaki, M.D., Ph.D. (Chief, Telepathology & Remote Diagnosis Promotion Center)

Associate Professor
Teppei Morikawa, M.D., Ph.D.*

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

Associate
Yukako Shintani, M.D., Ph.D.

Shigeki Morita, M.D., Ph.D.,

Hiroyuki Abe, M.D., Ph.D.,

Akimasa Hayashi, M.D., Ph.D.,

Atsushi Tanaka, M.D., Ph.D.
Ryu Miyagawa, Ph.D.* (Research, Investigation of Health Hazard by Radiation)
Mariko Tanaka, M.D., Ph.D. *Zen-ichi Tanei, M.D., Ph.D.*

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
University Hospital have been organized to function
as a unit.
We set up Telepathology & Remote Diagnosis
Promotion Center (TRDP Center), and started Outpatient Clinic of Pathology. Chief of TRDP Center, Dr.
Sasaki explained the detail of cancer pathology to thepatients with breast cancer.
To promote the genomic medicine in clinicalpractice, we set up Center for Genome Pathology

Standardization (assisted by Japan Agency for
Medical Research and Development) (http://genomeproject.jp/). The mission of the Center is to investigate
basic technologies for tissue banking, and to holdseminars for doctors and technicians (Drs. Sasaski,Morikawa, Kunita). Clinical Genome Conference
started in the University of Tokyo Hospital for theapplication of cancer clinical sequencing to medical
practice (Drs. T and A Ushiku) as a research project ofgenome medicine (Project organizer: Prof. HiroyukiMano).

455

Clinical activities (diagnostic
pathology and autopsy)
The annual statistics of the pathologic practice in 2016
fiscal year consisted of 17,101 cases of histologicalexamination (23,906 specimens), 17,781 cases ofcytology (22,388 specimens), 795 of frozen histology,
391 of intra-operative cytology, 55 cases of autopsy(17.7% of the autopsy rate), and 1 autopsy case froman outside hospital.
The following surgical pathology conferences are
regularly held with each clinical division for the casesof various tumors of organs; thoracic organs (Dr.
Shinozaki-Ushiku in charge), liver and pancreatobiliary tract (Drs. Ushiku, Hayashi, Tanaka), liver
metastasis (Dr. Abe), male genitourinary (Dr.
Morikawa) and female genital tracts (Dr. Ikemura),
breast (Drs. Ikemura, Sasaki), and bone and soft
tissues (Drs. Ushiku, A Tanaka). Biopsy conferences
are also held in the cases of kidney (Drs. Shintani,
Hayashi), and skin (Dr. M Tanaka).
Our aim in the pathologic practices is to provide
the correct diagnosis as soon as possible. We are
addressing ‘one-day pathology’ using a rapidhistoprocessing machinery. We also perform double
check for reviewing the reports and slides for all casesof histological examination to prevent a potential
misdiagnosis.
Virtual slide scanners have been installed, whichenabled us to deposit the biopsy specimens as digital
information. We are setting out a future providing
system of pathologic images for clinical divisions.
We hold autopsy case conferences on every
Monday. Hospital clinico-pathological conferences(CPC)is also held every month as mentioned above,and two cases are discussed in each CPC. The
contents are provided as CPC Digest by the hospitalinternet.

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. Four students
of 3rd grade took the elective clinical clerkship course.
We instructed all clinical residents (junior course)
to submit a report of CPC case as an obligatory

requirement of their medical training for each of them.
We have made out the digest version of CPC slides
open in the hospital (Drs. Shintani and Hayashi), andalso started e-learning program for interns to solve theproblems in CPC by themselves, thereby facilitating
their understanding (Dr. Ikemura).
The Division of Diagnostic Pathology received
eight junior residents (total 31 months) in 2016 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 pathologicaldiagnosis by automatic classification of renal biopsy
pathology images using Deep Learning Technology(Prof. Kazuhiko Ohe)”
We continue the study to investigate the usefulness of post mortem CT images for hospital autopsy(Drs. Shintani and Abe). We obtain postmortem
images with a CT apparatus in the autopsy-assisting
CT room, and compare the results with those of
autopsy in order to understand the patients’ pathophysiology (ref.25, 35 in Department of Pathology
and Diagnostic Pathology).
We continue the pathological studies ofneoplastic diseases on the basis of surgical pathology
conferences (see the pages of Department of
Pathology and Diagnostic Pathology). We also
cooperate for the projects developing PET and in vivo
imaging of cancers of Departments of Upper GI tract
Surgery (ref.27 in Department of Pathology and
Diagnostic Pathology) and Hepato-biliary & Pancreas
Surgery.
Dr. Miyagawa was a Research Associate ofDivision of Diagnostic Pathology, primarily engaged
in Investigation of Health Hazard by Radiation (ref.
17 in Department of Pathology and Diagnostic
Pathology).

456

References (Case Reports Only)
See the corresponding section of Department of
Pathology and Diagnostic Pathology(1) Arakawa K, Kiyomatsu T, Ishihara S, Ikemura M,
Hojo D, Takiyama H, Murono K, Otani K, Yasuda
K, Nishikawa T, Tanaka T, Kawai K, Hata K,
Nozawa H, Yamaguchi H, Watanabe T. A casereport of anorectal malignant melanoma withmucosal skipped lesion. Int J Surg Case Rep. 2016,24, 206-10(2) Ebisawa K, Koya J, Shinozaki-Ushiku A,
Nakamura F, Kurokawa M. Paraneoplastic limbic
encephalitis in B cell lymphoma unclassifiablewith features intermediate between diffuse large B
cell lymphoma and classical Hodgkin lymphoma.
Ann Hematol 2016, 95(6), 1011-2(3) Inoue M, Tanaka S, Nakatomi H, Takayanagi S,
Takahashi M, Tanaka M, Momose T, Mukasa A,
Saito N. Intracranial Infantile Myofibromatosis
Mimicking Malignant Brain Tumor: A Case
Report and Literature Review. World Neurosurg.
2016, 93, e15-20.
(4) Kanaoka R, Takahashi Y, Morita S, Dejima H,
Matsutani N, Kawamura M. Pulmonary artery
intramural leiomyosarcoma mimicking pulmonary
aneurysm. Asian Cardiovasc Thorac Ann. 2016,24(9), 896-898.
(5) Karasaki T, Murakawa T, Nagayama K, Nitadori J,
Anraku M, Kikuchi Y, Shinozaki-Ushiku A, Igaki
H, Nakajima J New onset of myasthenia gravis 10
years after proton beam therapy for thymoma.
Gen Thorac Cardiovasc Surg. 2016, 64(5), 290-3.
(6) Kawaguchi Y, Hasegawa K, Arita J, Mori K,
Yamamoto M, Ikemura M, Akamatsu N, Kaneko J,
Sakamoto Y, Kokudo N. Detection of a new
hepatic lesion suspicious for malignancy in aliving donor using intraoperative ultrasonography.
Transpl Int. 2016, 29(10), 1139-41.
(7) Koshino S, Hamaya H, Ishii M, Kojima T, Urano
T, Yamaguchi Y, Morita S, Ogawa S, Koya J,
Kurokawa, M. Efficacy of fine‐needle aspiration
cytology in the diagnosis of primary thyroid
lymphoma for elderly adults. J Am Geriatrics
Society. 2016, 64(9), e52-3.
(8) Nakamura F, Nakamura F, Ikemura M, Fukayama

M, Kurokawa M. Extraosseous plasmacytoma in
the nasal cavity after rituximab therapy against
pulmonary MALT lymphoma. Ann Hematol. 2016,
95(10), 1733-5.
(9) Namiki Y, Maeda E, Gonoi W, Akamatsu N,
Ikemura M, Ohtomo K. Pancreatic lipoma with asolid nodule mimicking invasion from adjoining
intraductal papillary mucinous neoplasm. Radiol
Case Rep. 2016 11(2), 50-3.
(10) Niikura R, Serizawa T, Yamada A, Yoshida S,
Tanaka M, Hirata Y, Koike K. Safety of
regular-dose imatinib therapy in patients withgastrointestinal stromal tumors undergoing
dialysis. Case Rep Gastroenterol. 2016, 10(1), 1723.
(11) Okuda K, Noguchi S, Narumoto O, Ikemura M,
Yamauchi Y, Tanaka G, Takai D, Fukayama M,
Nagase T. A case of Meigs' syndrome withpreceding pericardial effusion in advance of
pleural effusion. BMC Pulm Med. 2016, 16(1),71.
(12) Sugawara Y, Honda K, Katagiri D, Nakamura M,
Kawakami T, Nasu R, Hayashi A, Shintani Y, Tojo
A, Noiri E, Kurokawa M, Fukayama M, Nangaku
M. Umbilical cord blood transplantationassociated nephrotic syndrome successfully
treated by low-density lipoprotein apheresis.
Intern Med. 2016, 55(19), 2831-2836.
(13) Suzuki K, Nagasaka K, Oda K, Abe H, Maeda D,
Matsumoto Y, Arimoto T, Kawana K, Fukayama
M, Osuga Y, Fujii T. A case oflymphangioleiomyomatosis
associatedwithendometrial cancer and severe systemic lupus
erythematosus. BMC Cancer. 2016, 16, 390.
(14) Tachikawa Y, Nozawa H, Tanaka J, Nishikawa T,
Tanaka T, Kiyomatsu T, Hata K, Kawai K,
Kazama S, Yamaguchi H, Ishihara S, Sunami E,
Kitayama J, Fujisawa M, Takahashi K, Sakaguchi
Y, Ushiku T, Fukayama M, Watanabe T. Colonicperforation in a patient with systemic lupus
erythematosus accompanied by cytomegalovirus
infection: A case report. Int J Surg Case Rep. 2016,
23, 70-3.
(15) Tanaka T, Kawai K, Abe H, Murono K, Otani K,
Nishikawa T, Kiyomatsu T, Hata K, Nozawa H,
Yamaguchi H, Ishihara S, Fukayama M, Watanabe
T. Giant mucocele of the colon at the distal stump457

due to low-grade mucinous neoplasia. Surg Case
Rep. 2016, 2(1), 117.
(16) Taniguchi Y, Chikuda H, Oshima Y, Ohya J,
Matsubayashi Y, Morikawa T, Shirai H, Sasaki O,
Shibuya M, Fujio K, Yamamoto K, Tanaka S.
Thoracic intradural extramedullary lesions
causing progressive myelopathy as an initial
manifestation of granulomatosis with polyangiitis:
a case report and review of literature. J Spinal
Cord Med. 2016, 40(1), 122-125.
(17) Tojo A, Asaba K, Kinugasa S, Ikeda Y, Shintani Y,
Fukayama M, Nangaku M. The reduced
expression of proximal tubular transporters inacquired Fanconi syndrome with κ light chain
deposition. Med Mol Morphol. 2016, 49(1),48-52.
(18) Yamamoto M, Hasegawa K, Arita J, Maeno R,
Akamatsu N, Kaneko J, Watadani T, Okura N,
Hayashi A, Shibahara J, Sakamoto Y, Ohtomo K,
Fukayama M, Kokudo N. Primary hepatic
schwannoma: A case report. Int J Surg Case Rep.
2016, 29, 146-150.
(19) Yasui M, Morikawa T, Nakagawa T, Miyakawa J,
Maeda D, Homma Y, Fukayama M. Urinary
bladder carcinoma with divergent differentiation
featuring small cell carcinoma, sarcomatoid
carcinoma, and liposarcomatous component.
Pathol Res Pract. 2016, 212(9), 833-7.

458

Department of Corneal
Transplantation
Associate Professor
Tomohiko Usui, 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 of adirector (Associate Professor Tomohiko Usui).

Clinical activities
The clinical activities of this section include corneal
transplantation and outpatient clinics for various
corneal diseases as a consulting corneal service. The
director is 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 and contact lens clinic for special cases areheld every Wednesday and Friday. Contact lens clinic
for keratoconus and post-keratoplasty is held in theafternoon of Wednesday. At the corneal service, we
determine indication for corneal transplantation andfollow up patients after the surgery. Total 147 corneal
surgeries including keratoplasty were performed in2016. In addition to the full-thickness corneal
transplantation (penetrating keratoplasty), we havesuccessfully performed corneal endothelial transplantation for patients with bullous keratopathy, themost common disease of corneal transplantation.
Generally, corneal transplantation is performed as
emergency operation, because we need to transplant

corneas as soon as possible.
The other important activities of the section include
mediation of donor eyes to other university hospitals
and medical institutes that need donor eyes for corneal
transplantation with cooperation of Eyebank. We arealso performing corneal transplantation using corneas
from American Eyebank as needed.
Followings are our main clinical themes to be
pursued to improve the safety and prognosis 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 ofcorneal 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.

459

Research activities
We have pursued to apply regenerative medicine tocorneal diseases. In patients with chemical burn ofocular surface, Stevens-Johnson syndrome, and ocular
pemphigoid, we try to reconstruct the ocular surface
with autologous cultivated limbal, conjunctival andoral epithelial cells. We have established a novel
culture technique of limbal, conjunctival and oral
epithelial cells and tried a clinical examination withsuccessful results. We are also investigating regenerative medicine of corneal endothelial cells.
In addition, we are investigating the delivery of
nucleic acid based drug in corneal neovascularizationor corneal dystrophy, gene editing for corneal
dystrophy, the expression and function of novel mucin,
drug delivery system with soft contact lenses, corneal
graft rejection and statistical analysis of long term
results in corneal transplantation.

References
1. Taketani Y, Usui T, Toyono T, Shima N, Yokoo S,
Kimakura M, Yamagami S, Ohno S, Onodera R,
Tahara K, Takeuchi H, Kuroda M. Topical use ofangiopoietin-like protein 2 RNAi-loaded lipid
nanoparticles suppresses corneal neovascularizetion. Mol Ther Nucleic Acids 8;5:e292, 2016
2. Akiyama-Fukuda R, Usui T, Yoshida T,
Yamagami S. Evaluation of tear meniscus
dynamics using anterior segment swept-source
optical coherence tomography after topicalsolution instillation for dry eye. Cornea 35; 654658, 2016
3. Hayashi T, Usui T, Yamagami S. Suppression ofallograft rejection with soluble VEGF receptor 2
chimeric protein in a mouse model of corneal
transplantation. Tohoku J Exp Med 239; 81-88,
2016
4. Toyono T, Usui T, Villarreal G Jr, Kallay L,
Matthaei M, Vianna LM, Zhu AY, Kuroda M,
Amano S, Jun AS. MicroRNA-29b overexpression
decreases extracellular matrix mRNA and protein
production in human corneal endothelial cells.
Cornea 35; 1466-1470, 2016
5. Yamaguchi M, Shima N, Kimoto M, Ebihara N,
Murakami A, Yamagami S. Optimization ofcultured human corneal endothelial cell sheettransplantation
andpost-operative
sheet
evaluation in a rabbit model. Curr Eye Res 41;
1178-1184, 2016

460

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/

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 900 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 2016, 17 patients (including 2 children) received
autologous HSCT and 28 patients (including 10
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
harvest are performed for leukapheresis and preservation of autologous stem cell.

461

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. Mitsuhashi K, Kako S, Shigematsu A, Atsuta Y,
Doki N, Fukuda T, Kanamori H, Onizuka M,
Takahashi S, Ozawa Y, Kurokawa M, Inoue Y,
Nagamura-Inoue T, Morishima Y, Mizuta S,
Tanaka J; Adult Acute Lymphoblastic Leukemia
Working Group of the Japan Society for
Hematopoietic Cell Transplantation. Comparisonof Cyclophosphamide Combined with Total Body
Irradiation, Oral Busulfan, or Intravenous
Busulfan for Allogeneic Hematopoietic Cell

Transplantationin
Adultswith
Acute
Lymphoblastic Leukemia. Biol Blood Marrow
Transplant. 2016; 22:2194-2200.
2. Kanda J, Ikegame K, Fuji S, Kurokawa M, Kanamori H, Fukuda T, Ohashi K, Ishikawa J, Ogawa
H, Inoue M, Ichinohe T, Atsuta Y, Kanda Y; HLA
Working Group of the Japan Society for Hematopoietic Cell Transplantation. Haploidentical andMatched Sibling Donor Hematopoietic Cell
Transplantation for Patients with HLAHomozygous Haplotypes. Biol Blood Marrow
Transplant. 2016; 22:2031-2037.
3. Itonaga H, Iwanaga M, Aoki K, Aoki J, Ishiyama
K, Ishikawa T, Sakura T, Fukuda T, Najima Y,
Yujiri T, Mori T, Kurokawa M, Nawa Y, Uchida N,
Morishita Y, Hashimoto H, Eto T, Hirokawa M,
Morishima Y, Nagamura-Inoue T, Atsuta Y,
Miyazaki Y. Impacts of graft-versus-host diseaseon outcomes after allogeneic hematopoietic stem
cell transplantation for chronic myelomonocytic
leukemia: A nationwide retrospective study. LeukRes. 2016; 41:48-55.

462

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Mitsuhiro Fujishiro, 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 are only two doctors,
about 80 doctors from other departments including thedepartment of internal medicine, surgery, gynecology
and otorhinolaryngology, participate the endoscopic
procedures.

Clinical activities
Endoscopic procedures, including upper gastrointestinal endoscopy, colonoscopy, bronchoscopy,
otorhinolaryngological endoscopy and gynecologicalendoscopy, are performed from Monday to Friday.
Emergency endoscopy is performed in the nighttime
or holidays. The numbers of endoscopic procedures ineach field are increasing gradually year by year andthe total number during 2015 school year reached to
20,000. In the gastrointestinal tract, image enhanced
endoscopy for detail inspection and therapeuticendoscopy,
includingendoscopic
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, radiographic procedure rooms, surgery rooms
or intensive care units. All endoscopes are collectedin 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.

463

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

EGD*
Colonoscopy

8796
4360

9822
4679

10682
4996

10556
5152

10963
5208

11376
5688

11840
6000

11740
6043

11874
6394

11944
6814

Bronchoscopy

201

165

226

255

197

196

169

218

228

362

EUS**

484

402

518

551

630

698

763

766

882

1084

Enteroscopy

-

133

181

311

282

282

375

396

310

86

Laryngoscopy

91

63

75

70

108

83

128

102

105

125

Colposcopy

117

256

307

361

378

365

404

327

295

417

Total

14043

15520

16566

17256

17764

18688

19679

19592

20088

20832

*Esophagogastroduodenoscopy, **Endoscopic ultrasonography

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

References(1) Yamamichi N, Hirano C, Takahashi Y,
Minatsuki C, Nakayama C, Matsuda R,
Shimamoto T, Takeuchi C, Kodashima S, Ono S,
Tsuji Y, Fujishiro M, Wada R, Mitsushima T,
Koike K. Comparative analysis of uppergastrointestinalendoscopy,
double-contrast
upper gastrointestinal barium X-ray radiography,
and the titer of serum anti-Helicobacter pylori
IgG focusing on the diagnosis of atrophic
gastritis. Gastric Cancer. 2016 Apr;19(2):670-5.
(2) Ono H, Yao K, Fujishiro M, Oda I, Nimura S,
Yahagi N, Iishi H, Oka M, Ajioka Y, Ichinose M,
Matsui T. Guidelines for endoscopic submucosal
dissection and endoscopic mucosal resection forearly gastric cancer. Dig Endosc. 2016 Jan;28(1):3-15.
(3) Ono S, Sakaguchi Y, Tsuji Y, Kodashima S,
Yamamichi N, Fujishiro M, Koike K. Foam
plombage: a novel technique for optimal fixationof polyglycolic acid sheets positioned using "clipand pull" after esophageal endoscopic
submucosal dissection. Endoscopy. 2015;47
Suppl 1 UCTN:E435-6.
(4) Mori G, Nakajima T, Asada K, Shimazu T,
Yamamichi N, Maekita T, Yokoi C, Fujishiro M,

(5)

(6)

(7)

(8)

Gotoda T, Ichinose M, Ushijima T, Oda I.
Incidence of and risk factors for metachronous
gastric cancer after endoscopic resection andsuccessful Helicobacter pylori eradication:
results of a large-scale, multicenter cohort study
in Japan. Gastric Cancer. 2016 Jul;19(3):911-8.
Kataoka Y, Tsuji Y, Sakaguchi Y, Kodashima S,
Yamamichi N, Fujishiro M, Koike K. Preventing
esophageal stricture after endoscopic submucosal
dissection: steroid injection and shielding withpolyglycolic acid sheets and fibrin glue.
Endoscopy. 2015;47 Suppl 1:E473-4.
Nozawa H, Ishihara S, Fujishiro M, Kodashima
S, Ohtani K, Yasuda K, Nishikawa T, Tanaka T,
Tanaka J, Kiyomatsu T, Kawai K, Hata K,
Kazama S, Sunami E, Kitayama J, Watanabe T.
Outcome of salvage surgery for colorectal cancer
initially treated by upfront endoscopic therapy.
Surgery. 2016 Mar;159(3):713-20.
Tachimori Y, Ozawa S, Numasaki H, Fujishiro
M, MatsubaraH, Oyama T, Shinoda M, Toh Y,
Udagawa H, Uno T, The Registration Committee
for Esophageal Cancer of the Japan Esophageal
Society. Comprehensive Registry of Esophageal
Cancer in Japan, 2007, Esophagus 2015;12:101–
129
Tachimori Y, Ozawa S, Numasaki H, Fujishiro
M, MatsubaraH, Oyama T, Shinoda M, Toh Y,
Udagawa H, Uno T, The Registration Committee
for Esophageal Cancer of the Japan Esophageal
Society. Comprehensive Registry of Esophageal

