ISSN 1883-9606

2016

Vol.133

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2015 ---- March 2016

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2015-March 2016

Introduction
This is volume 133(the edition of year 2016) 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, 2016

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

1

Department of Cell Biology 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 Neurophysiology ···············································································

21

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

24

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

25

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

29

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

33

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

34

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

39

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

43

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

44

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

47

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

50

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

51

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

55

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

56

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

61

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

62

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

65

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

67

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

70

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

71

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

74

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

80

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

82

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

83

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

85

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

86

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

90

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

94

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

100

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

101

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

103

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

106

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

107

Department of Medical Informatics and Economics ························································

111

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

114

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

115

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

120

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

124

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

130

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

131

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

136

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

142

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

145

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

148

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

151

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

153

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.440] )Department of Transfusion Medicine ·········································································

154

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

157

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

158

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

160

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

163

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

165

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

167

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

168

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

173

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

177

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

178

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

183

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

184

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

188

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

193

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

196

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

201

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

206

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

212

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

215

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

217

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

218

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

222

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

227

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

232

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

238

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

243

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

248

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

250

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

251

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

254

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

259

Department of Health Sociology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.341] )Department of Mental Health ··················································································

260

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

264

Department of Social Gerontology(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.341] )Department of Biomedical Ethics & Department of Health Promotion Sciences ·······················

270

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

274

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

275

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

278

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

281

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

285

Department of Adult Health Nursing / Palliative Care Nursing ···········································

286

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

290

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

293

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

297

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

303

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

304

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

310

v

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

314

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

315

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

318

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

321

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

326

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

328

Department of Biostatistics (See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.264] )Department of Social and Preventive Epidemiology ························································

329

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

332

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

337

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

340

Department of Mental Health(See Department of Mental Health [P.260] )Department of Health Sociology and Health Education(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.341] )Departments of Health and Social Behavior & Health Education and Health Sociology ···············

341

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.270] )3. Health Services Sciences ·························································································

345

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.103] )Department of Healthcare Informatics (See Department of Medical Informatics and Economics [P.111] )Department of Clinical Information Engineering ····························································

346

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.107] )Endowed Department ···································································································

348

Department of Bone & Cartilage Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.489] )Department of Cartilage & Bone Regeneration (Fujisoft)(See Central Clinical Facilities Division of Tissue Engineering [P.489] )Department of Clinical Epidemiology and Systems ·························································

349

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

353

Science for joint reconstruction ( See Department of Orthopaedic Surgery [P.232] )Department of Chronic Kidney Disease (CKD) Pathophysiology ········································

355

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

358

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

360

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

363

vi

Department of Molecular Psychiatry ··········································································

365

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

366

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

370

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

372

Department of medical research and management of musculoskeletal pain ·····························374

AXA Chair on Health and Human Security ( See Department of Global Health Policy [P.304] )Department of Advanced Nephrology and Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.489] )Department of Molecular Sciences on Diabetes·······························································

378

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

380

Department of Immunotherapeutics (Medinet) ······························································

381

Division of Total Renal Care Medicine ·······································································

384

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

386

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

388

Department of Translational Research for Healthcare and Clinical Science ·····························

391

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

394

Department of Health Management and Policy ······························································

397

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

399

Department of Clinical Motor System Medicine ····························································

401

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

403

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

406

Department of Anti-Aging Medicine ··········································································

410

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

413

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

416

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

418

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

423

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

424

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

427

Functional Regulation of Adipocytes ··········································································

429

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

431

Social Cooperation Program (22nd Century Medical and Research Center) ···································

434

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

435

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University Hospital
Clinical Divisions ····································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.115] )Respiratory Medicine (See Department of Respiratory Medicine [P.120] )Gastroenterology (See Department of Gastroenterology [P.124] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.131] )Diabetes and Metabolic Diseases (See Department of Diabetes and Metabolic Diseases [P.136] )Hematology and Oncology (See Department of Hematology and Oncology [P.142] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.145] )Infectious Diseases (See Department of Infectious Diseases [P.148] )Neurology (See Department of Neurology [P.90] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.178] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.151] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.193] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.206] )Hepatobiliary Pancreatic Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.196] )Vascular Surgery (See Department of Vascular Surgery [P.212] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.215] )Artificial Organ and Transplantation Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.196] )Cardiovascular Surgery (See Department of Cardiac Surgery [P.188] )Thoracic Surgery (See Department of Thoracic Surgery [P.184] )Neurosurgery (See Department of Neurosurgery [P.94] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.251] )Urology and Andrology (See Department of Urology [P.201] )Gynecologic Surgery (See Obstetrics and Gynecology [P.157] )Sensory and Motor System Medicine
Dermatology and Photolaser Medicine (See Department of Dermatology [P.218] )Ophthalmology and Vision Correction (See Department of Ophthalmology [P.238] )

438

viii

Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.232] )Otorhinolaryngology, and Auditory and Voice Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.243] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.248] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.222] )Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.227] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.168] )Pediatrics Surgery (See Department of Pediatrics Surgery [P.173] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.158, 160, 163] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.86] )Radiology
Radiology (See Department of Radiology [P.56] )Central Clinical Facilities ···························································································

439

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

440

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

444

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

447

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

449

Department of Emergency Services(See Department of Emergency and Critical Care Medicine [P.254] )Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.154] )Delivery Unit ·····································································································

453

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

454

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

456

Department of Intensive Care Unit
(See Department of Emergency and Critical Care Medicine [P.254] )Division of Diagnostic Pathology ··············································································

458

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

462

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

464

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

466

ix

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

470

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

473

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.47] )Department of Planning, Information, and Management(See Department of Medical Informatics and Economics [P.111] )University Hospital Medical Information Network (UMIN) Center ······································

480

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

483

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

485

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

489

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

494

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

497

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

501

Department of Clinical Molecular Medicine ·································································

504

Center for Genome Medicine
Genome Informatics ··························································································

506

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

508

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

510

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

512

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

520

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

522

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

523

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

528

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

529

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

532

Laboratory of Regenerative Medical Engeneering ····························································

535

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

537

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

541

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

544

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

547

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

550

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

553

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

556

x

Office for Research Ethics Support ················································································

558

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

560

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

561

The Tokyo Journal of Medical Sciences. Vol. 133, October 2016

xi

History
1858

May

Practitioners, trained in Dutch (European) medicine in Edo (Tokyo), laid out money to establish
the Shutojo (vaccination center) in Kanda Mitamagaike.

Nov.

Shutojo was destroyed in a fire that had spread from Kanda Aioicho. Shutojo continued its
operations at other sites such as the residence of Ito Genboku.

1859

Sep.

Shutojo was reconstructed at Shitaya Izumibashi Dohri.

1860

Oct.

Shutojo became an official medical institution of the Shogunate Government.

1861

Oct.

Shutojo was renamed as Seiyo Igaku-Sho (Institute of Western Medicine) and offered courses ofWestern Medicine in the fields of Education, Autopsy, and Vaccination.

1863

Feb.

Seiyo Igaku-Sho was renamed as Igaku-Sho (Institute of Medicine).

1868

Jul.

Igaku-Sho, affiliated with the Military Hospital which had been moved from Yokohama to Todo
residence in Shitaya, was renamed as Daibyoin (the Great Hospital).

1869

1871

Feb.

The Daibyoin was renamed as Igakko-Ken-Byoin (Medical School and Hospital).

Dec.

Igakko-Ken-Byoin was renamed as Daigaku Toko (University East Building).

Jul.

The Ministry of Education was established and Daigaku-Toko was renamed as Toko (East
Building).

1872

Aug.

A School System was established. Toko was renamed as Daiichi-Daigaku-Ku- Igakko (The First
University District Medical School).

1874

May

Daiichi-Daigaku-Ku-Igakko was renamed as Tokyo-Igakko (Tokyo Medical School).

1876

Nov.

Tokyo-Igakko was moved to Hongo.

1877

Apr.

Tokyo Igakko, affiliated with Tokyo-Kaisei School, was renamed as The University of Tokyo.
Tokyo Medical School was renamed as The University of Tokyo Faculty of Medicine.

1886

Mar.

The University of Tokyo was renamed as Imperial University, and The University of Tokyo
Faculty of Medicine was renamed as the Imperial University Medical College. A Graduate
School was established.

1897

Jun.

The Imperial University was renamed as Tokyo Imperial University.

1917

Aug.

Eiraku Hospital, affiliated with the Ministry of Education Medical Practice License Examination,
moved to Tokyo Imperial University and was renamed as Koishikawa Hospital affiliated with
Tokyo Imperial University Medical College.

1919

Apr.

A faculty system was established renaming Tokyo Imperial University Medical College as theFaculty of Medicine.

1931

Feb.

The first building of the Faculty of Medicine was constructed.

1936

Jan.

The Brain Research Laboratory was built with funds donated by Mr. Hisasaburo Horikoshi.

Nov.

The second building of the Faculty of Medicine (main building) was constructed.

1947

Oct.

Tokyo Imperial University was renamed as The University of Tokyo.

1950

Apr.

The Institute of Nursing was renamed as The University Nursing School.

1953

Apr.

The School of Health Care and Nursing was founded.

xii

The Tokyo Journal of Medical Sciences. Vol. 133, October 2016

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.

xiii

The Tokyo Journal of Medical Sciences. Vol. 133, October 2016

2000

Apr.

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.

2004

Apr.

All

the

National

Universities owned

by

the

Japanese

Government

becameNational 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. 133, October 2016

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
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
Developmental Neuroscience

Graduate School of
Medicine

Neuroscience

Integrativ Medical Neurosciences

Cognitive Neuroscience
Systems Medical Neuroscience
Child Neuropsychiatry
Neuropsychiatry

Clinical Neuroscience

Neurology
Neurosurgery
Molecular Preventive Medicine

Occupational, Environmental andPreventive Medicine

Public HealthRadiological HealthSocial Medicine

Forensic Medicine, and Medical
Informatics and Economics

Forensic Medicine
Medical Informatics and Economics

Collaborative Department

Cancer Health Services Research

The Tokyo Journal of Medical Sciences. Vol. 133, October 2016

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. 133, October 2016
Health Sociology
Mental Health
Epidemiology and Preventive Health
Sciences
Health Sciences

Social Gerontology
Health Promotion Sciences
Biostatistics
Biomedical Ethics
Advanced Clinical Nursing

Health Sciences andNursingNursing Administration
Preventive and Administrative
Nursing

Family Nursing
Community Health Nursing
Public Health Nursing
Adult Health Nursing
Palliative Care Nursing

Clinical Nursing

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

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
Social and Preventive Epidemiology
Epidemiology and Health Sciences

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
Healthcare Informatics

Health Services Sciences

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

xvii

The Tokyo Journal of Medical Sciences. Vol. 133, October 2016

Office of International Academic Affairs
Medical Library
Medical Scientist Training Program
Museum of Health and Medicine
Institution

Office for Research Ethics Support
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
Total Renal Care Medicine
Advanced Clinical Science and Therapeutics
Joint Disease Research
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
Endowed Department

Ubiquitous Preventive Medicine
Science for Joint Reconstruction
Therapeutic Strategy for Heart Failure
Molecular Structure and Dynamics
Medical Genomics
Continence Medicine
Department of Life Support Technology (Molten)
Youth Mental Health
Advanced Nephrology and Regenerative Medicine
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

Ubiquitous Health Informatics
Lipidomics
Social Cooperation Program

Functional Regulation of Adipocytes
Advanced Nursing Technology
Verbal analysis of pathophysiology

General Affairs Office
Personnel Office
Research Support Office
Educational Affairs
Graduate Student Affairs

xviiiThe Tokyo Journal of Medical Sciences. Vol. 133, October 2016

Finance Office

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

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. 133, October 2016

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. 133, October 2016
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
Department of Performance
Monitoring and Risk
Management

Organization of ClinicalManagement Support
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

xxi

The Tokyo Journal of Medical Sciences. Vol. 133, October 2016

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
Department of Cell Biology and Anatomy

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

Masamitsu Iino

Professor

Hiroki Ueda

Professor

Masashi Fukayama

Professor

Kohei Miyazono

Professor

Masanori Hatakeyama

Professor

Kyoji Moriya

Professor

Hiroshi Takayanagi

Department of Radiology

Professor

Kuni Otomo

Department of Biomedical Engineering

Professor

Yasuteru Urano

Professor

Takeshi Iwatsubo

Professor

Haruhiko Bito

Professor

Kenzo Hirose

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. 133, October 2016

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

Yutaka Yatomi

Professor

Hitoshi Okazaki

Professor

Tomoyuki Fujii

Professor

Yutaka Osuga

Professor

Akira Oka

Professor

Hiroo Uchida

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

Department of Pediatric Science

Department of Aging Science
Surgical Sciences
Department of Surgery

Department of Sensory and Motor System Medicine

xxiiiThe Tokyo Journal of Medical Sciences. Vol. 133, October 2016

Department of Vital Care Medicine

Professor

Yoshitsugu Yamada

Professor

Naoki Yahagi

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

Kiyoshi Kita

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. 133, October 2016

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

Kazunori Kataoka

Laboratory of Animal Resources

Professor

Atsu Aiba

Laboratory of Molecular Radiology

Professor

Kiyoshi Miyagawa

International Research Center for Medical Education

Professor

Kiyoshi Kitamura

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 Research Ethics Support

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

Associate professor

Takeshi Miyamoto

Department of Cartilage & Bone Regeneration(Fujisoft)

Associate professor

Atsuhiko Hikita

Immunotherapeutics

Professor

Kazuhiro Kakimi

Total Renal Care Medicine

Associate professor

Norio Hanafusa

Department of Advanced Clinical Science and Therapeutics

Associate professor

Junichi Suzuki

Department of Joint Disease Research

Associate professor

Noriko Yoshimura

Health Management and Policy

Professor

Soichi Koike

Associate professor

Ryuichi Yamamoto

Professor

Naoto Hayashi

Associate professor

Kansei Uno

Associate professor

Takeharu Yoshikawa

Healthcare Safety Management (Tokio Marine & Nichido)

Associate professor

Masaki Anraku

The Department of Healthcare Quality Assessment

Professor

Hiroaki Miyata

Associate professor

Shun Kohsaka

Clinical Epidemiology and Systems

Associate professor

Daisuke Koide

Pharmacology and Pharmacokinetics

Associate professor

Masashi Honma

Ubiquitous Preventive Medicine

Associate professor

Yuichi Ikeda

Science for joint reconstruction

Associate professor

Toru Moro

Department of Molecular Structure and Dynamics

Professor

Nobutaka Hirokawa

Department of Medical Genomics

Associate professor

Eirin Sai

Continence medicine

Professor

Yasuhiko Igawa

Department of Life Support Technology (Molten)

Associate professor

Taketoshi Mori

Division of Research Resources and Support

Endowed Departments

Computational Diagnostic Radiology and Preventive Medicine

xxv

The Tokyo Journal of Medical Sciences. Vol. 133, October 2016

Department of Youth Mental Health

Associate professor

Department of Advanced Nephrology and Regenerative Medicine Associate professor

Tsuyoshi Araki
Keiichi Hishikawa

Sciences in the Super-aged Society
AXA Chair on Health and Human Security

Professor

Manami Inoue

Department of Advanced Translational Research andAssociate professor

Eiki Takimoto

Department of Immunotherapy Management

Associate professor

Hiroko Kanda

Chronic kidney disease pathophysiology

Associate professor

Reiko Inagi

Department of medical research and management for

Associate professor

Ko Matsudaira

Department of Molecular Science on DiabetesProfessor

Kohjiro Ueki

Department of Integrated Molecular Sciences on Metabolic

Associate professor

Masato Iwabu

Department of Ubiquitous Health Informatics

Associate professor

Kayo Waki

Department of Lipidomics

Professor

Takao Shimizu

Associate professor

Fuyuki Tokumasu

Functional Regulation of Adipocytes

Associate professor

Hironori Waki

Advanced Nursing Technology

Associate professor

Ryoko Murayama

Verbal analysis of pathophysiology

Associate professor

Shinichi Tokuno

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

Infectious Diseases

Head

Hiroshi Yotsuyanagi

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

Medicine in Management of Pulmonary Hypertension

musculoskeletal pain

Diseases

Social Cooperation Program

University Hospital
Clinical Divisions

xxvi

The Tokyo Journal of Medical Sciences. Vol. 133, October 2016

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

Kuni Ohtomo

Pharmaceutical Department

Head

Hiroshi Suzuki

Department of Clinical Laboratory

Head

Yutaka Yatomi

Surgical Center

Head

Hiroshi Yasuhara

Imaging Center

Head

Kuni Ohtomo

Emergency Service

Head

Naoki Yahagi

Department of Blood Transfusion

Head

Hitoshi Okazaki

Perinatal Center

Head

Tomoyuki Fujii

Rehabilitation Center

Head

Nobuhiko Haga

Department of Medical Engineering

Head

Kyouhiro ChouCentral Supply Service

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Naoki Yahagi

Pathology

Head

Masashi Fukayama

Department of Corneal Transplantation

Head

Satoru Yamagami

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

Central Clinical Facilites

xxviiThe Tokyo Journal of Medical Sciences. Vol. 133, October 2016

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

Takahiro Kiuchi

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

Susumu Nakajima

Department of Palliative Medicine

Head

Masahiko SumitaniChildren’s Medical Center

Head

Akira Oka

Department of Disaster Medical Management

Head

Masaomi Nangaku

International 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., Yosuke Takei, M. D.,

Lecturer and Associate
Yosuke Tanaka, M. D.,

Homepage

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. Morikawa, M., H. Yajima, R. Nitta, S. Inoue, T.
Ogura, C. Saito, and N. Hirokawa. X-ray andCryo-EM structures reveal mutual conformational changes of Kinesin and GTP-state
microtubules upon binding. EMBO J. 34:
1270-1286, 2015.
2. Farkhondeh, A., S. Niwa, Y. Takei, and N.
Hirokawa. Characterizing KIF16B in neurons
reveals a novel intramolecular "stalk inhibition"mechanism that regulates its capacity to potentiate the selective somatodendritic localizationof early endosomes. J. Neurosci. 35 : 5067–5086,
2015.
3. Hirokawa. N. Introduction to the ECR Special
Issue on Molecular Motors. Exp Cell Res 334:
1, 2015.
4. Hirokawa, N. and Y. Tanaka. Kinesin superfamily proteins (KIFs): Various functions andtheir relevance for important phenomena in lifeand diseases. (Review Article) Exp Cell Res
334: 16-25, 2015.
5. Ichinose, S., T. Ogawa, and N. Hirokawa.
Mechanism of Activity-dependent Cargo
Loading via the Phosphorylation of KIF3A by
PKA and CaMKIIa. Neuron 87: 1022–1035,
2015.
6. Ogawa, T. and N. Hirokawa. Microtubule
destabilizer
KIF2A
undergoes
distinctsite-specific phosphorylation cascades thatdifferentially affect neuronal morphogenesis.
Cell Reports 12: 1–15, 2015.
7. Takei, Y., Y. S. Kikkawa, N. Atapour, T. K.
Hensch, and N. Hirokawa. Defects in synaptic plasticity, reduced NMDA-receptor transport, and instability of PSD proteins in micelacking microtubule-associated protein 1A(MAP1A). J Neurosci 35(47): 15539 –15554,
2015.
8. 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: 1215-1229, 2016

4

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

Associate
Haruaki Yanagisawa, Ph. D, Toshiyuki Oda, 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 (Associate),
Toshiyuki Oda (Associate), Tsukasa Makino(Associate), Akihisa Tsutsumi (Associate), Yuma Tani,
Tatsuki Abe (MSTP students), Akiko Osakaya(Technician), Aya Okubo (Technician), and Mikako
Yanagiuchi (secretary).

Teaching activities
Our lab, together with Hirokawa 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 in combination 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 as a modelorganism for studying flagella. To identify moleculesthat are involved in regulating dynein, we use various
genetic tools, including classical mutagenesis, siRNA.

5

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. Oda T., H. A. Yanagisawa, and M. Kikkawa“Detailed Structural and biochemical characterization of the nexin-dynein regulatory complex.”
Molecular Biology of the Cell, 26:294-304, 2015

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

Research

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

Brain functions, which are dependent on mutualcommunication of a tremendous number of neuronalcells, regulate the behavior of animals and humans.
The main structure specifically differentiated for
information exchange between neurons is called"synapse". Long-term maintenance of synaptic
properties underlies stability and reproducibility of
behavior in responses to external stimuli. In turn,
alterations of synaptic properties are thought to be thebasis of behavioral change in the course of animal
development and also after learning. Therefore,
synapses should be stabilized for a long term to realize
fidelity of various animal behaviors, but also shouldbe altered rapidly when animals adapt to a newenvironment. Molecular basis of this dichotomy,
which is unique to synapses, is the main interest of ourlaboratory.
Synapse formation during development
Synapse is one of the major elements to transduce
information from neuron to neuron. Most of thesynapses are formed during the early development andthereafter they become stable after the intensive
pruning. We are interested in how synapse is formed
and maintained.
The postsynaptic densities (PSDs) are protein dense
structures which are located closely to postsynaptic
membranes. PSDs include a variety of receptors,

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

7

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

6.

7.

8.

Publications
1. Miyazaki, J., Iida, T., Tanaka, S., Hayashi-Takagi,A., Kasai, H., Okabe, S., Kobayashi, T.
Fast 3D visualization of endogenous brain signals
with high-sensitivity laser scanning photothermal
microscopy.
Biomed Opt Express., Apr 5;7(5):1702-10., 2016
2. Ochi, T., Nakatomi, H., Ito, A., Imai, H., Okabe,S., Saito, N.
Temporal changes in the response of SVZ neuralstem cells to intraventricular administration of
growth factors.
Brain Res., Apr 1;1636:118-29., 2016
3. Matlashov, M.E., Bogdanova, Y.A., Ermakova,
G.V., Mishina, N.M., Ermakova, Y.G., Nikitin,
E.S., Balaban, P.M., Okabe, S., Lukyanov, S.,
Enikolopov, G., Zaraisky, A.G., Belousov, V.V.
Fluorescent ratiometric pH indicator SypHer2:
Applications in neuroscience and regenerative
biology.
Biochim Biophys Acta., Nov;1850(11):2318-28.,
2015
4. Hayashi, A., Asanuma, D., Kamiya, M., Urano, Y.,
Okabe, S.
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., Jan;100:66-75., 2016
5. Fujita, K., Okabe, S.
For Microscopy special feature on 'superresolution microscopy'.

9.