464

Cancer in Japan, 2008, Esophagus 2015;12:130–
157(9) Tachimori Y, Ozawa S, Numasaki H, Fujishiro
M, MatsubaraH, Oyama T, Shinoda M, Toh Y,
Udagawa H, Uno T, The Registration Committee
for Esophageal Cancer of the Japan Esophageal
Society. Efficacy of lymph node dissection foreach station based on esophageal tumor location.
Esophagus. 2016;13:1-7.
(10) Yamamichi N, Hirano C, Ichinose M, Takahashi
Y, Minatsuki C, Matsuda R, Nakayama C,
Shimamoto T, Kodashima S, Ono S, Tsuji Y,
Niimi K, Sakaguchi Y, Kataoka Y, Saito I,
Asada-Hirayama I, Takeuchi C, Yakabi S,
Kaikimoto H, Matsumoto Y, Yamaguchi D,
Kageyama-Yahara N, Fujishiro M, Wada R,
Mitsushima T, Koike K. Atrophic gastritis andenlarged gastric folds diagnosed by doublecontrast upper gastrointestinal barium X-ray
radiography are useful to predict future gastriccancer development based on the 3-year
prospective observation. Gastric Cancer. 2016
Jul;19(3):1016-22.
(11) Niimi K, Aikou S, Kodashima S, Yagi K, Oya S,
Yamaguchi D, Yamashita H, Yamamichi N,
Fujishiro M, Koike K, Seto Y. Video of theMonth: A Novel Endoscopic Full-Thickness
Resection for Early Gastric Cancer. Am J
Gastroenterol. 2015 Nov;110(11):1535.
(12) Izumi M, Ikeda Y, Yamashita H, Asaoka Y,
Fujishiro M, Shin M, Abo Y. Safety andEffectiveness of Endovenous Laser Ablation
Combined With Ligation for Severe Saphenous
Varicose Veins in Japanese Patients. Int Heart J.
2016;57(1):87-90.
(13) Fujishiro M, Iguchi M, Kakushima N, Kato M,
Sakata Y, Hoteya S, Kataoka M, Shimaoka S,
Yahagi N, Fujimoto K. Guidelines for endoscopic managements of non-variceal uppergastrointestinal bleeding. Dig Endosc. 2016
May;28(4):363-78.
(14) Fujishiro M, Ikeda Y. Re-bleeding After
Endoscopic Hemostasis for Peptic Ulcer
Bleeding: Is eNough SAID or Are Other Factors
Important? Dig Dis Sci. 2016 Jun;61(6):1424-5.
(15) Sakaguchi Y, Tsuji Y, Yamamichi N, Fujishiro
M, Koike K. Successful closure of a large

perforation during colorectal endoscopic
submucosal dissection by application ofpolyglycolic acid sheets and fibrin glue.
Gastrointest Endosc. 2016 Aug;84(2):374-5.
(16) Tachimori Y, Ozawa S, Numasaki H, Fujishiro
M, Matsubara H, Oyama T, Shinoda M, Toh Y,
Udagawa H, Uno T; Registration Committee for
Esophageal Cancer of the Japan Esophageal
Society. Comprehensive Registry of Esophageal
Cancer in Japan, 2009. Esophagus. 2016;13:110137.
(17) Matsusaka K, Ishikawa S, Nakayama A, Ushiku
T, Nishimoto A, Urabe M, Kaneko N, Kunita A,
Kaneda A, Aburatani H, Fujishiro M, Seto Y,
Fukayama M. Tumor Content Chart-Assisted
HER2/CEP17 Digital PCR Analysis of Gastric
Cancer Biopsy Specimens. PLoS One. 2016 Apr
27;11(4):e0154430.
(18) Sakaguchi Y, Tsuji Y, Fujishiro M, Kataoka Y,
Takeuchi C, Yakabi S, Saito I, Shichijo S,
Minatsuki C, Asada-Hirayama I, Yamaguchi D,
Niimi K, Ono S, Kodashima S, Yamamichi N,
Koike K. Triamcinolone Injection and Shielding
with Polyglycolic Acid Sheets and Fibrin Gluefor Postoperative Stricture Prevention after
Esophageal Endoscopic Resection: A Pilot Study.
Am J Gastroenterol. 2016 Apr;111(4):581-3(19) Onoyama H, Kamiya M, Kuriki Y, Komatsu T,
Abe H, Tsuji Y, Yagi K, Yamagata Y, Aikou S,
Nishida M, Mori K, Yamashita H, Fujishiro M,
Nomura S, Shimizu N, Fukayama M, Koike K,
Urano Y, Seto Y. Rapid and sensitive detectionof early esophageal squamous cell carcinoma
with fluorescence probe targeting dipeptidylpeptidase IV. Sci Rep. 2016 Jun 1;6:26399(20) Niimi K, Goto O, Kawakubo K, Nakai Y,
Minatsuki C, Asada-Hirayama I, Mochizuki S,
Ono S, Kodashima S, Yamamichi N, Isayama H,
Fujishiro M, Koike K.
Endoscopic
ultrasound-guided fine-needle aspiration skill
acquisition of gastrointestinal submucosal tumor
by trainee endoscopists: A pilot study. Endosc
Ultrasound. 2016 May-Jun;5(3):157-64.
(21) Kataoka Y, Tsuji Y, Sakaguchi Y, Minatsuki C,
Asada-Hirayama I, Niimi K, Ono S, Kodashima
S, Yamamichi N, Fujishiro M, Koike K.
Bleeding after endoscopic submucosal dis-465

section: Risk factors and preventive methods.
World J Gastroenterol. 2016 Jul 14;22(26):5927-35.
(22) Fujishiro M, Yasuda I. Congress report:
Exchange of opinions in Tokyo, 2016 between
Japan Gastroenterological Endoscopy Society(JGES) and counterparts from abroad. Dig
Endosc. 2016 Sep;28(6):642-4.
(23) Ono S, Saito I, Ikeda Y, Fujishiro M, Komuro I,
Koike K. Current Practices in the Managementof Antithrombotic Therapy During the Periendoscopic Period for Patients With Cardiovascular
Disease. Int Heart J. 2016 Sep 28;57(5):530-4.
(24) Fujishiro M, Yoshida S, Matsuda R, Narita A,
Yamashita H, Seto Y. Updated evidence on
endoscopic resection of early gastric cancer fromJapan. Gastric Cancer. 2017 Mar;20(Suppl 1):
39-44.
(25) Asada-Hirayama I, Kodashima S, Sakaguchi Y,
Ono S, Niimi K, Mochizuki S, Tsuji Y,
Minatsuki C, Shichijo S, Matsuzaka K, Ushiku T,
Fukayama M, Yamamichi N, Fujishiro M, Koike
K. Magnifying endoscopy with narrow-band
imaging is more accurate for determination ofhorizontal extent of early gastric cancers thanchromoendoscopy. Endosc Int Open. 2016 Jun;
4(6):E690-8.
(26) Maeda M, Nakajima T, Oda I, Shimazu T,
Yamamichi N, Maekita T, Asada K, Yokoi C,
Ando T, Yoshida T, Nanjo S, Fujishiro M,
Gotoda T, Ichinose M, Ushijima T. High impact
of methylation accumulation on metachronous
gastric cancer: 5-year follow-up of a multicentre
prospective cohort study. Gut. 2016 Dec 21. pii:
gutjnl-2016-313387.
(27) Niikura R, Nagata N, Doyama H, Ota R, Ishii N,
Mabe K, Nishida T, Hikichi T, Sumiyama K,
Nishikawa J, Uraoka T, Kiyotoki S, Fujishiro M,
Koike K. Current state of practice for colonic
diverticular bleeding in 37 hospitals in Japan: Amulticenter questionnaire study. World J
Gastrointest Endosc. 2016 Dec 16;8(20):785794.
(28) Ota Y, Yamada A, Kobayashi Y, Niikura R,
Shimpoh T, Narita A, Yoshida S, Suzuki N,
Watabe H, Hirata Y, Ishihara S, Sunami E,
Watanabe T, Koike K. Diagnostic capability ofcolon capsule endoscopy for advanced colorectal
cancer: A pilot study. Dig Endosc. 2017 Mar 10.
doi: 10.1111/den.12862. [Epub ahead of print]
PubMed PMID: 28295697.
(29) Nakada A, Niikura R, Yamada A, Yoshida S,
Hirata Y, Koike K. The incidence of postcolonoscopy colorectal cancer: a retrospective
long-term cohort study using a colonoscopy
database. Int J Colorectal Dis. 2017 Jan 14. doi:
10.1007/s00384-017-2757-0. [Epub ahead ofprint] PubMed PMID: 28091843.
(30) Yamaji Y, Yasunaga H, Hirata Y, Yamada A,
Yoshida S, Horiguchi H, Fushimi K, Koike K.
Association Between Colorectal Cancer andAtherosclerotic Diseases: A Study Using a
National Inpatient Database in Japan. Dig Dis
Sci. 2016 Jun; 61(6): 1677-85. doi: 10.1007/s
10620-016-4041-5. Epub 2016 Feb 1. PubMed
PMID: 26831490.
(31) Niikura R, Yamada A, Nagata N, Kobayashi Y,
Okamoto M, Mitsuno Y, Ogura K, Yoshida S,
Shimbo T, Hirata Y, Koike K: New predictivemodel of rebleeding during follow-up of patents
with obscure gastrointestinal bleeding: A
multicenter cohort study. J Gastroenterol Hepatol.
2016 Apr;31(4):752-60. doi: 10.1111/jgh.13201.
PMID:26487158(32) Saito S, Yoshida S, Isayama H, Matsuzawa T,
Kuwai T, Maetani I, Shimada M, Yamada T,
Tomita M, Koizumi K, Hirata N, Kanazawa H,
Enomoto T, Sekido H, Saida Y. A prospective
multicenter study on self-expandable metallic
stents as a bridge to surgery for malignant
colorectal obstruction in Japan: efficacy andsafety in 312 patients. Surg Endosc. 2016 Sep;
30(9):3976-86. doi: 10.1007/s00464-015-4709-5.
Epub 2015 Dec 18. PMID: 26684205(33) Nishizawa T, Suzuki H, Arano T, Yoshida S,
Yamashita H, Hata K, Kanai T, Yahagi N,
Toyoshima O. Characteristics of gastric cancer
detected within 1 year after successful
eradication of Helicobacter pylori. J Clin
Biochem Nutr. 2016 Nov;59(3):226-230. Epub
2016 Aug466

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.

3.
4.

5.
6.
7.
8.
9.

Teaching activities
1.

2.
3.

Clinical activities
1.
2.

Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does

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

4.
5.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acutekidney injury and acute renal failure.
Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course to
second year residents on request.
Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRT

467

6.

Pocket 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.
Development and application of a non-invasive
pulse hemoglobin meter.
Genome wide association study for Nephrotic
syndrome and those functional analyses.
Association between factors at the initiation ofrenal replacement therapy and prognosis.
Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
AKI biomarkers and those clinical significance in
ICU/CCU.
Renal biomarker to determine clinicalactionability in CKD and type-2 DN.
The potentiality of urine biomarker tests fordeveloping country [JICA-JST: Science andTechnology Research Partnership for Sustainable
Development].

References
1. Isshiki R, Asada T, Sato D, Sumida M, Hamasaki Y,
Inokuchi R, Matsubara T, Ishii T, Yahagi N,
Nangaku M, Noiri E, Doi K. Association of
Urinary
Neutrophil
Gelatinase-AssociatedLipocalin With Long-Term Renal Outcomes in
ICU Survivors: A Retrospective Observational
Cohort Study. Shock. 46, 44-51 (2016)
2. 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)
3. Hasegawa S, Kato H, Hamasaki Y, Koiwa T,
Nangaku M. Positron emission tomography in the
diagnosis of cyst infections. Kidney Int. 91, 759(2017)
4. Katagiri D, Hamasaki Y, Doi K, Negishi K, Sugaya
T, Nangaku M, Noiri E. Interstitial renal fibrosis
due to multiple cisplatin treatments is amelioratedbysemicarbazide-sensitiveamineoxidaseinhibition. Kidney Int. 89, 374-385 (2016)
5. 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)
6. 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)
7. 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)
8. 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)
9. 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)
10. 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)11. 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)

468

12. 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)

469

Clinical Research Support Center
Professor, Director
Tsutomu Yamazaki, M.D., Ph.D.

Associate Professor
Chie Sakanaka, M.D., Ph.D.

Project Lecturer, Vice Director
Tetsuya Ueda, M.D., Ph.D.

Assistant Professor
Munenori Takata, M.D., Ph.D.
Yukari Uemura, Ph.D.

Project Assistant Professor
Akiko Kishi Svensson, M.D., Ph.D.
Mototsugu Tanaka, M.D., Ph.D.
Takuya Kawahara, Ph.D.
Gaku Oguri, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/~cresc-en/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
whole Clinical Research Center, and Central
Coordinating Unit, which provides coordinating
functions for research such as multicenter trials.
Site Coordinating Unit is comprised of theInstitutional Review Board (IRB) Secretariat Division,
Investigational Drug/Information Control Division
and Clinical Research Coordinator Division, eachcharged with IRB secretarial affairs, handling of drugs
used in clinical research and assistance with safety
information reporting, and clinical researchcoordination activities. In addition to the existing
Consultation Division, the Central Coordinating Unit
has added new divisions such as Operation Division,
Biostatistics Division, Data Management Division,
Monitoring Division and Safety Information Division.

470

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 canconduct 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 trials,
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 set up
independently from 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 duties, center will continue totake 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 conflicts ofinterest management, created educational environment
for clinical research personnel, formed collaboration
with the clinical evaluation and safety division tostrengthen safety management system. As a result the
University 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, to promote and secure safetyof regenerative, The Certified Special Committee forRegenerative Medicine was established at the Central
Administrative Office of the university. And ClinicalResearch Support Center undertook responsibilities
for secretarial and administrative duties.
We established 3 new divisions outside the unit,
education and training division, clinical trial
implementation division and university hospital
network promotion division. Moreover, in order tostrengthen the functions involved widely by theClinical Research Support Center, we established
Education and Training Division, Research
Implementation Division and University Hospital
Network Promotion Division outside the unit, last year.
In the current fiscal year, we further integrated safety
information functions of the Site Coordinating Unit
and the Central 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. However, while trying tostrengthen the functions, cases of interruption
occurred in advanced medical research, revealing lackof cooperation within the Clinical Research Support
Center. To prevent the recurrence of such interruptions,
we are reviewing our organizational structure aimed atstrengthening governance within the center.
As of March 2017, the Center has 9 staff members(1 professor, 1 associate professor, 1 project lecturer,
2 assistant professors, 4 project assistant professor,
there are 25 full-time staff members assigned to theSite Coordinating Unit (10 pharmacists, 6 nurses,
3 laboratory technicians, 3 clinical psychologists,
2 project academic support staff and 1 clerical staff.
The number of full-time staff assigned to the Central
Coordinating Unit is 21. (1 specially appointed staff,
6 pharmacists, 5 laboratory technicians, 4 project
academic support staff and 5 clerical staff members.
The P I Unit consist of 24 staff members (14 nurses,
2 full-time laboratory technicians, 6 concurrent
laboratory technicians 1 project academic support471

staff and 1 clerical staff.

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). To
further improve the quality of these research we
decided to adopt ICH-GCP guidance and compliedwith the following guidelines, procedure manuals,
styles and guidance etc.
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 the result we would avoid

re-examination of research.
The items processed by the Center as the IRB
secretariat in fiscal 2016 included, as for industrysponsored trials for marketing approval, 41 new
protocol applications, 73 study extension applications,392 protocol amendment applications, 861 SAE/safety
information reports, 46 study closure or termination
reports. As for investigator-initiated clinical research,
the Center processed 25 new protocols, 133applications for protocol amendment, 78 SAE/safety
information reports, and 8 reports for study closure or
termination.
Protocol presentations of industry-sponsored trials
prior to application to IRB totaled 15 applications.
Preliminary
consultation
andguidanceforinvestigator-initiated research application 27 and 53
applications, respectively.
Clinical Research Support Center managed
drug/device inventory for 110 clinical trials (drug 107,
devices 3) for regulatory approval, 5 post marketing
research, 33 investigator-initiated clinical research,and 10 cases of compassionate use, 2 tissueengineered medical products in fiscal 2016. The
number of prescriptions processed was 957 forresearch for approval and post marketing researchcombined, 704 for investigator-initiated clinicalresearch. We managed trial drugs centrally for 6
multicenter research shipped them for 74 times. We
masked investigational drugs for 3 double-blind
placebo controlled research.
Clinical research coordinators (CRC) of the Center
have been supporting all clinical trials for approvaland post marketing research since 2002. We started
supporting in part investigator-initiated research in2004. In 2005 we started providing CRC support toinvestigator-initiated research on a beneficiary-paysbasis. CRCs exclusively involved in investigatorinitiated research have been employed as needed. The
number of research participants that CRCs interactedwith was 5735 in 2016. The number of monitoring
visits was 838 in 2016.
As part of patient awareness campaign, we continued
updating the Center homepage, 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

472

or who are considering to enroll in a clinical trial inclose cooperation with the Patients Relations andClinical Ethics Center, Department of Medical
Community Network and Office of Medical
Accounting.

<Central Coordinating Unit>
Central Coordinating Unit, established in 2010, hasbeen implementing the system successively.
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 2016, we have accepted 41 clinicalresearch projects for providing support (28 validation
studies and 13 exploratory studies). Eight
investigator-initiated clinical trials (which include 2
trials on medical devices, 1 on regenerative medicine,
2 trials as support for other universities) 6 Advanced
Medical Care B Programs and 2 trials on regenerative
medicine.
With respect to investigator-led trials on medical
devices, application for manufacturing and marketing
approval was filed with regulatory authorities in
November 2014, and was approved on June 18, 2015.
Phase I and Phase II clinical trials investigatorinitiated trials are near completion.
One investigator-initiated clinical trial in regenerative
medicine is currently being conducted.
Besides, 4 clinical trials including investigatorinitiated and independent clinical trials to support
other facilities are also underway.
<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 fiscal year 2017, we completed;investigator-initiated phase I study for rareneurodegenerative disease drug, investigator-initiatedphase I study for rare pulmonary disease drug,
bioequivalence study for a generic drug, andindependent study for developing novel medical
device. In addition, we are currently conducting a
global phase III study 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 University of Tokyo the Institute ofMedical Science 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 anddevelopment of seeds. As part of the Allianceactivities the University of Tokyo developed a clinicalresearch support system UHCT ACReSS jointly with
Fujitsu in 2011, to support clinical researchers in thequality and project management. UHCT ACReSS caneasily be customized by researchers. The system isbeing used practically by 195 projects as of March2017. Currently, we are expanding the use of it toresearchers other 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 Divisionin 2015. Currently, we are expanding the use outside
the alliance members. Activities between the UHCT
Alliance and the University of Tokyo TR based
regional network started in 2014, as seeds
development project of Alliance members.

473<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 since the preparatory
meeting in July 2012. The initiative considered toshare 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 Council of Japan.
Feasibility assessment system was developed forinvestigator initiated clinical trial in order to support
and promote clinical trials conducted at the National
University Hospitals. Contract templates were createdfor investigator initiated research and provided to each
university hospital by the National University
Hospital Council of Japan.

Education/Training
The Center has been accepting medical students infinal year for training course in ‘Clinical Clerkship’since it become mandatory in 2013. In addition, we
accepted graduate students for 2 day training (enrolled
in Master’s and Doctoral courses) in the Faculty of
Medicine, Graduate School of Pharmaceutical
Sciences and the School of Engineering, who took
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 andTechnology). Also, we accepted 12 students enrolled
in graduate school and Faculty of Pharmaceutical
Sciences, both from inside and outside universities. In
addition, resident physicians underwent one-monthtraining at the Center, as a part of the M.D. residencytraining program.
Education and Training Division was established in2015 and has been providing education and training
for students and researchers. In particular, we havedeveloped 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, 3900 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 course for national, public andprivate university hospitals since 2010, commissionedby the Ministry of Education. In June 2016, 5-day
training was held under the auspices of the hospital, in
which 98 trainees from university hospitals across thecountry participated.
In addition, we held a joint workshop series with 8
alliance universities in the Kanto Koshinetsu area, (6organized by the University of Tokyo) which
consisted of 5 monitoring workshops, 5 clinicalresearch lecture series. Workshops were attended by
130, 137(45 participants from UTokyo) and 645 (224from UTokyo) respectively.
In 2016, Japan Agency for Medical Research andDevelopment (AMED) sponsored workshop on“training data managers” was held in Tokyo andOsaka (96 participants at each venue), training
workshop for clinical research personnel (1 day, heldat the University of Tokyo 46 participated), The
University of Tokyo – National University ofSingapore joint international symposium on “Human
Resources Development” was also held in November
2016.
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 will also beestablished within the Graduate School ofInterdisciplinary Information Studies. ClinicalResearch Support Center has established system toconduct practical training for course participants.
The Center holds annual “Clinical Research
Seminar” in March, nearly 300 people from academia
and companies participated last year.

474

Research Activities
An endowed course on clinical trial data
management was opened in April 2007 with thesupport of the Center and the Biostatistics Department,
Graduate School of Medicine, conducting researchand education on data management and biostatistics
focused on practical application to research.
As of fiscal 2016, the Center was involved in 18
presentations in scientific meetings, of which 15 wereas lead presenters, international conferences 2 (Y.
Uemura). The Japan Society of Clinical Pharmacology
and Therapeutics 6 (A. Okuma, M. Takata, S. Tanaka,
Takeda, Y. Uemura, Y.Omori), Conference on CRC
and Clinical Research 3 (N.Ogura, A.Nagamatsu,
A.Kishi) Japan Society of Clinical Trials and Research
2 (S.Karasawa, S.Nogawa) other presentations 2(T.Yamazaki, A. Kishi ) 13 lectures (T.Yamazaki, M.
Takata, A Kishi), 31 publications and academic papers
etc. (English papers 19, Japanese papers 0, review
papers 9 and 3 Japanese books)

Publications
1) Ueshima K., Itoh H., Kanazawa N., Komuro I.,
Nagai R., Takeuchi M.,and Yamazaki T., for the
EMPATHY study group: Rationale and Design of
the Standard Versus Intensive Statin Therapy for
Hypercholesterolemic Patients with Diabetic
Retinopathy (EMPATHY) Study: a Randomized
Controlled Trial. J Atheroscler Thromb 23:976990,2016
2) Kai H., Kohro T., Fukuda K., Yamazaki T., Nagai
R.: Impact of systolic blood pressure on
hemorrhagic stroke in patients with coronary
artery disease during anti-platelet therapy: The
Japanese Coronary Artery Disease (JCAD) study.
Int J Cardiol. 224:112-113,2016
3) Lee, S.L., Daimon M., Di Tullio MR, Homma S.,
Nakao T., Kimura K., Shinozaki T., Hirokawa M.,
Kato TS., Mizuno Y., Watanabe M., Yatomi Y.,
Yamazaki T., Komuro I. Relationship of left
ventricular diastolic function to obesity andoverweight in a Japanese population withpreserved left ventricular ejection fraction. Circ J.
80(9):1951-6,2016
4) Uchiyama S., Ishizuka N., Shimada K., TeramotoT., Yamazaki T., Oikawa S., Sugawara M., AndoK., Murata M., Yokoyama K., Minematsu K.,
Matsumoto M., Ikeda Y., JPPP study group:
Aspirin for stroke prevention in elderly patientswith vascular risk factors: Japanese primaryprevention project. Stroke. 47(6):1605-11,2016
5) Soroida Y., Sato M., Hikita H., Hagiwara S., Sato
M., Gotoh H., Kato S., Iwai T., Yamazaki T.,
Yatomi Y., Sasano T., Ikeda H.: Pancreatic cysts ingeneralpopulationonultrasonography:
Prevalence and development of risk score. J
Gastroenterol.51(12):1133-40, 20166) Lee, S.L., Daimon M., Nakao T., Singer DE,
Shinozaki T., Kawata T., Kimura K., Hirokawa M.,
Kato TS., Mizuno Y., Watanabe M., Yatomi Y.,
Yamazaki T., Komuro I. Factors influencing left
atrial volume in a population with preserved
ejection fraction: Left ventricular diastolic
dysfunction or clinical factors? J Cardiol. 68(4):275-81,2016
7) Hirokawa M., Daimon M., Lee, S.L., Nakao T.,
Kawata T., Kimura K., Kato TS., Mizuno Y.,
Watanabe M., Yatomi Y., Yamazaki T., Komuro I.
Early menopause does not influence left
ventricular diastolic dysfunction: A clinicalobservational study in healthy subjects. J Cardiol.
68(6):548-553,2016
8) Suzuki K., Koide D., Fujii K., Yamazaki T., Tsuji
S., Iwata A. Elevated serum uric acid levels are
related to cognitive deterioration in an elderly
Japanese population. Dement Geriatric Cognitive
Disorder Extra 6:580-8,2016
9) Takata, M., Amiya, E., Watanabe, M., Yamada, N.,
Watanabe, A., Kawarasaki, S., & Komuro, I.
(2016). The association between orthostaticincrease in pulse pressure and ischemic heartdisease. Clinical and Experimental Hypertension,
38(1), 23-29.
10) Amiya, E., Watanabe, M., Watanabe, S., Takata,M., & Komuro, I. (2016). Enhancement of arterial
pulsation during flow-mediated dilation is
impaired in the presence of ischemic heart disease.
SpringerPlus, 5(1), 1-8.
11) Takata, M., Amiya, E., Watanabe, M., Shintani, Y.,
Sakuma, K., Saito, A., ... & Komuro, I. (2016).
Phenotypic differences in aortic stenosis according
to calcification grade. International journal of
cardiology, 216, 118-120.

47512) Watanabe Y, Akizawa T, Saito A, Gejyo F, Suzuki M,
Nishizawa Y, Tomino Y, Tsubakihara Y, Akiba T,
Hirakata H, Kawanishi H, Bessho M, Udagawa Y,
Aoki K, Uemura Y, Ohashi Y, the Co-JET Study
Group. Effect of predialysis recombinant humanerythropoietin on early survival after hemodialysis
initiation in patients with chronic kidney disease:
Co-JET study. Therapeutic Apheresis and Dialysis.
2016;20(6): 598-607.
13) Ueda K, Kasao M, Shimamura, M, Haruta H, Nitta
S, Kaneko M, Uemura Y, Morita H, Komuro I,
Shirai T. Impact of Oral Treatment on Physical
Function in Older Patients Hospitalized for Heart
Failure: A Randomized Clinical Trial. Plos One.
2016;11(12): e0167933.
14) Akizawa T, Tsubakihara Y, Hirakata H, Watanabe Y,
Hase H, Nishi S, Babazono T, Kumagai M,
Katakura S, Uemura Y, Ohashi Y; JET-STREAM
Study Group. A prospective observational study ofearly intervention with erythropoietin therapy andrenal survival in non-dialysis chronic kidney disease
patients with anemia: JET-STREAM Study. Clin
Exp Nephrol. 2016;20(6): 885-95.
15) Miura M, Yamasaki M, Uemura Y, Yoshikawa M,
Miyauchi K, Tanaka H, Miyachi H, Yamashita J,
Suzuki M, Yamamoto T, Nagao K, Komuro I,
Takayama M. Effect of Statin Treatment and
Low-Density Lipoprotein-Cholesterol on ShortTerm Mortality in Acute Myocardial Infarction
Patients
UndergoingPrimary
PercutaneousCoronary Intervention - Multicenter Registry FromTokyo CCU Network Database. Circ J. 2016;80(2):461-8.
16) Taguchi S, Nakagawa T, Uemura Y, Matsumoto A,
Nagase Y, Kawai T, Tanaka Y, Yoshida K,
Yamamoto S, Enomoto Y, Nose Y, Sato T, Ishikawa
A, Fujimura T, Fukuhara H, Kume H, Homma Y.
Validation of major prognostic models for metastatic
urothelial carcinoma using a multi-institutional
cohort of the real world. World J Urol. 2016 Feb;
34(2):163-71.
17) Fujimoto C, Yamamoto Y, Kamogashira T,
Kinoshita M, Egami N, Uemura Y, Togo F,
Yamasoba T, and Iwasaki S. Noisy galvanic
vestibular stimulation induces a sustained
improvement in body balance in elderly adults.
Scientific Reports. 2016; in press.

18) Tsuruya K, Uemura Y, Hirakata H, Kitazono T,
Tsubakihara Y, Suzuki M, Ohashi Y. Association
between responsiveness to methoxy polyethylene
glycol-epoetin beta and renal survival in patientswith non-dialysis-dependent chronic kidney disease:a pooled analysis of individual patient-level datafrom clinical trials. Nephrology. 2016 Jun; in press.
19) Mieno MN, Tanaka N, Arai T, Kawahara T, Kuchiba
A, Ishikawa S, Sawabe M. Accuracy of deathcertificates and assessment of factors for
misclassification of underlying cause of death.
Journal of Epidemiology. 2016; 26(4):191-198.

476

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/

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.
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

477

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 440,000
registrants, and approximately 110,000,000 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• Drug information text database forpharmacists• Drug information text database for patients• Medical supplies and materials database• Classification for Nursing• Ministry of Education, Culture, Sports,
Science and Technology document public
information system• National university hospital-related medical
dispute report• Lists for people and committees• Various government official appointments,
administrative websites and ML
 General Services(1) General information and search• Medical / biology related websites• Medical terminology• A medical research organization / medical
institution database(2) Services for information providers•
Web service for public•
Web service for members•
Website preservation service(3) Communication support• E-mail• Listserv

478

•
•

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.

479

Organ Transplantation Service
Director
Norihiro Kokudo

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/1512ishokugeka/index.html

The University of Tokyo Hospital has aggressively
performed organ transplantation. In 1966, the firstkidney transplantation in Japan was performed. In
1996, the first living donor liver transplantation was
performed. Organ Transplant Service started tofunction since 2003. Until today, more than 570 casesof living donor liver transplantation and 25 deceased
donor liver transplantations have been performed, andthe 5-year survival rate is around 85% which is muchsuperior to the national average (~70%). The
University of Tokyo Hospital has been one of theauthorized institutions for heart transplantation, lungtransplantation,anddeceased
donor
liver
transplantation. So far 84 heart transplantations and 7
lung transplantations have been performed.

References (2016)
1. Yamashita S, Aoki T, Inoue Y, et al. Outcome ofsalvage hepatic resection for recurrent hepatocellular carcinoma after radiofrequency ablation
therapy. Surgery. 2015;157:463-72.
2. Kawaguchi Y, Sugawara Y, Akamatsu N,et al.
Perceptions of post-transplant recidivism in livertransplantation for alcoholic liver disease. World J
Hepatol. 2014;6:812-7.
3. Kawaguchi Y, Sugawara Y, Akamatsu N, et al.
Impact of early reoperation following livingdonor liver transplantation on graft survival. PLoS
One. 2014;9:e109731.
4. Akamatsu N, Sugawara Y, Nagata R, et al. Adultright living-donor liver transplantation withspecial reference to reconstruction of the middle
hepatic vein. Am J Transplant. 2014;14:2777-87.
5. Tanaka T, Sugawara Y, Akamatsu N,et al. Useof simeprevir following pre-emptive pegylated

interferon/ribavirin treatment for recurrent
hepatitis C in living donor liver transplant
recipients: a 12-week pilot study. J Hepatobiliary
Pancreat Sci. 2015;22:144-50.
6. Akamatsu N, Sugawara Y, Kokudo N. Livingdonor vs deceased-donor liver transplantation forpatients with hepatocellular carcinoma. World J
Hepatol. 2014;6:626-31.
7. Akamatsu N, Sugawara Y, Kokudo N. Living
donor liver transplantation for patients with
hepatocellular carcinoma. Liver Cancer. 2014;3:
108-18.
8. Tamura S, Sugawara Y, Kokudo N. Section 4.
Further expanding the criteria for HCC in living
donor liver transplantation: the Tokyo University
experience. Transplantation. 2014;97:S17-20.
9. Togashi J, Sugawara Y, Akamatsu N, et al.
A single-center experience of the use ofinterleukin-2 receptor antagonists for various
situations in liver transplant recipients. Transplant
Proc. 2014;46:739-43.
10. Akamatsu N, Sugawara Y, Kokudo N, et al.
Outcomes of living donor liver transplantation forhepatitis C virus-positive recipients in Japan:
results of a nationwide survey. Transpl Int. 2014;
27:767-74.
11. Harada N, Tamura S, Sugawara Y, et al. Impactof donor and recipient single nucleotide polymorphisms of IL28B rs8099917 in living donorliver transplantation for hepatitis C. PLoS One.
2014;9:e90462.
12. Shindoh J, Sugawara Y, Nagata R,et al.
Evaluation methods for pretransplant oncologic
markers and their prognostic impacts in patientundergoing living donor liver transplantation for480

hepatocellular carcinoma. Transpl Int. 2014;27:
391-8.
13. Tanaka T, Yamashiki N, Sugawara Y, et al.
Chronologic changes of explanted liver volume
and the use of ursodeoxycholic acid in patientswith end-stage primary biliary cirrhosis. Hepatol
Res. 2014;44:993-9.
14. Kokudo T, Hasegawa K, Yamamoto S,et al.
Surgical treatment of hepatocellular carcinoma
associated with hepatic vein tumor thrombosis. J
Hepatol. 2014;61:583-8.
15. Hasegawa K, Aoki T, Ishizawa T,et al.
Comparison of the therapeutic outcomes between
surgical resection and percutaneous ablation forsmall hepatocellular carcinoma. Ann Surg Oncol.
2014;21:S348-55.
16. Kaneko J, Sugawara Y, Yamaguchi T,et al.
Telaprevir-based triple therapy for hepatitis C null
responders among living donor liver transplant
recipients. Biosci Trends. 2014;8:339-45.

481

Center for Epidemiology andPreventive Medicine
Director & Professor
Tsutomu Yamazaki, M.D., Ph.D. (Clinical Research Support Center)

Associate Professor
Yuichi Ikeda, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Associate & Deputy Director
Yumiko Ohike, M.D., Ph.D.

Associates
Lumine Matsumoto, M.D., Ph.D. ,Atsuko Ozeki, M.D.,Ph.D. ,Keiko Niimi, M.D.,Ph.D.,
Satoshi Suzuki, M.D.,Ph.D., Yukari Masuda, M.D.,Ph.D.
Yoshiko Mizuno,M.D., Ph.D. (Department of Clinical Epidemiology and Systems)
Mikio Takanashi, M.D., Ph.D. (Department of Clinical Epidemiology and Systems)
Kazutaka Ueda, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Homepage:

http://www.h.u-tokyo.ac.jp/patient/depts/kenshin/index.html

Introduction and Organization
Following the inauguration of a new Central Clinical
Service Building (Central Care 2) in November 2006
(Heisei 18) in the University of Tokyo Hospital, theCenter for Epidemiology and Preventive Medicine
was established on January 1, 2007, within the Central
Clinical Facilities and the relevant regulations wererevised. On January 9, the Working Group for the
Establishment of the Center for Epidemiology andPreventive Medicine was organized; on April 1,
Steering Committee for the Establishment of theCenter for Epidemiology and Preventive Medicine
was organized; preparation for offering its services
continued until May 31; on June 4, the department
started offering its services on a trial basis (in-hospital
services) and was officially inaugurated in July,
starting to provide public services.
The principal objectives of the establishment of theCenter for Epidemiology and Preventive Medicine are1) to scientifically demonstrate the utility andeffectiveness of examinations and preventive interventions, 2) to integrate a vast amount of clinical data andhealth-related information to develop more efficientmodels for disease management, 3) by doing theabove 1) and 2), to promote preventive medicine andmedicine for health promotion in an effort tocontribute to the improvement of public health, and 4)
to train medical personnel who can put the above 1),2) and 3) into practice.
In the administrative organization of the Center for
Epidemiology and Preventive Medicine, its Director
directly under the Director of the Hospital is
responsible for the entire organization. The management of the Department is also supported by the
Department of Clinical Epidemiology and Systems
and the Department of Ubiquitous Preventive
Medicine. In addition, examinations in the Department
are administered in collaboration with three Central
Clinical Facilities (Clinical Laboratory Center,482

Radiological Center, and Department of Endoscopy
and Endoscopic Surgery) and five Clinical Divisions(Breast and Endocrine Surgery, Gynecologic Surgery,
Ophthalmology and Vision Collection, OralMaxillofacial Surgery, Dentistry and Orthodontics,
and Neurology).
The staff of the Center for Epidemiology andPreventive Medicine is composed of nine physicians(four regular physicians and five physicians from therelated departments). One of the regular physiciansalso performs upper gastrointestinal endoscopy andcolonoscopy in the Department of Endoscopy andEndoscopic Surgery. Our department also has fiveregular nurses and five regular secretaries. When our
department was established, the number of staff wasincreased in other divisions. Among our staff, one
nurse (full-time), three radiological technologists(full-time) and three medical technologists (full-time)
are assigned respectively to the Department ofEndoscopy and Endoscopic Surgery, the RadiologicalCenter and the Clinical Laboratory Center.

Clinical activities
In addition to basic examinations which are open to
the public, our department provides these elevenoptions: 1) comprehensive cardiovascular examinations, 2) home blood pressure screening, 3) comprehensive cerebrovascular examinations, 4) check up
dementia, 5) colorectal cancer screening, 6) uterine
cancer screening, 7) breast cancer screening, 8) lungcancer screening, 9) tumor marker diagnosis,10) estimation of gastric cancer risk, and 11) oral/
dental examinations. While meeting the needs of
examinees, we have increased the number of theoptional examinations and provided higher levels of
examinations.
The physicians of our department are responsible
for analyzing the results of examinations andscreenings, performing overall evaluations, andconsultations with examinees. One of our important
services is that we take approximately 30 minutes per
examinee to perform comprehensive medical
examinations. Formally, the examinee is notified inwriting of the results within approximately three
weeks after the examination. We also offer eachexaminee a free 20-minute consultation so that we canhelp him/her understand the results or decide whether
or not to have further work-up.

Teaching activities
Although our department has no students directly
under our supervision being a clinical service, weoffer education in epidemiology to graduate students
in the Department of Clinical Epidemiology and
Systems and the Department of Ubiquitous Preventive
Medicine.

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. In 2007, thefirst year of our department, we collected data on
examinees and designed a pilot database. From 2008
onward, we continue to collect data and conduct theircross-sectional and longitudinal analysis.

Past activities
In the fiscal year (FY) 2016from April 1, to March 31,
2017, the total number of examinees (who had basic
examinations and optional examinations) was 7,610,
including 2,803 in basic examinations, 544 incomplete cardiovascular examinations, 4 in home
blood pressure screening, 688 in complete cerebrovascular examinations, 89 in check up dementia, 346
in colorectal cancer screening, 545 in uterine cancer
screening, 676 in breast cancer screening, 586 in lungcancer screening, 1,060 in tumor marker diagnosis,
225 in estimation of gastric cancer risk, 18 in uppergastrointestinal endoscopy (later), and 46 in oral/dental
examinations.
When examinees visit other departments in our
hospital for a work-up or treatment, we write a letterof referral by request. In the FY 2016, we issued 769
letters of referral to other departments in our hospitaland 35 to other hospitals.

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We have expanded our public relations efforts andduring the FY 2016 15,000 brochure were delivered.
We also prepared posters which were placed within
our hospital and on the campus of the University ofTokyo as well. Our homepage (the above URL) has
been constantly updated to provide the latest
information for examinees.

References
Academic Papers in English
1. Ueshima K., Itoh H., Kanazawa N., Komuro I.,
Nagai R., Takeuchi M.,and Yamazaki T., for the
EMPATHY study group: Rationale and Design of
the Standard Versus Intensive Statin Therapy for
Hypercholesterolemic Patients with Diabetic
Retinopathy (EMPATHY) Study: a Randomized
Controlled Trial. J Atheroscler Thromb 23:976990,2016
2. Kai H., Kohro T., Fukuda K., Yamazaki T., Nagai
R.: Impact of systolic blood pressure on
hemorrhagic stroke in patients with coronary
artery disease during anti-platelet therapy: The
Japanese Coronary Artery Disease (JCAD) study.
Int J Cardiol. 224:112-113,2016
3. Lee, S.L., Daimon M., Di Tullio MR, Homma S.,
Nakao T., Kimura K., Shinozaki T., Hirokawa M.,
Kato TS., Mizuno Y., Watanabe M., Yatomi Y.,
Yamazaki T., Komuro I. Relationship of left
ventricular diastolic function to obesity andoverweight in a Japanese population withpreserved left ventricular ejection fraction. Circ J.
80(9):1951-6,2016
4. Uchiyama S., Ishizuka N., Shimada K., TeramotoT., Yamazaki T., Oikawa S., Sugawara M., AndoK., Murata M., Yokoyama K., Minematsu K.,
Matsumoto M., Ikeda Y., JPPP study group:
Aspirin for stroke prevention in elderly patientswith vascular risk factors: Japanese primaryprevention project. Stroke. 47(6):1605-11,2016
5. Soroida Y., Sato M., Hikita H., Hagiwara S., Sato
M., Gotoh H., Kato S., Iwai T., Yamazaki T.,
Yatomi Y., Sasano T., Ikeda H.: Pancreatic cysts ingeneralpopulationonultrasonography:
Prevalence and development of risk score. J
Gastroenterol.51(12):1133-40, 2016
6. Lee, S.L., Daimon M., Nakao T., Singer DE,

Shinozaki T., Kawata T., Kimura K., Hirokawa M.,
Kato TS., Mizuno Y., Watanabe M., Yatomi Y.,
Yamazaki T., Komuro I. Factors influencing left
atrial volume in a population with preserved
ejection fraction: Left ventricular diastolic
dysfunction or clinical factors? J Cardiol. 68(4):275-81,2016
7. Hirokawa M., Daimon M., Lee, S.L., Nakao T.,
Kawata T., Kimura K., Kato TS., Mizuno Y.,
Watanabe M., Yatomi Y., Yamazaki T., Komuro I.
Early menopause does not influence left
ventricular diastolic dysfunction: A clinicalobservational study in healthy subjects. J Cardiol.
68(6):548-553,2016
8. Suzuki K., Koide D., Fujii K., Yamazaki T., Tsuji
S., Iwata A. Elevated serum uric acid levels are
related to congnitive deterioration in an elderly
japanese population. Dement Geriatr Cogn Disord
Extra 6:580-8,2016
9. Suzuki JI., Sato H., Kaneko M., Yoshida A.,
Aoyama N., Akimoto S., Wakayama K., Kumagai
H., Ikeda Y., Akazawa H., Izumi Y., Isobe M.,
Komuro I.: Periodontitis and myocardial
hypertrophy. Hypertens Res. doi:10.1038/hr. Epubahead of print,2016
10. Zempo H., Suzuki JI., Watanabe R., Wakayama K.,
Kumagai H., Ikeda Y., Akazawa H., Komuro I.,
Isobe M.: Corrigendum: Cacao polyphenols
ameliorate autoimmune myocarditis in mice.
Hypertens Res. 39(11):828,2016
11. Sato H., Suzuki JI., Aoyama N., Watanabe R.,
Kaneko M., Shiheido Y., Yoshida A., WakayamaK., Kumagai H., Ikeda Y., Akazawa H., Komuro
I., Isobe M., Izumi Y.: A Periodontal pathogen
Porphyromonas
gingivalis
deteriorates
Isoproterenol-Induced myocardial remodeling in
mice. Hypertens Res. 40(1):35-40,2016
12. Ono S., Saito I., Ikeda Y., Fujishiro M., Komuro I.,
Koike K..: Current Practices in the Managementof Antithrombotic Therapy During the Periendoscopic Period for Patients With Cardiovascular
Disease. Int Heart J. 57(5):530-4,2016
13. Suzuki J., Imai Y., Aoki M., Fujita D., Takeda N.,
Aoyama N., Wakayama K., Ikeda Y., Kumagai H.,
Akazawa H., Izumi Y., Isobe M., Komuro I.,
Hirata Y.: Periodontitis May Deteriorate Sinus of
Valsalva Dilatation in Marfan Syndrome Patients.

484

Int Heart J. 57(4):456-60,2016
14. Kobayashi N., Suzuki JI., Aoyama N., Sato H.,
Akimoto S., Wakayama K., Kumagai H., Ikeda Y.,
Akazawa H., Komuro I., Izumi Y., Isobe M.:
Toll-like receptor 4 signaling has a critical role inPorphyromonas gingivalis-accelerated neointimal
formation after arterial injury in mice. Hypertens
Res. 39(10):717-22,2016
15. Shiheido Y., Maejima Y., Suzuki JI., Aoyama N.,
Kaneko M., Watanabe R., Sakamaki Y.,
Wakayama K., Ikeda Y., Akazawa H., Ichinose S.,
Komuro I., Izumi Y., Isobe M.: Porphyromonas
gingivalis, a periodontal pathogen, enhances
myocardial vulnerability, thereby promoting
post-infarct cardiac rupture. J Mol Cell Cardiol.
99:123-37,2016
16. Fujishiro M., Ikeda Y.: Re-bleeding After
Endoscopic Hemostasis for Peptic Ulcer
Bleeding: Is eNough SAID or Are Other Factors
Important? Dig Dis Sci. 61(6):1424-5,2016
17. Ikeda Y., Kumagai H., Motozawa Y., Suzuki J.,
Akazawa H., Komuro I.: Understanding Vascular
Diseases: Lessons From Premature Aging
Syndromes. Can J Cardiol. 32(5):650-8,2016
18. Izumi M., Ikeda Y., Yamashita H., Asaoka Y.,
Fujishiro M., Shin M., Abo Y.: Safety andEffectiveness of Endovenous Laser Ablation
Combined With Ligation for Severe Saphenous
Varicose Veins in Japanese Patients. Int Heart J.
57(1):87-90,2016
19. Ikeda Y., Kumagai H., Motozawa Y., Suzuki J.:
Growth Differentiation Factor 15 (GDF15) as a
Reliable Biomarker for Cardiovascular Risk
Assessment. Int Heart J. 57(1):1-2,2016
20. Zempo H., Suzuki J., Watanabe R., Wakayama K.,
Kumagai H., Ikeda Y., Akazawa H., Komuro I.,
Isobe M.: Cacao polyphenols ameliorate autoimmune myocarditis in mice. Hypertens Res. 39(4):203-9,2016
21. Watanabe R., Suzuki J., Wakayama K., Kumagai
H., Ikeda Y., Akazawa H., Komuro I., Isobe M.:
Angiotensin II receptor blocker irbesartan
attenuates cardiac dysfunction induced bymyocardial infarction in the presence of renal
failure. Hypertens Res. 39(4):237-44,2016
22. Suzuki J., Shimamura M., Suda H., Wakayama K.,
Kumagai H., Ikeda Y., Akazawa H., Isobe M.,

Komuro I., Morishita R.: Current therapies andinvestigational drugs for peripheral arterial
disease. Hypertens Res. 39(4):183-91,2016
23. Niimi K, Goto O, Kawakubo K, Nakai Y,
Minatsuki C, Asada-Hirayama I, Mochizuki S,
Ono S, Kodashima S, Yamamichi N, Isayama H,
Fujishiro M, Koike K.:Endoscopic ultrasoundguided fine-needle aspiration skill acquisition ofgastrointestinal submucosal tumor by traineeendoscopists: A pilot study. Endosc Ultrasound.
2016 May-Jun;5(3):157-64.
24. Kakushima N, Hori K, Ono H, Horimatsu T, Uedo
N, Ohata K, Doyama H, Kaneko K, Oda I, Hikichi
T, Kawahara Y, Niimi K, Takaki Y, Mizuno M,
Yazumi S, Hosokawa A, Imagawa A, Niimi M,
Yoshimura K, Muto M Proton pump inhibitor
after endoscopic resection for esophageal
squamous cell cancer: multicenter prospective
randomized controlled trial.. J Gastroenterol.
2016 Feb;51(2):104-11
25. Ueda K., Kasao M., Shimamura M., Haruta H.,
Nitta S., Kaneko M., Uemura Y., Morita H.,
Komuro I., Shirai T.: Impact of Oral Treatment on
Physical Function in Older Patients Hospitalizedfor Heart Failure: A Randomized Clinical Trial.
PLoS One. 11(12):e0167933,2016
26. Lu Q., Schnitzler GR., Vallaster CS., Ueda K.,
Erdkamp S., Briggs CE., Iyer LK., Jaffe IZ.,
Karas RH.: Unliganded estrogen receptor alpharegulates vascular cell function and gene
expression. Mol Cell Endocrinol. 442:12-23,2016
27. Maemura S., Amiya E., Seki H., Ueda K., Nitta D.,
Imamura T., Uehara M., Kawata T., Watanabe M.,
Hatano M., Kinugawa K., Komuro I.:
Endomyocardial Fibrosis Associated With ApicalCalcification and High Uptake on Myocardial
Gallium-67 Scintigraphy. Circ J. 80(9):2053-5,
2016
28. Ueda K., Fukuma N., Takimoto E.: Hydrogen
Sulfide, a Potential Cardioprotective Gas
Activating a Life Span Regulator. Int Heart J.
57(4):393-4,2016
29. Ueda K., Tagusari O., Kasao M.: Cystic tumour of
the atrioventricular node: can an electrophysiological study predict sudden death? Europace.
18(9):1334,2016
30. Nakagawa A., Naito AT., Sumida T., Nomura S.,

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Shibamoto M., Higo T., Okada K., Sakai T.,
Hashimoto A., Kuramoto Y., Oka T., Lee JK.,
Harada M., Ueda K., Shiojima I., Limbourg FP.,
Adams RH., Noda T., Sakata Y., Akazawa H.,
Komuro I.: Activation of endothelial β-cateninsignaling induces heart failure. Sci Rep. 6:25009,
2016
31. Lu Q., Schnitzler GR., Ueda K., Iyer LK.,
Diomede OI., Andrade T., Karas RH.: ER Alpha
Rapid Signaling Is Required for Estrogen Induced
Proliferation and Migration of VascularEndothelial Cells. PLoS One. 11(4):e0152807,
2016
32. Komuro J., Kaneko M., Ueda K., Nitta S., Kasao
M., Shirai T.: Adrenal insufficiency causes lifethreatening arrhythmia with prolongation of QTinterval. Heart Vessels. 31(6):1003-5,2016
International Conferences
1. Subclinical carotid atherosclerosis associates with
impairment in immediate memory
Lumine Matsumoto 1)2), Kazushi Suzuki 1)2),
Yoshiko Mizuno 2),Yumiko Ohike 2), Atsuko Ozeki2) ,Satoshi Ono 2), Mikio Takanashi 2), Daigo
Sawaki 2), Toru Suzuki 2), Tsutomu Yamazaki 2),
Shoji Tsuji 1), Atsushi Iwata 1),3)
1) Department of Neurology, The University ofTokyo2) Center for Epidemiology and Preventive
Medicine, The University of Tokyo
3) Japan Science and Technology Agency, PRESTO
The 68th Annual Meeting of the American Academyof Neurology
April 15- April 21, 2016
Vancouver, BC
2. Efficacy of non-exposed endoscopic wall-inversion
surgery (NEWS) as an advanced method offull-thickness resection for gastric tumor; KeikoNiimi, Takashi Mitsui, Susumu Aikou , Sinya
Kodashima, Nobutake Yamamichi , Hiroharu
Yamashita, Mitsuhiro Fujishiro, Yasuyuki Seto,
Kazuhiko Koike, UEGW 2016/10/19 (Vienna,
Austria)
3. American Heart Association Scientific Sessions
2016 (November 12-16 2016, New Orleans, USA)
Mikio Takanashi, Satoru Takase, Yoshino Taira,Takeshi Kimura, Sachiko Okazaki, Pengfei Xu,
Chengcheng Li, Futoshi Shionoiri, Yoko IIzuka,

Jun-ichi Osuga, Shun Ishibashi, Takashi Kadowaki,
Hiroaki Okazaki“Amelioration of streptozotocin-induced diabetic
hypertriglyceridemia in the absence of hormonesensitive lipase”

486

Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D., Ph.D.