Microscopy (Oxf)., Feb;64(4):225., 2015
Okabe, S.
Brain/MINDS - a new program for comprehensive
analyses of the brain.
Microscopy (Oxf)., Feb;64(1):3-4., 2015
Ohno, N., Okabe, S.
For Microscopy special issue on 'connectome'.
Microscopy (Oxf)., Feb;64(1):1.,2015
Ogura, T., Hamada, T., Matsui, T., Tanaka, S.,
Okabe, S., Kazama, T., Kobayashi, Y.
Neuroprotection by JM-1232(-) against oxygenglucose deprivation-induced injury in rat hippocampal slice culture.
Brain Res., Jan 12;1594:52-60., 2015
Oshiro, H., Hirabayashi, Y., Furuta, Y., Okabe, S.,
Gotoh, Y.
Up-regulation of HP1γ expression during neuronal maturation promotes axonal and dendritic
development in mouse embryonic neocortex.
Genes Cells., Feb;20(2):108-20., 2015

Molecular Cell Biology
2. Biochemistry and Molecular Biology

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

Associate Professor
Shigeki Jinno, Ph.D. (- 2015.3)

Lecturer
Hayashi Yamamoto, Ph.D. (2015.9 -)Associate
Akiko Kuma, Ph.D., Taki Nishimura, Ph.D.

Homepage

http://www.cellcycle.m.u-tokyo.ac.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

10

was a pioneer in glycolipid research and discovered
the involvement of sialic acid in the ABO blood typeantigens.
Professor Masami Muramatsu graduated from the
University of Tokyo Faculty of Medicine in 1955. He
began studies at the Department of Internal Medicine,and then went to Baylor College of Medicine to study
under Dr. H. Busch. After coming back to Japan, hetook a position at the Cancer Institute and the took up
a professorship at Tokushima University School of
Medicine. In 1982, he succeeded Professor Yamakawa.
He studied ribosomal RNA and cloned interferon andp450 genes.
Professor Hiroto Okayama graduated from Kumamoto
University School of Medicine in 1973. After taking a
Ph.D. degree at Kyoto University School of Medicine,
he went to Stanford University to study under Dr. P.
Berg. After working at the NIH, USA, he became
Professor of Molecular Genetics, at Osaka University
Institute for Infectious Diseases. In 1993 he succeeded
Professor Muramatsu. At Stanford and the NIH, hestudied gene cloning and developed a full length
cDNA cloning method and a cDNA expression
cloning vector system, and, after returning to Japan,
he studied cell cycle control and cancer.
Professor Noboru Mizushima graduated from Tokyo
Medical and Dental University, Faculty of Medicine in
1991. After receiving Ph.D., he studied at National
Institute for Basic Biology in Okazaki and started
works on autophagy in yeast and mammals at Dr.
Yoshinori Ohsumi’s laboratory. Taking a position as a
PI at the Tokyo Metropolitan Institute of Medical
Science in 2004, he started studies on physiologicalroles of autophagy. He was promoted to Professor of
Physiology and Cell Biology, in Graduate School andFaculty of Medicine at Tokyo Medical and Dental
University in 2006, and succeeded Professor Okayama
in 2012.

Research Activities
Our current study focuses on the understanding of themolecular mechanism and physiological roles of
autophagy.
1. Molecular mechanism of autophagy
Autophagy is one of the major degradation

pathways in the cell (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.
Yeast autophagy-initiating Atg1 kinase
complex, consists of Atg1, Atg13, Atg17, Atg29,
and Atg31, while the corresponding complex inmost other eukaryotes, including mammals, iscomposed of ULK1 (or ULK2), Atg13, FIP200(also known as RB1CC1), and Atg101. ULKs arehomologs of Atg1, and FIP200 is partiallyhomologous to Atg17. However, the sequence ofAtg101 is not similar to that of Atg29 or Atg31.
Although Atg101 is essential for autophagy andwidely conserved in eukaryotes, its precise
function and structure have remained largely
unknown. We determined the crystal structure offission yeast Atg101 in complex with the closed
HORMA domain of Atg13 and revealed that
Atg101 is required for stabilization of "uncapped"
Atg13 in most eukaryotes and also for recruitmentof downstream Atg proteins through the newly
identified WF motif. By contrast, S. cerevisiae has
stable "capped" Atg13, which does not require
Atg101 for its stabilization (Suzuki et al. Nat.
Struct. Mol. Biol.).
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,

11and 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.
This year, we reports that Atg13-deficient
mice show defective heart development and die inutero. This phenotype is similar to FIP200knockout mice, but is distinct from most othertypes of Atg-deficient mice reported previously. In
cultured fibroblasts, Atg13 deficiency not only
causes impairment of autophagy but also enhances
caspase-8 activation and apoptosis upon TNF-αtreatment. This work suggests that the role ofAtg13 is beyond of those of conventional Atg
proteins (Kaizuka et al. Mol Cell Biol).
We also identified a human neurodegenerative disease termed SENDA/BPAN, in which oneof the core autophagy genes WIPI4/WDR45 ismutated (Saitsu et al. 2013). In collaboration with
Dr. Zhang in China, we generated WIPI4
knockout mice and revealed that they developed
motor dysfunction (Zhao et al. Autophagy). Thus,
autophagy plays important roles in various
physiological and pathological processes.

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. Kaizuka, T., Mizushima, N. Atg13 is essential for
autophagy and cardiac development in mice. Mol.
Cell. Biol. 36: 585-595 (2015).
2. Hieke, N., Löffler, A.S., Kaizuka, T., Berleth, N.,
Böhler, P., Drießen, S., Stuhldreier, F., Friesen, O.,
Assani, K., Schmitz, K., Peter, C., Diedrich, B.,
Dengjel, J., Holland, P., Simonsen, A., Wesselborg,S., Mizushima, N., *Stork, B. Expression of a
ULK1/2 binding-deficient ATG13 variant canpartially restore autophagic activity in ATG13-

deficient cells. Autophagy. 11: 1471-83 (2015).
3. Suzuki, H., Kaizuka, T., *Mizushima, N., *Noda,
N. N. Structure of the Atg101–Atg13 complex
reveals essential roles of Atg101 in autophagy
initiation. Nat. Struct. Mol. Biol. 22: 572–580(2015).
4. Zhao, Y.G., Sun, L., Miao, G., Ji, C., Zhao, H.,
Sun, H., Miao, L., Yoshii, S.R., Mizushima, N.,
Wang, X., Zhang, H. The autophagy gene
Wdr45/Wipi4 regulates learning and memory
function and axonal homeostasis. Autophagy.
11:881-90 (2015).
5. Schlie, K., Westerback, A., DeVorkin, L.,
Hughson, L.R., Brandon, J.M., MacPherson, S.,
Gadawski, I., Townsend, K.N., Poon, V.I., Elrick,
M.A., Côté, H.C., Abraham, N., Wherry, E.J.,
Mizushima, N., Lum, J.J. Survival of Effector
CD8+ T Cells during Influenza Infection Is
Dependent on Autophagy. J Immunol. 194:4277-4286 (2015).
6. Ishihara, T., Ban-Ishihara, R., Maeda, M.,
Matsunaga, Y., Ichimura, A., Kyogoku, S., Aoki,
H., Katada, S., Nakada, K., Nomura, M.,
Mizushima, N., Mihara, K., Ishihara, N.
Dynamics of mitochondrial DNA nucleoids
regulated by mitochondrial fission is essential for
maintenance of homogeneously Active Mitochondria during neonatal heart development. Mol Cell
Biol. 35:211-23 (2015).
7. Suzuki, H., Kaizuka, T., Mizushima, N., Noda,
N.N. Open and closed HORMAs regulate
autophagy initiation. Autophagy. 11:2123-2124(2015).
8. Mizushima, N. Nbr1, a Receptor for ESCRTDependent Endosomal Microautophagy in Fission
Yeast. Mol. Cell. 59: 887-889 (2015).
9. Morishita, H., Mizushima, N. Autophagy in thelens. Exp. Eye Res. 144: 22-8 (2015).
10. Jiang, P., Mizushima, N. LC3- and p62-based
biochemical methods for the analysis of autophagy progression in mammalian cells Methods
75: 13-18 (2015).
11. Yoshii, SR, Mizushima, N. Autophagy machineryin the context of mammalian mitophagy. Biochim
Biophys Acta. 1853: 2797-2801 (2015).

12Department 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
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.

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.

Research activities
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 theirsequences. However, since gene fusions usually takeplace at intronic regions, such sequencing approachwith captured exons fails to discover fusion genes.

13Thus, 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.
BIRC2 and BIRC3 are closely related membersof the inhibitor of apoptosis (IAP) family of proteinsand play pivotal roles in regulation of NF-κB
signaling and apoptosis. We have revealed that BIRC2
and BIRC3 mutations are also present in a wide rangeof epithelial tumors and that most such nonsense orframeshift mutations confer direct transforming
potential. This oncogenic function of BIRC2/3
mutants is largely independent of their ability toactivate NF-κB signaling. Rather, all of thetransforming mutants lack an intact RING finger
domain, with loss of ubiquitin ligase activity being
essential for transformation irrespective of NF-κB
regulation. Identification of BIRC2/3 effectors may
provide a basis for the development of targeted agentsfor the treatment of lymphoid malignancies and othercancers with BIRC2/3 alterations.
Mammalian target of rapamycin (mTOR) is aserine/threonine kinase that acts downstream tophosphatidylinositol 3-kinase pathway, which
regulates a wide array of cellular functions such as
gene transcription, translation, cell proliferation,
apoptosis and autophagy. We here revealed thatmTOR(L2209V) manifests a marked transforming
potential in a focus formation assay with mouse 3T3
fibroblasts, and induces the phosphorylation of p70 S6
kinase 1, S6 ribosomal protein and eukaryotic
translation initiation factor 4E binding protein 1.
Examination of public databases and our in-house
database for cancer genome mutations identified
another 28 independent nonsynonymous mutations in
mTOR among various cancer subtypes, twelve of
which exhibit similar transforming ability. Suchoncogenic mutations cluster at the interface between
the kinase domain and the FAT (FRAP, ATM and

TRRAP) domain in the mTOR three-dimensional
structure. Transforming mTOR proteins also provide
cell-survival function. Our data, thus, proved thatmTOR becomes a transforming protein by genetic
changes in cancer, and suggest that such tumors may
be candidates for molecularly targeted therapies with
mTOR inhibitors.

References
1. Yamato A, Soda M, Ueno T, Kojima S, Sonehara
K, Kawazu M, Sai E, Yamashita Y, Nagase T,
Mano H. “Oncogenic activity of BIRC2 andBIRC3 mutants independent of nuclear factorkappaB-activating potential” Cancer Sci 106:1137-1142, 2015.
2. Yamaguchi H, Kawazu M, Yasuda T, Soda M,
Ueno T, Kojima S, Yashiro M, Yoshino I,
Ishikawa Y, Sai E, Mano H. “Transforming
somatic mutations of mammalian target of
rapamycin kinase in human cancer” Cancer Sci
106:1687-1692, 2015.
3. Suzuki HI, Katsura A, Yasuda T, Ueno T, Mano
H, Sugimoto K, Miyazono K. “Small-RNA
asymmetry is directly driven by mammalian
Argonautes” Nat Struct Mol Biol 22:512-521,
2015.
4. Mano H. “Second-generation ALK inhibitors”
Clin Adv Hematol Oncol 13:416-417, 2015.
5. Mano H. “The EML4-ALK oncogene: targetingan essential growth driver in human cancer” Proc
Jpn Acad Ser B Phys Biol Sci 91:193-201, 2015.
6. Ikeda K, Horie-Inoue K, Ueno T, Suzuki T, Sato
W, Shigekawa T, Osaki A, Saeki T, Berezikov E,
Mano H, Inoue S. “miR-378a-3p modulates
tamoxifen sensitivity in breast cancer MCF-7 cells
through targeting GOLT1A” Sci Rep 5:13170,
2015.
7. Hashizume O, Ohnishi S, Mito T, Shimizu A,
Iashikawa K, Nakada K, Soda M, Mano H,
Togayachi S, Miyoshi H, Okita K, Hayashi J.
“Epigenetic regulation of the nuclear-coded
GCAT and SHMT2 genes confers human ageassociated mitochondrial respiration defects” Sci
Rep 5:10434, 2015.

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. Kitazawa T, Takechi M, Hirasawa T, Adachi N,
Narboux-Nême N, Kume H, Maeda K, Hirai T,
Miyagawa-Tomita S, Kurihara Y, Hitomi J, Levi G,
Kuratani S, Kurihara H. Developmental genetic
bases behind the independent origin of the
tympanic membrane in mammals and diapsids.
Nat. Commun. 6:6853, 2015.
2. Kitazawa T, Fujisawa K, Narboux-Nême N,
ArimA Y, Kawamura Y, Inoue T, Wada Y, Kohro T,
Aburatani H, Kodama T, Kim K-S, Sato T,
Uchijima Y, Maeda K, Miyagawa-Tomita S,
Minoux M, Rijli FM, Levi G, Kurihara Y,
Kurihara H. Distinct effects of Hoxa2 overexpression in cranial neural crest populations
reveal that the mammalian hyomandibularceratohyal boundary maps within the styloid
process. Dev. Biol. 402(2):162-174, 2015.
3. Sugihara K, Nishiyama K, Fukuhara S, Uemura A,
Arima S, Kobayashi R, Köhn-Luque A,

16

4.

5.

6.

7.

8.

9.

Mochizuki N, Suda T, Ogawa H, Kurihara H.
Autonomy and non-autonomy of angiogenic cell
movements revealed by experiment-driven
mathematical modeling. Cell Rep. 13(9):18141827, 2015.
Hidaka T, Shimada A, Nakata Y, Kodama H,
Kurihara H, Tokihiro T, Ihara S. Simple model ofpH-induced protein denaturation. Phys. Rev. E
Stat. Nonlin. Soft Matter Phys. 92(1):012709,
2015.
Gordon CT, Weaver KN, Zechi-Ceide RM,
Madsen EC, Tavares AL, Oufadem M, Kurihara Y,
Adameyko I, Picard A, Breton S, Pierrot S,
Biosse-Duplan M, Voisin N, Masson C,
Bole-Feysot C, Nitschké P, Delrue MA, Lacombe
D, Guion-Almeida ML, Moura PP, Garib DG,
Munnich A, Ernfors P, Hufnagel RB, Hopkin RJ,
Kurihara H, Saal HM, Weaver DD, Katsanis N,
Lyonnet S, Golzio C, Clouthier DE, Amiel J.
Mutations in the endothelin receptor type A cause
mandibulofacial dysostosis with alopecia. Am. J.
Hum. Genet. 96(4):519-531, 2015.
Hamamoto H, Urai M, Ishii K, Yasukawa J,
Paudel A, Murai M, Kaji T, Kuranaga T, Hamase
K, Katsu T, Su J, Adachi T, Uchida R, Tomoda H,
Yamada M, Souma M, Kurihara H, Inoue M,
Sekimizu K. Lysocin E is a novel antibiotic thattargets menaquinone in the bacterial membrane.
Nat. Chem. Biol. 11(2):127-133, 2015.
Laumonnerie C, Bechara A, Vilain N, Kurihara Y,
Kurihara H, Rijli FM. Facial whisker pattern is
not sufficient to instruct a whisker-related topographic map in the mouse somatosensory brainstem. Development 142(21):3704-3712, 2015.
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.
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
mediate hepatocarcinogenesis in Mob1a/1bdeficient mice. Proc. Natl. Acad. Sci. U. S. A.

113(1):E71-80, 2016.
10. Takechi M, Kitazawa T, Hirasawa T, Hirai T, Iseki
S, Kurihara H, Kuratani S. Developmental
mechanisms of the tympanic membrane in mammals and non-mammalian amniotes. Congenit.
Anom. (Kyoto). 56(1):12-17, 2016.

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 FreeQuarter decided to get into the Ph-D. course after thecompletion of the 2-year clinical training and started
to study neurophysiology in our laboratory. Furthermore, we accepted a Ph-D.-M.D course student who
enjoyed his Free-Quarter and decided to get into the
Ph-D.-M.D course. Thus the Free-Quarter system has
proved to provide an excellent basis for bringing up
M.D. researchers for future Japanese basic medicine.
To facilitate communication among research groups
in our laboratory, a weekly conference is held for
discussing current research activities. We also have amonthly joint seminar with Department of Pharmacology, 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, information from different orientations would be mixed,19

and orientation selectivity would be largely lost. Sharp
orientation tuning without functional clusteringsuggests the existence of specific connections among
similarly tuned excitatory neurons. Indeed, networksof specifically connected subpopulation of excitatoryneurons — subnetworks — have been found in rodent
visual cortex, and they are related to the orientation
selectivity of these neurons. In our lab, we examine
whether a developmental 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 oforientation selectivity, but that the initial formation of

20

orientation 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) Murakami T, Yoshida T, Matsui T, Ohki K.：
Wide-field Ca(2+) imaging reveals visually
evoked activity in the retrosplenial area. Front
Mol Neurosci., (2015), Jun 8;8:20.
(2) Hagihara KM, Murakami T, Yoshida T, Tagawa
Y, Ohki K.： Neuronal activity is not required forthe initial formation and maturation of visual
selectivity. Nat Neurosci., (2015),18: 1780-8.
(3) Kondo S, Ohki K.： Laminar differences in theorientation selectivity of geniculate afferents inmouse primary visual cortex. Nat Neurosci.,(2016),19: 316-9.

21

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), 4 postdoctoral fellows, 13
graduate students, 3 undergraduate students and 4
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. In this year, we also took charge of thepractical courses for students to learn basic conceptsof the electrocardiography and those of the resting
membrane potential and action potential.
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 andDivision of Animal 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,

22morphology, and genetic engineering of mouse. We
particularly focus on observing neuronal activities inreal time in intact neurons. We use whole-cell patch
clamp recording, calcium imaging, two-photon
imaging and their combinations in various preparations (cultured neurons, brain slices and intact
animals) and investigate molecular mechanisms ofsynaptic transmission and plasticity.
The main subjects of our research are as follows(1) Refinement of synaptic organization during
cerebellar development:
In early postnatal days, all Purkinje cells in the
cerebellum are innervated by multiple climbing fibers.
These surplus climbing fibers are eliminatedeventually with the progress of postnatal development,
and most Purkinje cells become innervated by single
climbing fibers by the end of the third postnatal weekin mice. We investigate the mechanisms how single
climbing fibers are selected and how the surplus
climbing fibers are eliminated.
(2) Retrograde synaptic modulation mediated byendogenous cannabinoids:
We reported in 2001 that endogenous cannabinoids
are released from postsynaptic neurons in an
activity-dependent manner, act retrogradely onto
presynaptic cannabinoid receptors and suppress
transmitter release. Since then, we have been
investigating the mechanisms of this retrograde
modulation. We are also interested in elucidating thephysiological significance of this phenomenon
including learning and memory, addiction, andanxiety.
(3) Synaptic integration in intact animals:
To understand the physiological function ofsynapses in vivo, we analyze synaptic transmission
and integration in single neurons in the intact brain byusing in vivo two-photon imaging and whole-cellrecording. We also develop new methods toimplement these experiments.

References(1) Soltesz I, Alger BE, Kano M, Lee S-H, Lovinger
DM, Ohno-Shosaku T, Watanabe M: Weeding out

(2)

(3)

(4)

(5)

(6)

(7)

bad waves: Towards selective cannabinoid circuit
control in epilepsy. Nat Rev Neurosci 16: 264277, 2014
Aida T, Yoshida J, Nomura M, Tanimura A, Iino Y,
Soma M, Bai N, Ito Y, Cui W, Aizawa H,
Yanagisawa M, Nagai T, Takata N, Tanaka K,
Takayanagi R, Kano M, Götz M, Hirase H,
Tanaka K: Astroglial glutamate transporter
deficiency increases synaptic excitability andleads to pathological repetitive behaviors in mice.
Neuropsychopharmacology 40: 1569-1579,
2015
Kishimoto Y, Cagniard B, Yamazaki M,
Nakayama J, Sakimura K, Kirino Y, Kano M:
Task-specific enhancement of hippocampusdependent learning in mice deficient inmonoacylglycerol lipase, the major hydrolyzing
enzyme of the endocannabinoid 2-arachidonoylglycerol. Front Behav Neurosci 9: Article 134,
2015
Kishimoto Y, Yamamoto S, Suzuki K, Toyoda H,
Kano M, Tsukada H, Kirino Y: Implicit memory
in monkeys: Development of a delay eyeblinkconditioning system with parallel electromyographic and high-speed video measurements.
PLoS ONE 10: e0129828, 2015
Kita Y, Yoshida K, Tokuoka SM, 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
Nakazawa T, Hashimoto R, Sakoori K, Sugaya Y,
Tanimura A, Hashimotodani Y, Ohi K, Yamamori
H, Yasuda Y, Umeda-Yano S, Kiyama Y, Konno
K, Inoue T, Yokoyama K, Inoue T, Numata S,
Ohnuma T, Iwata N, Ozaki N, Hashimoto H,
Watanabe W, Manabe T, Yamamoto T, Takeda M,
Kano M: Emerging roles of ARHGAP33 inintracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders. Nat
Commun 7:10594, 2016
Ly R, Bouvier G, Szapiro G, Prosser H, Randall
AD, Kano M, Sakimura K, Isope P, Barbour BJ,
Feltz A: Contribution of postsynaptic T-type
calcium channels to parallel fibre-Purkinje cell
synaptic responses. J Physiol (Lond) 594:
915-936, 2016

23(8) Ichikawa R, Hashimoto K, Miyazaki T,
Uchigashima M, Yamasaki M, Aiba A, Kano M,
Watanabe M: Territories of heterologous inputs
onto Purkinje cell dendrites are segregated by
mGluR1-dependent parallel fiber synapse
elimination. Proc Natl Acad Sci USA 113:2282-2287, 2016
(9) Leto K, Arancillo M, Becker EB, Buffo A,
Chiang C, Ding B, Dobyns WB, Dusart I,
Haldipur P, Hatten ME, Hoshino M, Joyner AL,
Kano M, Kilpatrick DL, Koibuchi N, Marino S,
Martinez S, Millen KJ, Millner TO, Miyata T,
Parmigiani E, Schilling K, Sekerková G, Sillitoe
RV, Sotelo C, Uesaka N, Wefers A, Wingate RJ,
Hawkes R: Consensus Paper: Cerebellar Development. Cerebellum, in press

Functional Biology
2. Pharmacology

25

Department of Cellular
and Molecular Pharmacology
Professor
Masamitsu Iino, 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

26

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27

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) 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. in press

28(2) Okubo, Y., Suzuki, J., Kanemaru, K., Nakamura,N., Shibata, T., Iino, M. Visualization of Ca2+
filling mechanisms upon synaptic inputs in theendoplasmic reticulum of cerebellar Purkinjecells. J. Neurosci. 35, 15837–15846, 2015.
(3) Murayama, T., Kurebayashi, N., Yamazawa, T.,
Oyamada, H., Suzuki, J., Kanemaru, K., Oguchi,
K., Iino, M., Sakurai, T. Divergent activity
profiles of type 1 ryanodine receptor channels
carrying malignant hyperthermia and central coredisease mutations in the amino-terminal region.
PLoS ONE 10(6): e0130606, 2015.
(4) Ino, D., Sagara, H., Suzuki, J., Kanemaru, K.,
Okubo, Y., Iino, M. Neuronal regulation of
Schwann cell mitochondrial Ca2+ Signaling
during myelination. Cell Rep. 12, 1951-1959,
2015.
(5) Kanemaru, K., Sekiya, H., Xu, M., Satoh, K.,
Kitajima, N., Yoshida, K., Okubo, Y., Sasaki, T.,
Moritoh, S., Hasuwa, H., Mimura, M., Horikawa,K., Matsui, K., Nagai, T., Iino, M., and Tanaka,
K.F. In vivo visualization of subtle, transient, andlocal activity of astrocytes using an ultrasensitive
Ca2+ indicator. Cell Rep. 10, 311-318, 2014.
(6) Suzuki, J., Kanemaru, K., Ishii, K., Ohkura, M.,
Okubo, Y., and Iino, M. Imaging intraorganellar
Ca2+ at subcellular resolution using CEPIA. Nat.
Commun. 5:4153, 2014.