Vice Director
Kazuto Hoshi, M.D., Ph.D.

Project Associate Professors
Atsuhiko Hikita, M.D., Ph.D.,

Keiichi Hishikawa, 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.,

Osamu Takase, M.D., Ph.D.,

Taro Tsujimura, 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. Division of Tissue Engineering consists of
Department of Bone & Cartilage Regenerative
Medicine, Department of Vascular Regeneration,
Department of Advanced Nephrology & Regenerative Medicine, Department of Cartilage & BoneRegeneration, Project for Regeneration Medicine of
Hematopoiesis, Corneal Tissue Regeneration Project,and Laboratory for Pediatric Regenerative Medicine.
We have invited talented personnel of various fields
from home and abroad. One project associate
professor and one or two project research associates
who are assigned to each department are conducting
research with many post graduate students. Aiming at
clinical application within a few years, 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

487

Medicine for Hematopoiesis founded by a donationfrom KIRIN Brewery Co., Ltd.
November, 2002 Department of Clinical Renal
Regeneration founded by a donation from MOCHIDA
Pharmaceutical Co., Ltd.
November, 2002 Department of MENICON
Cartilage & Bone Regeneration founded by a donationfrom MENICON Co., Ltd.
March, 2003 The Cell Processing Center set up on
the 8th floor of the In-patient Ward B.
June, 2005 Department of Corneal Tissue Regeneration was renewed by a donation from AMNIOTEC Co., Ltd.
July, 2005 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom TAKEDA Chemical Industries Co., Ltd.
September, 2005 Department of Regeneration
Medicine for Hematopoiesis was renewed by adonation from KIRIN Brewery Co., Ltd.
November, 2005 Department of Clinical Renal
Regeneration was renewed by a donation fromMOCHIDA Pharmaceutical Co., Ltd.
November, 2005 By a donation from FUJISOFTABC Co., Ltd. Department of MENICON Cartilage &Bone Regeneration was renewed to Department 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
Regenerativen 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.

Research activities
As for bone and cartilage regeneration, we aim todevelop easy, precise, non-invasive systems to detect
osteoblastic and chondrocytic differentiation, todetermine a finite set of signaling factors sufficient for
induction of osteoblasts and chondrocytes, to develop
a cell-sheet culture system for bone and cartilage, todevise a method to induce osteogenesis andangiogenesis simultaneously, to screen for compounds
that induce bone and cartilage regeneration, todevelop non-viral gene transfer methods by nanomicelle technology and to generate, to devise methods
to precisely control 3D shape of biomaterials, and totransplant regenerated bone and cartilage. To achievethese goals, we are conducting research on bone andcartilage biology, developmental biology, stem cellbiology and regenerative medicine. Regarding theclinical study “Development of implant-type tissueengineered cartilage for patients with nasal deformity
in cleft lip and palate”, which was authorized to of
conduct on Mar 18th 2011, we have completed thetransplantation on 3 patients as had been planned. The
outcomes have been good so far with no majorcomplications.
As for renal regeneration, we aim at specificmethod to differentiate human iPS cells to kidney cells.
We also try to clarify the epigenetic regulation of
BMP7. To achieve these goals, we are conducting
epigenetic analysis of human kidney derived iPS cells.
Moreover, we are trying to establish 3-D culture
system for safe clinical application of human iPS cells,
and determining new target of cancer therapy bycomprehensive epigenetic analysis of cancer dereived
iPS cells.
In the department donated by FUJISOFT ABC, 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488

investigator-initiated clinical trial “A clinical trial forthe validation of safety and efficacy of theimplant-type tissue-engineered cartilage using
autologous 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.
Basic Research on human ES cells
Besides, to promote basic research on humanembryonic stem cells with our eyes set on applicationsin the future, Department of Clinical Renal Regeneration is carrying forward the application procedures toobtain human ES cells from Institute for Frontier
Medical Sciences, Kyoto University, which will beapproved shortly.

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” have been carried out. As statedabove, we are proceeding translational researchaiming at clinical application of tissue engineering andregenerative 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.
Department of Plastic Surgery is conducting researchusing this facility.

References
1. Kobahashi H, Chang SH, Mori D, Itoh S, Hirata
M, Hosaka Y, Taniguchi Y, Okada K, Mori Y,
Yano F, Chung UI, Akiyama H, Kawaguchi K,
TanakaS, and Saito T. Biphasic regulation ofchondrocytes by Rela through induction of antiapoptotic and catabolic target genes. Nat Commun.
2016; 7:13336. doi: 10.1038/ncomms13336.
2. Chang SH, Yasui T, Taketomi S, Matsumoto T,
Kim-Kaneyama J, Omiya T, Hosaka Y, Inui H,
Omata Y, Yamagami R, Mori D, Yano F, Chung
UI, Tanaka S, and Saito T. Comparison of mouseand human ankles and establishment of mouse
ankle osteoarthritis models by surgically-induced
instability. Osteoarthritis Cartilage. 2016;24:68897. doi: 10.1016/j.joca.2015.11.008.
3. Omata Y, Nakamura S, Koyama T, Yasui T, Hirose
J, Izawa N, Matsumoto T, Imai Y, Seo S,
Kurokawa M, Tsutsumi S, Kadono Y, Morimoto C,
Aburatani H, Miyamoto T, andTanaka S.
Identification of Nedd9 as a TGF-β-Smad2/3
Target Gene Involved in RANKL-induced Osteoclastogenesis by Comprehensive Analysis. PLoS
One. 2016; 11(6):e0157992.
4. Pellegrini MJ, Glisson RR, Matsumoto T, Schiff
A, Laver L, Easely ME, and Nunley JA 2nd
Allograft reconstructon vs. tenodesis for
irreparable peroneus brevis tears. Empiricalmeasurement of effectiveness in a cadaveric
model. Foot and Ankle Int. 2016;37(8):803-8.
5. Matsumoto T, Glisson RR, Reidl M, and Easley
ME: Compressive force with 2-screw and 3-screw
subtalar joint arthrodesis with headless compression screws. Foot and Ankle Int. 2016;37(12):357-63.
6. Okubo K, Kamiya M, Urano Y, Nishi H,
Herter JM, Mayadas T, Hirohama D, Suzuki K,
Kawakami H, Tanaka M, Kurosawa M, Kagaya S,
Hishikawa K, Nangaku M, Fujita T, Hayashi M,
and Hirahashi J.
Lactoferrin Suppresses
Neutrophil Extracellular Traps Release in Inflammation. EBioMedicine. 2016 Aug;10: 204-15.
7. Tsujimura T, Idei M, Yoshikawa M, Takase O, andHishikawa K. Roles and regulation of bonemorphogenetic protein-7 in kidney development
and diseases. World J Stem Cells. 2016;8:288-96.

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8. Kanno Y, Nakatsuka T, Saijo H, Fujihara Y, Hikita
A,, Chung UI, Takato T, and Hoshi K. Computed
tomographic evaluation of novel custom-madeartificial bones, “CT-bone”, applied for maxillafacial reconstruction. Regenerative Therapy.
2016;Dec:5:1–8.
9. Saijo H, Fujihara Y, Kanno Y, Hoshi K, Hikita A,
Chung UI, and Takato T. Clinical experience offull custom-made artificial bones for the
maxillofacial region. Regenerative Therapy. 2016
Dec;5:72–8.
10. Komura M, Komura H, Komuro H, Ikebukuro K,
Hikita A, Hoshi K, and Takato T. Tracheal
cartilage growth by intratracheal injection of basic
fibroblast growth factor. J Pediatr Surg. 2017 Feb;
52(2):235-38. Epub 2016 Nov 1.
11. Satake R, Komura M, Komura H, Kodaka T,
Terawaki K, Ikebukuro K, Komuro H, Yonekawa
H, Hoshi K, Takato T, and Nakayama Y. Patch
tracheoplasty in body tissue engineering using
collagenous connective tissue membranes(biosheets). J Pediatr Surg. 2016 Feb;51(2):244-8.
doi: 10.1016/j.jpedsurg.2015.10.068. Epub 2015
Nov 5.

490

Department of Clinical Research
GovernanceDirector & Project Professor
Takashi Moritoyo M.D.,Ph.D.

Research Associate
Keiko Ueda, M.D.,Ph.D. (From May, 2016~)

Homepage

http://www.h.u-tokyo.ac.jp/english/centers-services/organization/

History and Overview of theOrganization
The Department of Clinical Research Governance
was established independently from the ClinicalResearch Support Center on January 1, 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 iscomposed of three offices: 1) Office of TR Strategy
Promotion, 2) Office for Clinical Research Education,and 3) Office of Clinical Quality Assurance &Compliance. These offices mutually cooperate topromote and strengthen governance functions within
the hospital.
The following activities are carried out by the
Office of TR Strategy Promotion: (1) formulating
comprehensive
strategies
forresearchanddevelopment 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) examinating 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 for Clinical Research
Education are as follows: (1) educational activities forclinical researchers; and (2) the dissemination ofworkshop summaries.
The activities of the Office of Clinical Quality
Assurance & Compliance are as follows: (1) quality
assurance-related activities, such as the auditing ofclinical trials and clinical studies and administrative
structure/system audits as well as improvement
proposals; (2) proposals related to the establishment ofa quality assurance system; (3) reliability-related
guidance, advice and consultation; (4) support for
responding to compliance reviews, etc., for clinical
trials and clinical studies conducted by the Universityof Tokyo Hospital, as well as the centralized

491

management of results; (5) the centralized
management of audit results; and (6) confirmation of
the implementation of corrective and preventive
measures based on audit/inspection findings.
The Department of Clinical Research Governanceconsists of one manager (a full-time post from August,2015) and two staff members of the Office of TR
Strategy Promotion (one special researcher/URA andone clerical staff [temporary]), as of March 2017. The
Office for Clinical Research Education consists of one
member (one research associate). The Office ofClinical Quality Assurance consists of one head(project senior specialist) and two staff members (aproject specialist and a project academic support
staff) .

Medical Care and Activities
The Office of TR Strategy Promotion has
undertaken the following activities.
1) Organization coordination activities: assisting theSpecial Clinical Research Steering Committee,
assisting the Special Clinical Research Checkup
Committee, assisting with the assembly of a structure
for a regenerative therapy provision plan, andassisting the preparation of reports on clinical research
activities at core hospitals under the Medical Service
Law (approved on March 25, 2016) and for surveys
conducted by the Ministry of Health, Labour andWelfare.
2) Activities related to TR Promotion: adopting therole of administrative headquarters when applying for
Projects of Translational and Clinical Research Core
Centers, hosting medical-engineering collaborative
meetings (cooperation with Ota-ku), and organizing
the meeting to exchange opinions with the president of
AMED.
3) Intellectual property-related activities: evaluationof intellectual properties for network programs foraccelerating the work of bridging research, organizing
two seminars for intellectual properties, andconducting 10 consultations regarding intellectual
properties (10 patent cases).
4) Others: reviews of application forms for
Grants-in-Aid for Scientific Research and for the
University of Tokyo Research Grant, investigations ofresearch paper publication activities, hosting of the“Forum for Development of Seeds for Advanced
Medicine, 2017” (administrative office), and support
for the Center of Innovation Program of the Universityof Tokyo (support for departmental cooperation,
support for holding one symposium, and support forholding two seminars).
The Office of Clinical Quality Assurance &Compliance was newly established in April 2015 andhas undertaken the following quality assurance
activities.
1) Quality assurance-related activities:1. Regarding 3
investigator-initiated clinical trials at the University ofTokyo Hospital, a total of 6 cases were audited.
Regarding 2 investigator-initiated clinical trials (amulti-center clinical trial and a trial for a medical
device) at other university hospitals, 2 cases wereaudited. 2. Regarding clinical research, 1 case ofclinical research at other university hospitals was
audited. Regarding clinical research at the Universityof Tokyo Hospital, 2 cases of advanced medical care
B were audited and the audit procedures and protocols
for 2 clinical studies were prepared. The members of
the office explained the audit schedule and contents,
etc. Preparations for other audits have also been
initiated. 3. When research funding was secured, theaudit was entrusted to the external audit organization
under supervision by the Office.
2) Support for responses to various inspections:Regarding surveys for TR centers, AMED, andclinical research core hospitals, the members attended
and explained the structure for quality assurance. The
members also attended the inspections performed by
the FDA.
3) Educational activities:1. For a “Lecture Series”
conducted by the clinical research support center, theoffice was involved in making programs, inviting
lecturers, and conducting the seminar. 2. Supervisionsof quality assurance were conducted for members of
the clinical research support center.
4) Other activities:1. Regarding the activities of the
UCHT Alliance, mutual visits among 8 university
hospitals were conducted and the structure for quality
assurance was evaluated. 2. For the National
University Hospital Clinical Research Promotion
Initiative (NUH-CRPI), a member joined and led the492

discussion on quality assurance. 3. The members
attended the Japan Society of Quality Assurance andthe Annual Scientific Meeting of the Japanese Societyof Clinical Pharmacology and Therapeutics, and ananalysis of audit results was reported.

References
1. Moritoyo T. Guideline for the review of drug
application on novel medical products for thetreatment of Alzheimer’s disease ~The trend of
FDA, EMA and PMDA~. Journal of Clinical andExperimental Medicine. 2016;257(5):561-567.

493

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 fordevelopmentally disabled children established in theformer 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 of Pediatrics and Graduate School of
Education in the University of Tokyo but also several
other educational and/or clinical facilities on mental
development or developmental disorders. The
Department of Child Psychiatry complemented theClinical Education Center by providing fieldwork forclinical training and offered clinical services topatients with various development problems also.
The Clinical Education Center of Mental
Development was closed in March 2010 because oftime limit of the fund, and Department of Child
Neuropsychiatry, Graduate School of Medicine wasestablished in April 2010. The Department of Child
Psychiatry, as the clinical counterpart to thedepartment in graduate school, focuses on clinicalactivity related to research as well as quality practiceof child psychiatry and education of leading childpsychiatrists and allied professionals. In addition toprofessors of the graduate school, 3 psychiatrists and 3
psychologists (2 full-time ones for a definite term and1 part-time one) are officially assigned to the Department of Child Psychiatry. One psychiatric social
worker works mainly for the Department of Child
Psychiatry since 2013 also.

Clinical activities
In the year 2016, the Department of Child
Psychiatry consisted of 14 psychiatrists and 7
psychologists (full-time and part-time). Althoughpatients with various disorders are seen, the focus of
the department is mainly on patients with developmental disorders. We offer services to patients with abroad range of developmental disorders including
Autism Spectrum Disorder (ASD), Attention-Deficit/
Hyperactivity Disorder (ADHD), Learning Disabilities(LD), Mental Retardation (MR), tic disorders and child& adolescent Obsessive-Compulsive Disorders (OCD).
Number of new patients in 2016 was 251 andslightly larger than that in 2015. A large part of the
new patients consisted of patients with ASD, ADHD
or tic disorders. Out of 251 patients, children ofelementary school age were 111, and children of
junior high school age were 41. In other words,
children of elementary or junior high school age wereabout two-thirds of the patients. Number of preschool
children was 64, and about twice of that in 2015,
suggesting an increase in needs for early diagnosis
and intervention.
The follow-up clinic consisted of general clinic andspecial clinic (Tic/OCD clinic). At the general clinic, a494

rigorous 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 psychologicalconsultation as well as psychological examination.
Patients involved in those are mainly individuals with
developmental disabilities, and individualized
treatment focusing on developmental viewpoint isplanned for each. Psychological consultation includes
services in the following areas: (1) evaluation of
cognitive and behavioral development, (2) individualized treatment of the disabled individual (3)counseling of parents and providing information to thedisabled individual’s support network (relatives,
schools) and environmental coordination. In addition
to psychologists, psychiatric social worker participatesin actual environmental coordination. Cognitive
behavior therapy for obsessive-compulsive symptoms
or anxiety 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
especially pediatrics.

the

University

hospital,

Education
Undergraduates of the University of Tokyo haveopportunities to participate in an assessment anddiagnosis session at the general first visit outpatient
clinic and intervention for preschool children.
Graduate students in clinical psychology course fromthe University of Tokyo participate in intervention forpreschoolers also.
One month training course is offered to juniorresidents especially in pediatric specialty course. This
course includes intake interview of first visit patients,
observation of assessment and treatment for follow-up
patients and intervention for preschoolers, and visit tocommunity hospital and intervention/guidance
facilities for child and adolescent mental health. For
general psychiatrists including senior residents of the
Department of Neuropsychiatry, round for developmental disorders and an inpatient program of assessment about developmental disorders are provided asopportunity to get knowledge and experience ofdevelopmental disorders.
In response to the increasing interest to adults with
developmental disorders, a seminar of developmental
disorders was held in October 2016, and about 160
medical doctors, psychologists, and allied professionals attended.

Research
We participate in investigation of etiology anddevelopment of effective treatment on ASD and
ADHD, which are organized in collaboration with the
Department of Neuropsychiatry and other research,educational and clinical facilities. In addition, research
related specifically to the clinical activities in the
Department of Child Psychiatry is currently being
investigated.
Clinical evaluation and treatment
Effectiveness study of early intervention for autisticpreschoolers is being undertaken.
Effectiveness of a program of group cognitive
behavior therapy for adults with high-functioning
ASD the revised program is investigated in a495

randomized control trial.
The possible relations among clinical characteristics
such as tics and obsessive-compulsive symptoms in
Tourette syndrome (chronic tic disorder with multiple
motor tics and one or more vocal tics) and child &adolescent OCD are being evaluated.
Comprehensive Behavioral Intervention for Tics
(CBIT) is provided for children and adolescents with
Tourette syndrome, and preliminary study of its
effectiveness is undertaken.
We started survey of tics and related symptoms incommunity 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
and assisted reproduction technologies on emergenceof ASD. We are analyzing samples of individuals froma multiplex family of ASD by exome sequencing also.
We are collecting and analyzing DNA samples ofpatients with Tourette syndrome and their parents also.
Neuroimaging
Studies include structural MRI, Near-Infrared Spectroscopy (NIRS) and functional MRI with exploring
the pathogenesis of developmental disorders such as
ASD. One of the intensive study is the examination of
prefrontal blood flow in ASD and ADHD by NIRS
which is non invasive and easily applicable to children
and developmentally disabled individuals. Possibilityof NIRS as a predictor of efficacy of methylphenidate
for children with ADHD is intensively examined also.
Functional MRI study of adults with ADHD andadults with Tourette syndrome by delayed reward task
is in process.

References
1. Ando S, Kuwabara H, Araki T, Kanehara A,
Tanaka S, Morishima R, Kondo S, Kasai K,
Mental Health Problems in a Community Afterthe Great East Japan Earthquake in 2011: A
Systematic Review. Harv Rev Psychiatrty, 25(1):15-28, 2017.
2. Watanabe T, Otowa T, Abe O, Kuwabara H, Aoki
Y, Natsubori T, Takao H, Kakiuchi C, Kondo K,
Ikeda M, Iwata N, Kasai K, Sasaki T, Yamasue H.
Oxytocin receptor gene variations predict neuraland behavioral response to oxytocin in autism.
Soc Cogn Affect Neurosci, 12(3): 496-506, 2017.
3. Yamasaki M, Miyagawa T, Toyoda H, Khor SS,
Liu X, Kuwabara H, Kano Y, Shimada T,
Sugiyama T, Nishida H, Sugaya N, Tochigi M,
Otowa T, Okazaki Y, Kaiya H, Kawamura Y,
Miyashita A, Kuwano R, Kasai K, Tanii H, Sasaki
T, Honda Y, Honda M, Tokunaga K. Evaluation ofpolygenic risks for narcolepsy and essential
hypersomnia. J Hum Genet, 61(10): 873-878,
2016.
4. Takasaki Y, Koide T, Wang C, Kimura H, Xing J,
Kushima I, Ishizuka K, Mori D, Sekiguchi M,
Ikeda M, Aizawa M, Tsurumaru N, Iwayama Y,
Yoshimi A, Arioka Y, Yoshida M, Noma H,
Oya-Ito T, Nakamura Y, Kunimoto S, Aleksic B,
Uno Y, Okada T, Ujike H, Egawa J, Kuwabara H,
Someya T, Yoshikawa T, Iwata N, Ozaki N.
Mutation screening of GRIN2B in schizophrenia
and autism spectrum disorder in a Japanese
population. Sci Rep, 6: 33311,2016.
5. Yahata N, Morimoto J, Hashimoto R, Lisi G,
Shibata K, Kawakubo Y, Kuwabara H, Kuroda M,
Yamada T, Megumi F, Imamizu H, Náñez JE Sr,
Takahashi H, Okamoto Y, Kasai K, Kato N,
Sasaki Y, Watanabe T, Kawato M. A small numberof abnormal brain connections predicts adultautism spectrum disorder. Nat Commun, 7: 11254,
2016.
6. Sakakibara E, Homae F, Kawasaki S, Nishimura Y,Takizawa R, Koike S, Kinoshita A, Sakurada H,
Yamagishi M, Nishimura F, Yoshikawa A, Inai A,
Nishioka M, Eriguchi Y, Matsuoka J, Satomura Y,
Okada N, Kakiuchi C, Araki T, Kan C, Umeda M,
Shimazu A, Uga M, Dan I, Hashimoto H,

496

Kawakami N, Kasai K. Detection of resting statefunctional connectivity using partial correlation
analysis: A study using multi-distance andwhole-head probe near-infrared spectroscopy.
Neuroimage, 142: 590-601, 2016.

497

Department of Pain and Palliative
Medicine
Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/pailiative/

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, thenumber achieved to more than total 900 cases. To date
we have become to collaborate with almost all departments treating cancer in our hospital. These results
indicate that the hospital understands the significanceof palliative care well 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.

4981) 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 theiraccepting realities and expecting hopes. We practiceaccording to the guidelines of communication that isrecommended 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 thecompletion of all the requested consulting of theday.
･ 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.