29

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

Lecturer
Kazuki Tainaka, Ph.D.

Associate
Koji L. Ode, Ph.D., Etsuo A. Susaki, M.D., 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. Also we are planning 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 of genetargeted ES cells is injected into host embryos(typically blastocysts) to generate chimera micecomprising a mixture of ES- and host-derived cells. In
addition, multiple mating procedures are needed to30generate the desired genetically modified mouse strain,
which typically takes from 9 months to several years.
The efficient production of biallelic KO mice can befacilitated by recently developed genome editing
techniques, including ZFNs (zinc-finger nucleases),
TALENs(transcription-activator-like
effector
nucleases), and the CRISPR/Cas nuclease systems.
Unlike the protein-based ZFNs and TALENs, the
CRISPR/Cas system uses RNA-based DNA recognition derived from a bacterial adaptive immune system.
This method accelerates the generation of KO animals
via the co-injection of RNA encoding the Cas9 protein
and target-locus-specific guide RNAs (gRNAs) into
embryos. Several modifications of the CRISPR/Cas9
system have been also introduced to improve theefficiency and specificity of targeted mutations in agenome. However, two problems remain: (1)first-generation mice often contain a mosaic ofwild-type and KO cells, and (2) the rate of complete
biallelic mutant mice generated is relatively low(usually 60%–80% at best). Therefore, the highly
efficient (>90%) production of whole-body biallelic
KO in a single generation remains a fundamental
challenge for organism-level systems biology.
Recently, we developed a simple theory to predict theminimum efficacy of different CRISPR methods forthe highly efficient production of whole-body biallelic
KO mice (Sunagawa et al., Cell Reports, 2016). As we
predicted, triple-target CRISPR elicited almost perfect(96%–100%) whole-body KO of the Tyrosinase (Tyr)gene, which is functionally evaluated by animal coatcolor. Mammalian reverse genetics without crossing(called ‘‘next-generation’’ mammalian reverse
genetics) now allows us to test-in whole organismshypotheses that are derived from the past knowledge.
For example, a computational model of slow-wave
sleep that provides explanations for the observed
complex dynamics of sleep/wake states, along withpredictions for the important molecular pathways
regulating these states, could be extremely powerful.
Previously, it was difficult to test such predictions, atleast without years of labor. However, the present
study demonstrated that the importance of a predicted
molecular pathway can be efficiently tested using
next-generation reverse genetics.

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31

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). CUBIC
provides information on previously unattainable 3D
gene expression profiles and neural networks at thesystems 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 shorten 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 sleep/awake states,
which occurs in a time scale of minutes to hours.
Considering that numbers of researches encompass
model mice for sleep and sleep-related disorders, we
envisage that a series of knock out mice with altered
sleep phenotype will contribute the understanding ofsuch disorders including psychiatric disorders andneurodegenerative disorders.

References
1. Tainaka K, Kuno A, Kubota SI, Murakami T,
Ueda HR. Chemical Principles in Tissue Clearing
and Staining Protocols for Whole-Body Cell

32

2.

3.

4.

5.

6.

7.

Profiling. Annu Rev Cell Dev Biol 2016. [Epubahead of print]
Narumi R, Shimizu Y, Ukai-Tadenuma M, Ode
KL, Kanda GN, Shinohara Y, Sato A, Matsumoto
K, Ueda HR. Mass spectrometry-based absolute
quantification reveals rhythmic variation ofmouse circadian clock proteins. Proc Natl Acad
Sci U S A 2016:113(24):E3461-7.
Okamoto M, Miyata T, Konno D, Ueda HR,
Kasukawa T, Hashimoto M, Matsuzaki F,
Kawaguchi A. Cell-cycle-independent transitionsin temporal identity of mammalian neuralprogenitor cells. Nat Commun 2016:7:11349.
Tatsuki F, Sunagawa GA, Shi S, Susaki EA,
Yukinaga H, Perrin D, Sumiyama K,
Ukai-Tadenuma M, Fujishima H, Ohno R, Tone D,
Ode KL, Matsumoto K, Ueda HR. Involvement of
Ca2+-Dependent Hyperpolarization in Sleep
Duration in Mammals. Neuron 2016:90(1):70-85.
Susaki EA, Ueda HR. Whole-body andWhole-Organ Clearing and Imaging Techniqueswith Single-Cell Resolution: Toward OrganismLevel Systems Biology in Mammals. Cell Chem
Biol 2016:23(1):137-57.
Sunagawa GA, Sumiyama K, Ukai-Tadenuma M,
Perrin D, Fujishima H, Ukai H, Nishimura O, Shi
S, Ohno R, Narumi R, Shimizu Y, Tone D, Ode
KL, Kuraku S, Ueda HR. Mammalian Reverse
Genetics without Crossing Reveals Nr3a as a
Short-Sleeper Gene. Cell Rep 2016:14(3):662-77.
Susaki EA, Tainaka K, Perrin D, Yukinaga H,
Kuno A, Ueda HR. Advanced CUBIC protocols
for whole-brain and whole-body clearing andimaging. Nat Protoc 2015:10(11):1709-27.

Pathology, Immunology andMicrobiology
1. Pathology

34

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

Associate Professor
Junji Shibahara, M.D., Ph.D.,

Tetsuo Ushiku, M.D., Ph.D.

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

Lecturer
Teppei Morikawa, M.D., Ph.D.*
Masako Ikemura, M.D., Ph.D. (Office for “Promotion of CPC Education and General
Integrative Medicine”)

Lecturer (Hospital)
Aya Shinozaki-Ushiku, M.D., Ph.D.

Associates
Akiko Kunita, Ph.D.,

Shogo Tajima, M.D.

Mariko Tanaka, 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.*,

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”.
The University of Tokyo headquarters has
redistributed one position of associate professor for“Promotion Center of CPC Education and General
Integrative Medicine”. Dr. Masako Ikemura waspromoted as Lecturer for the Office of Promotion
Center. Dr. Shigeki Morita moved from Tekikyo
University.
Three postgraduate students (Ichimura, Rokutan,
Tanaka, Numakura) finished the course and received
Ph.D. In the new fiscal year, 2016, three new students
will enter the postgraduate course, and there will be
18 postgraduates.
We are responsible for the pathology practice of

35

the University Hospital, and are carrying forward themorphology-based research targeting human diseases.
As for the education for 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 the application of development ofgenomic medicine to clinical practice, we set up
Center for Genome Pathology Standardization (Japan
Agency for Medical Research and Development). The
mission of the Center is to investigate basic
technologies for tissue banking, and to hold seminars
for doctors and technicians (see the section of
Diagnostic Pathology Division).

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.
Six students chose the clinical clerkship courserdfor 3 grade medical students. As for the free quarter
program, we received two and three 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 are focusing on
abnormalities of microRNA molecules and stem cellbiology in the development and progression of EBVassociated GC in addition to its DNA methylation
abnormality. Dr. Shinozaki-Ushiku (ref.26) identified
the profile of EBV-derived microRNAs in EBVassociated gastric cancer, and found that miRBART4-5p represses the apoptosis-promoting
molecule Bid, contributing to development of this

36

type of gastric cancer.
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).
The third theme is to re-evaluate the disease
entities and tumor entities from the standpoint ofclassical histopathology. Dr. Sibahara proposed a
subgroup of HCC, steatohepatitic HCC, which showedhistological features of steatohepatitis and investigated its molecular abnormalities (ref.4).
Dr. Miyagawa was a Research Associate ofDivision of Diagnostic Pathology, primarily engaged
in Investigation of Health Hazard by Radiation (ref.
21).
The research works closely related withpathology practice are described in Diagnostic
Pathology Division.

References(including those of Diagnostic Pathology Division)
Case reports are listed in the section of Diagnostic
Pathology Division.
(1) Abe H, Kaneda A, Fukayama M. Epstein-Barrvirus-associated gastric carcinoma: use of hostcell machineries and somatic gene mutations.
Pathobiology. 2015, 82(5): 212-23(2) Abe Y, Kawakami H, Oba K, Hayashi T, Yasuda I,
Mukai T, Isayama H, Ishiwatari H, Doi S,
Nakashima M, Yamamoto N, Kuwatani M,
Mitsuhashi T, Hasegawa T, Hirose Y, Yamada T,
Tanaka M, Sakamoto N. Effect of a stylet on ahistological specimen in EUS-guided fine-needle
tissue acquisition by using 22-gauge needles: amulticenter, prospective, randomized, controlled
trial. Gastrointest Endosc. 2015 Nov, 82(5),:837-84.
(3) Ando M, Saito Y, Morikawa T, Omura G,
Kobayashi K, Akashi K, Yoshida M, Ebihara Y,
Fujimoto C, Fukayama M, Yamasoba T, Asakage
T. Maxillary carcinosarcoma: Identification of anovel MET mutation in both carcinomatous andsarcomatous components through next generation
sequencing. Head Neck. 2015 Feb 37(12):E179-85.
(4) Ando S, Shibahara J, Hayashi A, Fukayama M.
β-catenin alteration is rare in hepatocellular
carcinomawithsteatohepatitic
features:immunohistochemical and mutational study.
Virchows Arch. 2015 Nov, 467(5): 535-42.
(5) Fujiwara K, Koyama K, Suga K, Ikemura M,
Saito Y, Hino A, Iwanari H, Kusano-Arai O,
Mitsui K, Kasahara H, Fukayama M, Kodama T,
Hamakubo T, Momose T. 90Y-Labeled antiROBO1 monoclonal antibody exhibits antitumor
activity against small cell lung cancer xenografts.
PLoS One. 2015 May, 10(5): e0125468(6) Fukuda T, Wada-Hiraike O, Oda K, Tanikawa M,
Makii C, Inaba K, Miyasaka A, Miyamoto Y,
Yano T, Maeda D, Sasaki T, Kawana K,
Fukayama M, Osuga Y, Fujii T. Putative tumor
suppression function of SIRT6 in endometrial
cancer. FEBS Lett. 2015 Aug, 589(17): 2274-81.
(7) Hakimi AA, Tickoo SK, Jacobsen A, Sarungbam
J, Sfakianos JP, Sato Y, Morikawa T, Kume H,
Fukayama M, Homma Y, Chen YB, Sankin AI,
Mano R, Coleman JA, Russo P, Ogawa S, SanderC, Hsieh JJ, Reuter VE. TCEB1-mutated renal
cell carcinoma: a distinct genomic and morphological subtype. Mod Pathol. 2015 Jun, 28(6):845-53.
(8) Ikeda Y, Oda K, Ishihara H, Wada-Hiraike O,
Miyasaka A, Kashiyama T, Inaba K, Fukuda T,
Sone K, Matsumoto Y, Arimoto T, Maeda D,
Ikemura M, Fukayama M, Kawana K, Yano T,
Aoki D, Osuga Y, Fujii T. Prognostic importanceof CDK4/6-specific activity as a predictive
marker for recurrence in patients with endometrial cancer, with or without adjuvant chemotherapy.
Br J Cancer. 2015 Nov, 113(10): 1477-83.
(9) Ishida M, Gonoi W, Hagiwara K, Okuma H,
Shirota G, Shintani Y, Abe H, Takazawa Y,
Fukayama M, Ohtomo K. Early postmortem
volume reduction of adrenal gland: initial
longitudinal computed tomographic study. Radiol
Med. 2015 Jul, 120(7): 662-9.
(10) Ishida M, Gonoi W, Okuma H, Shirota G,
Shintani Y, Abe H, Takazawa Y, Fukayama M,
Ohtomo K. Common postmortem computed
tomography findings following atraumatic death:
Differentiation between normal postmortem

37changes and pathologic lesions. Korean J Radiol,2015 Jul-Aug, 16(4), 798-809(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 Feb, 46(2): 185-9.
(12) Kato Y, Kunita A, Abe S, Ogasawara S, Fujii Y,
Oki H, Fukayama M, Nishioka Y, Kaneko MK.
The chimeric antibody chLpMab-7 targeting
human podoplanin suppresses pulmonary metastasis via ADCC and CDC rather than via its
neutralizing activity. Oncotarget. 2015 Nov,
6(34): 36003-18.
(13) Khalili H, Morikawa T (39th/60), et al; GECCO
and CCFR. Identification of a common variant
with potential pleiotropic effect on risk of
inflammatory bowel disease and colorectal cancer.
Carcinogenesis. 2015 Sep, 36(9): 999-1007.
(14) Kobayashi K, Ando M, Saito Y, Kondo K, Omura
G, Shinozaki-Ushiku A, Fukayama M, Asakage T,
Yamasoba T. Nerve growth factor signals as
possible pathogenic biomarkers for perineural invasion in adenoid cystic carcinoma. Otolaryngol
Head Neck Surg. 2015 Aug, 153(2): 218-24.
(15) Maeda D, Akiyama Y, Morikawa T, Kunita A,
Ota Y, Katoh H, Niimi A, Nomiya A, Ishikawa S,
Goto A, Igawa Y, Fukayama M, Homma Y.
Hunner-type (classic) interstitial cystitis: A
distinct inflammatory disorder characterized bypancystitis, with frequent expansion of clonal
B-cells and epithelial denudation. PLoS One.
2015 Nov, 10(11): e0143316(16) Mehta RS, Chong DQ, Song M, Meyerhardt JA,
Ng K, Nishihara R, Qian Z, Morikawa T, Wu K,
Giovannucci EL, Fuchs CS, Ogino S, Chan AT.
Association between plasma levels of macrophage inhibitory cytokine-1 before diagnosis ofcolorectal cancer and mortality. Gastroenterology.
2015 Sep, 149(3): 614-22.
(17) Miyagawa R, Mizuno R, Ijiri K. Formation ofKlotho Granules in Oxidative Stress-induced
Human Cancer Cells. Bioimages. 2015, 22:17-21(18) Nishioka Y, Shindoh J, Yoshioka R, Gonoi W,
Abe H, Okura N, Yoshida S, Oba M, Hashimoto

M, Watanabe G, Hasegawa K, Kokudo N.
Radiological morphology of colorectal liver
metastases after preoperative chemotherapy predicts tumor viability and postoperative outcomes.
J Gastrointest Surg. 2015 Sep, 19(9): 1653-61.
(19) Okumura Y, Aikou S, Onoyama H, Jinbo K,
Yamagata Y, Mori K, Yamashita H, Nomura S,
Takahashi M, Koyama K, Momose T, Abe H,
Matsusaka K, Ushiku T, Fukayama M, Seto Y.
Evaluation of 18F-FDG uptake for detecting
lymph node metastasis of gastric cancer: aprospective pilot study for one-to-one comparisonof radiation dose and pathological findings.
World J Surg Oncol. 2015 Dec, 13: 327.
(20) Saito S, Morishima K, Ui T, Hoshino H,
Matsubara D, Ishikawa S, Aburatani H,
Fukayama M, Hosoya Y, Sata N, Lefor AK,
Yasuda Y, Niki T. The role of HGF/MET and
FGF/FGFR in fibroblast-derived growth stimulation and lapatinib- resistance of esophageal
squamous cell carcinoma. BMC Cancer. 2015
Feb, 25:15:82.
(21) Sakumi A, Miyagawa R, Tamari Y, Nawa K,
Sakura O, Nakagawa K. External effective doseof workers in restricted area of Fukushima
Daiichi Nuclear Power Plant during the third year
after the Great East Japan Earthquake. J Radiat
Res. 2015, 57: 178-181(22) Seiki T, Nagasaka K, Kranjec C, Kawana K,
Maeda D, Nakamura H, Taguchi A, Matsumoto Y,
Arimoto T, Wada-Hiraike O, Oda K, Nakagawa S,
Yano T, Fukayama M, Banks L, Osuga Y, Fujii T.
HPV-16 impairs the subcellular distribution andlevels of expression of protein phosphatase 1γ in
cervical malignancy. BMC Cancer. 2015 Apr, 15:230(23) Shichijo S, Hirata Y, Sakitani K, Yamamoto S,
Serizawa T, Niikura R, WatAbe H, Yoshida S,
Yamada A, Yamaji Y, Ushiku T, Fukayama M,
Koike K. Distribution of intestinal metaplasia as apredictor of gastric cancer development. J
Gastroenterol Hepatol. 2015 Aug, 30(8): 1260-4.
(24) 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 to38

diffuse lesions and tissue cell activation insilica-induced pulmonary fibrosis in mice. Am J
Pathol. 2015 Nov, 185(11): 2923-38.
(25) Shinozaki-Ushiku A, Kunita A, Fukayama M.
Update on Epstein-Barr virus and gastric cancer(review). Int J Oncol. 2015 Apr, 46(4): 1421-34(26) Shinozaki-Ushiku A, Kunita A, Isogai M, Hibiya
T, Ushiku T, Takada K, Fukayama M. Profilingof virus-encoded microRNAs in Epstein-Barrvirus-associated gastric carcinoma and their roles
in gastric carcinogenesis. J Virol. 2015 May,
89(10): 5581-91.
(27) Shirota G, Gonoi W, Ishida M, Okuma H,
Shintani Y, Abe H, Takazawa Y, Ikemura M,
Fukayama M, Ohtomo K. Brain swelling and lossof gray and white matter differentiation in humanpostmortem cases by computed tomography.
PLoS One. 2015 Nov, 10(11): e0143848(28) Taguchi S, Fukuhara H, Shiraishi K, Nakagawa K,
Morikawa T, Kakutani S, Takeshima Y, Miyazaki
H, Fujimura T, Nakagawa T, Kume H, Homma Y.
Radical prostatectomy versus external beam
radiotherapy for cT1-4N0M0 prostate cancer:
Comparison of patient outcomes including
mortality. PLoS One. 2015 Oct, 10(10):e0141123.
(29) Takahashi M, Ikemura M, Oka T, Uchihara T,
Wakabayashi K, Kakita A, Takahashi H, Yoshida
M, Toru S, Kobayashi T, Orimo S. Quantitative
correlation between cardiac MIBG uptake andremaining axons in the cardiac sympathetic nerve
in Lewy body disease. J Neurol Neurosurg
Psychiatry. 2015 Sep, 86(9): 939-44.
(30) Takahashi M, Kume H, Koyama K, Nakagawa T,
Fujimura T, Morikawa T, Fukayama M, Homma
Y, Ohtomo K, Momose T. Preoperative Evaluation of Renal Cell Carcinomaby Using 18F-FDG
PET/CT. Clin Nucl Med. 2015 Dec, 40(12):936-40.
(31) Tu HC, Schwitalla S, Qian Z, LaPier GS,
Yermalovich A, Ku YC, Chen SC, Viswanathan
SR, Zhu H, Nishihara R, Inamura K, Kim SA,
Morikawa T, Mima K, Sukawa Y, Yang J,
Meredith G, Fuchs CS, Ogino S, Daley GQ.
LIN28 cooperates with WNT signaling to drive
invasive intestinal and colorectal adenocarcinoma
in mice and humans. Genes Dev. 2015 May,29(10): 1074-86(32) Uehara Y, Oda K, Ikeda Y, Koso T, Tsuji S,
Yamamoto S, Asada K, Sone K, Kurikawa R,
Makii C, Hagiwara O, Tanikawa M, Maeda D,
Hasegawa K, Nakagawa S, Wada-Hiraike O,
Kawana K, Fukayama M, Fujiwara K, Yano T,
Osuga Y, Fujii T, Aburatani H. Integrated copy
number and expression analysis identifies
profilesof whole-arm chromosomal alterations
and subgroups with favorable outcome in ovarian
clear cell carcinomas. PLoS One. 2015 June,
10(6): e0128066 (Correction: PLoS One. 2015 Jul,
10(7): e0132751).
(33) Watanabe K, Amano Y, Ishikawa R, Sunohara M,
Kage H, Ichinose J, Sano A, Nakajima J,
Fukayama M, Yatomi Y, Nagase T, Ohishi N,
Takai D. Histone methylation-mediated silencingof miR-139 enhances invasion of non-small-celllung cancer. Cancer Med. 2015 Oct, 4(10):1573-82.
(34) Yamamoto K, Tanei Z, Hashimoto T,
Wakabayashi T, Okuno H, Naka Y, Yizhar O,
Fenno LE, Fukayama M, Bito H, Cirrito JR,
Holtzman DM, Deisseroth K, Iwatsubo T.
Chronic optogenetic activation augments aβpathology in a mouse model of Alzheimer disease.
Cell Rep. 2015 May, 11(6): 859-65(35) Yoshida A, Yoshida H, Yoshida M, Mori T,
Kobayashi E, Tanzawa Y, Yasugi T, Kawana K,
Ishikawa M, Sugiura H, Maeda D, Fukayama M,
Kawai A, Hiraoka N, Motoi T. Myoepitheliomalike tumors of the vulvar region: A distinctive
group of SMARCB1-deficient neoplasms. Am J
Surg Pathol. 2015 Aug, 39(8): 102-13

39

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

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

Project Lecturer
Shogo Ehata, M.D., Ph.D.

Assistant Professors
Caname Iwata, M.D., Ph.D., Masato Morikawa, M.D., Ph.D. (from January 2016)

Project Assistant Professor
Yoko Katsuno, Ph.D. (from June 2015)

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 January
2016, Dr. Masato Morikawa joined the Department as
an assistant professor. In March 2016, the Department
consists of a professor, an associate professor, aproject lecturer, two assistant professors, a project
assistant professor, technical assistants, and someresearch fellows, including 8 graduate students, amaster course student, and a post-doctoral fellow.