499

Research
The clinical information accumulated from thepalliative care consultation is input to the concise
database simultaneously and utilized for various kindsof clinical researches to submit to the international
medical journal such as "International Journal of
Radiation Oncology Biology Physics", "Journal ofPain and Symptom Management" and so on.
To date, we the Department of Palliative Medicine
have contributed to the progress of following fields ofinvestigations. Please refer to our homepage forresults in details and acquisition of the research fund.
1) Evaluation and quality assurance of special pain
and palliative care team2) Cancer Survivorship
3) Investigating cognitive dysfunction induced bypain4) Cancer treatments-induced neurological side
effect5) Synergistic influence between sleep disorder andpain6) Assessment of neuropathic pain
7) Relationships among our university hospital andlocal hospitals and clinics
8) Palliative care supporting metastatic breast cancer
patient9) In palliative medicine field, clinical researchesand questionnaires

Publications
1. Inoue R, Sumitani M, Yasuda T, Tsuji M,
Nakamura M, Shimomura I, Shibata M, Yamada Y.
Independent risk factors for positive and negative
symptoms in patients with diabetic polyneuropathy. J Pain Palliat Care Pharmacother2016; 30: 178-83
2. Sumitani M, Ogata T, Natori A, Hozumi J,
Shimojo N, Kida K, Yamauchi H, Yamauchi T.
Poor efficacy of the phosphorylated highmolecular-weight neurofilament heavy subunit, abiomarker of axonal damage, as a marker ofchemotherapy-induced peripheral neuropathy.
BioMed Rep 2016; 4: 758-60
3. Sano Y, Ichinose A, Wake N, Osumi M, Sumitani
M, Kumagaya S, Kuniyoshi Y. Reliability ofphantom pain relief in neurorehabilitation using a

multimodal virtual reality system. Conf Proc
IEEE Eng Med Biol Soc. 2015; 2482-5
4. Hozumi J, Sumitani M, Matsubayashi Y, Abe H,
Ohshima Y, Chikuda H, Takeshita K, Yamada Y.
Relationship between neuropathic pain andobesity. Pain Prac Res 2016; 2487924
5. Sumitani M, Ueda H, Hozumi J, Inoue R, Kogure
T, Ogata T, Yamada Y. Minocycline does notdecrease intensity of neuropathic pain, but
improves its affective dimension. J Pain Palliat
Care Pharmacother 2016; 30: 31-5
6. Sano Y, Wake N, Ichinose A, Osumi M, Oya R,
Sumitani M, Kumagaya S, Kuniyoshi Y. Tactile
feedback for relief of deafferentation pain using
virtual reality system: a pilot study. J Neuro
Engineering Rehabil 2016; 13: 61
7. Yozu A, Sumitani M, Shin M, Ishii K, Osumi M,
Katsuhira J, Chiba R, Haga N. Effect of spinal
cord stimulation on gait in a patient with thalamic
pain. Case reports in Neurol Med 2016; 2016:8730984
8. Isomura T, Sumitani M, Matsudaira K,
Kawaguchi M, Inoue R, Hozumi J, Tanaka T,
Oshima H, Mori K, Takemoto S, Inui H, Tahara K,
Yamagami R, Hayakawa K. Development of theJapanese version of the Leeds Assessment of the
Neuropathic Symptoms and Signs Pain Scale(LANSS-J): Diagnostic Utility in a clinical setting.
Pain Prac 2016 (in press)
9. Ushida T, Shibata M, Kitahara M, Yabuki S,
Sumitani M, Murakami T, Iseki M, Hosoi M,
Shiokawa H, Tetsunaga T, Nishie H, Fukui S,
Kawasaki M, Inoue S, Nishihara M, Aono S,
Ikemoto T, Kawai T, Arai YC. The effect of
guidance regarding Home Exercise and ADL onadolescent females suffering from adverse effects
after HPV vaccination in Japanese multidisciplinary pain centers. Pain Res Manag 2016;3689352
10. Kanai Y, Takaesu Y, Nakai Y, Ichiki M, Sato M,
Matsumoto Y, Ishikawa J, Ono Y, Murakoshi A,
Tanabe H, Kusumi I, Inoue T. The influence ofchildhood abuse, adult life events, and affective
temperaments on the well-being of the general,
nonclinical adult population. Neuropsychiatr Dis
Treat 2016; 12: 823-32(And, more than 27 Japanese articles)

500

Department of Cancer Resource
CenterChief
Sachiyo Nomura, M.D.,Ph.D.

Associate chief
Takako Wakeda, M.D.,Ph.D.

Counseling staff
Nobuko Yamaji, RN., Megumi Yasuda, RN.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/cancer_support/

Introduction and Organization
As part of national efforts to address cancer, thegovernment has been establishing a network of“cancer care hub hospitals.” In response to its being
designated as a regional cancer care hub hospital in2008, the University of Tokyo Hospital established theCancer Patient Support Center to provide
consultations to cancer patients and their families aswell as residents in neighboring communities with theaim of leading them to appropriate departments andfacilities.

Medical Services
Provision of information if patient contracts cancer
If a person gets cancer, the first thing they need to do
is collect information on cancer. The Cancer
Counseling and Support Center provides information
and booklets on different types of cancer. Furthermore,in order to select the best treatment for oneself fromamong the therapies presented by doctors, the person
needs to accurately understand the doctors’
explanations. At the Cancer Counseling and Support
Center, we explain difficult medical terms in simple
language, and we help patients understand theirdoctors’ advice.

Various kinds of advice related to the medical careof cancer
If a person contracts cancer, besides the medical
problem of what kind of treatment to undergo andwhere, there are also issues related to medical carewhen receiving treatment, such as medical expenses,
how to get along after being discharged from hospital,and nursing services. The Cancer Counseling andSupport Center provides patients with advice andsupport so that they can resolve such worries.
Provision of information on second opinions
The Center provides information on how to get asecond opinion and on facilities that provide second
opinions.
Provision of general information and advice on
cancer
The Center sends out and provides information topeople who do not have cancer but who want to findout about cancer, for instance the treatment andscreening for it.

Open hours
If you have any queries, please contact us on
03-5800-9061 between 9am-4pm weekdays (except 12
noon-1pm). Our center provide advices for nothing.

501

Research activities
Our research field covers the relation between
appearance changes caused by cancer therapy andPatients’ quality of life.

References and Presentation
1. Takako W. Benefits of cover makeup for survivors.
Journal of Clinical Oncology 34, no. 26_suppl(October 2016) 259-259. http://ascopubs.org/doi/
abs/10.1200/jco.2016.34.26_suppl.259
2. Takako W. Benefits of cover makeup for survivors.
Palliative care in oncology Symposium
3. Takako W. Appearance care service in The
University of Tokyo Hospital. The 54th Annual
Meeting of Japan Society of Clinical Oncology(JSCO)

502

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 applicationof results of recently advanced human genetics
and genomics. In addition, the unit contributes totraining and educating specialists of clinicalepidemiology and human genetics. Our section also
supported designing of clinical / genetic studies. It
consists of one professor and different specialties
participating in the department. They include
cardiologists, diabetologists, 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 theJapanese population. We are now performing agenome-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 the1000 Genomes Project Phase 3 reference panel in
35,000 cases and more than 54,000 controls. We
also found that one gene was associated withdiabetic nephropathy and two genes were associatedwith diabetic retinopathy.
We conducted whole genome sequence andanalyzed the sequence data of the subjects with type2 diabetes in collaboration with RIKEN and

BioBank Japan. We are exploring the genetic andenvironmental factors by selecting case and control
from BioBank Japan for genome-wide analysis
concerning deterioration of diabetes and diabetic
complications (diabetic nephropathy and diabetic
retinopathy). We are developing the methods topredict diabetic complications and deterioration ofdiabetes by bioinformatics algorithms including thePenalized regression method, often used in machinelearning and public OmiX database.
The insulin receptor gene mutations wereanalyzed in four patients with severe insulin
resistance 1). Using online databases, we analyzed
insulin receptor gene missense mutations anddemonstrated that mutations causing Donohue
syndrome were more frequently located in the
fibronectin type III domain (FnIII) than thosecausing the milder insulin resistance. We revealed
that the mutant insulin receptor genes in the FnIII
reduced insulin proreceptor processing, byfunctional analysis using cultured cells. In silico
structural analysis revealed that missense mutations
predicted to severely impair hydrophobic coreformation and stability of the FnIII domains. These
results suggest the importance of the FnIII domains,provide insight into the molecular mechanism ofsevere insulin resistance, and will aid early
diagnosis.
In cardiology and vascular medicine, we focusedon atherosclerotic diseases such as coronary stenosis
and myocardial infarction. It is important toaccumulate and analyze data obtained in practice andgenetic data to gain insight into a clinical picture.
Analyzing data collected provide detailed genetic
factors of the coronary atherosclerotic diseases and503

their clinical outcome.

3．References
1. Jun Hosoe, Hiroko Kadowaki, Fuyuki Miya,
Katsuya Aizu, Tomoyuki Kawamura, Ichiro
Miyata, Kenichi Satomura, Takeru Ito, Kazuo
Hara, Masaki Tanaka, Hiroyuki Ishiura, Shoji
Tsuji, Ken Suzuki, Minaka Takakura, Keith A.
Boroevich, Tatsuhiko Tsunoda, Toshimasa
Yamauchi, Nobuhiro Shojima and Takashi
Kadowaki. Structural Basis and Genotypephenotype Correlations of INSR Mutations
Causing Severe Insulin Resistance. Diabetes,
August 01, 2017 Online Ahead of Print

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Department of Clinical Genomics,
Medical Genome Center
Director & Professor
Shoji Tsuji, M.D., Ph.D.

Organization
The Department of Clinical Genomics started as a
special unit conducting genomic medicine or clinicalhuman genetics services in 2003. Our department
functions as the core unit to accomplish an appropriate
and efficient application of results of recently
advanced human genetics and genomics to clinicalpractice in the hospital and as the unit of training andeducating specialists of human genetics practice. It
consists of one professor and many different
specialties participate in the department. They include
pediatricians, obstetricians, internist (cardiologists,diabetologists, and neurologists), surgeons, and staffs
of the Departments of Clinical Laboratory Medicine,
Human Genetics and Nursing Science.

Activities
The exclusive consultation room (Room 200) is
allocated in the outpatient clinic. Consultation andcounseling is performed by a team of medical doctor
and non-M.D. staffs. All cases are reviewed anddiscussed at the conference which is held on the 1st
Monday every month. Counseling of participants inresearches including genome or gene analysis is aduty with which the hospital and the faculty charge
the department. To build suitable clinical systems
including modern genomic medicine we arecooperating with other departments. We areparticipating in Marfan’s Syndrome Clinic which ismanaged collaboratively by the Departments of
Cardiovascular Surgery, Cardiovascular Medicine,
Pediatrics, Spinal Surgery and Ophthalmology.In
collaboration with Clinical Laboratory Center,
Pharmaceutical Services, Departments of Planning

Information and Management, and several clinicaldepartments, pharmacogenetics tests including thosefor proton inhibitor, warfarin, irinotecan, andtacrolimus, are conducted.

Publications
1. Ichinose Y, Koh K, Fukumoto M, Yamashiro N,
Kobayashi F, Miwa M, Nagasaka T, Shindo K,
Ishiura H, Tsuji S, Takiyama DY. Exome
sequencing reveals a novel missense mutation in
the KIAA0196 gene in a Japanese patient with
SPG8. Clin Neurol Neurosurg. 2016 May;144:
36-8.
2. Mano KK, Matsukawa T, Mitsui J, Ishiura H,
Tokushige S, Takahashi Y, Sato NS, Nakamoto
FK, Ichikawa Y, Nagashima Y, Terao Y, Shimizu
J, Hamada M, Uesaka Y, Oyama G, Ogawa G,
Yoshimura J, Doi K, Morishita S, Tsuji S, Goto J.
Atypical parkinsonism caused by Pro105Leu
mutation of prion protein: A broad clinicalspectrum. Neurol Genet. 2016 Jan 7;2(1):e48.
3. Okuma H, Saito F, Mitsui J, Hara Y, Hatanaka Y,
Ikeda M, Shimizu T, Matsumura K, Shimizu J,
Tsuji S, Sonoo M. Tubular aggregate myopathy
caused by a novel mutation in the cytoplasmic
domain of STIM1. Neurol Genet. 2016 Feb 1;2(1):e50.
4. Amiya E, Morita H, Hatano M, Nitta D, Hosoya
Y, Maki H, Motozawa Y, Sato N, Ishiura H,
Numakura S, Shintani Y, Kinugawa K, Takeda N,
Shimizu J, Tsuji S, Komuro I. Fukutin genemutations that cause left ventricular noncompaction. Int J Cardiol. 2016 Nov 1;222:7279.
5. Udagawa T, Jo T, Yanagihara T, Shimizu A,

505

Mitsui J, Tsuji S, Morishita S, Onai R, Miura K,
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 steroidresistant nephrotic syndrome. Pediatr Nephrol.
2017 May;32(5):801-809.
6. 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.

506

Department of Genome Analysis,
Medical Genome Center
Director and Professor
Shoji Tsuji, M.D., Ph.D.

The Department of Genome Analysis started as acore facility at the University of Tokyo Hospital in
2011. Next generation sequencers (NGSs), whichhave been installed until now, include three Illumina
HiSeq2500s, one Pacific Biosciences RS II, Oxford
Nanopore MinION system, and one Illumina MiSeq.
Robotics for preparation of samples has also been
installed. Computer servers for processing of massive
amount of genome data have been installed in theserver room, which are connected to NGs via network
system isolated from the internet.

Activities
The core facility offers genome sequencing
employing NGSs for other laboratories in the
University of Tokyo Hospital as well as for the inhouse projects. The core facility further offers genome
sequencing employing NGSs for laboratories outsideof the University of Tokyo. Approximately 2,000
samples per year have been analyzed.

Research Accomplishments
Collaborative researches have achieved multiple
accomplishments including identification of thecausative gene for autosomal recessive CharcotMarie-Tooth disease (MME), familial amyotrophic
lateral sclerosis (CCNF), and progressive neurodegenerative encephalopathy with atypical infantile
spinal muscular atrophy (TBCD), development of areference database of genetic variations in theJapanese population, and case reports of SPG8 andtubular aggregate myopathy.

Publications
1. Nishikawa A, Mori-Yoshimura M, Segawa K,
Hayashi YK, Takahashi T, Saito Y, Nonaka I,
Krahn M, Levy N, Shimizu J, Mitsui J, Kimura E,
Goto J, Yonemoto N, Aoki M, Nishino I, Oya Y,
Murata M. Respiratory and cardiac function injapanese patients with dysferlinopathy. Muscle
Nerve. 2016 Mar;53(3):394-401.
2. Nakamura R, Sone J, Atsuta N, Tohnai G,
Watanabe H, Yokoi D, Nakatochi M, Watanabe H,
Ito M, Senda J, Katsuno M, Tanaka F, 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,
Tsuji S, Nakashima K, Kaji R, Sobue G; Japanese
Consortium for Amyotrophic Lateral Sclerosis
Research (JaCALS). Next-generation sequencingof 28 ALS-related genes in a Japanese ALS cohort.
Neurobiol Aging. 2016 Mar;39:219.e1-8.
3. Qu W, Tsukahara T, Nakamura R, Yurino H,
Hashimoto S, Tsuji S, Takeda H, Morishita S.
Assessing Cell-to-Cell DNA Methylation
Variability on Individual Long Reads. Sci Rep.
2016 Feb 18;6:21317.
4. Higasa K, Miyake N, Yoshimura J, Okamura K,
Niihori T, Saitsu H, Doi K, Shimizu M,
Nakabayashi K, Aoki Y, Tsurusaki Y, Morishita
S, Kawaguchi T, Migita O, Nakayama K,
Nakashima M, Mitsui J, Narahara M, Hayashi K,
Funayama R, Yamaguchi D, Ishiura H, Ko WY,
Hata K, Nagashima T, Yamada R, Matsubara Y,
Umezawa A, Tsuji S, Matsumoto N, Matsuda F.
Human genetic variation database, a reference
database of genetic variations in the Japanese
population. J Hum Genet. 2016 Jun;61(6):547-53.

507

5. Ichinose Y, Koh K, Fukumoto M, Yamashiro N,
Kobayashi F, Miwa M, Nagasaka T, Shindo K,
Ishiura H, Tsuji S, Takiyama DY. Exome
sequencing reveals a novel missense mutation in
the KIAA0196 gene in a Japanese patient with
SPG8. Clin Neurol Neurosurg. 2016 May;144:
36-8.
6. Higuchi Y, Hashiguchi A, Yuan J, Yoshimura A,
Mitsui J, Ishiura H, Tanaka M, Ishihara S, Tanabe
H, Nozuma S, Okamoto Y, Matsuura E, Ohkubo
R, Inamizu S, Shiraishi W, Yamasaki R, Ohyagi
Y, Kira J, Oya Y, Yabe H, Nishikawa N,
Tobisawa S, Matsuda N, Masuda M, Kugimoto C,
Fukushima K, Yano S, Yoshimura J, Doi K,
Nakagawa M, Morishita S, Tsuji S, Takashima H.
Mutations in MME cause an autosomal-recessive
Charcot-Marie-Tooth disease type 2. Ann Neurol.
2016 Apr;79(4):659-72.
7. Mano KK, Matsukawa T, Mitsui J, Ishiura H,
Tokushige S, Takahashi Y, Sato NS, Nakamoto
FK, Ichikawa Y, Nagashima Y, Terao Y, Shimizu
J, Hamada M, Uesaka Y, Oyama G, Ogawa G,
Yoshimura J, Doi K, Morishita S, Tsuji S, Goto J.
Atypical parkinsonism caused by Pro105Leu
mutation of prion protein: A broad clinicalspectrum. Neurol Genet. 2016 Jan 7;2(1):e48.
8. Okuma H, Saito F, Mitsui J, Hara Y, Hatanaka Y,
Ikeda M, Shimizu T, Matsumura K, Shimizu J,
Tsuji S, Sonoo M. Tubular aggregate myopathy
caused by a novel mutation in the cytoplasmic
domain of STIM1. Neurol Genet. 2016 Feb 1;2(1):e50.
9. Williams KL, Topp S, Yang S, Smith B, Fifita JA,
Warraich ST, Zhang KY, Farrawell N, Vance C,
Hu X, Chesi A, Leblond CS, Lee A, Rayner SL,
Sundaramoorthy V, Dobson-Stone C, Molloy MP,
van Blitterswijk M, Dickson DW, Petersen RC,
Graff-Radford NR, Boeve BF, Murray ME,
Pottier C, Don E, Winnick C, McCann EP, Hogan
A, Daoud H, Levert A, Dion PA, Mitsui J, Ishiura
H, Takahashi Y, Goto J, Kost J, Gellera C, Gkazi
AS, Miller J, Stockton J, Brooks WS, Boundy K,
Polak M, Muñoz-Blanco JL, Esteban-Pérez J,
Rábano A, Hardiman O, Morrison KE, Ticozzi N,
Silani V, de Belleroche J, Glass JD, Kwok JB,
Guillemin GJ, Chung RS, Tsuji S, Brown RH Jr,
García-Redondo A, Rademakers R, Landers JE,

Gitler AD, Rouleau GA, Cole NJ, Yerbury JJ,
Atkin JD, Shaw CE, Nicholson GA, Blair IP.
CCNF mutations in amyotrophic lateral sclerosis
and frontotemporal dementia. Nat Commun.
2016 Apr 15;7:11253.
10. Suzuki Y, Korlach J, Turner SW, Tsukahara T,
Taniguchi J, Qu W, Ichikawa K, Yoshimura J,
Yurino H, Takahashi Y, Mitsui J, Ishiura H, Tsuji
S, Takeda H, Morishita S. AgIn: measuring thelandscape of CpG methylation of individual
repetitive elements. Bioinformatics. 2016 Oct 1;
32(19):2911-9.
11. Amiya E, Morita H, Hatano M, Nitta D, Hosoya
Y, Maki H, Motozawa Y, Sato N, Ishiura H,
Numakura S, Shintani Y, Kinugawa K, Takeda N,
Shimizu J, Tsuji S, Komuro I. Fukutin genemutations that cause left ventricular noncompaction. Int J Cardiol. 2016 Nov 1;222:727-9.
12. Fujimori K, Tezuka T, Ishiura H, Mitsui J, Doi K,
Yoshimura J, Tada H, Matsumoto T, Isoda M,
Hashimoto R, Hattori N, Takahashi T, Morishita
S, Tsuji S, Akamatsu W, Okano H. Modelingneurological diseases with induced pluripotent
cells reprogrammed from immortalized lymphoblastoid cell lines. Mol Brain. 2016 Oct 3;9(1):88.
13. 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.
14. Udagawa T, Jo T, Yanagihara T, Shimizu A,
Mitsui J, Tsuji S, Morishita S, Onai R, Miura K,
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 steroidresistant nephrotic syndrome. Pediatr Nephrol.
2017 May;32(5):801-809.
15. 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.

508

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

509

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 place

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, a fourdimensional 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 analysed 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 activities

Research and development of micro-neurosurgicalrobotic systems
Department of Neurosurgery, The University of Tokyo
Hospital
Mitsuishi-Sugita
Laboratory,
DepartmentofDevelopment of Advanced Stereotactic Radiation
Cancer Therapy System
Department of Radiology

Laboratory of Nano-crystals in Oncology
Department of Chemical System Engineering
Department of Surgical Oncology
To develop an exact diagnosis and treatment system
for the micro-metastasis of neoplasm by using
nano-crystal particles, and to introduce it to clinicaluse. To visualize peritoneum metastases (peritonitis)
and micro-metastasis of neoplasm which cannot bechecked in naked eye, and apply it to an operation or
the determination of a medical treatment plan. To
search for the new method for treating neoplasm byusing biological changes of the cells after up taking
nano-crystal particles.

510

Mechanical Engineering, School of Engineering
Development of micro-neurosurgical robotic systems
and advanced microscopic image processing forautomated surgical task recognition.
Laboratory of Cavitation & Lithotripsy
Department of Urology, Faculty of Medicine
Department of Mechanical Engineering, School ofEngineering
Development of a new method of lithotripsy using
high intensity focused ultrasound induced cavitation.
Development of Support Systems for Risk
Reduction in the Clinical Process
Chemical System Engineering
Center for Epidemiology and Preventive Medicine
Our specific targets are research and education on the
integration of biological and clinical information
including genome. In particular, they consist of establishment of personalized medicine as translational
research, selection of drug targets by proteomics,
interpretation of transcriptional regulations and drug
development by targeting transcription factors in
cardiovascular diseases (arteriosclerosis, cardiac
hypertrophy, cardiac failure, etc.). Other analyses anddevelopment are also quite active, such as creation oftransgenic animals, analyses of genomic functions,clinical safety monitoring by clinical database andassessments of clinical information systems.
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 (BNCT) using
small neutron accelerator equipped to hospital andalso aim to augment cancer therapy combined withimmunotherapeutic approaches.
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
Laboratory of Regenerative Medical Engineering,
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.

511

We try to develop a new adhesion model by hepatic
resection, instead of a usual peritoneal abrasion model.
Also, we develop new materials for preventing theadhesions.
Development of new therapy of life style-relateddeseases by Applied Metabolic Biotechnology
Department of Cardiovascular Medicine, Graduate
School of Medicine
Department of Metabolic Diseases, Graduate Schoolof 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
andvascularregeneration.
Regeneration of bone and cartilage tissue in vitro
promoted by physical 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 chondrocytic 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 the512targeted 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.

2.

3.
Intervention study of exercise therapy for patientswith gluteal claudication after abdominal aortic or
iliac arterial surgery.
Mechano-Informatics,
Graduate
SchoolofInformation Science and Technology, The Universityof Tolyo
Department of Vascular Surgery, Faculty of Medicine,
The University of Tokyo
After minimally invasive endovascular aortic and iliac
repair for aneurysm with stent grafts and coilembolization, we apply intervention with exercise
therapy in case of postoperative gluteal claudication.
We aim to explore the mechanism of improving
gluteal claudication and establish the optimal exercise
therapy, by analyzing the biomechanical motion ofwalking with motion capture method before and after
the exercise therapy.
Analysis of the role of nitric oxide in themechanisms of renal and vascular injuries by theprobes for active oxygen and nitric oxide.
Department of Cardiovascular Medicine
Laboratory of Chemistry and Biology, Graduate
School of Pharmaceutical Sciences
It has been elucidated that the oxidative stress andnitric oxide have injurious and protective roles forrenal and vascular dysfunction, respectively. However,
it is difficult to detect them correctly in cells because
they are unstable. We aim to develop the way to detect
active oxygen and nitric oxide by using the in vivo
and in vitro models of renal and vascular dysfunction.

4.

5.

6.

7.

8.