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 61st Annual
Autumn Congress of the Japanese Society of
Pathology as the co-chairman, together with Dr.
Yuichi Ishikawa (Japanese Foundation for Cancer
Research) on November 5 and 6 at the Yasuda
Auditorium (The University of Tokyo). Because 2015is the 100-year memorial year of the successful
induction of cancer by treatment with coal tars in
rabbit years by Prof. Katsusaburo Yamagiwa, a special
lecture on “The achievement of Katsusaburo
Yamagiwa (by Dr. Tomoyuki Kitagawa, JapaneseFoundation for Cancer Research)” and a symposium
on “Making the move from carcinogenic pathology to40

genomic pathology - Lessons from Katsusaburo
Yamagiwa’s achievements” were organized. In
addition, Dr. Carl-Henrik Heldin (Chairman of theNobel Foundation, and Director, Ludwig Institute forCancer Research, Uppsala University, Sweden) was
invited to the congress, and gave a special lecture on“Mission and vision of the Nobel Prize”.
Our research projects has been supported by
KAKENHI (Innovative Area on “Integrative researchon cancer microenvironment network”) from the
Ministry of Education, Culture, Science, Sports andTechnology (MEXT) (http://cancer-microenvironment.jp) until 2014, and we have extended our
projects on the effects of TGF-β family proteins on
cancer microenvironment until 2015. From 2015, ourresearch projects are mainly supported by aGrant-in-Aid for Scientific Research (S) on“Transcriptional regulation by TGF-β signaling and its
relation to progression of cancer” from the JapaneseSociety for the Promotion of Science (JSPS).
We have been doing collaboration with the Ludwig
Institute for Cancer Research, Uppsala, Sweden for
more than 15 years (http://c2ctgfb.umin.jp/). We haveannual TGF-β meeting in Sweden or in the
Netherlands every year, and three graduate students
participated in the TGF-β meeting in Uppsala in 2015.
Four of our graduate students are supported by the
GPLLI Graduate Program for Leaders in Life
Innovation at the University of Tokyo from the MEXT.
GPLLI was designed for the purpose of guiding
outstanding students to be globally active leaders inindustry, academia and government. This program
also stimulates interaction between students andscientists in the program as well as those from otherlaboratories (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.
We are also interested in the regulation of biosynthesis
and function of microRNAs.
EZH2 promotes progression of small cell lungcancer by suppressing the TGF-β-Smad-ASCL1
pathway: TGF-β induces apoptosis in many types ofcancer cells and acts as a tumor suppressor in thesecells. We performed a functional analysis of TGF-βsignaling to identify molecular mechanism(s) that
regulate cell survival and apoptosis in small cell lungcancer cells. Among various TGF-β signaling
components, we found low expression of TGF-β typeII receptor (TβRII) in most small cell lung cancer cells
and tissues compared to normal lung epithelial cells
and normal lung tissues, respectively. When wild-type
TβRII was exogenously expressed in small cell lungcancer cells, TGF-β inhibited cell proliferation in vitro
and tumor formation in vivo through induction of
apoptosis. Components of polycomb repressive
complex 2, including enhancer of zeste 2 (EZH2),
were highly expressed in small cell lung cancer cells.
This led to epigenetic silencing of TβRII expression
and suppression of TGF-β-mediated apoptosis in small
cell lung cancer cells. Achaete-scute family bHLH
transcription factor 1 (ASCL1; also known as ASH1),
was identified as a Smad-dependent target of TGF-β,
and was found to induce cell survival in small celllung cancer cells. Thus, EZH2 promoted small celllung cancer progression by suppressing the TGF-βSmad-ASCL1 pathway (Murai et al. Cell Discovery
2015)
The Arkadia-ESRP2 axis suppresses tumor
progression: Analyses in clear-cell renal cell
carcinoma: Tumor-specific alternative splicing is
implicated in the progression of cancer, including
clear-cell renal cell carcinoma (ccRCC). Using ccRCC
RNA sequencing data from The Cancer Genome Atlas,
we found that epithelial splicing regulatory protein 2(ESRP2), one of the key regulators of alternative
splicing in epithelial cells, is expressed in ccRCC.
Levels of mRNA expression of ESRP2 did notcorrelate with the overall survival rate of ccRCC
patients, while the expression of some ESRP-target
exons correlated with the good prognosis and with theexpression of Arkadia (also known as RNF111) in
ccRCC. Arkadia protein physically interacted with
ESRP2, induced polyubiquitination and modulated its
splicing function. Arkadia and ESRP2 suppressed
ccRCC tumor growth in a coordinated manner.
Moreover, lower expression of Arkadia correlatedwith advanced tumor stages and poor prognosis in
ccRCC patients. These findings revealed a novel
tumor-suppressive role of the Arkadia-ESRP2 axis in

41

ccRCC (Mizutani et al. Oncogene in press [Epubahead of print]).
RBM47 inhibits Nrf2 activity to suppress tumor
growth in lung adenocarcinoma: RNA-binding
proteins function as a posttranscriptional regulator of
RNA during cancer progression. We identified
RNA-binding motif protein 47 (RBM47) as a target of
TGF-β signaling in mouse mammary gland epithelial
cells (NMuMG cells) that have undergone anepithelial-to-mesenchymal transition (EMT). TGF-β
repressed RBM47 expression in NMuMG cells andsome lung cancer cell lines. Expression of RBM47
correlated with good prognosis in patients withvarious cancers, including lung, breast and gastriccancer. RBM47 suppressed the expression of cell
metabolism-related genes, which were the directtargets of Nrf2 (also known as NFE2L2). RBM47
interacted with KEAP1 and Cullin 3 mRNAs, andsilencing of RBM47 expression inhibited the KEAP1
and Cullin 3 protein expression, resulted in increased
binding of Nrf2 to target genomic regions. Silencing
of RBM47 expression also induced the expression ofsome Nrf2 activators, i.e. p21/CDKN1A and MafK
induced by TGF-β. Both mitochondrial respiration
rates and the side population cells analyzed by FACS
in lung cancer cells were increased in the absence ofRBM47. Tumor formation and metastasis of
xenografted mice were enhanced by knockdown of theRBM47 expression. These findings suggested
tumor-suppressive roles of RBM47 by inhibition of
Nrf2 activity (Sakurai et al. Oncogene in press).

References
1. Hoshino, Y., Nishida, J., Katsuno, Y., Koinuma,
D., Aoki, T., Kokudo, N., Miyazono, K., andEhata, S. (2015) Smad4 decreases the populationof pancreatic cancer-initiating cells through transcriptional repression of ALDH1A1. The American
Journal of Pathology 185 (5), 1457-1470.
2. Suzuki, H. I., Katsura, A., Yasuda, T., Ueno, T.,
Mano, H., Sugimoto, K., and Miyazono, K.
(2015) Small-RNA asymmetry is directly driven
by mammalian Argonautes. Nature Structural andMolecular Biology 22 (7), 512-521.

3. Ihida-Stansbury, K., Ames, J., Chokshi, M., Aiad,
N., Sanyal, S., Kawabata, K. C., Levental, I.,
Sundararaghavan, H. G., Burdick, J. A., Janmey, P.,
Miyazono, K., Wells, R. G., and Jones, P. L.
(2015) Role played by Prx1-dependent extracellular matrix properties in vascular smoothmuscle development in embryonic lungs.
Pulmonary Circulation 5 (2), 382-397.
4. Takahashi, K., Nagai, N., Ogura, K., Tsuneyama,
K., Saiki, I., Irimura, T., and Hayakawa, Y. (2015)
Mammary tissue microenvironment determines T
cell-dependent breast cancer-associated inflammation. Cancer Science 106 (7), 867-874.
5. Suzuki, H. I., Katsura, A., and Miyazono, K.
(2015) A role of uridylation pathway for blockadeof let-7 microRNA biogenesis by Lin28B. Cancer
Science 106 (9), 1174-1181.
6. Murai, F., Koinuma, D., Shinozaki-Ushiku, A.,
Fukayama, M., Miyazono, K., and Ehata, S.
(2015) EZH2 promotes progression of small celllung cancer by suppressing the TGF-β-SmadASCL1 pathway. Cell Discovery 15026.
7. Sugimoto, K., Suzuki, H. I., Fujimura, T., Ono, A.,
Kaga, N., Isobe, Y., Sasaki, M., Taka, H.,
Miyazono, K., and Komatsu, N. (2015) A
clinically attainable dose of L-asparaginasetargets glutamine addiction in lymphoid cell lines.
Cancer Science 106 (11), 1534-1543.
8. Muthusamy, B. P., Budi, E. H., Katsuno, Y., Lee,
M. K., Smith, S. M., Mirza, A. M., Akhurst, R. J.,
and Derynck, R. (2015) ShcA protects against
epithelial-mesenchymaltransition
throughcompartmentalized inhibition of TGF-β-induced
Smad activation. PLoS Biology 13 (12),e1002325.
9. Saito, T., Kurashige, J., Nambara, S., Komatsu, H.,
Hirata, H., Ueda, M., Sakimura, S., Uchi, R.,
Takano, Y., Shinden, Y., Iguchi, T., Eguchi, H.,
Ehata, S., Murakami, K., Sugimachi, K., andMimori, K. (2015) A long non-coding RNA
activated by transforming growth factor-β is anindependent prognostic marker of gastric cancer.
Annals of Surgical Oncology 22 (Suppl. 3),
S915-922.

42

10. Suzuki, H. I., Katsura, A., Matsuyama, H., andMiyazono, K. (2015) MicroRNA regulons intumor microenvironment. Oncogene 34 (24),3085-3094.
11. Mizutani, A., Koinuma, D., Seimiya, H., andMiyazono, K. The Arkadia-ESRP2 axis
suppresses tumor progression: Analyses in clearcell renal cell carcinoma. Oncogene [Epub 2015
Nov 2].
12. Katsura, A., Suzuki, H. I., 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-β. Genes to Cells 21 (1), 99-116.
[Epub 2015 Dec 10].

Pathology, Immunology andMicrobiology
2. Microbiology

44

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 22 members; 1 professor (Dr. Hatakeyama),
1 senior lecturer (Dr. Kamiya), 2 research associates(Drs. Takahashi and Hayashi), 2 project research
associates (Drs. Fujii and Nishikawa), 1 post-doctoral
fellow (Dr. Kikuchi), 3 academic assistants (Ms.
Kanemitsu, Shimada, Komatsu), 11 graduate school
students (Ms. and Mrs. Senda, Noda, Hashi, Bingo,
Ooki, Nojima, Ben, Lu, Tang, Knight, Inoue), and 1
research student (Mr. Tang).

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

45

1. Relationship between the Helicobacter pylori
oncoprotein CagA and inflammation inpathogenesis
Upon delivery into gastric epithelial cells via type IV
secretion, CagA undergoes tyrosine phosphorylation
by Src family kinases (SFKs) or c-Abl kinase at the
Glu-Pro-Ile-Tyr-Ala (EPIYA) motif. Tyrosinephosphorylated CagA acquires the ability to
specifically bind to and aberrantly activate SHP2
tyrosine phosphatase, causing aberrant activation of
the Ras-Erk MAP kinase signaling pathway. CagA
also binds to partitioning-defective 1 (PAR1)/
microtubule affinity-regulating kinase (MARK) andinhibits the kinase activity to cause junctional andpolarity defects independently of tyrosine phosphorylation.
Chronic inflammation provides a microenvironmental milieu that fosters cancer-predisposed cells.
Given that cagA-positive H. pylori not only delivers
CagA but also induces chronic inflammation in thestomach mucosa, it is tempting to speculate that
inflammation synergizes with the bacterial oncoprotein in the development of neoplasias.
To experimentally investigate the pathophysiological interplay between CagA and inflammation, transgenic mice systemically expressing thebacterial cagA gene were treated with a colitis inducer,
dextran sulfate sodium (DSS). Compared with control
mice, DSS-induced colitis was markedly deteriorated
in cagA-transgenic mice. In the colonic epithelia of
cagA-transgenic mice, there was a substantial decreasein the level of IκB, which binds and sequesters NF-κB
in the cytoplasm. This IκB reduction was due to
CagA-mediated inhibition of PAR1, which may
stimulate IκB degradation by perturbing microtubule
stability. Whereas the CagA-mediated IκB reduction
did not automatically activate NF-κB, it lowered thethreshold of NF-κB activation by inflammogenic
insults, thereby contributing to colitis exacerbation incagA-transgenic
mice.
CagA also
activates
inflammasomes independently of NF-κB signaling,which further potentiates inflammation. The incidenceof colonic dysplasia was elevated in DSS-treatedcagA-transgenic mice due to a robust increase in thenumber of pre-cancerous flat-type dysplasias. Thus,
CagA deteriorated inflammation, whereas inflammation strengthened the oncogenic potential of CagA.

This work revealed that H. pylori CagA and inflammation reinforce each other in creating a downward
spiral that instigates neoplastic transformation.
2. Relationship between SHP2 binding activity of
CagA and gastric cancer risk
Once inside the host cells, CagA is tethered to theinner plasma membrane, where it interacts with thecancer-causing protein tyrosine phosphatase SHP2 andthereby aberrantly activates the phosphatase activity.
East Asian CagA and Western CagA are two major
CagA species produced by H. pylori circulating in
East Asian countries and in the rest of the world,
respectively. The SHP2 binding site of Western CagA,
termed the EPIYA-C segment, variably duplicates(mostly one to three times) and infection with H.
pylori carring Western CagA with multiple EPIYA-C
segments is a distinct risk factor of gastric cancer.
However, the molecular mechanism of this action
remained unknown.
We showed that duplication of EPIYA-C from one
to two or more increases SHP2 binding of Western
CagA by more than one hundred of times. Based on
the decisive difference in SHP2 binding, Western
CagA can be divided into two types: type I CagA
carrying a single EPIYA-C segment and type II CagA
carring multiple EPIYA-C segments. Gastricepithelial cells expressing type II CagA acquire theability to invade extracellular matrices, a malignant
cellular trait associated with deregulated SHP2. A big
leap in SHP2 binding activity may therefore provide
molecular basis that makes type II Western CagA adistinct gastric cancer risk.
3. Catalytic activity of LEOPARD syndromeassociated SHP2 mutants
SHP2, encoded by the PTPN11 gene, is a protein
tyrosine phosphatase that plays a key role in the
proliferation of cells via Ras-Erk activation. SHP2
also promotes Wnt signaling by dephosphorylating
parafibromin. Germline missense mutations of
PTPN11 are found in more than half of patients with
Noonan syndrome (NS) and LEOPARD syndrome(LS), both of which are congenital developmental
disorders with multiple common symptoms. However,previous biochemical studies using a standard in vitro
phosphatasesubstrate,
p-nitrophenylphosphate

46(pNPP), showed that NS-associated PTPN11
mutations give rise to gain-of-function SHP2 mutants,
but that LS-associated PTPN11 mutations generate
loss-of-function mutants.
To determine the phosphatase activity ofLS-associated SHP2 mutants more appropriately, we
performed an in vitro phosphatase assay using
tyrosine-phosphorylated parafibromin, a biologically
relevant substrate of SHP2 and the positive regulatorof Wnt signaling that is activated throughSHP2-mediated dephosphorylation. We found that
LS-associated SHP2 mutants (Y279C, T468M, Q506P,
and Q510E) exhibited a substantially reduced
phosphatase activity toward parafibromin whencompared with wild-type SHP2. Furthermore, each of
the LS-associated mutants displayed a differential
degree of decrease in phosphatase activity. Deviationof the SHP2 catalytic activity from a certain range,
either too strong or too weak, may therefore lead tosimilar clinical outcomes in NS and LS, possibly
through an imbalanced Wnt signal caused byinadequate dephosphorylation of parafibromin.

Publications
1. Suzuki, N., Murata-Kamiya, N., Yanagiya, K.,
Suda, W., Hattori, M., Kaneda, H., Bingo, A.,
Fujii, Y., Maeda, S., Koike, K. and Hatakeyama,
M. Mutual reinforcement of inflammation andcarcinogenesis by the Helicobacter pylori CagA
oncoprotein. Sci. Rep. 5: 10024 (2015)
2. Nagase, L., Hayashi, T., Senda, T. andHatakeyama, M. Dramatic increase in SHP2binding activity of Helicobacter pylori Western
CagA by EPIYA-C duplication: its implications ingastric carcinogenesis. Sci. Rep. 5: 15749 (2015)
3. Noda, S., Takahashi, A., Hayashi, T., Tanuma, S.
and Hatakeyama, M. Determination of thecatalytic activity of LEOPARD syndromeassociated SHP2 mutants toward parafibromin, abona fide SHP2 substrate involved in Wnt
signaling. Biochem. Biophys. Res. Commun. 469(4): 1133-1139 (2016)

47

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

Lecturer
Shu Okugawa, M.D., Ph.D.

Hospital Lecturer
Masashi Suzuki, M.D., Ph.D.

Research Associate
Keita Tatsuno, M.D., Ph.D.
Kazuhito Yuhashi, MD., Ph.D.
Mahoko Ikeda, MD., Ph.D.
Nobuhiko Satoh, MD., Ph.D.

Homepage

http://www.cc.h.u-tokyo.ac.jp/mulins/kansen/index.html(inside the hospital only)

Introduction and Organization
The Department of Infection Control and Prevention
started at first as the Division of Hospital Infection
Control Services on January 23, 1991. This divisiondeveloped into the Division of Infection Control andPrevention on September l, 1993 and the present
department on June 4, 1994. Currently, our faculty
consists of one professor, five guest lecturers, four
research associates, 11 laboratory technicians, and two
office assistants. For isolation and identification of
microorganisms from clinical specimens, we
amalgamated the microbiology unit from the
Department of Clinical Laboratory in 2001.

Clinical activities
Our daily activities are as follows:
1) Surveillance and control of hospital-acquired
infection, such as infection or colonization ofmethicillin-resistant Staphylococcus aureus andother drug-resistant microbes.

2) Investigation of trends in weekly bases andmonthly reports to all departments; Screening ofcolonization; monitoring of appropriate use ofantibiotics 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

48

clinical microbiology. We are also engaged in the
education of graduate students as well as hospital
staff.
For postgraduate education, we have been committed
to the guidance for new postgraduates and residents on
the hospital and occupational infection control. We
have been also offering our information and 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. Ikeda M, Yagihara Y, Tatsuno K, Okazaki M,
Okugawa S, Moriya K. Clinical characteristics
and antimicrobial susceptibility of Bacillus cereus
blood stream infections. Ann Clin Microbiol
Antimicrob. 2015;14:43.
2. Ishii K, Tabuchi F, Matsuo M, Tatsuno K, Sato T,
Okazaki M, Hamamoto H, Matsumoto Y, Kaito C,
Aoyagi T, Hiramatsu K, Kaku M, Moriya K,
Sekimizu
K.
Phenotypicandgenomic
comparisons of highly vancomycin-resistant
Staphylococcus aureus strains developed frommultiple clinical MRSA strains by in vitro

mutagenesis. Sci Rep. 2015;5:17092.
3. Ito S, Hirabayashi K, Moriishi K, Matsui Y,
Moriya K, Koike K, Matsuura Y, Shiota K, Yagi S.
Novel sex-dependent differentially methylated
regions are demethylated in adult male mouse
livers. Biochem Biophys Res Commun. 2015;
462(4):332-8.
4. Kato I, Fujimoto F, Higurashi Y, Yamaguchi R,
Takayama K, Suzuki M, Okugawa S, Okazaki M,
Moriya K. Antibiotic Susceptibilities of
Pseudomonas aeruginosa Isolated from Blood
Samples and Antibiotic Utilization in a University
Hospital in Japan. Infect Dis Ther. 2015;4(2):213-8.
5. Koyano S, Tatsuno K, Okazaki M, Ohkusu K,
Sasaki T, Saito R, Okugawa S, Moriya K. A Caseof Liver Abscess with Desulfovibrio desulfuricans
Bacteremia. Case Rep Infect Dis. 2015;2015:
354168.
6. Minami T, Tateishi R, Kondo M, Nakagomi R,
Fujiwara N, Sato M, Uchino K, Enooku K,
Nakagawa H, Asaoka Y, Kondo Y, Moriya K,
Shiina S, Koike K. Serum Alpha-Fetoprotein Has
High Specificity for the Early Detection of
Hepatocellular Carcinoma After Hepatitis C Virus
Eradication in Patients. Medicine (Baltimore).
2015;94(23):e901.
7. Misawa Y, Yoshida A, Okugawa S, Moriya K.
First reported case of Staphylococcus condimenti
infection associated with catheter-related bacteraemia. New Microbes New Infect. 2015;3:18-20.
8. Nakamura M, Satoh N, Suzuki M, Kume H,
Homma Y, Seki G, Horita S. Stimulatory effect of
insulin on renal proximal tubule sodium transport
is preserved in type 2 diabetes with nephropathy.
Biochem Biophys Res Commun. 2015;461(1):154-8.
9. Nakamura M, Yamazaki O, Shirai A, Horita S,
Satoh N, Suzuki M, Hamasaki Y, Noiri E, Kume
H, Enomoto Y, Homma Y, Seki G. Preserved
Na/HCO3 cotransporter sensitivity to insulin may
promote hypertension in metabolic syndrome.
Kidney Int. 2015;87(3):535-42.
10. Ogishi M, Yotsuyanagi H, Tsutsumi T, Gatanaga
H, Ode H, Sugiura W, Moriya K, Oka S, Kimura
S, Koike K. Deconvoluting the composition of
low-frequency hepatitis C viral quasispecies:

49

comparison of genotypes and NS3 resistanceassociated variants between HCV/HIV coinfected
hemophiliacs and HCV monoinfected patients inJapan. PLoS One. 2015;10(3):e0119145.
11. Okushin K, Takahashi Y, Yamamichi N,
Shimamoto T, Enooku K, Fujinaga H, Tsutsumi T,
Shintani Y, Sakaguchi Y, Ono S, Kodashima S,
Fujishiro M, Moriya K, Yotsuyanagi H,
Mitsushima T, Koike K. Helicobacter pylori
infection is not associated with fatty liver disease
including non-alcoholic fatty liver disease: alarge-scale cross-sectional study in Japan. BMC
Gastroenterol. 2015;15:25.
12. 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 histological progression of nonalcoholic fatty liver disease. J
Gastroenterol. 2015.
13. Saito R, Koyano S, Dorin M, Higurashi Y,
Misawa Y, Nagano N, Kaneko T, Moriya K.
Evaluation of a simple phenotypic method for thedetection of carbapenemase-producing Enterobacteriaceae. J Microbiol Methods. 2015;108:45-8.
14. Satoh N, Nakamura M, Suzuki M, Suzuki A, Seki
G, Horita S. Roles of Akt and SGK1 in theRegulation of Renal Tubular Transport. Biomed
Res Int. 2015;2015:971697.
15. Sekine S, Ito K, Watanabe H, Nakano T, Moriya K,
Shintani Y, Fujie H, Tsutsumi T, Miyoshi H,
Fujinaga H, Shinzawa S, Koike K, Horie T.
Mitochondrial iron accumulation exacerbates
hepatic toxicity caused by hepatitis C virus coreprotein. Toxicol Appl Pharmacol. 2015;282(3):237-43.
16. 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. 2015.
17. Uni M, Shinohara A, Nukina A, Nakamura F,
Nannya Y, Mizoguchi M, Okazaki M, Tatsuno K,
Moriya K, Kurokawa M. Successful managementof Rothia aeria pneumonia during the peritrans-

plant period: first reported case in allogeneic
hematopoietic stem cell transplant. Leuk
Lymphoma. 2015;56(1):248-50.
18. Wada K, Yoshikawa T, Yoshikawa JJ, Mitsuda T,
Kidouchi K, Kurosu H, Morisawa Y, Aminaka M,
Okubo T, Kimura S, Moriya K. Sharp injuries inJapanese operating theaters of HIV/AIDS referral
hospitals 2009-2011. Ind Health. 2015.

Pathology, Immunology andMicrobiology
3. Immunology

51

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

Associate Professor
Takeshi Nitta, Ph.D.

Assistant Professor
Kazuo Okamoto, Ph.D.; Shinichiro Sawa, M.D., Ph.D.

Project Assistant Professor
Noriko Komatsu, 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 2015, 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).

52

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 marrow
have not been clarified. We aim to identify groups ofcells and molecules (within the marrow microenvironment) that support lymphoid lineage
development.
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 Albers-Schoenberg's
disease. 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 osteoclastdifferentiation (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 of bridging
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 absorption 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).
Most recently, we reported that, using abone-fracture model in mouse, the cytokine IL-17
promotes bone fracture healing via osteoblastic boneformation and that γδT cells are the major source of
IL-17 produced in the bone injury site (Ono et al., Nat
Commun. 2016). Although it has been known that
IL-17 enhances osteoclastic bone resorption in certain
pathological situations, our current results clearlyshow the promoting effect of IL-17 on bone formation,
providing a new paradigm for physiological interaction between bone and immune system.
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 peripheral organs, mammals harbor large
numbers of lymphocytes such as T, B and recently

53

re-categorized innate lymphoid cells, which lackantigen receptors (Sawa et al., Science. 2010;
Furusawa et al., J Immunol. 2013). Focusing on the
nuclear hormone receptor RORγt expressing innate
lymphoid cell, we are trying to understand the cellularand molecular mechanisms that underlie maintenanceof the gut immune system in the steady state, and thepathogenicity of such innate lymphoid cells in the
inflammatory state.
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-destractive
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. Self-

tolerance 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
underlying the immune tolerance and autoimmune
diseases.

References
1. Ono T, Okamoto K, Nakashima T, Nitta T, Hori S,
Iwakura Y, Takayanagi H. IL-17-producing γδ T
cells enhance bone regeneration. Nat Commun. 7,10928 (2016)
2. Nitta T, Suzuki H. Thymic stromal cell subsets for
T cell development. Cell Mol Life Sci, 73, 10211037 (2016)
3. Yoshikawa S, Usami T, Kikuta J, Ishii M, Sasano
T, Sugiyama K, Furukawa T, Nakasho E, Takayanagi H, Tedder TF, Karasuyama H, Miyawaki A,
Adachi T. Intravital imaging of Ca2+ signals in
lymphocytes of Ca2+ biosensor transgenic mice:indication of autoimmune diseases before thepathological onset. Sci Rep. 6, 18738 (2016)
4. Guerrini MM, Okamoto K, Komatsu N, Sawa S,
Danks L, Penninger JM, Nakashima T, Takayanagi H. Inhibition of the TNF Family Cytokine
RANKL Prevents Autoimmune Inflammation in
the Central Nervous System. Immunity. 43, 11741185 (2015)

54

5. Takaba H, Morishita Y, Tomofuji Y, Danks L,
Nitta T, Komatsu N, Kodama T, Takayanagi H.
Fezf2 Orchestrates a Thymic Program of
Self-Antigen Expression for Immune Tolerance.
Cell. 163, 975-987 (2015)
6. Sumiya E, Negishi-Koga T, Nagai Y, Suematsu A,
Suda T, Shinohara M, Sato K, Sanjo H, Akira S,
Takayanagi. Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets
in osteoclast differentiation. Biochem Biophys
Res Commun. 463, 1284-1290 (2015)
7. Danks L, Komatsu N, Guerrini MM, Sawa S, Armaka M, Kollias G, Nakashima T, Takayanagi H.
RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint
inflammation. Ann Rheum Dis. 75, 1187-1195(2015)

Radiology and Biomedical
Engineering
1. Radiology

56

Department of Radiology
Professor
Kuni Ohtomo, M.D., Ph.D.

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

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

Akira Kunimatsu, M.D., Ph.D.

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

Jiro Sato, M.D.,

Hidemasa Takao, M.D., Ph.D.

Hidenori Yamashita, M.D., Ph.D.

Assistant Professor
Kenshirou Shiraishi, M.D., Ph.D.,

Miwako Takahashi, M.D., Ph.D.,

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

Shouhei Hanaoka, M.D., Ph.D.,

Shiori Amemiya, M.D., Ph.D.,

Kae Okuma, M.D., Ph.D.,

Naoki Okura, M.D.,

Wataru Gonoi, M.D., Ph.D.,

Keitaro Koyama, M.D., Ph.D.,

Masaki Katsura, M.D., Ph.D.

Akihiro Haga, Ph.D.,

Wataru Takahashi, M.D., Ph.D.

Homepage

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

57

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 fifth/sixth-year students are taking partin mini-lectures and practice to learn basics ofdiagnostic radiology, advanced medical techniques ofRadiation Oncology and Nuclear Medicine. They willlearn detailed principles of image constructions invarious 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 C-arm andmultileaf collimator systems was developed andinstalled, which is utilized mainly for non-coplanar
radiation therapy in many patients especially withbrain tumor or head and neck tumor. Dynamic conicalconformal radiotherapy (Dyconic therapy) formetastatic brain tumors using the accelerator is underevaluation. In addition to gamma knife radiosurgery,this new accelerator based stereotactic radiotherapy
for brain diseases has been undergone, and stereotactic
radiotherapy (SRT) for body tumors, such as head andneck cancer, prostate cancer, rectal cancer and lungcancer, has been investigated (intensity modulation
radiation therapy; IMRT) for the reduction of theadverse radiation damage. A new technology to track
mobile tumors, represented by lung tumors is underinvestigation in collaboration with accelerator makers.

58

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.

3.

4.

5.

6.

7.

References
1. Amemiya S, Takahashi K, Mima T, Yoshioka N,
Miki S, Ohtomo K.
Reversible alterations of the neuronal activity inspontaneous intracranial hypotension.
Cephalalgia 36(2): 162-71, 2016
2. Fujisawa N, Oya S, Mori H, Matsui T.
Chronic Lymphocytic Inflammation with Pontine

8.

9.

Perivascular Enhancement Responsive to Steroids
with a Significant Elevation of β-2 Microglobulin
Levels.
J Korean Neurosurg Soc 58(5): 487-90, 2015
Fujiwara K, Koyama K, Suga K, Ikemura M,
Saito Y, Hino A, Iwanari H, Kusano-Arai O,
Mitsui K, Kasahara H, Fukayama M, Kodama T,
Hamakubo T, Momose T.
90Y-Labeled Anti-ROBO1 Monoclonal Antibody
Exhibits Antitumor Activity against Small Cell
Lung Cancer Xenografts.
PLoS One 10(5): e0125468, 2015
Hagiwara A, Akai H, Kosaka T, Suyama Y, Ogura
K, Kawauchi N.
A Dorsal Pancreatic Artery Originating from theRight Inferior Phrenic Artery.
J Vasc Interv Radiol 27(1): 143-5, 2016
Hagiwara A, Hori M, Suzuki M, Andica C,
Nakazawa M, Tsuruta K, Takano N, Sato S,
Hamasaki N, Yoshida M, Kumamaru KK, Ohtomo
K, Aoki S.
Contrast-enhanced synthetic MRI for the detection of brain metastases.
Acta Radiol Open 5(2): 2058460115626757, 2016
Higo T, Kobayashi T, Yamazaki S, Ando S, Gonoi
W, Ishida M, Okuma H, Nakamura F, Ushiku T,
Ohtomo K, Fukayama M, Kurokawa M.
Cerebral embolism through hematogenous dissemination of pulmonary mucormycosis complicating relapsed leukemia.
Int J Clin Exp Pathol 8(10): 13639-42, 2015
Irie R, Suzuki M, Yamamoto M, Takano N, Suga
Y, Hori M, Kamagata K, Takayama M, Yoshida M,
Sato S, Hamasaki N, Oishi H, Aoki S.
Assessing Blood Flow in an Intracranial Stent: A
Feasibility Study of MR Angiography Using a
Silent Scan after Stent-Assisted Coil Embolization
for Anterior Circulation Aneurysms.
AJNR Am J Neuroradiol 36(5): 967-70, 2015
Ishida M, Gonoi W, Okuma H, Shirota G, Shintani
Y, Abe H, Takazawa Y, Fukayama M, Ohtomo K.
Common Postmortem Computed Tomography
Findings Following Atraumatic Death: Differentiation between Normal Postmortem Changes andPathologic Lesions.
Korean J Radiol 16(4): 798-809, 2015
Kamiya K, Amemiya S, Suzuki Y, Kunii N, Kawai

59

K, Mori H, Kunimatsu A, Saito N, Aoki S,
Ohtomo K.
Machine Learning of DTI Structural Brain Connectomes for Lateralization of Temporal Lobe
Epilepsy.
Magn Reson Med Sci 15(1): 121-9, 2016
10. Kobayashi R, Shiraishi K, Iwase S, Ohtomo K,
Nakagawa K.
Omission of axillary lymph node dissection forclinically node negative early-stage breast cancer
patients.
Breast Cancer 22(6): 657-63, 2015
11. Kobayashi R, Yamashita H, Okuma K, Ohtomo K,
Nakagawa K.
Details of recurrence sites after definitive radiation therapy for cervical cancer.
J Gynecol Oncol 27(2): e16, 2016
12. Nagai M, Yamaguchi M, Mori K, Furuta T,
Ashino H, Kurosawa H, Kasahara H, Minami M,
Fujii H.
Magnetic Resonance-Based Visualization of
Thermal Ablative Margins Around Hepatic
Tumors by Means of Systemic Ferucarbotran
Administration Before Radiofrequency Ablation:
Animal Study to Reveal the Connection Between
Excess Iron Deposition and T2*-Weighted
Hypointensity in Ablative Margins.
Invest Radiol 50(6): 376-83, 2015
13. Nakayama A, Morita H, Hayashi N, Nomura Y,
Hoshina K, Shigematsu K, Ohtsu H, Miyata T,
Komuro I.
Inverse Correlation Between Calcium Accumulation and the Expansion Rate of Abdominal Aortic
Aneurysms.
Circ J 80(2): 332-9, 2016
14. Namiki C, Takita Y, Iwata A, Momose T, Senda M,
Okubo Y, Joshi AD, Lu M, Agbulos A, Breault C,
Pontecorvo MJ.
Imaging characteristics and safety of florbetapir((18)F) in Japanese healthy volunteers, patientswith mild cognitive impairment and patients with
Alzheimer's disease.
Ann Nucl Med 29(7): 570-81, 201515. Nishioka Y, Shindoh J, Yoshioka R, Gonoi W, Abe
H, Okura N, Yoshida S, Oba M, Hashimoto M,
Watanabe G, Hasegawa K, Kokudo N.
Radiological Morphology of Colorectal Liver

Metastases after Preoperative Chemotherapy
Predicts Tumor Viability and Postoperative
Outcomes.
J Gastrointest Surg 19(9): 1653-61, 2015
16. Oichi T, Chikuda H, Morikawa T, Mori H,
Kitamura D, Higuchi J, Taniguchi Y,
Matsubayashi Y, Oshima Y, Tanaka S.
Concurrent spinal schwannoma and meningioma
mimicking a single cervical dumbbell-shaped
tumor: case report.
J Neurosurg Spine 23(6): 784-7, 201517. Okumura Y, Aikou S, Onoyama H, Jinbo K,
Yamagata Y, Mori K, Yamashita H, Nomura S,
Takahashi M, Koyama K, Momose T, Abe H,
Matsusaka K, Ushiku T, Fukayama M, Seto Y.
Evaluation of 18F-FDG uptake for detecting
lymph node metastasis of gastric cancer: aprospective pilot study for one-to-one comparisonof radiation dose and pathological findings.
World J Surg Oncol 13: 327, 201518. Shinya Y, Miyawaki S, Nakatomi H, Okano A,
Imai H, Shin M, Sato K, Tsuchida T, Hayashi T,
Terao Y, Numakura S, Morikawa T, Shibahara J,
Kikuta S, Kondo K, Tatsuno K, Mori H,
Kunimatsu A, Tsuji S, Saito N.
Recurrent cerebral aneurysm formation andrupture within a short period due to invasive
aspergillosis of the nasal sinus; pathologicalanalysis of the catastrophic clinical course.
Int J Clin Exp Pathol 8(10): 13510-22, 201519. Shirota G, Gonoi W, Ishida M, Okuma H, Shintani
Y, Abe H, Takazawa Y, Ikemura M, Fukayama M,
Ohtomo K.
Brain Swelling and Loss of Gray and White
Matter Differentiation in Human Postmortem
Cases by Computed Tomography.
PLoS One 10(11): e0143848, 2015
20. Taguchi S, Fukuhara H, Shiraishi K, Nakagawa K,
Morikawa T, Kakutani S, Takeshima Y, Miyazaki
H, Fujimura T, Nakagawa T, Kume H, Homma Y.
Radical Prostatectomy versus External BeamRadiotherapy for cT1-4N0M0 Prostate Cancer:
Comparison of Patient Outcomes Including
Mortality.
PLoS One 10(10): e0141123, 2015
21. Takahashi M, Kume H, Koyama K, Nakagawa T,
Fujimura T, Morikawa T, Fukayama M, Homma Y,

60

Ohtomo K, Momose T.
Preoperative evaluation of renal cell carcinoma byusing 18F-FDG PET/CT.
Clin Nucl Med 40(12): 936-40, 2015
22. Takami H, Mukasa A, Ikemura M, Shibahara J,
Takahashi M, Momose T, Saito N.
Findings from positron emission tomography andgenetic analyses for cerebellar liponeurocytoma.
Brain Tumor Pathol 32(3): 210-5, 2015
23. Watanabe T, Hanajima R, Shirota Y, Tsutsumi R,
Shimizu T, Hayashi T, Terao Y, Ugawa Y, Katsura
M, Kunimatsu A, Ohtomo K, Hirose S, Miyashita
Y, Konishi S
Effects of rTMS of pre-supplementary motor area
on fronto basal ganglia network activity duringstop-signal task.
J Neurosci 35(12): 4813-23, 201524. Yamashita H, Onishi H, Murakami N, Matsumoto
Y, Matsuo Y, Nomiya T, Nakagawa K; JapaneseRadiological Society multi-institutional SBRT
study group (JRS-SBRTSG).
Survival outcomes after stereotactic body radiotherapy for 79 Japanese patients with hepatocellular carcinoma.
J Radiat Res 56(3): 561-7, 2015
25. Yamashita H, Takenaka R, Omori M, Imae T,
Okuma K, Ohtomo K, Nakagawa K.
Involved-field radiotherapy (IFRT) versus elective
nodal irradiation (ENI) in combination with concurrent chemotherapy for 239 esophageal cancers:a single institutional retrospective study.
Radiat Oncol 10: 171, 2015
26. Yamashita H, Haga A, Takenaka R, Kiritoshi T,
Okuma K, Ohtomo K, Nakagawa K.
Efficacy and feasibility of ambulatory treatmentbased monthly nedaplatin plus S-1 in definitive or
salvage concurrent chemoradiotherapy for early,
advanced, and relapsed esophageal cancer.
Radiat Oncol 11(1): 4, 201627. Yasaka K, Katsura M, Akahane M, Sato J,
Matsuda I, Ohtomo K.
Model-based iterative reconstruction and adaptive
statistical iterative reconstruction: dose-reduced
CT for detecting pancreatic calcification.
Acta Radiol Open 5(1): 2058460116628340, 201628. Yasaka K, Katsura M, Hanaoka S, Sato J, Ohtomo
K.

High-resolution CT with new model-based
iterative reconstruction with resolution preference
algorithm in evaluations of lung nodules: Comparison with conventional model-based iterative
reconstruction and adaptive statistical iterative
reconstruction.
Eur J Radiol 85(3): 599-606, 201629. Yoshino M, Kin T, Ito A, Saito T, Nakagawa D,
Kamada K, Mori H, Kunimatsu A, Nakatomi H,
Oyama H, Saito N.
Diffusion tensor of normal facial and vestibulocochlear nerves.
Int J Comput Assist Radiol Surg 10(4): 383-92,
2015
30. Yoshino M, Kin T, Ito A, Saito T, Nakagawa D,
Ino K, Kamada K, Mori H, Kunimatsu A,
Nakatomi H, Oyama H, Saito N.
Feasibility of diffusion tensor tractography forpreoperative prediction of the location of the
facial and vestibulocochlear nerves in relation tovestibular schwannoma.
Acta Neurochir (Wien) 157(6): 939-46, 201531. Yoshino M, Kin T, Ito A, Saito T, Nakagawa D,
Ino K, Kamada K, Mori H, Kunimatsu A,
Nakatomi H, Oyama H, Saito N.
Combined use of diffusion tensor tractography
and multifused contrast-enhanced FIESTA for
predicting facial and cochlear nerve positions inrelation to vestibular schwannoma.
J Neurosurg 123(6): 1480-8, 2015

Radiology and Biomedical
Engineering
2. Biomedical Engineering

62

Department of System Physiology
Lecturer
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 lecturer.

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 relation-

ships 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
antithrombotic molecule, in ECs. In contrast, it63decreased 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
the cell interior. Strong shearing forces induced by

64

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 methylβ-cyclodextrin or by adding cholesterol resulted in amarked inhibition of the EC response specific to shear
stress and stretch, i.e., phosphorylation of VEGFR2
and phosphorylation of PDGFR, respectively. Thesefindings indicate that EC plasma membranes
differently respond to shear stress and stretch bychanging their lipid order, fluidity, and cholesterol
content in opposite directions and that these changes
in membrane physical properties are involved in themechanosensing mechanisms and the mechanotransduction that activates membrane receptors
specific to each force.

References
1. Yamamoto K 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.
2. Senju Y, Rosenbaum E, Shah C, HamadaNakahara S, Itoh Y, Yamamoto K, HanawaSuetsugu K, Daumke O, and Suetsugu S. Protein
kinase C (PKC)-mediated phosphorylation of
PACSIN2 triggers the removal of caveolae fromthe plasma membrane.

J. Cell Sci. 128:2766-

2780, 2015.
3. Kamiya A, Shibata M, and Yamamoto K.
Assessment of Myogenic Power Expenditure Due
to Arterial Wall Smooth Muscle Contraction
Based upon the Fractal Nature of Vascular Trees.
Applied Mathematics. 5:1750-1762, 2014.
4. Obi S, Yamamoto K, and Ando J, Effects of shear
stress on endothelial progenitor cells, J. Biomed.
Nanotechnol., 10:2586-2597, 2014.
5. Yamamoto K and Ando J, Vacular mecanobiology; Mechanobiology; Kagakudojin: Kyoto,
Chapter 11 (pp. 143-157), 2015.
6. Yamamoto K, Biotechnology: Cell Engineering and
Genetic Engineering, J. Jap. Soc. Mech. Eng. 118:457-458、2015.

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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, 6 PhD students, 1 master course student
and one technical staff by the end of FY2015.

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 three 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 FY2015.

Research activities
Our lab aims at developing novel fluorescence probes
and applying these molecules to biology and medicine.
Two specialized rooms for chemical syntheses weresettled, equipped with various instruments forchemical syntheses, purification, and characterization.
Further, various instruments for live imaging of cells
and animals, instruments for cell culture and DNA
work were already settled in our laboratory. Therefore,
molecular design, chemical syntheses, purification,
characterization, evaluation of novel probes in vitro,in cellulo and in vivo can be done in our laboratory.
By using above instruments, we are now conducting
various projects for establishing novel bioimaging
techniques based on the development of new
fluorescence probes. So far, we have succeeded inestablishing rational design strategies of fluorescenceand luminescence probes based on photoinduced
electron transfer and intramolecular spirocyclization
mechanism. In 2015, we have succeeded to develop
various novel fluorescence probes by utilizing theconcept of both mechanisms.
For example, a sensitive bioluminogenic probe forhighly reactive oxygen species (hROS) was developed
based on the concept of bioluminescence emission bymeans of bioluminescent enzyme-induced electrontransfer (BioLeT). This probe enables non-invasive
visualization of physiologically relevant amounts of
hROS generated deep inside the body of living rats. It
is expected to serve as a practical analytical tool forinvestigating a wide range of biological functions of
hROS in vivo (Reference 4).
Another achievement is application of our previously reported fluorescence probe for γ-glutamyltranspeptidase (GGT), which is overexpressed in various

66

types of cancers, to clinical specimens resected fromcancer patients. For example, in collaboration with Dr.
Mimori at Kyusyu University and Dr. Ueo at Ueo
Breast Surgery Hospital, we found that our probe for
GGT is useful for rapid intraoperative visualization ofbreast lesions (Reference 6). Further, we have
expanded fluorescence probe library for elucidating
characteristic features of live cancer cells. We arecollaborating with surgeons including those in Tokyo
University Hospital in order to examine the efficacy ofthese new probes.
We also developed a novel asymmetricallymodified rhodamine with suitable absorption/emission,brightness and equilibrium constant of intramolecularspirocyclization, working in the yellow/orange region.
As a proof of concept, a probe targeting GGT wasdeveloped on the basis of the new scaffold, andsimultaneous visualization and discrimination ofdifferent types of tumors were achieved in a mousemodel in vivo (Reference 1).
We also tried to expand the design of spontaneously
blinking fluorophores for super-resolution imaging(Reference 7).