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Chung UI, Tanaka S. Hyaline Cartilage Formation
and Tumorigenesis of Implanted Tissues Derived
from Human Induced Pluripotent Stem Cells.
Biomed Res. 36:179-86, 2015. doi: 10.2220/
biomedres.36.179.
Sugita S, Hosaka Y, Okada K, Mori D, Yano F,

513

Kobahashi H, Taniguchi Y, Mori Y, Okuma T,
Chang SH, Kawata M, Taketomi S, Chikuda H,
Akiyama H, Kageyama R, Chung UI, Tanaka S,
Kawaguchi H, Ohba S, Saito T*. Transcription
factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulindependent protein kinase 2. Proc Natl Acad Sci
U S A. 112: 3080-5, 2015. doi: 10.1073/pnas.
1419699112.
10. Tokuyama N, Hirose J, Omata Y, Yasui T, Izawa
N, Matsumoto T, Masuda H, Ohmiya T,Yasuda H,
Saito T, Kadono Y, Tanaka S. Individual andcombining effects of anti-RANKL monoclonal
antibody and teriparatide in ovariectomized mice.
Bone Reports. 2:1-7, 2015.
11. Okuma T, Hirata M, Yano F, Mori D, Kawaguchi
H, Chung UI, Tanaka S, Saito T. Regulation of
Mouse Chondrocyte Differentiation by CCAAT/
Enhancer-binding Proteins. Biomed Res. 36:21-9,
2015. doi: 10.2220/biomedres.36.21.
12. Omata Y, Yasui T, Hirose J, Izawa N, Imai Y,
Matsumoto T, Masuda H, Tokuyama N, Nakamura
S, Tsutsumi S, Yasuda H, Okamoto K, Takayanagi
H, Hikita A, Imamura T, Matsuo K, Saito T,
Kadono Y, Aburatani H, Tanaka S. Genome-wide
comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKL-induced
osteoclastogenesis. J Bone Miner Res. 30:869-77,
2015. doi: 10.1002/jbmr.2418.
13. Takatori Y, Moro T, Ishihara K, Kamogawa M,
Oda H, Umeyama T, Kim YT, Ito H, Kyomoto
M, Tanaka T, Kawaguchi H, Tanaka S: Clinicaland radiographic outcomes of total hip
replacement with poly(2-methacryloyloxyethyl
phosphorylcholine)-grafted highly cross-linked
polyethylene liners: Three-year results of aprospective consecutive series. Mod Rheumatol
2015; 25(2): 286-291
14. Ito H, Takatori Y, Moro T, Oshima H, Oka H,
Tanaka S: Total hip arthroplasty after rotational
acetabular osteotomy. J Arthroplasty 2015; 30:
403-406
15. Kyomoto M, Moro T, Takatori Y, Tanaka S,
Ishihara K: Multidirectional wear and impact-towear tests of phospholipid-polymer-grafted andvitamin E-blended crosslinked polyethylene: apilot study Clin Orthop Relat Res 2015; 473(3):942-951
16. Moro T, Takatori Y, Kyomoto M, Ishihara K,
Kawaguchi H, Hashimoto M, Tanka T, Oshima H,
Tanaka S: Wear resistance of the biocompatible
phospholipid polymer-grafted highly cross-linked
polyethylene liner against larger femoral head. J
Orthop Res 2015; 33(7): 1103-1110
17. Oka T, Abawi CF, Sugita N, Chikuda H, Sugita S,
Tanaka T, Oshima H, Moro T, Tanaka S, Mitsuishi
M: Hand-held bone-cutting tool with autonomous
penetration detection for spinal surgery. IEEE/
ASME Trans Mechatronics 2015; 20(6): 30183027
18. Yarimitsu S, Moro T, Kyomoto M, Watanabe K,
Tanaka S, Ishihara K, Murakami T: Influences ofdehydration and rehydration on the lubrication
properties of phospholipid polymer grafted crosslinked polyethylene. Proc Inst Mech Eng H 2015;
229(7): 506–514
19. Watanabe K, Kyomoto M, Saiga K, Taketomi S,
Kadono Y, Takatori Y, Tanaka S, Ishihara K, Moro
T: Effects of surface modification and bulk
geometry on the biotribological behavior ofcross-linked polyethylene: Wear testing and finite
element analysis. Biomed Res Int 2015: Article ID
435432 (10 pp), 2015. doi:10.1155/2015/435432
20. Kyomoto M, Shobuike T, Moro T, Yamane S,
Takatori Y, Tanaka S, Miyamoto H, Ishihara K:
Prevention of bacterial adherence and biofilm
formation on a vitamin E-blended, cross-linked
polyethylene
surfacewithapoly(2methacryloyloxyethyl phosphorylcholine) layer.
Acta Biomaterialia 2015; 24: 24-34
21. Yamashita H, Takenaka R, Sakumi A, Haga A,
Otomo K, Nakagawa K: Analysis of motion of therectum and bladder during preoperative intensity
modulated radiation therapy for rectal cancer
using
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Radiation Oncology, 2015;10:2: 1-7.
22. Kida S, Masutani Y, Nakano M, Imae R,
Nakagawa K, Haga A, 逐次最適化散乱補正ア
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23. Chhatkuli RB, Demachi K, Miyamoto N, Uesaka
M, Haga A, Dynamic Image Prediction Using
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514

Spectral Analysis: A Feasibility Study, Open
Journal of Medical Imaging, 2015;5:133-42.
24. Ikeda Y., Kumagai H., Okazaki H., Fujishiro M.,
Motozawa Y., Nomura S., Takeda N., Toko H.,
Takimoto E., Akazawa H., Morita H., Suzuki J.,
Yamazaki T., Komuro I.: Monitoring β-arrestin
recruitment via β-lactamase enzyme fragmentcomplementation: purification of peptide E as a
low-affinity ligand for mammalian bombesin
receptors. PLOS ONE 2015,0127445
25. Kumagai H., Ikeda Y., Motozawa Y., Fujishiro M.,
Okamura T., Fujio K., Okazaki H., Nomura S.,
Takeda N., Harada M., Toko H., Takimoto E.,
Akazawa H., Morita H., Suzuki J., Yamazaki T.,
Yamamoto K., Komuro I., Yanagisawa M.:
Quantitative measurement of GPCR endocytosis
via pulse-chase covalent labeling. PLoS One2015,
10(5): 0129394
26. Kaneko M, Ohnishi I, Matsumoto T, Ohashi S,
Bessho M, Hayashi N, Tanaka S: Prediction ofproximal femur strength by a quantitative
computed tomography-based finite element
method--Creation of predicted strength data of theproximal femur according to age range in anormal population.Mod Rheumatol. 2016;26(1):151-5.
27. Ohashi S, Ohnishi I, Oka H, Matsumoto T, Bessho
M, Nakamura K, Tanaka S.The effect of cartilage
degeneration on ultrasound speed in humanarticular cartilage. Mod Rheumatol. 2016;26(3):426-34.
28. Kubota N, Kubota T, Kajiwara E, Iwamura T,
Kumagai H, Watanabe T, Inoue M, Takamoto I,
Sasako T, Kumagai K, Kohjima M, Nakamuta M,
Moroi M, Sugi K, Noda T, Terauchi Y, Ueki K,
Kadowaki T: Differential hepatic distribution of
insulin receptor substrates causes selective insulin
resistance in diabetes and obesity. Nat Commun
7:12977, 2016.
29. Kubota T, Kubota N, Sato H, Inoue M, Kumagai
H, Iwamura T, Takamoto I, Kobayashi T, Moroi
M, Terauchi Y, Tobe K, Ueki K, Kadowaki T:
Pioglitazone Ameliorates Smooth Muscle Cell
ProliferationinCuff-Induced
Neointimal
Formation by Both Adiponectin-Dependent and-Independent Pathways. Sci Rep 6:34707, 2016.
30. Obata A, Kubota N, Kubota T, Iwamoto M, Sato

H, Sakurai Y, Takamoto I, Katsuyama H, Suzuki Y,
Fukazawa M, Ikeda S, Iwayama K, Tokuyama K,
Ueki K, Kadowaki T: Tofogliflozin Improves
Insulin Resistance in Skeletal Muscle andAccelerates Lipolysis in Adipose Tissue in MaleMice. Endocrinology 157:1029-1042, 2016.
31. Dewi N, Mi P, Yanagie H, Sakurai Y, Morishita Y,
Yanagawa M, Nakagawa T, Shinohara A,
Matsukawa T, Yokoyama T, Cabral H, Suzuki M,
Sakurai Y, Tanaka H, Ono K, Nishiyama N,
Kataoka K and Takahashi H : In vivo Evaluationof Neutron Capture Therapy Effectivity Using
Calcium Phosphate-based Nanoparticles as
Gd-DTPA Delivery Agent, J Cancer Res Clin.
Oncol., 142: 767-775 (2016).
32. Furuya Y, Hiroshima K, Wakahara T, Akimoto H,
Yanagie H, Harigaya K and Yasuhara H :Undifferentiated carcinoma of the gallbladderwith endothelial differentiation: A case report andliterature review, Mol Clin Oncol, Dec;5(6),773-776 (2016). doi: 10.3892/mco.2016.1046.
33. Morita A, Sora S, Nakatomi H, Harada K, Sugita
N, Saito N, Mitsuishi M: Medical Engineeringand Microneurosurgery: Application and Future.
Neurologia medico-chirurgica 2016;56(10):64152.
34. Kashiwagi M, Hojo H, Kitaura Y, Maeda Y, Aini
H, Takato T, Chung UI, Ohba S. Local
administration of a hedgehog agonist accelerates
fracture healing in a mouse model. Biochem
Biophys Res Commun. 2016 Oct 28;479(4):772-778. doi: 10.1016/j.bbrc.2016.09.134.
35. Kobahashi H, Chang SH, Mori D, Itoh S, Hirata
M, Hosaka Y, Taniguchi Y, Okada K, Mori Y,
Yano F, Chung UI, Akiyama H, Kawaguchi K,
TanakaS , and Saito T. Biphasic regulation ofchondrocytes by Rela through induction ofanti-apoptotic and catabolic target genes. Nat
Commun. 7: 13336, 2016. doi: 10.1038/ncomms
13336.
36. Aini H, Itaka K, Fujisawa A, Uchida H, Uchida S,
Fukushima S, Kataoka K, Saito T, Chung UI,
Ohba S. Messenger RNA delivery of a
cartilage-anabolic transcription factor as adisease-modifying strategy for osteoarthritis
treatment. Sci Rep. 6:18743, 2016. doi: 10.1038/
srep18743.

515

37. Chang SH, Yasui T, Taketomi S, Matsumoto T,
Kim-Kaneyama J, Omiya T, Hosaka Y, Inui H,
Omata Y, Yamagami R, Mori D, Yano F, Chung
UI, Tanaka S, Saito T . Comparison of mouse andhuman ankles and establishment of mouse ankle
osteoarthritis models by surgically-induced
instability. Osteoarthritis Cartilage. 24:688-97,
2016. doi: 10.1016/j.joca.2015.11.008.
38. Yamane S, Kyomoto M, Moro T, Watanabe K,
Hashimoto M, Takatori Y, Tanaka S, Ishihara K:
Effects of extra-irradiation on surface and bulk
properties of PMPC-grafted cross-linked polyethylene. J Biomed Mater Res A 2016; 104: 35–45
39. Uehara S, Yarimitsu S, Moro T, Kyomoto M,
Watanabe K, Tanaka S, Ishihara K, Murakami T:
Evaluation of wear suppression for phospholipid
polymer-grafted ultra-high molecular weight
polyethylene at concentrated contact. Tribology
International 2016; 101: 264-272
40. Magome T, Froelich J, Takahashi Y, Arentsen L,
Holtan S, Brown K, Haga A, Nakagawa K, Holter
J, Giebel S, Wong J, Dusenbery K, Storme G, Hui
S, Evaluation of functional marrow irradiation
based on skeletal marrow composition obtainedusing dual-energy CT, International Journal of
Radiation Oncology, Biology, Physics, 2016;96:679-87.
41. Takenaka R, Haga A, Yamashita H, Nakagawa K,
Adequate target volume in total body irradiation
by intensity-modulated radiation therapy using
helical tomotherapy: a simulation study, Journalof Radiation Research, 2016;58:1–7.
42. Ueshima K., Itoh H., Kanazawa N., Komuro I.,
Nagai R., Takeuchi M.,and Yamazaki T., for the
EMPATHY study group: Rationale and Design of
the Standard Versus Intensive Statin Therapy for
Hypercholesterolemic Patients with Diabetic
Retinopathy (EMPATHY) Study: a Randomized
Controlled Trial. J Atheroscler Thromb 2016,23:
976-990
43. Kai H., Kohro T., Fukuda K., Yamazaki T., Nagai
R.: Impact of systolic blood pressure on
hemorrhagic stroke in patients with coronary
artery disease during anti-platelet therapy: The
Japanese Coronary Artery Disease (JCAD) study.
Int J Cardiol. 2016,224:112-113
44. Lee, S.L., Daimon M., Di Tullio MR, Homma S.,

Nakao T., Kimura K., Shinozaki T., Hirokawa M.,
Kato TS., Mizuno Y., Watanabe M., Yatomi Y.,
Yamazaki T., Komuro I. Relationship of left
ventricular diastolic function to obesity andoverweight in a Japanese population withpreserved left ventricular ejection fraction. Circ J.
2016,80(9):1951-6
45. Uchiyama S., Ishizuka N., Shimada K., TeramotoT., Yamazaki T., Oikawa S., Sugawara M., AndoK., Murata M., Yokoyama K., Minematsu K.,
Matsumoto M., Ikeda Y., JPPP study group:
Aspirin for stroke prevention in elderly patientswith vascular risk factors: Japanese primaryprevention project. Stroke. 2016,47(6):1605-11
46. Soroida Y., Sato M., Hikita H., Hagiwara S., Sato
M., Gotoh H., Kato S., Iwai T., Yamazaki T.,
Yatomi Y., Sasano T., Ikeda H.: Pancreatic cysts ingeneralpopulationonultrasonography:
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47. Lee, S.L., Daimon M., Nakao T., Singer DE,
Shinozaki T., Kawata T., Kimura K., Hirokawa M.,
Kato TS., Mizuno Y., Watanabe M., Yatomi Y.,
Yamazaki T., Komuro I. Factors influencing left
atrial volume in a population with preserved
ejection fraction: Left ventricular diastolic
dysfunction or clinical factors? J Cardiol. 2016,
68(4):275-81
48. Hirokawa M., Daimon M., Lee, S.L., Nakao T.,
Kawata T., Kimura K., Kato TS., Mizuno Y.,
Watanabe M., Yatomi Y., Yamazaki T., Komuro I.
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2016,68(6):548-553
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related to congnitive deterioration in an elderly
japanese population. Dement Geriatr Cogn Disord
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517

Department of Disaster Medical
Management
Professor
Naoto Morimura, M.D.,Ph.D.

Lecturer
Masataka Gunshin, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/dmm/index.html

Introduction and Organization
Responding to the Great East Japan Earthquake in2011, the University of Tokyo Hospital has decided to
set out to establish “disaster medical management
studies” in terms of need not only to provide medical
treatment at the time of disaster but also to develop a
new academic field that provides bird’s-eye view on
overall disaster medicine. In March 2012, we made anannouncement to establish “Department of Disaster
Medical Management” in the Public Comment.
In July 2012, Associate Professor Dr. Hiroyuki
Nakao was assigned the post as the first General
Manager of the Department of Disaster Medical
Management.
Afterwards, in January 2015,
Professor Dr. Tadashi Iwanaka, the Hospital Vice
Director, was assigned the post as the second General
Manager. In April 2015, Professor Dr. Masaomi
Nangaku, the Hospital Vice Director in charge ofcrisis management and disaster prevention, wasassigned the post as the third 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 ofdeveloping leadership of health care professionals
who can provide ideal medical care in times ofdisaster. Also, we are cooperating holding and518

teaching MCLS, Mass Casualty Life Support, coursesof Japan Association for Disaster Medicine, and
JATEC, Japan Advanced Trauma Evaluation and Care,courses of Japanese Association for Acute Medicine,and so on.

Research activities
We are seeking ways of cooperation between
institutions through workshops with relevant
institutions from the perspective that day-to-day
cooperation with relevant institutions can be alsoutilized at the time of disaster. We consider that it canbe also utilized for cross-business formation oforganizations at the time of disaster.
Other than that, we are holding outside researchgroups and cooperating for building up a functional
emergency medical system at the time of disaster.

References
1. 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

519

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.
In the past, some foreign patients have successfullyreceived treatment thanks to the support of individual
departments. However, from henceforth, theInternational Medical Center will cater to the various
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 and language-training
programs so as to further develop the hospital’s
capabilities to become an international hub in thefield.

520

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 the start 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 eachpatient was instituted for the first time in Japan. In
1950, a national-hospital complete food service
system was announced, and the nutrient content
provided was standardized. The nutrient content
provision for patient meals at the time was 2400
kcal/day. In 1952, the inpatient meal service wasofficially outsourced to a foundation.
In 1957, the first nationwide meeting of
national-university-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, andthe managerial dietitian system was established by apartial revision of the Nutritionists Act. In 1972,
nutritional guidance was actively provided to
inpatients and outpatients with the aim of obtaining
approval to charge fees, and in 1978 a medical dietcharge and nutrition guidance charge were established.
In 1988, a timely tray service achieved by using hot
and cold food-tray carts was instituted in order todispel the “too early, 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 bynationwide national-university-hospital managerial
dietitian staff members. At the same time, the nutrition
sections of the main hospital and branch hospital wereconsolidated, and the head of the Department of
Nutrition Management, who was a managerial
dietitian, assumed the section manager post to form asystem composed of 5 managerial dietitians at themain hospital and 3 managerial dietitians at the branchhospital.
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521

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
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, andwhenever necessary members from other fields(pharmacists,
medicaltechnologists,
physicaltherapists) joined, and they held a hospital ward
meeting once a week. In 2010, an NST committee wascreated as a result of the establishment of charges for
NSTs. The NST director up until that time became amember of the committee and played an active role as
the center of in-hospital NST activities. The additionof one managerial dietitian to the staff (full time) as afull-time employee to calculate the billing charges for
the NST was approved. In 2011, the inauguration of anutritional guidance service for recipients of healthcheckups in the Department of Epidemiology andPreventive Medicine was accompanied by the additionof 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 amanagerial strategic personnel distribution, 5 newmanagerial dietitians (full-time) have also been
assigned this fiscal year. Along with the increase inwork of managerial dietitians for strengthening thenutrition management system and expanding thenumber of clinical trials in P1 unit, another managerial
dietitian (limited-term employment) was added to thestaff in May 2015. The renovation of the main kitchen
was determined for the purpose of introduction of the
New Cook Chill System.

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 (455 without charge) and 5503 instances of
outpatient nutritional guidance (275 without charge).
The results for group nutritional guidance showed thatduring the year there had been 292 outpatient diabetes
classes and 217 inpatient diabetes classes (for some ofwhich there was a charge), and that there had been 115
best-weight classes, 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522

131 guidance sessions in 2015.
In April 2014, the department started calculating
charges for NST and counted 1261 instances in thefirst fiscal 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 the fiscal year of 2016, 8858 instanceswere monitored in this system.
In April 2015, alternative initial screening criteria
specific for pediatric and pregnant patients were added
to the procedure manual of nutritional management,
respectively.
・Educational Activities
The Department accepts managerial dietitian
clinical trainees. In 2015, the department accepted 41
trainees from 7 training schools: Ochanomizu
University, Tokyo Kasei University, Otsuma Women’s
University, Kagawa Education Institute of Nutrition,
Jissen Women’s Educational Institute, Japan Women’s
University, and Wayo Women’s University.
In 2011, the Department began accepting NST
trainees. From 1 to 4 or 5 terms are conducted a year
(5 days/ 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 by academic societies or to become afull-time employee to calculate the billing charges for
the NST. There were 17 participants (7 managerial
dietitians, 5 pharmacists, 5 nurses) in 2015.
To disseminate NST activities fully in the hospital,
the department organizes NST Seminar for
Doctor-in-training and Clinical Nutrition Seminarthroughout the year. The department also organizes
NST Conference and Joint Conference of Team
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 knowledgeof nutritional management procedure. The ratio ofcompletion reached 99.0% in March 2016. 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 Manual of The
Department of Clinical Nutrition Therapy 2015-2016”
was published.

Research・Joint research with the Department of Stomach andEsophageal Surgery
Research topics: “Evaluation of nutrition indexes
after proximal gastrectomy”“Multi-center randomized controlled study of theeffects of early post-gastrectomy oral feeding
support”“A randomized study of post-operative invasivenessand systematic post-operative functional assessmentin esophageal cancer comparing the operation
procedures”
・Joint research with the Department of Hepatobiliaryand Pancreatic Surgery
Research topic: “Assessment of perioperative
improvement in nutrition status by an open trial of
an immune-enhancing diet in patients who haveundergone pancreaticoduodenectomy”

References<Publications (English)>
1. Ikenoue T, Terakado Y, Nakagawa H, Hikiba Y,
Fujii T, Matsubara D, Noguchi R, Zhu C,
Yamamoto K, Kudo Y, Asaoka Y, Yamaguchi K,
Ijichi H, Tateishi K, Fukushima N, Maeda S,
Koike K, Furukawa Y. :A novel mouse model of
intrahepatic cholangiocarcinoma induced by liverspecific Kras activation and Pten deletion.;.Sci
Rep. ;6:23899,2016 Apr
2. Ihara S, Hirata Y, Serizawa T, Suzuki N, Sakitani
K, Kinoshita H, Hayakawa Y, Nakagawa H, Ijichi
H, Tateishi K, Koike K. : TGF-β Signaling in
Dendritic Cells Governs Colonic Homeostasis byControlling Epithelial Differentiation and the
Luminal Microbiota. J Immunol. 196(11): 4603-

523

3.

4.

5.

6.

7.

8.

9.

13, 2016 Jun
Masamoto Y, Arai S, Sato T, Yoshimi A, Kubota N,
Takamoto I, Iwakura Y, Yoshimura A, Kadowaki T,
Kurokawa M: Adiponectin Enhances Antibacterial
Activity of Hematopoietic Cells by Suppressing
Bone Marrow Inflammation. Immunity 44(6):1422-1433, 2016 Jun
Mohri D, Ijichi H, Miyabayashi K, Takahashi R,
Kudo Y, Sasaki T, Asaoka Y,Tanaka Y, Ikenoue T,
Tateishi K, Tada M, Isayama H, Koike K : A
potent therapeutics for gallbladder cancer by
combinatorial inhibition of the MAPK and mTOR
signaling networks. 2016 Jul; J Gastroenterol.
51(7):711-21,2016 Jul
Suyama S, Maekawa F, Maejima Y, Kubota N,
Kadowaki T, Yada T: Glucose level determines
excitatory or inhibitory effects of adiponectin on
arcuate POMC neuron activity and feeding. Sci
Rep 6: 30796, 2016 Aug
Yamamoto K, Tateishi K, Kudo Y, Hoshikawa M,
Tanaka M, Nakatsuka T, Fujiwara H, Miyabayashi
K, Takahashi R, Tanaka Y, Ijichi H, Nakai Y,
Isayama H, Morishita Y, Aoki T, Sakamoto Y,
Hasegawa K, Kokudo N, Fukayama M, Koike K:
Stromal remodeling by the BET bromodomain
inhibitor JQ1 suppresses the progression ofhuman pancreatic cancer. Oncotarget.; 7(38):61469- 61484,2016 Sep
Nakai Y, Isayama H, Sasaki T, Takahara N, Saito
K, Takeda T, Umefune G, Saito T, Takagi K,
Watanabe T, Hamada T, Uchino R, Mizuno S,
Yamamoto K, Kogure H, Matsubara S, Yamamoto
N, Ijichi H, Tateishi K, Tada M, Koike K.: No
Survival Benefit from the Inhibition ofRenin-Angiotensin System in Biliary Tract Cancer.
Anticancer Res. 36(9):4965-70,2016 Sep
Kishikawa T, Otsuka M, Yoshikawa T, Ohno M,
Ijichi H, Koike K.:Satellite RNAs promote
pancreatic oncogenic processes via the dysfunction of YBX1. Nat Commun. 7:13006,2016
Sep
Kubota T, Kubota N, Sato H, Inoue M, Kumagai
H, Iwamura T, Takamoto I, Kobayashi T, Moroi
M, Terauchi Y, Tobe K, Ueki K, Kadowaki T:
Pioglitazone Ameliorates Smooth Muscle Cell
ProliferationinCuff-Induced
Neointimal
Formation by Both Adiponectin-Dependent and-Independent Pathways. Sci Rep 6: 34707, 2016
Oct
10. Kubota N, Kubota T, Kajiwara E, Iwamura T,
Kumagai H, Watanabe T, Inoue M, Takamoto I,
Sasako T, Kumagai K, Kohjima M, Nakamuta M,
Moroi M, Sugi K, Noda T, Terauchi Y, Ueki K,
Kadowaki T: Differential hepatic distribution of
insulin receptor substrates causes selective insulin
resistance in diabetes and obesity. Nat Commun 7:
12977, 2016 Oct
11. Sato H, Kubota N, Kubota T, Takamoto I,
Iwayama K, Tokuyama K, Moroi M, Sugi K,
Nakaya K, Goto M, Jomori T, Kadowaki T:
Anagliptin increases insulin-induced skeletal
muscle glucose uptake via an NO-dependent
mechanism in mice. Diabetologia 59(11): 24262434, 2016 Nov
12. Kubota T, Kubota N: Cuff-Induced Neointimal
Formation in Mouse Models. In Mouse Models of
Vascular Diseases, Sata M. ed., Springer Japan,
21-41, 2016 Dec
13. Uehata Y, Yoshida M, Yabunaka K, Minematsu
T, Tamai N, Sugama J, Sanada H.: Relationshipof skin hardness of the temporal region to
nutritional status. Journal of Nursing Science andEngineering. 4(1):49-57, 2017 Jan
14. Suyama S, Lei W, Kubota N, Kadowaki T, Yada
T.: Adiponectin at physiological level glucoseindependently enhances inhibitory postsynaptic
current onto NPY neurons in the hypothalamicarcuate nucleus. Neuropeptides in press,2017 Mar

Center for Disease Biology andIntegrative Medicine

525

Laboratory of Molecular
Biomedicine for Pathogenesis
Professor
Toru Miyazaki, M.D., Ph.D.