References
1. Iwatate RJ, Kamiya M, Urano Y: Asymmetric
Rhodamine-Based Fluorescence Probes forMulti-colour In Vivo Imaging. Chemistry - A
European Journal. 2016; 22: 1696-1703.
2. Hirakawa Y, Yoshihara T, Kamiya M, Mimura I,
Fujikura D, Masuda T, Kikuchi R, Takahashi I,
Urano Y, Tobita S, Nangaku M: Quantitating
intracellular oxygen tension in vivo by phosphorescence lifetime measurement. Sci Rep.
2015;5:17838.
3. 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. 2016;55:560-565.
4. Kojima R, Takakura H, Kamiya M, Kobayashi E,
Komatsu T, Ueno T, Terai T, Hanaoka K, Nagano
T, Urano Y: Development of a Sensitive Bioluminogenic Probe for Imaging Highly Reactive

Oxygen Species in Living Rats. Angew Chem Int
Ed Engl, 2015;54:14768-14771.
5. Hirabayashi K, Hanaoka K, Takayanagi T, Toki Y,
Egawa T, Kamiya M, Komatsu T, Ueno T, Terai T,
Yoshida K, Uchiyama M, Nagano T, Urano Y:
Analysis of Chemical Equilibrium of SiliconSubstituted Fluorescein and Its Application to
Develop a Scaffold for Red Fluorescent Probes.
Anal Chem, 2015; 87:9061-9069.
6. Ueo H, Shinden Y, Tobo T, Gamachi A, Udo 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
intraoperative visualization of breast lesions with
γ-glutamyl hydroxymethyl rhodamine green.
Scientific Reports, 2015; 5:12080.
7. Uno S, D.K.Tiwari, Kamiya M, Arai Y, Nagai T,
Urano Y: A guide to use photocontrollable fluorescent proteins and synthetic smart fluorophores
for nanoscopy, 2015; dfv037.

67

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, a project researcher, 10 graduate students, 16
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 3rd 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.

68

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 dynamic (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, highefficiency, good controllability, and excellent biologicalcompatibility, which can be implanted in the body ofsmall stature like Japanese. To meat the purpose, we
had been developing the TAH using undulation pumps,
named undulation pump TAH (UPTAH). The
undulation pump is our original blood pump invented
in 1992. The UPTAH revealed to have an excellent
performance and the goat whose heart was replacedwith the UPTAH survived for 153 days. However, the
UPTAH had a problem in the durability of the complex
drive shaft mechanism. To improve the problem of the
UPTAH, a new blood pump, named the helical flow
pump (HFP), was invented in our laboratory in 2005.
The HFP is a novel blood pump having a hydrodynamic levitating impeller, which promises highdurability. The animal experiment of the helical flow
TAH (HFTAH) had started in 2011. The HFTAH could

be implanted in the goat successfully with goodanatomical fitting. To date, the goat whose heart was
replaced with the HFTAH survived for 100 days. We
are expecting to develop an ideal TAH that surpass theoutcome of the heart transplantation with combinationof the technologies of the physiological control andhybrid 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.
Concerning the materials, we have been developing a

69

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 lungassist device has been started in 2004. The device
consists of a blood pump, an oxygenator, a drive andcontrol unit, and a battery unit. To realize severalmonths support with the ELSS, a new blood pump
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 indiameter 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 are trying to detect the
respiratory frequency using the three-axis acceleration
sensor contained in the unit.

References
1. Abe Y, Isoyama T, Saito I, Inoue Y, Ishii K, Sato
M, Hara S, Yurimoto T, Li X, Murakami H,
Ariyoshi K, Kawase Y, Ono T, Fukazawa K,
Ishihara K. Animal experiments of the helicalflow total artificial heart. Artif Organs, 2015:39;
670-80, DOI 10.1111/aor.12543.
2. Ishii K, Hosoda K, Nishida M, Isoyama T, Saito I,
Ariyoshi K, Inoue Y, Ono T, Nakagawa H, Sato M,
Hara S, Lee X, Wu S, Imachi K, Abe Y.
Hydrodynamic characteristics of the helical flow
pump. J Artif Organs, 2015;18:206-12, DOI 10.
1007/s10047-015-0828-y.
3. Fukuda H, Hara S, Asakawa K, Ishikawa H,
Noshiro M, Katuya M. Computer simulation ofcolor confusion for dichromats in video device
gamut under proportionality law. IPSJ Trans
Comp Vision Appl, 2015;7:41-49, DOI 10.2197/
ipsjtcva.7.41.

Neuroscience
1. Basic Neuroscience71

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

72

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,

73

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 35 clinicalsites nationwide, and preparing all the infrastructures
required for the large-scale clinical study. The J-ADNI
group is starting to recruit participants on June 2008
(total, 600 cases for 5 years), and the instruments andframework of J-ADNI are being adopted in multiple
global clinical trials in Japan.

4)

5)

6)

7)

References
1) Tagawa K, Homma H, Saito A, Fujita K, Chen X,
Imoto S, Oka T, Ito H, Motoki K, Yoshida C,
Hatsuta H, Murayama S, Iwatsubo T, Miyano S,
Okazawa H: Comprehensive phosphoproteome
analysis unravels the core signaling network that
initiates the earliest synapse pathology inpreclinical Alzheimer’s disease brain. Hum Mol
Genet 24: 540-558, 20152) Goto M, Abe O, Aoki S, Hayashi N, Ohtsu H,
Takao H, Miyati T, Matsuda H, Yamashita F,
Iwatsubo T, Mori H, Kunimatsu A, Ino K, Yano K,
Ohtomo K: Longitudinal gray-matter volume
change in the default-mode network: utility ofvolume standardized with global gray-mattervolume for Alzheimer's disease: a preliminary
study. Radiol Phys Technol 8:64-72, 2015
3) Takasugi N, Shinohara M, Sasaki T, Iwatsubo T,
Tomita T: Synthetic ceramide analogues increaseAβ42 production by modulating γ-secretaseactivity. Biochem Biophys Res Commun 457:8)

194-199, 2015
Takagi-Niidome S, Sasaki T, Osawa S, Sato T,
Morishima K, Cai T, Iwatsubo T, Tomita T:
Cooperative roles of hydrophilic loop 1 and the C
terminus of presenilin 1 in the substrate-gating
mechanism of γ-secretase. J Neurosci 35: 26462656, 2015
Kukharsky MS, Quintiero A, Matsumoto T,
Matsukawa K, Hashimoto T, Iwatsubo T,
Buchman VL, Shelkovnikova TA: Calciumresponsive transactivator (CREST) protein sharesa set of structural and functional traits with otherproteins associated with amyotrophic lateralsclerosis. Molecular Neurodegeneration 10:20,
2015
Yamamoto K, Tanei Z, Hashimoto T,
Wakabayashi T, Okuno H, Naka Y, Yizhar O,
Fenno LE, Fukayama M, Bito H, Cirrito JR,
Holtzman DM, Deisseroth K, Iwatsubo T:
Chronic optogenetic activation augments Aβpathology in a mouse model of Alzheimer disease.
Cell Reports 11:859-865, 2015
Hori Y, Hashimoto T, Nomoto H, Hyman BT,
Iwatsubo T: Role of apolipoprotein E in
β-amyloidogenesis: isoform-specific effects on
protofibril to fibril conversion of Aβ in vitro andbrain Aβ deposition in vivo. J Biol Chem 290:
15163-15174, 2015
Doody RS, Raman, R Sperling RA, Siemers E,
Sethuraman G, Mohs R, Farlow MR, Iwatsubo T,
Vellas B, Sun X, Ernstrom K, Thomas RG, Aisen
PS; Alzheimer’s Disease Cooperative Study:
Peripheral and central effects of γ-secretaseinhibition by semagacestat in Alzheimer's disease.
Alzheimer's Research & Therapy 7:36, 2015

74

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

Lecturer
Sayaka Takemoto-Kimura, M.D., Ph.D.

Assistant Professor
Hajime Fujii, Ph.D.

Homepage

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

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

What are the precise nature and the whole
spectrum of the molecular changes in the neurons that
undergo heavy or patterned electrical activity? What
are the molecular rules that govern these local andglobal changes, both electrical and chemical? How arethese events, in turn, converted into more profoundmodifications of the synaptic wiring mechanisms?
And finally do these alterations genuinely underlie
certain kinds of information processing and storage?
To address these issues, this Department currently focuses its resources into two basic aims:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calcium-dependent
synaptic modification, especially during signalingfrom synapse-to-nucleus, and back from nucleusto-synapses.
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon
terminals.
Following the retirement of Professor Tatsuya
Haga (who became the President of Life Sciences
Institute at the Faculty of Science at Gakushuin
Univisersity) in March 2001, and the departure of
Associate Professor David Saffen to initially University of Minnesota and then to Ohio State University inAugust 2001, Associate Professor Haruhiko Bito was
appointed as Head of Department since January 2003.
The Department is located on the 6th floor, in the West75

wing of the third building of the Medical School. The
Department currently enrolls one professor, four
assistant professors, six postdoctoral scholars, one
technical staff member, three Ph.D. graduate students,
three rotating medical students, three technicalassistants 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 modifi-

cations 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).

76

Furthermore,
CaMKIV-KO,
CaMKK-KO
and
CaMKIV-dominant negative transgenic studies bymany laboratories have confirmed the critical role for
CaMKIV as synaptic activity-triggered CREB kinase.
We subsequently also showed that CaMKIV inthe cerebellar granule cells played a critical role intuning the pCREB response necessary for
depolarization-mediated neuronal survival, and that 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 whererby 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

77have developed a method named dFOMA (dual FRET
imaging with optical manipulation) to simultaneously
measure activities of two distinct signaling moleculesin living neurons. Applying originally developed
FRET probes to dFOMA method enabled us tomeasure activities of CaMKII, calcineurin and Ca2+,
when a neuron received various frequencies ofsynaptic inputs. These experiments provided evidence
that CaMKIIα and calcineurin are fine-tuned to uniquebandwidths and compute input variables in an
asymmetric manner (Fujii et al., Cell Reports 2013).
In line with the visualization of neuronal activity
and Ca2+ signaling, we have developed R-CaMP2, a
red genetically-encoded Ca2+ indicator that has singleaction-potential sensitivity based on rational designthat takes advantage of our long-standing effort andknowledge about CaMKK-CaMKIV signaling (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 ea 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 spatiallysegretated patterns of actin cytoskeletal reorganization,with variable impact on either neuronal morphology
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

78

growth cone motility, Rho/ROCK activity in fact acted
as a negative gate that tightly controls the timing withwhich the first processes are initiated out from theround cell soma (Bito et al., Neuron, 2000).
Disruption of Rho/ROCK activity was sufficient toimmediately initiate neuritogenesis. This indicatedthat endogenous Rho activators, by titrating ROCK
activity, continuously antagonized process/ branchformation and that local gradient of Rho activators
might play a crucial role in shaping the timing and theextent of process formation (Bito, J. Biochem., 2003).
Consistent with this idea, we found that in cerebellar
granule cells, a chemokine SDF-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 tighly 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 2015- December 2015)
1. Inoue M, Takeuchi A, Horigane S, Ohkura M,
Gengyo-Ando K, Fujii H, Kamijo S, TakemotoKimura S, Kano M, Nakai J, Kitamura K, Bito
H.Rational design of a high-affinity, fast, redcalcium indicator R-CaMP2. Nat Methods 12(1):64-70, 2015.
2. Fukuchi M, Nakashima F, Tabuchi A, Shimotori M,
Tatsumi S, Okuno H, Bito H, Tsuda M. Class I
histone deacetylase-mediated repression of theproximal promoter of the activity-regulated
cytoskeleton-associated protein gene regulates its
response to brain-derived neurotrophic factor. J Biol
Chem. 290(11):6825-6836, 2015.
3. Fukuchi M, Tabuchi A, Kuwana Y, Watanabe S,
Inoue M, Takasaki I, Izumi H, Tanaka A, Inoue R,
Mori H, Komatsu H, Takamori H, Okuno H, Bito H,
Tsuda M. Neuromodulatory effect of Gαs- orGαq-coupled GPCR on NMDAR selectively
activates the NMDAR/Ca2+/calcineurin/CREBregulated transcriptional coactivator 1 (CRTC1)
pathway to effectively induce Bdnf expression inneurons. J Neurosci. 35(14):5606-24, 2015.
4. Yamamoto K, Tanei Z, Hashimoto T, Wakabayashi T,
Okuno H, Naka Y, Yizhar O, Fenno LE, Fukayama
M, Bito H, Cirrito JR, Holtzman DM, Deisseroth K,
Iwatsubo T. (2015) Chronic optogenetic activation

79

augments Abeta pathology in a mouse model of
Alzheimer disease. Cell Rep 11(6):859-65, 2015.
5. Vousden DA, Epp J, Okuno H, Nieman BJ, vanEede M, Dazai J, Ragan T, Bito H, Frankland PW,
Lerch JP, Henkelman RM. Whole-brain mapping of
behaviourally induced neural activation in mice.
Brain Struct Funct. 220(4): 2043-2057, 2015.

80

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.

813) 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.
4) Novel technology for construction of genomewide RNAi library
RNA interference (RNAi) using short hairpin RNAexpressing vectors (shRNA vectors) is a powerful maneuver for functional genomics. We have previously
reported a method called EPRIL (enzymatic production of RNAi library) by which shRNA vectors areproduced from a cDNA fragment through multiple
enzyme reactions. Recently, we have tried to improve
the original EPRIL method to enable constructing agenome-wide RNAi library. The improved EPRIL
method was successfully adapted to 96-well plate
format which allows high-throughput production ofshRNA vectors. Using EPRIL technology and imaging
techniques, we explore physiologically functional
molecules by a high-throughput screening system.

References
1. Isa M, Namiki S, Asanuma D, Hirose K.
Spatiotemporal Control of Receptor Tyrosine
Kinase Activity by Caged Ligands. Chemistry
Letters 44(2) 150-1 2015.

Neuroscience
2. Integrative Medical Neuroscience83

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

Assistant professor
Ayaka Ishii-Takahashi, M.D., Ph.D., Yuki Kawakubo, Ph.D.

Homepage

http://childpsy.umin.jp/

Introduction and Organization

conference and journal club was arranged.

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. Three
professors are administrating Department of Child
Psychiatry, the University Hospital also, and trying toutilize its clinical activities for research more
effectively.

Research activities

Teaching activities
In the year of 2015, we had 8 graduate students.
In addition to research training, educational program
including full-year lectures of child psychiatry, case

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 2015 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

84

References
1. Kuwabara H, Araki T, Yamasaki S, Ando S,
Kano Y, Kasai K. Regional differences in posttraumatic stress symptoms among children
after the 2011 tsunami in Higashi-Matsushima,
Japan. Brain Dev. 37(1): 130-136, 2015.
2. Kano Y, Matsuda N, Nonaka M, Fujio M,
Kuwabara H, Kono T. Sensory phenomena in
relation to tics, obsessive-compulsive symptoms,
and global functioning in patients with Tourette
syndrome. Compr Psychiatry. 62: 141-146, 2015.
3. Nonaka M, Matsuda N, Kono T, Fujio M, Scahill
L, Kano Y. Preliminary study of behavioral
therapy for Tourette Syndrome patients inJapan. Children’s Health Care. 44(3): 293-306,
2015.
4. 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. 25(6):256-258, 2015.
5. Ishii-Takahashi A, Takizawa R, Nishimura Y,
Kawakubo Y, Hamada K, Okuhata S, Kawasaki
S, Kuwabara H, Shimada T, Todokoro A,
Igarashi T, Watanabe K, Yamasue H, Kato N,
Kasai K, Kano Y. Neuroimaging-aided prediction of the effect of methylphenidate in children
with attention deficit hyperactivity disorder：
A randomized controlled trial. Neuropsychopharmacology. 40(12): 2676-2685, 2015.
6. Inada N, Ito H, Yasunaga K, Kuroda M,
Iwanaga R, Hagiwara T, Tani I, Yukihiro
R,Uchiyama T, Ogasahara K, Hara K, Inoue M,
Murakami T, Someki F, Nakamura K,
Sugiyama T, Uchida H, Ichikawa H, Kawakubo
Y, Kano Y, Tsujii M. Psychometric properties of
the Repetitive Behavior Scale-Revised forindividuals with autism spectrum disorder inJapan. Res Autism Spectr Disord. 15-16: 60-68,
2015.
7. Aoki Y, Watanabe T, Abe O, Kuwabara H,
Yahata N, Takano Y, Iwashiro N, Natsubori T,
Takao H, Kawakubo Y, Kasai K, Yamasue H.
Oxytocin's neurochemical effects in the medial

prefrontal cortex underlie recovery of taskspecific brain activity in autism: a randomized
controlled trial. Mol Psychiatry. 20(4): 447-453,
2015.
8. Watanabe T, Kuroda M, Kuwabara H, Aoki Y,
Iwashiro N, Tatsunobu N, Takao H, Nippashi Y,
Kawakubo Y, Kunimatsu A, Kasai K, Yamasue
H. Clinical and neural effects of six-weekadministration of oxytocin on core symptoms ofautism. Brain. 138(Pt 11): 3400-3412, 2015.
9. Kinoshita A, Takizawa R, Koike S, Satomura Y,
Kawasaki S, Kawakubo Y, Marumo K, Tochigi
M, Sasaki T, Nishimura Y, Kasai K. Effect of
metabotropic glutamate receptor-3 variants on
prefrontal brain activity in schizophrenia: An
imaging genetics study using multi-channel
near-infrared spectroscopy. Prog Neuropsychopharmacol Biol Psychiatry. 62: 14-21, 2015.
10. Matsuda N, Kono T, Nonaka M, Fujio M, Kano
Y. Self-initiated coping with Tourette’s syndrome: Effect of tic suppression on QOL. Brain
Dev. (in press).
11. Okada N, Takahashi K, Nishimura Y, Koike S,
Ishii-Takahashi A, Sakakibara E, Satomura Y,
Kinoshita A, Takizawa R, Kawasaki S,
Nakakita M, Ohtani T, Okazaki Y, Kasai K.
Characterizing prefrontal cortical activity
during inhibition task in methamphetamineassociated psychosis versus schizophrenia: amulti-channel near-infrared spectroscopy study.
Addict Biol. (in press).
12. 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. (in press).

Neuroscience
3. Clinical Neuroscience86

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

Associate Professor
Hidenori Yamasue, M.D., Ph.D.

Chihiro Kakiuchi, M.D., Ph.D.

Lecturer
Seiichiro Jinde, M.D., Ph.D.

Research Associate
Shinsuke Kondo, M.D.

Kayo Ichihashi, M.D.

Kenji Otowa, M.D., Ph.D.

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

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

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

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

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

Tomoko Ando, M.D.

Yoshihiro Satomura, 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 beennormalized and restarted to play a leading role inpsychiatry in Japan. Since 2005, we have begun tofocus on basic and clinical neuroscience in autism
spectrum disorder (ASD). Since 2006, we have beenworking in the new closed ward and in the open ward.
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 outpatient services, we have more than 20 staff

psychiatrists, 4 clinical psychologists and 2 psychiatric social workers. Approximately 800 new patients
visited yearly (2014), and the total visits per day was
about 150.
The secluded ward has 26 beds including 3
seclusion rooms. We also have 28 beds for the open
general ward. Approximately 500 patients withvarious psychiatric disorders were admitted in a year.
Recently, the number of patients who were referredfrom the emergency unit is increasing. The age ofpatients is variable from teenager to senior. The
majority of the patients are schizophrenia, mood disorder and psychosis based on the somatic disease.
Mean hospitalization is 30 day long, and modified
electro-convulsive therapy was performed for over
400 patients.
We established day care unit for outpatients withschizophrenia in 1974, and the patients are engaged inrehabilitation and re-work programs. We also haveJapan's first child psychiatry day care unit in national
university hospitals since 1967, and mainly patients87with pervasive developmental disorders are engaged
in clinical and educational activities.

disorders including schizophrenia, autism, theirspectrum disorders and anxiety disorder (mainly panic
disorder).

Education
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 (2nd year),bedside learning (3rd year), and clinical clerkship(elective for 4th-year students). For postgraduate,
currently 18 neuropsychiatry Ph.D. students are
studying.

Research
Our mission in research is to clarify the pathophysiology of the mental illness to develop better
treatment approach.
1) Neuroimaging
Our research plays a leading role in psychiatricneuroimaging in Japan and aims at multi-modality
neuroimaging (structural and functional MRI, MR
spectroscopy, EEG, MEG, near-infrared spectroscopy[NIRS], PET) in schizophrenia, mood disorders,pervasive developmental disorders, and posttraumaticstress disorder (PTSD).
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 the

Publications(1) Sugawara H, Bundo M, Asai T, Sunaga F, Ueda J,
Ishigooka J, Kasai K, Kato T, Iwamoto K Effectsof quetiapine on DNA methylation in neuroblastoma
cells.
Progressin
NeuroPsychopharmacology and Biological Psychiatry
56C 117-121 2014
(2) Hashimoto R, Ikeda M, Yamashita F, Ohi K,
Yamamori H, Yasuda Y, Fujimoto M, Fukunaga
M, Nemoto K, Takahashi T, Tochigi M, Onitsuka
T, Yamasue H, Matsuo K, Iidaka T, Iwata N,
Suzuki M, Takeda M, Kasai K, and Ozaki N.
Common variants at 1q36 are associated withsuperior frontal gyrus volume. Translational
Psychiatry 4:e472 2014
(3) Takizawa R, Nishimura Y, Yamasue H, Kasai K.
Anxiety and Performance: The disparate roles ofprefrontal sub-regions under maintained psychological stress. Cerebral Cortex 24 1858-1866
2014(4) Takizawa R*, Fukuda M*, Kawasaki S, Kasai K,
Mimura M, Pu S, Noda T, Niwa SI, Okazaki Y.
Neuroimaging-aided differential diagnosis of thedepressive state. NeuroImage 85 498-507 2014(5) Sakakibara E*, Takizawa R*, Nishimura Y,
Kawasaki S, Satomura Y, Kinoshita A, Koike S,
Marumo K, Kinou M, Tochigi M, Nishida N,
Tokunaga K, Eguchi S, Yamasaki S, Natsubori T,
Iwashiro N, Inoue H, Takano Y, Takei K, Suga M,
Yamasue H, Matsubayashi J, Kohata K, Shimojo
C, Okuhata S, Kono T, Kuwabara H, IshiiTakahashi A, Kawakubo Y , Kasai K. Genetic
influences on frontal activation during a verbal
fluency task: A twin study based on multichannel
near-infrared spectroscopy. NeuroImage 85 508517 2014(6) Marumo K*, Takizawa R*, Kinou M, Kawasaki S,
Kawakubo Y, Fukuda M, Kasai K. Functional
abnormalities in the left ventrolateral prefrontal
cortex during a semantic fluency task, and theirassociation with thought disorder in patients withschizophrenia. NeuroImage 85 516-526 2014

88(7) Nishimura Y, Takizawa R, Koike S, Kinoshita A,
Satomura Y, Kawasaki S, Yamasue H, Tochigi M,
Kakiuchi C, Sasaki T, Iwayama Y, Yamada K,
Yoshikawa T, Kasai K. Decreased prefrontal
hemodynamic response during a verbal fluency
task associated with EGR3 gene polymorphism inboth patients with schizophrenia and healthy
individuals. NeuroImage 85 527-534 2014
(8) Chou PH, Koike S, Nishimura Y, Kawasaki S,
Satomura Y, Kinoshita A, Takizawa R, Kasai K.
Distinct effects of duration of untreated psychosison brain cortical activities in different treatment
phases of schizophrenia: A multi-channel nearinfrared spectroscopy study. Prog Neuropsychopharmacol Biol Psychiatry 49 63-69 2014(9) Satomura Y, Takizawa R, Koike S, Kawasaki S,
Kinoshita A, Sakakibara E, Nishimura Y, Kasai K.
Potential biomarker of subjective quality of life:
prefrontal activation measurement by nearinfrared spectroscopy. Social Neuroscience 9 6373 2014(10) Takizawa R, Maughan B, Arseneault L. Adult
health outcomes of childhood bullying victimization: Evidence from a 5-decade longitudinal
British cohort. American Journal of Psychiatry
171 777-784 2014(11) Koike S, Bundo M, Iwamoto K, Suga M,
Kuwabara H, Ohashi Y, Shinoda K, Takano Y,
Iwashiro N, Satomura Y, Nagai T, Natsubori T,
Tada M, Yamasue H, Kasai K A snapshot ofplasma metabolities in first-rpisode schizophrenia: A capillary electrophoresis time-of-flightmass spectrometry study. Transl Psychiatry 42014(12) Natsubori T, Hashimoto R, Yahata N, Inoue H,
Takano Y, Iwashiro N, Koike S, Gonoi W, Sasaki
H, Takano H, Abe O, Kasai K, Yamasue H An
fMRI study of visual lexical decision in patientswith schizophrenia and clinical high-risk
individuals. Schizophr Res. 157 218-224 2014(13) Aoki Y, Yahata N, Watanabe T, Takano Y,
Kawakubo Y, Kuwabara H, Iwashiro N, Natsubori
T, Inoue H, Suga M, Takao H, Sasaki H, Gonoi W,
Kunimatsu S, Kasai K, Yamasue H Oxytocin
improves behavioural and neural deficits in
inferring others’ social emotions in autism. Brain
137 3073-3086 2014(14) Tada M, Nagai T, Kirihara K, Koike S, Suga M,
Araki T, Kobayashi T, Kasai K Differential
alterations of auditory gamma oscillatory responses between pre-onset high-risk individuals
and first-episode schizophrenia. Cereb Cortex.
2014(15) Watanabe T, Abe O, Kuwabara H, Yahata N,
Takano Y, Iwashiro N, Natsubori T, Aoki Y, Takao
H, Kawkubo Y, Kamio Y, Kato N, Miyashita Y,
Kasai K, Yamasue H Mtigation of sociocommunicational deficits of autism throughoxytocin-induced recovery of medial prefrontal
activity: a randomized trial. JAMA Psychiatry. 71
166-175 2014(16) Watanabe T, Yahata N, Kawakubo Y, Inoue H,
Takano Y, Iwashiro N, Natsubori T, Takao H,
Sasaki H, Gonoi W, Murakami M, Katsura M,
Kunimatsu A, Abe O, Kasai K, Yamasue H
Network structure underlying resolution of conflicting nonverbal and verbal social information.
Soc Cogn Affect Neurosci 9 767-775 2014(17) Miyashita M, Arai M, Yuzawa H, Niizato K,
Oshima K, Kushima I, Hashimoto R, Fukumoto
M, Koike S, Toyota T, Ujike H, Arinami T, Kasai
K, Takeda M, Ozaki N, Okazaki Y, Yoshikawa T,
Amano N, Miyata T, Itokawa M Replication ofenhanced carbonyl stress in a subpopulation ofschizophrenia. Psychiatry Clin Neurosci 68 83-84
2014(18) Bundo M, Toyoshima M, Okada Y, Akamatsu W,
Ueda J, Nemoto-Miyauchi T, Sunaga F, Toritsuka
M, Ikawa D, Kakita A, Kato M, Kasai K,
Kishimoto T, Nawa H, Okano H, Yoshikawa T,
Kato T, Iwamoto K Increased l1 retrotransposition in the neuroral genome in schizophrenia. Neuron 81 306-313 2014(19) Murata Y, Nishioka M, Bundo M, Sunaga F,
Kasai K, Iwamoto K Comprehensive DNA
methylation analysis of human neuroblastoma
cells treated with blonanserin. Neurosci Lett 563
123-128 2014(20) Imamura K, Kawakami N, Furukawa T,
Matsuyama Y, Shimazu A, Umanodan R,
Kasakami S, Kasai K Effects of an Internet-Based
Cognitive Behavioral Therapy (iCBT) Program in
Manga Format on Improving Subthreshold
Depressive Symptoms among Healthy Workers: A

89

Randomized Controlled Trial. PLOS ONE 9 2014(21) Saito Y, Suga M, Tochigi M, Abe O, Yahata N,
Kawakubo Y, Liu X, Kawamura Y, Sasaki T,
Kasai K, Yamasue H Neural correlate ofautistic-like traits and a common allele in theoxygen receptor gene. Soc Cogn Affect Neurosci
9 1443-1450 2014(22) Natsubori T, Inoue H, Abe O, Takano Y, Iwashiro
N, Aoki Y, Koike S, Yahata N, Katsura M, Gonoi
W, Sasaki H, Takao H, Kasai K, Yamasue H
Reduced frontal glutamate+glutamine andN-acetylaspartate levels in patients with chronic
schizophrenia but not in those at clinical-high riskfor psychosis or with first-episode schizophrenia.
Schizophr Bull 40 1128-1139 2014(23) Ando S, Yasugi D, Matsumoto T, Kanata S, Kasai
K Serious outcomes associated with overdose of
medicines containing barbiturates for treatment of
insomnia. Psychiatry Clin Neurosci 68 721 2014(24) Okamura T, Ito K, Morikawa S, Awata S. Suicidal
behavior among homeless people in Japan.
Social Psychiatry and Psychiatric Epidemiology
49 573-582 2014(25) Ito K, Morikawa S, Okamura T, Shimokado K,
Awata S. Factors associated with mental
well-being of homeless people in Japan.
Psychiatry and Clinical Neurosciences 68
145-153 2014(26) Okamura T, Arai H, Furukawa M, Tanaka O,
Hosoda M, Nakajima S, Furuta K, Ito K, Awata S,
Matsushita M Case of “Premonitory Depression”
in Patient with Major Depressive Disorder
Followed by Pancreatic Cancer Activ Nerv Super56 135-139 2014(27) Watanabe T, Takezawa M, Nakawake Y,
Kunimatsu A, Yamasue H, Nakamura M,
Miyashita Y, and Masuda N. Two distinct neuralmechanisms underlying indirect reciprocity. Proc
Natl Acad Sci U S A. 111 3990-3995 2014(28) Aoki Y, Inokuchi R, Nakao T and Yamasue H.
Neural bases of antisocia behavior: a voxel-based
meta-analysis. Soc Cogn Affect Neurosci 91223-1231 2014(29) Kubota-Sakashita M, Iwamoto K, Bundo M, Kato
T. A role of ADAR2 and RNA editing ofglutamate receptors in mood disorders andschizophrenia. Molecular Brain 7 2014(30) Mehta D, Iwamoto K, Ueda J, Bundo M, Adati N,
Kojima T, Kato T Comprehensive survey of
CNVs influencing gene expression in the humanbrain and its implications for pathophysiology.
Neuroscience Research 79 2014(31) Iwata A, Nagata K, Hatsuta H, Takuma H, Bundo
M, Iwamoto K, Tamaoka K, Murayama S, Saido
T, Tsuji S. Altered CpG methylation in sporadic
Alzheimer's disease is associated with APP and
MAPT dysregulation. Human Molecular Genetics
23 648-656 2014(32) Sakakibara E, Takahashi Y, Murata Y, Taniguchi
G, Sone D, and Watanabe M Chronic periodic
lateralised epileptic discharges and anti-Nmethyl-D-aspartate receptor antibodies Epileptic
Disorders 16 218-222 2014(33) Taniguchi G, Miyajima M, WatanabeM, Murata
Y,Sone D, Okazaki Y, Kobayashi-Kimura N, Kato
M, Onuma T Nonconvulsive status epilepticus in
the elderly associated with newer antidepressantsat therapeutic doses: A repot of threee cases
Epilepsy Behav Case Rep 4 8-11 2014(34) Aoki R, Matsumoto M, Yomogida Y, Izuma K,
Murayama K, Sugiura A, Camerer CF, Adolphs
R, Matsumoto K Social equality in the numberof choice options is represented in the ventromedial prefrontal cortex. The Journal of neuroscience 34 6413-6421 2014

90

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-91

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 hereditaryspinocerebellar atrophy (SCA34), a case report of
SCA23, Boucher-Neuhäuser syndrome, and adultonset vanishing white matter disease. Applicationof next generation sequencers for moleculardiagnosis for various diseases has been intensively
investigated. (Tsuji, S., Date, H., Suzuki, K.,
Mitsui, J., Ishiura, H., Matsukawa, T., Hatano, K.,
Sato, N., Yasuda, T., Naruse, H., Kawabe, 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.,
Unuma, 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.,
Ikenaga C., Uchio N., Taira K.).
Biochemistry lab is currently working on neuroepigenetics using post-mortem brains of Alzheimer’s
disease (AD), Lewy body disease, multiple system

92

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.).

3.

4.

5.

6.

7.

8.

Publication
1. Fujisawa T, Yamaguchi N, Kadowaki H,
Tsukamoto Y, Tsuburaya N, Tsubota A, Takahashi
H, Naguro I, Takahashi Y, Goto J, Tsuji S,
Nishitoh H, Homma K and Ichijo H. A systematic
immunoprecipitation approach reinforces the concept of common conformational alterations inamyotrophic lateral sclerosis-linked SOD1
mutants. Neurobiol Dis 82: 478-486, 2015. (DOI:
10.1016/j.nbd.2015.08.010)
2. Hanajima R, Shadmehr R, Ohminami S, Tsutsumi
R, Shirota Y, Shimizu T, Tanaka N, Terao Y, Tsuji
S, Ugawa Y, Uchimura M, Inoue M and Kitazawa

9.

S. Modulation of error-sensitivity during a prism
adaptation task in people with cerebellar
degeneration. J Neurophysiol 114: 2460-71, 2015.
(DOI: 10.1152/jn.00145.2015)
Ishiura H and Tsuji S. Epidemiology andmolecular mechanism of frontotemporal lobar
degeneration/amyotrophic lateral sclerosis withrepeatexpansion
mutation in C9orf72.
Neurogenet 29: 85-94, 2015. (DOI: 10.3109/
01677063.2015.1085980)
Kanbayashi T, Saito F, Matsukawa T, Oba H,
Hokkoku K, Hatanaka Y, Tsuji S, and Sonoo M.
Adult-onset vanishing white matter disease withnovel missense mutations in a subunit oftranslational regulator, EIF2B4. Clin Genet 88:
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Koh K, Kobayashi F, Miwa M, Shindo K, Isozaki
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Y. Sporadic late-onset nemaline myopathy as arare cause of slowly progressive muscle weakness
with young adult onset. Muscle Nerve. 51:772-4,
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Matsuda S, Matsumoto H, Furubayashi T, Fukuda
H, Hanajima R, Tsuji S, Ugawa Y, and Terao Y.
Visual scanning area is abnormally enlarged inhereditary pure cerebellar ataxia. Cerebellum. 14:
63-71,2015.(DOI:10.1007/s12311-014-0600-5)
Matsuda S, Matsumoto H, Furubayashi T,
Hanajima R, Tsuji S, Ugawa Y,and Terao Y. The
3-second rule in hereditary pure cerebellar ataxia:
a synchronized tapping study. PLoS One. 10:
e0118592, 2015. (DOI: 10.1371/journal.pone.
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Mitsui J, Matsukawa T, Sasaki H, Yabe I,
Matsushima M, Dürr A, Brice A, Takashima H,
Kikuchi A, Aoki M, Ishiura H, Yasuda T, Date H,
Ahsan B, Iwata A, Goto J, Ichikawa Y, Nakahara
Y, Momose Y, Takahashi Y, Hara K, Kakita A,
Yamada M, Takahashi H, Onodera O, Nishizawa
M, Watanabe H, Ito M, Sobue G, Ishikawa K,
Mizusawa H, Kanai K, Hattori T, Kuwabara S,
Arai K, Koyano S, Kuroiwa Y, Hasegawa K,
Yuasa T, Yasui K, Nakashima K, Ito H, Izumi Y,

93

Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi M,
Kondo T, Murayama S, Hattori N, Yamamoto M,
Murata M, Satake W, Toda T, Filla A, Klockgether
T, W?llner U, Nicholson G, Gilman S, Tanner CM,
Kukull WA, Stern MB, Lee VM-Y, Trojanowski
JQ, Masliah E, Low PA, Sandroni P, Ozelius LJ,
Foroud T, and Tsuji S. Variants associated with
Gaucher disease in multiple system atrophy. Ann
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10. Miyagawa T, Tsuji S, Iwata A. Large subdural
hematoma in advanced Huntington's disease.
Intern Med. 54:1461, 2015. (DOI: 10.2169/
internalmedicine.54.4159)
11. Namiki C, Takita Y, Iwata A, Momose T. Senda M,
Okubo Y, Joshi AD, Lu M, Breault C and
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Morishita S, Higashi M, Sekiguchi T, Koyama K,
Ueda N, Miura Y, Miyatake S, Matsumoto N,
Yokota T, Tanaka F, Tsuji S, Mizusawa H, andIshikawa K. A Novel Mutation in ELOVL4
Leading to Spinocerebellar Ataxia (SCA) With the
Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34.
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Samukawa M, Ichikawa Y, Goto J, Tsuji S, andKusunoki S. The first Japanese familial case ofspinocerebellar ataxia 23 with a novel mutation in
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Imai H, Shin M, Sato K, Tsuchida T, Hayashi T,
Terao Y, Numakura S, Morikawa T, Shibahara J,
Kikuta S, Kondo K, Tatsuno K, Mori H,
Kunimatsu A, Tsuji S and Saito N. Recurrent
cerebral aneurysm formation and rupture within ashort period due to invasive aspergillosis of thenasal sinus; pathological analysis of the catastro-

phic clinical course. Int J Clin Exp Pathol 8:13510-13522, 2015.
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94

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.,

Masaaki Shojima, M.D., Ph.D.

Associate
Takashi Ochi, M.D.

Shota Tanaka, M.D.

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

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

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

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

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

Homepage

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

Introduction and Organization

Clinical activities

The Department of Neurosurgery at the Universityof Tokyo Hospital consists of 14 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research, and education. The staffs
include a professor/chairman, an associate professor,
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 2015 toMarch 2016, 16,715 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 2015, 869 patients wereadmitted to the neurosurgery ward. 429 surgicalprocedures and 116 gamma knife procedures were
performed in 2015. Our practice covers a wide varietyof neurosurgical diseases including malignant andbenign brain tumors, hemorrhagic and thromboembolic cerebrovascular diseases, spinal disorders,
epilepsy, pain and movement disorders.

95

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-ofthe-art techniques including intraoperative computeraided navigation and intravascular procedures help
our continuous effort to increase the safety of surgicaltreatment.
Our department is affiliated with 30 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 9000
cases.

Research activities

Teaching activities

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.

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 and 4 residents in2016 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.

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: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 withwhole exome sequencing, RNA sequencing,expression profiling, and methylation analysis. Ourparticular interest lies in tumor heterogeneity and96malignant 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 ofgamma knife radiosurgery in the future.

97

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Cortex 25(5):1265-1277, 201512. Miyawaki S., Imai H., Shimizu M., Yagi S., Ono
H., Nakatomi H., Shimizu T., Saito N. Genetic
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Stroke Cerebrovasc Dis 24(5):1075-1079, 2015
13. Obuchi M., Sumitani M., Shin M., Ishii K.,
Kogure T., Miyauchi S., Yamada Y. Spinal cord
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sleep disorders: a case series. Neuromodulation
18(3):191-193; discussion 193, 201514. Shimada S., Kunii N., Kawai K., Usami K.,
Matsuo T., Uno T., Koizumi T., Saito N.
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Presenting with Epilepsy: Report of Two Cases.
World Neurosurg 84(3):867.e861-866, 201515. Shin M., Kondo K., Kin T., Suzukawa K., Saito N.
Endoscopic transnasal interseptal approach forinvasive clival tumors: development of an
approach method regarding maximal preservationof the nasal anatomy. Neurol Med Chir (Tokyo)
55(4):336-344, 201516. Shin M., Kondo K., Hanakita S., Suzukawa K.,
Kin T., Shojima M., Nakagawa D., Saito N.
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Imai H., Shin M., Sato K., Tsuchida T., Hayashi T.,
Terao Y., Numakura S., Morikawa T., Shibahara J.,
Kikuta S., Kondo K., Tatsuno K., Mori H.,
Kunimatsu A., Tsuji S., Saito N. Recurrent
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98short period due to invasive aspergillosis of thenasal sinus; pathological analysis of thecatastrophic clinical course. Int J Clin Exp
Pathol 8(10):13510-13522, 2015
18. Takami H., Yoshida A., Fukushima S., Arita H.,
Matsushita Y., Nakamura T., Ohno M., Miyakita
Y., Shibui S., Narita Y., Ichimura K. Revisiting
TP53 Mutations and Immunohistochemistry--A
Comparative Study in 157 Diffuse Gliomas.
Brain Pathol 25(3):256-265, 2015
19. Takami H., Mukasa A., Ikemura M., Shibahara J.,
Takahashi M., Momose T., Saito N. Findings frompositron emission tomography and genetic
analyses for cerebellar liponeurocytoma. Brain
Tumor Pathol 32(3):210-215, 2015
20. Takami H., Fukushima S., Fukuoka K., Suzuki T.,
Yanagisawa T., Matsushita Y., Nakamura T., Arita
H., Mukasa A., Saito N., Kanamori M., KumabeT., Tominaga T., Kobayashi K., Nagane M., Iuchi
T., Tamura K., Maehara T., Sugiyama K., Nakada
M., Kanemura Y., Nonaka M., Yokogami K.,
Takeshima H., Narita Y., Shibui S., Nakazato Y.,
Nishikawa R., Ichimura K., Matsutani M. Humanchorionic gonadotropin is expressed virtually in
all intracranial germ cell tumors. J Neurooncol
124(1):23-32, 2015
21. Tateishi K., Wakimoto H., Iafrate A. J., Tanaka S.,
Loebel F., Lelic N., Wiederschain D., Bedel O.,
Deng G., Zhang B., He T., Shi X., Gerszten R. E.,
Zhang Y., Yeh J. R., Curry W. T., Zhao D.,
Sundaram S., Nigim F., Koerner M. V., Ho Q.,
Fisher D. E., Roider E. M., Kemeny L. V.,
Samuels Y., Flaherty K. T., Batchelor T. T., Chi A.
S., Cahill D. P. Extreme Vulnerability of IDH1
Mutant Cancers to NAD+ Depletion. Cancer cell28(6):773-784, 2015
22. Uno T., Kawai K., Sakai K., Wakebe T., Ibaraki T.,
Kunii N., Matsuo T., Saito N. Dissociated roles of
the inferior frontal gyrus and superior temporalsulcus in audiovisual processing: top-down andbottom-up mismatch detection. PLoS One 10(3):e0122580, 201523. van Thuijl H. F., Mazor T., Johnson B. E., Fouse S.
D., Aihara K., Hong C., Malmstrom A., Hallbeck
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H., Mukasa A., Berger M. S., Soderkvist P.,

Taylor B. S., Molinaro A. M., Wesseling P.,
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Nakatomi H., Oyama H., Saito N. A Microscopic
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25. Yoshino M., Kin T., Ito A., Saito T., Nakagawa D.,
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Ino K., Kamada K., Mori H., Kunimatsu A.,
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Social Medicine
1. Occupational, Environmental
and Preventive Medicine

101

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.

102

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.

103Department 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
Fumiaki Nakamura, M.D., Ph.D. (Until September, 2015)

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 2015, the Department
consists of four faculty members above listed, aproject lecturer (part-time), two project researchers(part-time), two supporting staffs, 18 graduate
students (17 in PhD program and one temporary
supervised), 17 part-time lecturers, and 22 visiting
fellows.

104

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 spring 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.