Associate Professor
Satoko Arai, Ph.D.

Assistant Professor
Nobuko Mori, D.V.M., Ph.D.

Official Website

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

Research
Our laboratory focuses on clarification of thepathogenesis of various diseases and the related
physiological machineries in cellular and molecular
aspects. Based on our technical advantage in genemanipulation via gene knockout and transgenesis, wegive high priorities to in vivo analyses. This willdefinitively contribute to the direct therapeutic
application of our findings. Since our rationale is tochallenge to uncharacterized disease mechanisms andphysiologies, we will not restrict our interest, strategy
or technique employed, in certain specific field.
Rather, we will expand our research area by
establishing different collaborations with a broad
spectrum of researchers. We believe this fits to thepolicy of the CDBIM, which aims the development of
a comprehensive science including the fundamental
and clinical medicines, and the biotechnology. Overall,
we will attempt to discover novel biological insights
rather than to study details of previously characterized
physiologies, by targeting molecules newly identified
by ourselves. Now, we are focusing on the following
major projects.
AIM (Apoptosis Inhibitor of Macrophage) as amaster switch 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 showedthat AIM plays an important role in regulating thepathological condition of the modern diseases.
AIM is produced by macrophage and largely
presents in bloodstream as a soluble molecule. Once
AIM is incorporated into adipose tissue, it
decomposes fatty droplets resulting in controlling the
progression of obesity. However, when this process
undergoes effectively and excessively under the obese
condition, oppositely to control the progression ofobesity, chronic inflammation of adipose tissue andinsulin resistance are triggered and Type II diabetes
and atherosclerosis are worsen.
Moreover, because AIM binds to IgM in bloodstream, it leads to production of various auto-

526

antibodies, 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
Joint Meeting
In 2016, several medical laboratories from Shimane
University and our laboratory jointly held a Scientific
Meeting in Oki Island. The members from the both
universities including the teaching staffs, graduate
students and researchers, as well as some high school
students in Oki Island, fully enjoyed this retreat,
having intense research sessions with lively
discussions, which can lead to future collaborations.
We could also strike up a friendship through thedinners and recreations during the two days.
Similar meetings are organized by our laboratory
every year, e.g. Taiwan-Japan Joint Meeting in 2013
(hosted by National Taiwan University, National Yang
Ming University, and the University of Tokyo), andthe CREST joint meetings in 2014 and 2015 (hosted
by Kumamoto University and the University ofTokyo). We will keep planning such Joint Meetings in
the future.
Seminar hosted by our lab (co-sponsorship: MPUTC,
Laboratory of Animal Resouces)
Title: RNA modified bases & grammar education for
the naïve immune system / Dr. Vincent P. Kelly(Trinity College Dublin, Ireland)
In July 2016, we organized an invited lecture by Dr.
Vincent P. Kelly introducing his continuing efforts tounderstand the function and activity of a highly
unusual RNA base referred to as queuine.

List of labs:
Prof. Wan-Wan Lin’s Laboratory, National Taiwan
University
Prof. Shie-Liang Hsieh’s Laboratory, National Yangming University
Prof. Ken-ichi Yamamura’s Laboratory, The University of Kumamoto
Prof. Toru Nabika’s Laboratory, Shimane University
Prof. Seiji Yamaguchi, Shimane University
Prof. Toru Miyazaki’s Laboratory, The University ofTokyo
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 juniorresearchers.
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527

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, and Prof. D. Mathis and Prof. C. Benoist(immunology) from Harvard University in fiscal 2007,
all of whom belonged to our lab as a guest professor
for three months respectively.

Publications
Arai, S., Kitada, K., Yamazaki, T., Takai, R.,
Zhang, X., Tsugawa, Y., Sugisawa, R., Matsumoto,A., Mori, M., Yoshihara, Y., Doi, K., Maehara, N.,
Kusunoki, S., Takahata, A., Noiri, E., Suzuki, Y.,
Yahagi, N., Nishiyama, A., Gunaratnam, L.,
Takano, T., Miyazaki, T. Apoptosis inhibitor ofmacrophage protein enhances intraluminal debris
clearance and ameliorates acute kidney injury in
mice- Nat Med. 22, 183-93 (2016).
2. Sugisawa, R., Hiramoto, E., Matsuoka, S., Iwai,
S., Takai, R., Yamazaki, T., Mori, N., Okada, Y.,
Takeda, N., Yamamura, KI., Arai, T., Arai, S.,
Miyazaki, T. Impact of feline AIM on the susceptibility of cats to renal disease- Sci Rep. 6, 35251(2016).
3. Ozawa, T., Maehara, N., Kai, T., Arai, S., Miyazaki, T. Dietary fructose-induced hepatocellular
carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM)Genes Cells. 21, 1320-1332 (2016).
4. Yamazaki, T., Sugisawa, R., Hiramoto, E., Takai,R., Matsumoto, A., Senda, Y., Nakashima, K.,
Nelson, P. S., Lucas, J. M., Morgan, A., Li, Z.,
Yamamura, KI., Arai, S., Miyazaki, T. A proteolytic modification of AIM promotes its renal excretion- Sci Rep. 6, 38762 (2016).
1.

528

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Lecturers
Noriko Takahashi, M.D., Ph.D.

Research Associates
Sho Yagishita, M.D. Ph.D.

Homepage

http://www.bm2.m.u-tokyo.ac.jp/

Introduction and Organization

Research activities

The Center for Disease Biology and Integrative
Medicine (CDBIM) has been established in 2003, andelected Dr. Kasai as the professor of the Division of
Basic Medical Sciences (2) of CDBIM in July of 2004.
Dr. Kasai was in the National Institute forPhysiological Sciences, and officially took office 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.

Functional imaging is a central theme in modern
biology and medicine. All biological functions involvea multitude of interactions at the molecular, cellular,
and system levels, and it is ultimately desirable toperform molecular and cellular imaging in intact
preparations in which the original in vivo functions
are preserved. We have been exploring two-photon
excitation microscopy with a new type of laser, an
infrared femtosecond-pulse laser, as a means toachieve this goal. The two-photon microscope has theability to penetrate deep into tissues and is the only
imaging instrument that allows investigations of intact
tissues at the cellular and molecular levels. Twophoton microscopy can also be readily combined withmolecular biological and other physiological methods,
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. We will explain one
representative work (Ref. 4) of this year in somedetail.

Teaching activities
We have 1 master course and 4 doctor course
students in 2016. We were also responsible forundergraduate education of physiology, and organized
all lectures, student experiments and examinations.
We gave all together 8 lectures of physiology forundergraduate students, and 5 lectures of physiology
and neuroscience for master course students. Fourundergraduate students join the activity of ourlaboratory for free quarter (FQ).

529

The majority of excitatory synaptic contacts areformed by small dendritic protrusions in the cerebral
cortex, commonly referred to as dendritic spines. The
growth and shrinkage of dendritic spines are typicallydetermined by cytosolic Ca2+ levels, and they,
respectively, underlie the long-term potentiation anddepression of synaptic connectivity._In addition, thegeneration and elimination of spines are reported to be
induced by tasks involving learning and memory,albeit at a slower rate than processes governing
enlargement and shrinkage4-6. Spine turnover has been
traditionally observed following activity-dependent
plasticity induced by cytosolic increases in Ca2+
concentration, but has also been identified in theabsence of specific learning tasks. Such intrinsic
dynamics are reported to occur in vitro in aCa2+-independent manner. However, to the best of theauthors’ knowledge, no study has directly investigatedwhether the baseline rate of spine turnover reflects
non-specific learning under normal rearing conditions,or activity-independent intrinsic dynamics in vivo.
Notably, the baseline rate of spine turnover isreported to be augmented in several in vivo models ofautistic spectrum disorder (ASD). Fragile X
syndrome, the most prevalent monogenic form of
ASD, is caused by the expansion of CGG repeats
upstream of the coding region in the FMR1 gene,leading to reduction of the fragile X mental
retardation protein (FMRP). Fmr1 knockout (KO)mice present with many of the neural abnormalities
observed in patients with fragile X syndrome,
includingabnormalities
indendritic
spinemorphology, synaptic plasticity, and learning andmemory. Moreover, spine turnover is similarly
increased in Fmr1 KO mice, as observed in othermodels of ASD. However, no studies have examined
whether the increased rate of baseline turnoverobserved in ASD models reflects activity-dependent
plasticity or activity-independent intrinsic dynamics,
and therefore the mechanism responsible for increased
spine turnover in ASD models remains largely elusive.
With regard to previous in vivo neuroimaging
techniques, studying the activity-dependent nature ofbasal spine turnover in the neocortex was difficult
using methods such as cranial glass windows or
thinned skulls. Because animals are unable to survive
when cortical activity is abolished, neuronal Ca2+

signaling must be locally silenced in small regions,wherein the time-lapse imaging of dendritic spines canbe performed. To resolve this issue, inhibitors of Ca2+
signaling were infused locally into the visual cortex
via a microfluidic brain interface, and two-photon
time-lapse imaging was performed in this region. Ca2+
signaling and learning-induced spine turnover were
evaluated in wild-type and Fmr1 KO mice after
treatment with Ca2+ signal inhibitors. Reports indicatethat matrix metalloproteinase 9 (MMP9) KO rescues
various abnormalities observed in Fmr1 KO mice,
including structural spine abnormalities. As MMP9
inhibitors have also been linked to changes in spine
structure.
In wild-type and Fmr1 KO mice, the majority ofbaseline turnover was found to be activityindependent. Accordingly, the application of matrix
metalloproteinase-9 inhibitors selectively restored theabnormal spine dynamics observed in Fmr1 KO mice,
without affecting the intrinsic dynamics of spine
turnover in wild-type mice. Such findings indicate thatthe baseline turnover of dendritic spines is mediatedby activity-independent intrinsic dynamics. Furthermore, these results suggest that the targeting ofabnormal intrinsic dynamics might pose a novel
therapy for ASD (Ref.4).

References
1. Hayashi-Takagi, A., Yagishita, S., Nakamura, M.
Shirai, F., Wu, Y., Loshbaugh, A.L., Kuhlman,
B., Hahn, K.M. and Kasai, H. (2015). Labellingand optical erasure of synaptic memory traces in
the motor cortex. Nature (Article), 525:333-338.
2. Takahashi, N., Sawada, W., Noguchi, J., Watanabe,S., Ucar, H., Hayashi-Takagi, A., Yagishita, S.,
Ohno, M., Tokumaru, H. & Kasai, H. (2015).
Two-photon fluorescence lifetime imaging ofprimed SNARE complexes in presynaptic
terminals and β cells. Nature Communications 6:8531.
3. Komori, N, Jakkampudi, S., Motoishi, R., Abe, M.,
Kamada, K., Furukawa, K., Katan, C., Sawada,W., Takahashi, N., Kasai, H., Xue, B., Kobayashi,
T. (2015). Design and synthesis of a new
chromophore, 2-(4-nitrophenyl)benzofuran, for
two-photon uncaging using near-IR light.

530

Chemical Communications 52: 331-334.
4. Nagaoka, A., Takehara, A., Hayashi-Takagi, A.,
Shirai, F., Ishii, K., Noguchi, J., Ichiki, K. & Kasai, H. (2016) Abnormal intrinsic dynamics ofdendritic spines in a fragile X syndrome mousemodel in vivo. Scientific Reports 6: 26651.
5. Takehara, H., Nagaoka, A., Noguchi, J., Akagi, T.,
Kasai, H. & Ichiki, T. (2016) Implantablemicrofluidic device with hydrogel permeable
membrane for delivering chemical compounds
and imaging neural cells in living mice. Journalof Photopolymer Science and Technology 29:
513-518.
6. Jakkampudi, S., Abe, M.*, Komori, N., Takagi, R.,
Furukawa, K., Katan, C., Sawada, W., Takahashi,
N. & Kasai, H. (2016) Design and synthesis of a
4‑nitrobromobenzene derivative bearing an
ethylene glycol tetraacetic acid unit for a newgeneration of caged calcium compounds with
two-photon absorption properties in the near-IR
region and their application in vivo. ACS Omega
1(2): 193-201.
7. Noguchi, J., Hayama, T., Watanabe, S., Ucar, H.,
Yagishita, S., Takahashi, N. & Kasai, H. (2016)
State-dependent diffusion of actin-depolymerizing
factor/cofilin underlies the enlargement andshrinkage of dendritic spines. Scientific Reports 6:32897.
8. Kunii, M., Ohara-Imaizumi, M., Takahashi, N.,
Kobayashi, M., Kawakami, R., Kondoh, Y.,
Shimizu, T., Simizu, S., Lin, B., Nunomura, K.,
Aoyagi, K., Ohno, M., Ohmuraya, M., Sato, T.,
Yoshimura, S., Sato, K., Harada, R., Kim, Y.,
Osada, H., Nemoto, T., Kasai, H., Kitamura, T.,
Nagamatsu, S., & Harada, A. (2016) The opposite
roles of SNAP23 in the exocrine and endocrine
pancreas. J. Cell Biol. 215:121-138.

531

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 ofEngineering. 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 of Engineering. Prof. Ito gives a lecture
concerning biosystem engineering, separation
technology I, biotechnology II, Basic Biology, andOverview of Chemical Bioengineering at theChemical System Engineering course and Bioengineering course at Graduate School of Engineering
School.

Research activities
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

532

equipment and systems
We are developing an intracranial ultrasonicirradiation system and conduct research aiming to
induce action potential and stimulated motion byadding mechanical stimulus to nerve cells. In addition,
we are also developing therapy monitoring method
aiming at high accuracy of minimally invasive
treatment.
2) Ultrasonic drug delivery system
We are also developing ultrasonic drug delivery as atherapeutic application of ultrasound. In particular, we
aim to realize the enhancement of drug permeabilityof the cerebrovascular barrier by combining
ultrasound and microbubbles.
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) H. Lin, T. Azuma, X. Qu, and S. Takagi, "Robust
contrast source inversion method with automatic
choice rule of regularization parameters forultrasound waveform tomography", Jpn. J. Appl.
Phys., 2016(55) 07KB08(3) X. Qu, T. Azuma, T. Yogi, S. Azuma, H. Takeuchi, S.
Tamano, S. Takagi, "Synthetic aperture ultrasoundimaging with a ring transducer array: preliminary exvivo results", J. Med. Ultrasonics, 2016(43) 461471(4) Tatsuto Kageyama, Tatsuya Osaki, Junko Enomoto,Dina Myasnikova, Tadashi Nittami, Takuro Hozumi,
Taichi Ito, and Junji Fukuda, In situ cross-linkablegelatin-CMC hydrogels designed for rapid
engineering of perfusable vasculatures, ACS
Biomaterials Science and Engineering, 2016, 2(6)1059-1066(5) Seiichi Ohta, Syota Hiramoto, Yuki Amano, Mayu
Sato, Yukimitsu Suzuki, Marie Shinohara,
Shigenobu Emoto, Hironori Yamaguchi, Hironori
Ishigami, Yasuyuki Sakai, Jyoji Kitayama, andTaichi Ito , Production of cisplatin-incorporating
hyaluronan nanogels via chelating ligand-metal
coordination, Bioconjugate Chemistry, 2016(27)504-508

533

Laboratory of Clinical
Biotechnology
Professor
Yuichi Tei/ Ung-il Chung, M.D.,Ph.D. (November, 2016－)

Associate Professor
Kanjiro Miyata, Ph.D.

Project Associate Professor
Keiji Itaka, M.D.,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 thecharacteristics 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 the Vice Program
Coordinator of the Graduate Program for Leaders inLife Innovation (GPLLI) and as Research Leader of
The University of Tokyo Center for Innovation (COI)
Self-Managing Healthy Society. In collaboration withthese programs, we are also working on theestablishment of an Open Innovation Platform and thepromotion of industry-academia collaborations for thesocial implementation of research products.

534

Education
The development of advanced medical systems, suchas regenerative medicine and medical devices, is an
important and globally growing research field inwhich medical biology and engineering are integrated
and play important roles. Since the medicineengineering cooperation that has occurred to date has
been mainly research collaborations, the developmentof theoretical systems as well as education systems forthe integrated field have been delayed. This oftencauses a mismatch between clinical needs andtechnological seeds. The delay is likely due todifficulties in identifying basic principles that underlie
both of the quite different fields of medical biology
and engineering, when they are integrated.
Through multi-discipline and cross-sectional
research projects integrating medical biology andengineering, we aim to train biomedical professionals
who themselves integrate medicine and engineering;that is, engineers who understand medical needs andmedical researchers who understand technologicalseeds. We are offering students with varying
backgrounds opportunities to study a broad spectrumof biomedical engineering — from basic principles ofliving organisms to advanced medical systems — on
the basis of each student's expertise. We alsocollaborate with The University of Tokyo COI
Self-Managing Healthy Society, in order to utilize theOpen Innovation Platform in which all stakeholders
from industry, government, academia, and the private
sector join the program as equals from the start, as apractical education tool for developing the
aforementioned biomedical professionals.

Research
We pursue two scientific interests with a particularfocus on skeletal tissues (bones and cartilage): (1) the
manipulation of progenitor cell differentiation andproliferation based on the understanding of molecularmechanisms underlying cell fate specification, and (2)the development of novel biomaterials fulfilling thecharacteristics required for in vivo use as scaffolds.
We aim to develop novel systems for skeletal tissue
engineering and regenerative medicine in which celldifferentiation and proliferation are directly regulated
in situ. The following four projects are ongoing.

1. Understanding of epigenome dynamics and gene
regulatory networks during cell fate specification
processes
Organogenesis depends on cell fate specification andthe subsequent differentiation and maturation of
specified cells. Gene transcription underlies a series ofprocesses; appropriate genes are transcribed withappropriate amounts and at the appropriate timing for
inducing cell activities and characteristics. In thiscontext, the epigenome works as a main switch forgene expression. Transcription factors, which bind to
the genome in a sequence-dependent manner, in turnincrease the amount of transcripts, in a manner that is
analogous to turning up the volume of a radio.
Against this background, we seek to understandthe mechanisms of cell fate specification, celldifferentiation, and cell maturation during skeletal
development with a particular focus on epigenome
dynamics and genomic targets of transcription factors.
We also plan to apply the knowledge gained to thedevelopment of regenerative therapies for skeletal
tissue defects. Here we rely on the following
approaches: (1) observations of intracellular events bydirect and comprehensive techniques, (2) the construction of hypotheses driven by these observations,and (3) verification of the hypotheses. Thus, theapproach starts with the collection of genome-scaledata on gene expression, epigenome, and transcription
factor binding sites by taking advantage ofnext-generation sequencers. The data are analyzed bybioinformatics approaches, leading to the constructionof a new biological hypothesis. Each hypothesis isverified by molecular-biological approaches andmouse genetics. With this research strategy, we areinvestigating the regulatory landscape on the genomethat determines the specification of bone- andcartilage-forming cells, osteoblasts and chondrocytes,
respectively, and their phenotypes. A series of studies
reveals transcriptional networks that mediate
pluripotency and the differentiation of pluripotent
stem cells (Stem Cells 31:2667, 2013), epigenome
dynamics and modes of action of master transcription
factors that specify osteoblasts and chondrocytes, andthe gene regulatory networks mediated by thosemaster transcription factors (Cell Reports 12:229,
2015; Developmental Cell 37:238, 2016; Development
143:3012, 2016; Trends in Genetics 32:774, 2016). A535

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.
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. Such culture
systems in combination with human PSCs could
enable us to reproduce human bone development andmetabolism in a physiologically relevant manner.
These systems will also allow us to visualize bonemetabolism in vitro with imaging techniques,contributing to drug discoveries for the treatment ofvarious bone diseases such as osteoporosis, and to ourunderstanding of the diseases' pathophysiology and of
the molecular mechanisms underlying skeletal
formation and maintenance.
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).
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
andmaturation(Developmental Cell 14:689, 2008; PLOS ONE, 2014).
These studies further extend to the development of thesmall molecule-based treatment of bone fractures,using the Hh signaling-activator molecule SAG(Biochemical
andBiophysicalResearch
Communications
479:772,
2016)
and
bone
regenerative therapy with SAG-loaded calcium
phosphate artificial bones (Biomaterials 34:5530,
2013). By combining biological findings withengineering 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),

536

through the screening of compound libraries withcell-based sensors enabling the high-throughput
detection of osteoblast and chondrocyte differentiation(Biochemical
andBiophysicalResearch
Communications 376:375, 2008; Journal of Bone andMineral 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
custom-made calcium phosphate artificial bone(CT-bone) that is manufactured using 3D printers andhave applied them 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 andapplication of tetrapod-shaped calcium phosphate
artificial bone (Tetrabone), which is fabricated at1-mm size by injection molding, and a custom-madetitanium mesh cage 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 theirperformance. A candidate for the integrating interface
unit is a high-performance hydrogel unit, which
maintains the spatial arrangement of signaling factors
and can deliver them to target cells at a selected
timing by temporally controlled degradation. However,conventional hydrogels do not provide thecharacteristics 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). The high-performance hydrogel unit would
integrate signaling factors with shape-controlled
scaffold materials, leading to the development of
implant devices that work as scaffolds for tissue repair
and also as carriers of bioactive factors. Through aseries of these studies, we are aiming to create a"four-dimensional scaffold system" that achieves
efficient tissue regeneration by controlling cellproliferation and differentiation in temporal andspatial manners. The system will not only beapplicable to the regeneration of other tissues; it will
also contribute to the development of basic
technologies for the temporal-spatial control of in situ
tissue formation, which is versatile in the prevention,
diagnosis, and treatment of various diseases.

Publications
1. Hojo H, McMahon AP, Ohba S. An emerging
regulatory landscape for skeletal development.
Trends Genet 2016;32(12):774-87.
2. Kashiwagi M, Hojo H, Kitaura Y, Maeda Y, Aini
H, Takato T, Chung UI, Ohba S. Local

537

3.
4.

5.

6.

administration of a hedgehog agonist accelerates
fracture healing in a mouse model. Biochem
Biophys Res Commun 2016;479(4):772-8.
Ohba S. Hedgehog signaling in endochondral
ossification. J Dev Biol 2016;4(2):20.
He X, Ohba S, Hojo H, McMahon AP. AP-1
family members act with Sox9 to promotechondrocyte hypertrophy. Development 2016;143(16):3012-23.
Hojo H, Ohba S, He X, Lai LP, McMahon AP.
Sp7/Osterix is restricted to bone-forming
vertebrates where it acts as a Dlx co-factor in
osteoblast specification. Dev Cell 2016;37(3):238-53.
Aini H, Itaka K, Fujisawa A, Uchida H, Uchida S,
Fukushima S, Kataoka K, Saito T, Chung UI,
Ohba S. Messenger RNA delivery of a cartilageanabolic transcription factor as a diseasemodifying strategy for osteoarthritis treatment.
Sci Rep 2016;6:18743.

538

Laboratory of Environmental
Health Sciences
Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Introduction
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 ClinicalResearch Center-A on October 2016. One associate
professor, one temporal researcher, one visiting
researcher, two doctoral students, two master course
student students, and a graduation trainee conducted
researches together during the year of 2016.
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.

Research activities
Laboratory of Environmental Health Sciences wasconstituted by members who were formerly working
in the National Institute for Environmental Studies.
The laboratory focused on influence the low-level
exposure of the environmentally pollutant chemicals
to the fetal and neonatal periods which is thevulnerable developmental stage. To study thepathology and developmental abnormalities after
adulthoods, toxicity studies by orthodox animal
experiments were employed to clarify the involvementof related molecules in pathogenesis.
DOHaD (Developmental Origin of Health andDiseas) is a generalized academic concept in recent
years, and chemical exposure is regarded as animportant environmental factor in DOHaD. Until now,
in our laboratory, we were investigating what kind ofadverse effect will be left to offspring that have beenborn by administering dioxin (TCDD) and bisphenol

A (BPA). These compounds are exposed to human in
an inevitable unintended way from the environment.
Although the dioxin problem seems to have calmed
down by strengthening the installation standard of theincinerator which is a major source of dioxin, however,there are still many unknown parts regarding themolecular mechanism of its various toxicity
manifestations, especially the endocrine disrupting
mechanism. In addition, BPA is experimentally shown
the influence on reproductive function and brain
development in plastics materials used all over theworld. Regulations in Canada and Europe are
becoming more stringent in recent years.
The above-mentioned substances are only an
example, and tens of thousands of new chemical
substances unknown toxic influence in the world are
diffused globally when they appear constantly. It is aninevitable process for modern civilization to regulate
each time with scientific grounds. The mission of thislaboratory is to identify the substances of concern
before actual damage of ecological impact / healtheffects occurs, and further to determine what kind of
biological effects are present from animal
experiments.
Epigenetic Toxicology: DOHaD has been payedattentions because the effects of unbalanced nutritionand chemical exposures may remain as epigenetic
changes imprinted by the fetal environment, not but as
non-genetic phenotype. In our laboratory, I found that
DNA methylation level of the promoter region of drug
metabolizing enzyme gene (Cyp1a1) in the mouse
liver is down-regulated by TCDD exposure and thishypomethylation is dependent on Ahr gene. I also
found that this hypomethylation is irreversibly causedby fetal exposure. Since the dissociation tendency of539

Dnmt3b was observed at the beginning of birth, I
hypothesized that it may be passive demethylation.
However, even when administered to matureindividuals of high-dose TCDD, the hypomethylation
occurred in a very short time without cell division,and thus it was considered to be an active
demethylation mechanism. Therefore, we found thatmolecules that control base excision repair (Tet1, Tet2,
Tet3, Tdg, Apex1) are also activated by Ahr-TCDD
and for the first time, nuclear receptor-dependent
demethylation mechanism (Amenya et al., 2016).
MSD-AFLP method: In order to analyze theexhaustive methylation profile of genome-wide athigh accuracy, next-generation sequencers are
currently used. In these methods, high depth isrequired, therefore there is a problem of cost
efficiency. In environmental toxicology and molecularepidemiology of humans, it is necessary to reduce
expenses in order to analyze multiple samples.
MSD-AFLP method was developed by our laboratory
as a low-cost genome-wide CpG methylation analysis.
A unique library preparation protocol, MSD, foramplifying only a DNA restriction enzyme fragment
having methylated CpG at the ends was combinedwith an AFLP method. This technique is able to detect
differences in methylation of 5% between samples
with specific CpG (Aiba et al., 2017).

Teaching activities
The Laboratory of Environmental Health Sciences
has important missions to train postdoctoral fellows to
become promising scientist leaders in the field ofenvironmental toxicology and to give toxicology andenvironmental health courses for graduate andundergraduate students. The following lectures havebeen provided to students.
Graduate education
Lectures, Seminar, and laboratory practice, as wellas guidance for the dissertation for the Master’s andDoctor’s degrees have been provided.
Master Course in the Graduate School of Medical
Sciences: Toxicology (Lecture)
Master and Doctor Courses in the Graduate Schoolof International Health: International Environmental
Medicine (Lecture and Laboratory Practice)
Master Course in the School of Public Health:Environmental Health Medicine (Lecture)

Publications
Original article:
1. Aiba T, Saito T, Hayashi A, Sato S, Yunokawa H,
Maruyama T, Fujibuchi W, Kurita H, Tohyama C,
Ohsako S. Methylated site display (MSD)-AFLP,a sensitive and affordable method for analysis of
CpG methylation profiles. BMC Mol Biol 18(1):7,(2017)
2. Amenya HZ, Tohyama C, Ohsako S. Dioxin
induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse
liver. Scientific Reports 6:34989, (2016)
3. Yamane J, Aburatani S, Imanishi S, Akanuma H,
Nagano R, Kato T, Sone H, Ohsako S, Fujibuchi
W. Prediction of developmental chemical toxicity
based on gene networks of human embryonicstem cells. Nucleic Acids Res. 44(12):5515-28.
(2016)

540

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, 3 technical support staffs, an assistantmanager of CDBIM, an administrative staff, a project
academic support specialist, 4 assistant laboratory
animal technicians, and 3 assistant clerks. In addition,
about 15 contracted employees are involved in animal
breeding and maintenance of the animal facility.
The laboratory animals in our facility include
macaque monkeys, dogs, swine, rabbits, rats, mice,and marmosets. The number of registered users of ourfacility was 917 at the end of academic year 2016.
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.

541

1. Cryopreservation of marmoset embryos
Common marmoset (Callithrix jacchus) is a nonhuman primate and recently used for human model,
especially focusing on brain function. We haveestablished the techniques for in vitro fertilization. We
have cryopreserved 8-cell embryos by vitrification
technique, and stored in liquid nitrogen. Frozen
embryos were thawed and subjected to blastomere
ablation experiments. After ablation, we succeeded in
extracting genomic DNA from blastomeres forgenotyping.
2. Generation of knock-in mice by CRISPR/Cas
systemThe CRISPR/Cas system has rapidly emerged recently
as a new tool for genome engineering, and is expected
to allow for controlled manipulation of specificgenomic elements in a variety of species. A number ofrecent studies have reported the use of CRISPR/Cas
for gene disruption (knockout) or targeted insertion offoreign DNA elements (knock-in). Despite the ease of
simple gene knockout, small insertions or nucleotide
substitutions in mouse embryos, targeted insertion oflarge DNA elements remains an apparent challenge.
We tried to quantify knock-in efficiency using
sgRNAs or crRNA/tracrRNA targeting for mouse
Grm1 locus, single stranded oligo DNAs as donors
and Cas9. We have succeeded to maximize knock-in
efficiency (63.0%), when purified Cas9 protein was
injected with crRNA/tracrRNA and donor DNA.
3. Generation of calsyntenin triple KO mice
Calsyntenins are membrane proteins belonging tocadherin superfamily. In C. elegans, a calsynteninhomolog CASY-1 is required for taste avoidance
learning. There are three mouse calsyntenins(CLSTN1, 2, and 3), which are predominantly expressed in the central nervous system (CNS). To
investigate the role of CLSTNs in the CNS, we plan togenerate Clstn triple KO mice. We have injected Cas9mRNA with sgRNA targeting Clstn 1, 2 and 3 into
mouse embryos and have obtained founder mice
which carry several mutant alleles of Clstn genes. By
crossing these mice, we have established Clstn triple
KO mice. Clstn triple KO mice are viable. We
examined long-term potentiation (LTP) in the TKO
hippocampus and found that they induce normal LTP.

We are currently examining the behavior andanalyzing the brain structure by immunehistochemistry.
4. 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.
These
miceshowedabnormalities in heart and thymus that are often
observed in 22q11.2DS patients.

References
1. Kikuchi I, Takahashi-Kanemitsu A, Sakiyama N,
Tang C, Tang PJ, Noda S, Nakao K, Kassai H,
Sato
T,
Aiba
A,
Hatakeyama
M.
Dephosphorylated parafibromin is a transcripttional coactivator of the Wnt/Hedgehog/Notch
pathways. Nat Commun. 2016 Sep; 7:12887.
2. Narushima M, Uchigashima M, Yagasaki Y,
Harada T, Nagumo Y, Uesaka N, Hashimoto K,
Aiba A, Watanabe M, Miyata M, Kano M. The
Metabotropic Glutamate Receptor Subtype 1
Mediates Experience-Dependent Maintenance ofMature Synaptic Connectivity in the Visual
Thalamus. Neuron. 2016 Sep; 91(5):1097-109.
3. Nagase M, Kurihara H, Aiba A, Young MJ, Sakai
T. Deletion of Rac1GTPase in the Myeloid
Lineage Protects against Inflammation-MediatedKidney Injury in Mice. PLoS One. 2016 Mar;11(3):e0150886.
4. Ichikawa R, Hashimoto K, Miyazaki T,
Uchigashima M, Yamasaki M, Aiba A, Kano M,
Watanabe M. Territories of heterologous inputs

542

5.

6.

7.

8.

9.

onto Purkinje cell dendrites are segregated by
mGluR1-dependent parallel fiber synapse
elimination. Proc Natl Acad Sci U S A. 2016 Feb;
113(8):2282-7.
Matsuda I, Shoji H, Yamasaki N, Miyakawa T,
Aiba A. Comprehensive behavioral phenotypingof a new Semaphorin 3 F mutant mouse. Mol
Brain. 2016 Feb; 9:15.
Nagahama R, Yamada A, Tanaka J, Aizawa R,
Suzuki D, Kassai H, Yamamoto M, Mishima K,
Aiba A, Maki K, Kamijo R. Rho GTPase protein
Cdc42 is critical for postnatal cartilage development. Biochem Biophys Res Commun. 2016 Feb;
470(4):813-7.
Oshima-Nakayama M, Yamada A, Kurosawa T,
Aizawa R, Suzuki D, Saito Y, Kassai H, Sato Y,
Yamamoto M, Shirota T, Aiba A, Maki K, Kamijo
R. Cdc42 is crucial for facial and palatalformation during craniofacial development. Bone
Rep. 2016 Jan; 5:1-6.
Nakao H, Harada T, Nakao K, Kiyonari H, Inoue
K, Furuta Y, Aiba A. A possible aid in targeted
insertion of large DNA elements by CRISPR/Cas
in mouse zygotes. Genesis. 2016 Feb; 54(2):6577.
Ayuzawa N, Nagase M, Ueda K, Nishimoto M,
Kawarazaki W, Marumo T, Aiba A, Sakurai T,
Shindo T, Fujita T. Rac1-Mediated Activation of
Mineralocorticoid Receptor in Pressure OverloadInduced Cardiac Injury. Hypertension. 2016 Jan;67(1):99-106.

543

Laboratory of Molecular Radiology
Professor
Kiyoshi Miyagawa, M.D., Ph.D.

Lecturer
Noriko Hosoya, M.D., Ph.D., Atsushi Enomoto, Ph.D.

Associate
Takaaki Yasuhara, Ph.D., 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

544

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 or cisplatin, and are characterized byincreased aneuploidy. As these phenotypes are
consistent with those of defective HR, we screened themolecule that co-localizes with SYCP3 byimmunofluorescence. Consequently, we identified thatthe tumor suppressor BRCA2 co-localizes withSYCP3. We also confirmed that these proteins form acomplex. Furthermore, we found that binding of
SYCP3 to BRCA2 inhibits the HR repair activity
mediated by binding 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.
In addition to Rad51, Rad51 paralogs, Rad54, andRad54B are also involved in HR. While Rad51
paralogs and Rad54 were shown to assist theRad51-dependent cascade, the involvement of
Rad54B in HR is not closely associated with
Rad51and Rad54. This fact led us to hypothesize that
Rad54B has a role distinct from other HR factors. We
found that levels of Rad54B are inversely correlatedwith protein levels of p53 both after DNA damage andRad54B knockout cells. Protein interaction analysis
revealed that Rad54B promotes proteasome-dependentdegradation 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 this biological
function, high levels of Rad54B were shown tocorrelate with poor prognosis in colorectal cancers.
Thus, our studies on the mechanisms underlying
HR contribute to the establishment of important
strategies against cancer. Radiation and many
DNA-damaging chemotherapeutic agents induce DNA
DSBs, which can be normally repaired by the intrinsic
repair pathways. The induced breaks therefore do notalways lead to apoptosis. If we will understand thedetails of the repair pathways, the molecules in thispathway will be the therapeutic targets. From theclinical point of view, we are continuing the research
exploring the principle in this field.

Publications
1. Katsura M, Cyou-Nakamine H, Zen Q, Zen Y,
Nansai H, Amagasa S, Kanki Y, Inoue T, Kaneki
K, Taguchi A, Kobayashi M, Kaji T, Kodama T,
Miyagawa K, Wada Y, Akimitsu N, Sone H:
Effects of chronic low-dose radiation on humanneural progenitor cells. Sci Rep 6:20027, 2016

545

2. Zhan H, Aizawa K, Sun J, Tomida S, Otsu K,
Conway SJ, McKinnon PJ, Makabe I, Komuro I,
Miyagawa K, Nagai R, Suzuki T: Ataxia
telangiectasia mutated in cardiac fibroblasts
regulates doxorubicin-induced cardiotoxicity.
Cardiovascul Res 110:85-95, 2016
3. Hashimoto T, Horikawa DD, Saito Y, Kuwahara
H, Kozuka-Hata H, Shin-I T, Minakuchi Y,
Ohishi K, Motoyama A, Aizu T, Enomoto A,
Kondo K, Tanaka S, Hara Y, Koshikawa S,
Sagara H, Miura T, Yokobori S, Miyagawa K,
Suzuki Y, Kubo T, Oyama M, Kohara Y,
Fujiyama A, Arakawa K, Katayama T, Toyoda A,
Kunieda T: Extremotolerant tardigrade genome
and improved radiotolerance of human cultured
cells by tardigrade-unique protein. Nat Commun
7:12808, 2016

546

Office ofInternational Academic Affairs
HeadYasuyuki Seto

Assistant Professors
Joseph Green
Christopher Holmes
Keiko Nanishi

Homepage 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 2016 academic year (April 1, 2016
through March 31, 2017).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2016, there were 133 foreign students (38countries) 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 51 suchinquiries.
Many currently enrolled foreign students received
counseling at this office concerning their studies andlife at the University of Tokyo and the requirementsfor 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 thisoffice or 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
get-together of foreign students and University ofTokyo 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 2016, at the
Sanjo Kaikan, a reception hall on the Hongo campus.
A formal agreement for academic exchange
between the University of Pennsylvania and the
University of Tokyo was renewed in May 2004. Since
that time, sixteen University of Tokyo students havetaken research electives at the University ofPennsylvania, and two students from the University ofPennsylvania have taken clinical electives at the
University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the547

University of Tokyo and Johns Hopkins University inDecember 2002. Since the start of the program in
2002, twenty-nine University of Tokyo students havevisited to attend clinical electives at Johns Hopkins
University, and four students from Johns Hopkins
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 University of Michigan
Medical School in January 2005. Since the start of the
program in 2005, twenty-one University of Tokyo
students have attended clinical electives at the
University of Michigan Medical School, and elevenstudents 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,
fourteen University of Tokyo students have visited toattend research electives at Munich University, and ten
students from Munich 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 College of Medicine of
Taipei Medical University in November 2005. Since
the start of the program in 2005, five University ofTokyo students have visited to attend clinical electives
at Taipei Medical University and fifteen students from
Taipei Medical 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 College of Medicine of
National Taiwan University in October 2012. Since
the start of the program in 2012, six University ofTokyo students have visited to attend clinical electives
at National Taiwan University and eight 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, three University of Tokyo students havevisited to attend clinical electives at the University of
Chicago Medicine.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and Sydney Medical School inJune 2015. Since the start of the program in 2015,
three University of Tokyo students have visited toattend clinical electives at Sydney Medical School andthree students from Sydney Medical School havetaken clinical electives at the University of 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 forcounselingregarding
pre-graduationor
post-graduation studies abroad are received by the
Office of International Academic Affairs. The office
responds to these requests by providing information,
advice, and letters of recommendation.
2. Education and research
2.1 Education
In 2016, 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.
Mr. Christopher Holmes taught Medical English 1
and 2, which are required for all medical students.
The Office also organized classes in English for the
Health Sciences. In 2016, Mr. Holmes also arranged
and led ad hoc sessions in Oral Presentation Training
and extracurricular activities in English for medical
students and graduate students. These sessions wereopen to all students and teaching staff in the Graduate
School of Medicine and the Faculty of Medicine.
Dr. Green and Dr. Nanishi conducted several
international health studies.
2.2 Publications
1: Pokhrel K, Nanishi K, Poudel KC, Pokhrel KG,
Tiwari K, Jimba M. Undernutrition Among
Infants and Children in Nepal: Maternal HealthServices and Their Roles to Prevent it. Matern
Child Health J. 2016 Oct;20(10):2037-49.

548

2: Maulida R, Nanishi K, Green J, Shibanuma A,
Jimba M. Food-choice motives of adolescents in
Jakarta, Indonesia: the roles of gender and family
income. Public Health Nutr. 2016 Oct;19(15):2760-8.
3: Enuameh YA, Okawa S, Asante KP, Kikuchi K,
Mahama E, Ansah E, Tawiah C, Adjei K,
Shibanuma A, Nanishi K, Yeji F, Agyekum EO,
Yasuoka J, Gyapong M, Oduro AR, Quansah
Asare G, Hodgson A, Jimba M, Owusu-Agyei S;
Ghana EMBRACE Implementation Research
Project Team. Factors Influencing Health Facility
Delivery in Predominantly Rural Communities
across the Three Ecological Zones in Ghana: A
Cross-Sectional Study. PLoS One. 2016 Mar 31;
11(3):e0152235.
4: Holmes C. Have you ever read a medical novel? J
Med Eng Educ. 2016; 15(3): 133-137.

549

MD Scientist Training Program
Professor and Director
Haruhiko Bito, M.D., Ph.D.

Assistant Professor
Yuki Sugaya, M.D., Ph.D.
Ikuko Honda, 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 Ikuko Honda, and over 80
students who are seeking extracurricular basic medical
research training through the Program’s framework.
With the help of two assistants for clerical work, it
provide a variety of support programs to assist the
research activities of medical students. From 2011 on,
the MDSTP at the University of Tokyo has cooperated
with its sister programs at Kyoto University, Osaka
University and Nagoya University, and has received
governmental funding support to dramatically boost
its activities.
The number of the enrolled students during the launchyear (2008) of the MDSTP was 6. Since then, theProgram has expanded and now enrolls more than 80
students (during Year 3 to 6 of the Medical School).
Around 10 students write research honors theses
during their final year, which they defend to become
certificated as MDSTP graduates. The number of
research publications in scientific journal or awards atinternational scientific meetings, which resulted fromthese 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

550

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 2016, a total of 4 students
received the Program’s support for carrying out basic
medical research abroad (in US, Europe andAustralasia) for more than a month and to present
their research 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 2016, a
total of 16 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 March, 19-20, 2017 topresent ongoing research progress in a closed meeting

among peers. More than 40 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, Annual Joint Retreats were held topromote communication and networking among the
medical students with research minds. The latest
retreat was organized on March, 21-22, 2015 in Kobe,
at the occasion of the joint annual meeting of The
Japanese Association of Anatomists and PhysiologicalSociety of Japan. More than 100 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. Eight selected students presented theirresearch achievements in a joint symposium session ofthis meeting, held in the Main Hall of Kobe
International Convention Center.
The MSDTP also currently cooperates with 9 otheruniversities in eastern Japan to organize annual
research students’ retreats. In 2016, this was held on
August, 18-19 in Ikaho, Gunma under the auspices ofGunma University. Around 70 people participated in
the retreat and presented their ongoing research
progress and future plans.

551

Activities (2016)
The number of registered students: 80 (3rd grade: 26,
4th: 23, 5th: 13, 6th: 18)
Lectures for students in Years 1 and 2
Introduction to Medical Biology: 13 lectures
Group reading of Molecular Biology of the Cell: 11
lectures
Seminar for students (in Year 3 or above)
Journal Club for basic medical research: 7 lectures
Medical Research Communications: 28 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: 20
The number of Year 6 students who passed theirhonors thesis defense: 8 (the Dean’s Prize wasawarded to 2 students)
Publications:
Sugaya Y, Medical Scientist Training Program of The
University of Tokyo, Japanese journal of biologicalpsychiatry, 2016, Sep., 27(3), 147-150

552

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
117,578 people had visited by the end of FY2016.

553

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.

554

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/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.
・Examination of case documents in connection with,-High risk elective operations,-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 2016
・Research Ethics Committee (except for clinical
trial, GCP):
383 new applications, 773 minor alterations ofapproved studies, and 20 documentary examinations
・New clinical documentary examinations: 61555

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 2016 with 1669 people attended.
OHRS makes efforts to educate researchers through its
research ethics support services. Additionally, the skill
development and support of the secretariat staff is oneof our important tasks.
OHRS also aims to advance research ethics standards
by cooperating and consulting with Ethics Consultant
specified by each laboratory.

556

The Office for Clinical Practiceand Medical Education
Professor
Tatsuya Yamasoba, M.D.,Ph.D.

Assistant Professor
Takeya Tsutsumi, M.D.,Ph.D.

Homepagenone

Introduction and Organization
The Office for Clinical Practice and Medical
Education was established in April 2015, to support
and promote medical education, especially clinicalpractice at grade 5 and 6. The office used to be theClinical Clerkship Support Center, which wasestablished to meet the change from bedside learning
to clinical clerkship in February 2013. Our aim is torun clinical clerkship smoothly, as well as to improvethe curriculum and evaluation method by listening toteachers and students. In addition, we try to support anindividual student in cooperation with tutors, theinstruction department and the office for student
assistance in the faculty of medicine. The office now
consists of a general manager (professor), an assistantprofessor, and three clerical assistants.

Activities
Before clinical clerkship begins in January for 4th
grade medical students, we have a meeting to explain
the details to the students, and then make a scheduleof clinical clerkship based on the questionnaire. Just
before the start, we hold a ceremony to name students“student doctors”, which the dean of the medical
faculty of The University of Tokyo, and the director
and the chief nursing officer of The University ofTokyo Hospital attend.
After clinical clerkship starts, we support teachers andstudents to run the clerkship smoothly by making
necessary contacts with them. Since the opportunities

of clinical practice outside the university increased
after clinical clerkship began, we have clerical tasks
such as mutual contact and paperwork. In addition, we
handle problems and considerations occurred during
the practice if needed. Particularly, we manage andsupport students who have difficulties, with the
instruction department, a tutor, and the office forstudent assistance in the faculty of medicine.
Twice a year, we hold a meeting with teachers who arein charge of students’ clinical practice. In this meeting,we provide teachers feedback about comments fromstudents’ questionnaires, and share the informationand comments from teachers, and discuss the
problems raised by them. Based on the discussion, we
make a response or modification to improve clinicalclerkship. On the other hand, we have an opportunity
to discuss the present condition of clinical clerkshipwith students, and try to respond to comments fromthem.
Moreover, we aim at starting the academic affairs
system for medical students in UTokyo until the next
spring.

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The International Research Center
for Medical Education (IRCME)
Director & Professor
Kazuhiko Yamamoto, M.D., Ph.D.

Professor
Kiyoshi Kitamura, M.D., Ph.D.

Lecturer
Hirotaka Onishi, M.D., M.H.P.E.
Daisuke Son, M.D., Ph.D., Ph.D.

Homepage

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

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 IRCME includes promotion of
medical education not only in Faculty of Medicine of
the University of Tokyo but also of the whole country,
and international cooperation in medical education
area in developing countries. 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) Research in international cooperation in medical
education area
To find a generalizable methodology for international
cooperation in medical education area we contributeto international cooperation for improvement ofundergraduate and postgraduate education in thecontext of status quo of each developing country.
(3) 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 of Each Department
1. Medical Education Studies
This department promotes research related to
medical education field (including health professions
education). As the studies of medical education
develop very rapidly all over the world, the department expands research to construct theories andemphasizes activities of educational practice or
improvement.

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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 managers’ meeting. Moreover,the department offers direct educational activities suchas PBL (problem-based learning) and clinical skill
practical training. Medical students are welcomed forfree quarter for practical work for research. The
department supervises CAT-OSCE (common achievement test-objective structured clinical examination)and gives advices from expert perspectives.
Medical education seminars of the University ofTokyo and basic courses of medical education aremonthly held. The department also runs and manages“Tsutsuji no kai” under the consortium with Tokyo
Medical Dental University to develop standardized
patients indispensable for education of medical
interview.
2. International Cooperation for Medical Education
This department participates in international
cooperation projects and practically works for the
research and educational developments in medical
education field, undergraduate and postgraduate
education in medicine, dentistry, pharmacy, nursing,public health, rehabilitation, etc. in countries mainlyin Asia. Furthermore, the department collects information and exchanges human relations for international
cooperation in medical education areas domesticallyand internationally, and supports projects related to
medical education.
IRCME invites international experts distinguishedin medical education practices or research as visiting
faculty members approximately six months per year.
Such faculty advises and teaches for planning andimplementing the activities of IRCME, and promotes
collaborative research.
In 2013, we welcomed a visiting faculty: Dr.
Mary Y. Lee (1 Oct 2014 – 27 Mar 2015), Professor of
Medicine, Tufts University School of Medicine,Special Advisor for Education Innovation, Tufts
Medical Center, Boston, USA

International Invited Faculty
Dr. Linda Snell