105

References
1. Maeda E, Sugimori H, Nakamura F, Kobayashi Y,
Green J, Suka M, Okamoto M, Boivin J, Saito H.
A cross sectional study on fertility knowledge inJapan, measured with the Japanese version of
Cardiff Fertility Knowledge Scale (CFKS-J).
Reproductive Health 12 (1) : 10, doi:10.1186/
1742-4755-12-10, 2015.
2. Maeda E, Iwata T, Murata K. Effects of workstress and home stress on autonomic nervous
function in Japanese male workers. Industrial
Health 53(2): 132–138, 2015.
3. Kondo N, Nakamura F, Yamazaki S, Yamamoto Y,
Akizawa T, Akiba T, Saito A, Kurokawa K,
Fukuhara S. Prescription of potentially inappropriate medications to elderly hemodialysis
patients: Prevalence and predictors. Nephrology
Dialysis Transplantation doi: 10.1093/ndt/gfu070,
2015.
4. Sugiyama T, Hasegawa K, Kobayashi Y,
Takahashi O, Fukui T, Tsugawa Y. Differential
time trends of outcomes and costs of care for
acute myocardial infarction hospitalizations by ST
elevation and type of intervention in the UnitedStates, 2001-2011. Journal of the American Heart
Association doi: 10.1161/JAHA.114.001445,2015.
5. Stickley A, Koyanagi A, Leinsalu M, Ferlander S,
Sabawoon W, McKee M. Loneliness and health inEastern Europe: Findings from Moscow, Russia.
Public Health 129 (4): 403-410, doi: org/10.1016/j.
puhe.2014.12.021, 2015.
6. Sugiyama T, Steers WN, Wenger NS, Duru OK,
Mangione CM. Effect of a community-based
diabetes self-management empowerment program
on mental health-related quality of life: A causal
mediation analysis from a randomized controlled
trial. BMC Health Services Research 15:115, doi:
10.1186/s12913-015-0779-22015, 2015.
7. Morioka N, Tomio J, Seto T, Kobayashi Y. Trends
in the geographic distribution of nursing staff
before and after the Great East Japan Earthquake:
A longitudinal study. Human Resources for Health
13:70, doi: 10.1186/s12960-015-0067-6, 2015.
8. Kamitani S, Nakamura F, Itoh M, Sugiyama T,
Toyokawa S, Kobayashi Y. Differences in medical
school type and year of establishment: Effect of
new schools built under government policy. BMC

Health Services Research 15:581, doi: 10.1186/
s12913-015-1240-22015, 2015.
9. Nakahara S, Tomio J, Ichikawa M, Nakamura F,
Nishida M, Takahashi H, Morimura N, Sakamoto
T. Association of bystander interventions withneurologically intact survival among patients withbystander-witnessed out-of-hospital cardiac arrestin Japan. The Journal of the American Medical
Association 314(3): 247-54, 2015.
10. Tsukada Y, Nakamura F, Iwamoto M, Terahara A,
Higashi T. Patterns of prescribing radiotherapy
and bevacizumab in nationwide practice Analysis of 101 designated cancer care hospitals
in Japan. Journal of Radiation Research 2015 Dec
9. pii: rrv080. [Epub ahead of print]
11. Iwamoto M, Nakamura F, Higashi T. Monitoringand evaluating the quality of cancer care in Japan
using administrative claims data. Cancer Science
doi: 10.1111/cas.12837, 2015
12. Arima N, Nakamura F, Yabe T, Tanaka J, Fuji S,
Ohashi K, Fukuda T, Miyamura K, Iwato K, Eto T,
Mori T, Kobayashi N, Hoshino T, Kato C,
Kanamori H, Nakamae H, Atsuta Y, Morishima Y,
Kanda Y. Influence of differently licensed
KIR2DL1-positive natural killer cells in transplant recipients with acute leukemia: a Japanesenational registry study. Biology of Blood andMarrow Transplantation doi: 10.1016/j.bbmt.2015.
09.029, 2015
13. Tsukada Y, Nakamura F, Iwamoto M, Nishimoto
H, Emori Y, Terahara A, Higashi T. Are hospitals
in Japan with larger patient volume treating
younger and earlier-stage cancer patients? Ananalysis of hospital-based cancer registry data inJapan. Japanese Journal of Clinical Oncology
45(8):719-26, 2015.
14. Noguchi S, Toyokawa S, Miyoshi Y, Suyama Y,
Inoue K, Kobayashi Y. Five-year follow-up studyof the association between periodontal disease andmyocardial infaction among Japanese maleworkers: MY Health Up Study. Journal of Public
Health 37(4): 605-611, 2015.
15. Zaitsu M, Toyokawa S, Tonooka A, Nakamura F,
Takeuchi T, Homma Y, Kobayashi Y. Sex
differences in bladder cancer pathology andsurvival: Analysis of a population-based cancer
registry. Cancer Medicine 4 (3): 363-370, 2015.

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

107

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 University of Tokyo since 1881
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 componet. He helped foundation of national
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) has started by
the cooperation with Chiba University. We arepreparing to teach practice and research for the future
forensic pathologists.

Postmortem examination
The determination of precise cause of death is themost important mission of 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 examine thepathological, alcohol, toxicological, and blood type
testing of each case, too. Finally, forensic pathologists
in our department diagnose the cause of death. Expert
opinions expresses the cause of death and forensic
judgment for each case.

108

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, each student experiences the process from
autopsy to presentation of expert opinion.
In addition, students of school of public health and(undergraduate & graduate) law school are provided
with somewhat practical lectures with exercises. We
have provided opportunity for PhD students of Schoolof Hearth Science, and master course of Medical
Science.

Research
By the 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 study about a method of theartery using angioscopy. We also study about theusefulness of coronary angiography using 3D-CT.
As to pathological reserach, we investigate about
the lipid peroxidation in 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 and liaise 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 study about the redistribution of some drugs by
experiments using animals. We try to figure out thestandardized method of drug testing in the field ofJapanese forensic medicine.
4. Forensic Odontology
A new method of personal identification (estimation of age, sex) and drug analysis using a single
tooth at once is developed.
5. Forensic Genetics
We try to find gene alterations that cause anindividual to a sudden death. We also try to figureout new methods to predict the birth place of the
cadaver using DNA analysis for parasites.
6. Forensic Radiology
Using 3D-CT, we develop new methods topredict the stature or sex from the form or
measurement of bones. We investigate the merit anddemerit of post-mortem imaging to determine thecause of desth.

Publications
1. Yajima D, Asari M, Okuda K, Maseda C, Yamada
H, Ichimaru C, Matsubara K, Shiono H, Iwase H,
Makino Y, Shimizu K. An objective approach
using three indexes for determining fatal
hypothermia due to cold exposure; statisticalanalysis of oxyhemoglobin saturation data. Leg
Med (Tokyo). 2015 Nov;17(6):451-8.
2. Yamaguchi R, Makino Y, Chiba F, Torimitsu S,
Yajima D, Shinozaki T, Iwase H. Fluid-Fluid
Level and Pericardial Hyperdense Ring
Appearance Findings on Unenhanced Postmortem
CT Can Differentiate Between Postmortem andAntemortem Pericardial Hemorrhage. AJR Am J
Roentgenol. 2015 Dec;205(6):W568-77.

109

3. 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. Morphometric analysis of sex
differences in contemporary Japanese pelvesusing multidetector computed tomography.
Forensic Sci Int. 2015 Dec;257:530.e1-7.
4. Nara A, Nagai H, Yamaguchi R, Makino Y, Chiba
F, Yoshida K, Yajima D, Iwase H. An unusual
autopsy case of lethal hypothermia exacerbated bybody lice-induced severe anemia. Int J Legal Med.
2016 May;130(3):765-9.
5. Inokuchi G, Makino Y, Yajima D, Motomura A,
Chiba F, Torimitsu S, Hoshioka Y, Iwase H. A
case of acute subdural hematoma due to ruptured
aneurysm detected by postmortem angiography.
Int J Legal Med. 2016 Mar;130(2):441-6.
6. Watanabe M, Unuma K, Makino Y, Noritake K,
Yamada A, Iwase H, Uemura K. An Autopsy
Case of Acute Massive Hematochezia Caused bySuperior Mesenteric Vein Thrombosis: A First
Report in Forensic Medicine. J Forensic Sci. 2016
Jan;61(1):271-3.
7. Makino Y, Abe H, Yokoyama M, Torimitsu S,
Chiba F, Yokota H, Oka T, Iwase H. Mercury
embolism of the lung and right ventricle revealedby postmortem computed tomography and X-ray
analytic microscopy. Forensic Sci Med Pathol.
2015 Sep;11(3):464-7.
8. Inokuchi G, Makino Y, Motomura A, Chiba F,
Torimitsu S, Hoshioka Y, Iwase H. Fatal rightcoronary artery rupture following blunt chest
trauma: detection by postmortem selective
coronary angiography. Int J Legal Med. 2016
May;130(3):759-63.
9. Makino Y, Inokuchi G, Yokota H, Hayakawa M,
Yajima D, Motomura A, Chiba F, Torimitsu S,
Nakatani Y, Iwase H. Sudden death due tocoronary artery dissection associated withfibromuscular dysplasia revealed by postmortem
selective computed tomography coronary angiography: A case report. Forensic Sci Int. 2015 Aug;
253:e10-5.
10. Yamaguchi R, Makino Y, Chiba F, Motomura A,
Inokuchi G, Yajima D, Iwase H. Fatal
Clostridium perfringens septicemia suggested bypostmortem computed tomography: A medico-

legal autopsy case report. Forensic Sci Int. 2015
Aug;253:e4-9.
11. Torimitsu S, Nishida Y, Takano T, Yajima D,
Inokuchi G, Makino Y, Motomura A, Chiba F,
Yamaguchi R, Hashimoto M, Hoshioka Y, Iwase
H. Differences in biomechanical properties andthickness among frontal and parietal bones in a
Japanese sample. Forensic Sci Int. 2015 Jul;252:
190.e1-6.
12. Makino Y, Yamamoto S, Shiotani S, Hayakawa H,
Fujimoto H, Yokota H, Horikoshi T, Iwase H,
Uno T. Can ruptured abdominal aortic aneurysm
be accurately diagnosed as the cause of death
without postmortem computed tomography when
autopsies cannot be performed? Forensic Sci Int.
2015 Apr;249:107-11.
13. Torimitsu S, Makino Y, Saitoh H, Sakuma A,
Ishii N, Inokuchi G, Motomura A, Chiba F,
Hoshioka Y, Iwase H. Estimation of sex in
Japanese cadavers based on sternal measurements
using multidetector computed tomography. Leg
Med (Tokyo). 2015 Jul;17(4):226-31.
14. Torimitsu S, Nishida Y, Takano T, Koizumi Y,
Hayakawa M, Yajima D, Inokuchi G, Makino Y,
Motomura A, Chiba F, Iwase H. Statisticalanalysis of biomechanical properties of the adultsagittal suture using a bending method in a
Japanese forensic sample. Forensic Sci Int. 2015
Apr;249:101-6.
15. Torimitsu S, Makino Y, Saitoh H, Sakuma A,
Ishii N, Hayakawa M, Inokuchi G, Motomura A,
Chiba F, Hoshioka Y, Iwase H. Stature estimationin Japanese cadavers based on the second cervicalvertebra measured using multidetector computed
tomography. Leg Med (Tokyo). 2015 May;17(3):145-9.
16. Sakuma A, Makino Y, Saitoh H, Chiba F, Ishii N,
Iwase H. Evaluation of a personal identification
method using the fusion function of CT images
and dental radiographs. Dentomaxillofac Radiol.
2015;44(2):20140137.
17. Nagasawa S, Yajima D, Torimitsu S, Chiba F,
Iwase H. Postmortem memantine concentration ina non-intoxication case, and the possibility of
postmortem redistribution: A case report. Forensic
Sci Int. 2015 Dec;257:e12-5.

110

18. Nagasawa S, Torimitsu S, Chiba F, Kubo Y,
Yajima D, Iwase H. Donepezil distribution in
postmortem cases and potential for redistribution.
Forensic Sci Int. 2015 Jun;251:132-8.
19. Nara A, Nagai H, Shintani-Ishida K, Ogura S,
Shimosawa T, Kuwahira I, Shirai M, Yoshida K.
Pulmonary arterial hypertension in rats due toage-related arginase activation in intermittent
hypoxia. Am J Respir Cell Mol Biol. 2015 Aug;53(2):184-92.
20. Nara A, Nagai H, Yamaguchi R, Yoshida K,
Iwase H, Mizuguchi M. An unusual autopsy caseof cytokine storm-derived influenza-associatedencephalopathy without typical histopathologicalfindings: autopsy case report. Am J Forensic Med
Pathol. 2015 Mar;36(1):3-5.

111

Department of Medical
Informatics and Economics
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,
medicalknowledge
engineering,
hospital
epidemiology, quality assessment of healthcare,clinical and bioinformatics engineering, privacy
protection and encryption, analysis of hospitalmanagement, 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.

112

Teaching activities
Teaching staffs and the collaborative members are
Professor Kazuhiko Ohe, Associate Professor Kengo
Miyo(-2014.12), Assistant Professor Katsuya Tanaka,
Hidenao Atarashi, Takeshi Imai, Research Associate
Shinichiro Yokota, Yoshimasa Kawazoe, Takashi
Noguchi and Daisuke 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 FY2014 are three in doctor’s course
for Medical Informatics and Economics, two inmaster’s course for Health Informatics.
The their researches cover various topics; development of medical decision support system, analysis of
medical human resources in Japan, research for
medical and pharmacological ontology, etc.

Research activities
The research domains are 1) application studies ondevelopments of clinical information systems, hospital
information system and electronic health records
system, 2) studies on medical safety information
systems, 3) medical knowledge discovery and analysisof medical economics indicators by using databases of
hospital information system and electronic healthrecords system, 4) structured representations andstandardization of medical terms and concepts, 5)privacy protection and security in healthcare
information systems, 6) analysis of localization andrestructuring of medical human resources.
In these domains, major research topics are as listed
below.
1) A study on development methods for large scale
ontology databases of medical terms andconcepts :This research is to develop a methods to build alarge scale medical ontology, which is a databasefor hundreds of thousand of clinical terms andconcepts and their relationships. The medical
ontology covers over 6000 diseases and whole ofhuman anatomical structures using HOZO
ontology describing tool, and the ontology wasconverted 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/

1132) Development of Multi-purpose Clinical Dara
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.

4.

5.

6.

7.
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. Yokota S, Ohe K. Construction and evaluation of
FiND, a fall risk prediction model of inpatientsfrom nursing data. Japan Journal of Nursing
Science. 2016; 13(2): 247–255. doi:10.1111/jjns.
12103
2. Waki K, Aizawa K, Kato S, Fujita H, Lee H,
Kobayashi H, Ogawa M, Mouri K, Kadowaki T,
Ohe K.:DialBetics With a Multimedia Food
Recording Tool, FoodLog: Smartphone-Based
Self-Management for Type 2 Diabetes.,J Diabetes
Sci Technol. 2015 May;9(3):534-40.
3. Takeuchi I, Fujita H, Yanagisawa T, Sato N,
Mizutani T, Hattori J, Asakuma S, Yamaya T,
Inagaki T, Kataoka Y, Ohe K, Ako J, AsariY.:Impact of Doctor Car with Mobile Cloud ECG
in reducing door-to- balloon time of Japanese
ST-elevation myocardial infarction patients.,Int

8.

Heart J. 2015;56(2):170-3.
Kozaki K, Yamagata Y, Mizoguchi R, Imai T and
Ohe K. Disease Compass – Navigation System for
Disease Knowledge based on Ontology and
Linked Data Techniques. In Proc. of the 4thInternational Conference on Biomedical Ontology(ICBO 2015), Lisbon, Portugal, pp.77-81, July
27-30, 2015
Nakaya J, Imai T, Hiroi K, Watari M, Tanaka H.
Progress around Clinical Omics sub information
model for ICD11 (iCOs). WHO Family ofInternational Classifications (WHO-FIC) Network
Annual Meeting 2015, Manchester, United
Kingdom, October 17-23,2015.
Osumi H, Shinozaki E, Osako M, Kawazoe Y,
Oba M, Misaka T, Goto T, Kamo H, Suenaga M,
Kumekawa Y, Ogura M, Ozaka M, Matsusaka S,
Chin K, Hatake K, Mizunuma N, Cetuximab
treatment for metastatic colorectal cancer with
KRAS p.G13D mutations improves progressionfree survival. Mol Clin Oncol. 2015 Sep;3(5):1053-1057.
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., Int J
Health Geogr. 2016 Jan 22;15:4.
Koike S, Shimizu A, Matsumoto M, Ide H,
Atarashi H, Yasunaga H, Career pathways ofboard-certified surgeons in Japan. Surg Today.
2016 Jun;46(6):661-7.

Internal Medicine
1. Medicine Ⅰ

115

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

http://plaza.umin.ac.jp/~utok-card/

Introduction and Organization

members, 36 graduate school students.

The Department of Cardiovascular Medicine isactively involved in clinical medicine, basic researchand teaching. In line with the rapidly evolving andprogressing nature of modern treatment ofcardiovascular diseases, our department has changed
dynamically during the recent years. Not only do wehave the most highly advanced equipment andfacilities (e.g. 24-hour cardiac care unit), but are
personnel also highly trained to be well knowledged
and expert in the most modern methods of diagnosis
and treatment. As a teaching and research hospital, we
also emphasize the development and incorporation of
new treatments if they may benefit the patient. From a
research standpoint, our interests range throughout all
fields of cardiovascular medicine ranging frommolecular biology to clinical research including
genomics. Importantly, our research interests are
aimed at making possible new diagnostics andtreatment of cardiovascular diseases. Finally, we havea particular interest in teaching not only for medical
students but also for residents which is important for
the future of cardiovascular medicine.

Clinical activities

Staff: one professor (Issei Komuro), 4 lecturers, 1
hospital lecturer, 16 research associates, 10 staff

In 2015, 1,850 patients were newly admitted to our
hospital ward of approximately 60 beds. Duration of
hospitalization is on average 12.7 days. Cardiovascular angiograms were conducted in 1,686 patients,of which 568 cases were interventional procedures.
CT coronary angiography was examined in 409 patients and cardiovascular MRI in 76. For arrhythmias,
there were 299 cases of catheter ablation, 73 cases of
implantation or replacement of a pacemaker, and otherspecialized pacemaker devices such as 29 cases of
implantation or replacement of an implantablecardioverter-defibrillator (ICD) and 7 cases of implantation or replacement of a cardiac resynchronization device (CRTD).
As we are an authorized facility for heart transplantation, left ventricular assist device (LVAD) use
for severe heart failure cases has been increasing. In
2006, the first case of heart failure from our department underwent a heart transplant procedure at the
Department of Cardiovascular Surgery. The hearts
were transplanted to 16 cases in 2015 (total 66 cases).
March 2014, our facility was also authorized for lungtransplantation.

116

Out-patient clinics are available as part of the
Department of Medicine or as a specialized department. The profile of diseases includes ischemic heartdisease, heart failure and arrhythmia in addition to
hypertension and peripheral artery disease. Outpatient clinics are open both mornings and afternoons
from Monday to Friday. Approximately 218.5 patients
visit each day. Acute cases of coronary heart disease
and aortic disease are also a focus of the department,
as emergent catheterization is available on a 24-hours
basis.

Education
As a division of the Department of Medicine,
medical diagnostics training, general cardiovascular
medicine, clinical lectures and bedside teaching arecourses available at the medical school. For bedsideteaching, three or four students are placed under theguidance of one research associate allowing forteaching in small groups. Specialized groups provide
lectures. As for post-graduate education, residents are
educated through specialized group conferences,
grand rounds and clinical conferences.

Research activities
Areas of interest are as follows:
1. Molecular mechanisms of human heart diseases using iPS cells 2. Interplay between organs, cells, and molecules inchronic inflammation
3. Cardiac hypertrophy and heart failure: analyses ofpathogenic mechanisms and development of novel
therapies (gene therapy, etc.)
4. Transcriptional regulation of various genes
involved in cardiovascular development andpathogenesis
5. Differentiation of smooth muscle cells (atherosclerosis and restenosis after vascular interventions)
6. Nitric oxide and endothelial function
7. Mechanisms for cardiorenal association
8. Regeneration therapy for cardiovascular disease
9. Roles of hypoxia signaling in cardiovascular diseases
10. Genetic polymorphisms and risk factors in
cardiovascular disease

11. Optimization of individual treatment using theComputer Heart Simulator
12. Investigation of disease pathophysiology anddevelopment of novel therapies (severe heart
failure, cardiac transplantation, congenital heartdisease)
13. Diagnosis and treatment of Marfan syndrome andadult congenital heart disease
14. New treatment for pulmonary hypertension
15. Ischemic heart disease in patients with diabetic
retinopathy
16. Aerobic threshold and cardiac rehabilitation
17. Imaging techniques (echocardiography, MRI, CT,
SPECT) in cardiovascular diseases

Publications (2015)
1. Yabumoto C, Akazawa H, Yamamoto R, Yano M,
Kudo-Sakamoto Y, Sumida T, et al. Angiotensin
II receptor blockade promotes repair of skeletal
muscle through down-regulation of agingpromoting C1q expression. Scientific reports.
2015;5:14453.
2. Ikeda Y, Kumagai H, Motozawa Y, Suzuki J,
Komuro I. Next Generation ARBs. Going Beyond
Modulation of the Renin-Angiotensin System.
International heart journal. 2015;56(6):585-6.
3. Yamaguchi T, Amiya E, Watanabe M, Komuro I.
Improvement of Severe Heart Failure after
Endovascular Stent Grafting for Thoracic Aortic
Aneurysm. International heart journal. 2015;
56(6):682-5
4. Nitta D, Kinugawa K, Imamura T, Hatano M, Ono
M, Nakamura F, et al. How Should We Treat
Early Post-Transplant Lymphoproliferative Disease After Heart Transplantation? International
heart journal. 2015;56(6):676-8
5. Yano M, Akazawa H, Oka T, Yabumoto C,
Kudo-Sakamoto Y, Kamo T, et al. Monocytederived extracellular Nampt-dependent biosynthesis of NAD(+) protects the heart againstpressure overload. Scientific reports. 2015;5:
15857.
6. Imamura T, Kinugawa K, Nitta D, Komuro I.
Complete left bundle branch block and smaller
left atrium are predictors of response to cardiac
resynchronization therapy in advanced heart

117

failure. Circulation journal : official journal of theJapanese Circulation Society. 2015;79(11):2414-21. Epub 2015/09/18.
7. Nitta D, Kinugawa K, Imamura T, Endo M,
Amiya E, Inaba T, et al. An Experience ofLandiolol Use for an Advanced Heart Failure
Patient With Severe Hypotension. International
heart journal. 2015;56(5):564-7
8. Nakayama A, Morita H, Nakao T, Yamaguchi T,
Sumida T, Ikeda Y, et al. A Food-Derived
Flavonoid Luteolin Protects against Angiotensin
II-Induced Cardiac Remodeling. PloS one. 2015;
10(9):e0137106.
9. Ikeda Y, Kumagai H, Motozawa Y, Suzuki J,
Komuro I. Biased Agonism of the Angiotensin II
Type I Receptor. International heart journal. 2015;
56(5):485-8.
10. Sakamoto A, Higashikuni Y, Hongo M, Imai Y,
Koike K, Nagai R, et al. Pioglitazone Reduces
Vascular Lipid Accumulation in Angiotensin IIInduced Hypertensive Rat. Journal of atherosclerosis and thrombosis. 2015;22(12):1225-34.
11. Motozawa Y, Uozumi H, Maemura S, Nakata R,
Yamamoto K, Takizawa M, et al. Acute
Myocardial Infarction That Resulted From Poor
Adherence to Medical Treatment for GiantCoronary Aneurysm. International heart journal.
2015;56(5):551-4.
12. Muraoka H, Imamura T, Hatano M, Maki H, Yao
A, Kinugawa K, et al. Secure Combination
Therapy With Low-Dose Bosentan andAmbrisentan to Treat Portopulmonary Hypertension Minimizing Each Adverse Effect.
International heart journal. 2015;56(4):471-3.
13. Ikeda Y, Kumagai H, Okazaki H, Fujishiro M,
Motozawa Y, Nomura S, et al. Monitoring betaarrestin recruitment via beta-lactamase enzyme
fragment complementation: purification of
peptide E as a low-affinity ligand for mammalianbombesin receptors. PloS one. 2015;10(6):e0127445.
14. Kumagai H, Ikeda Y, Motozawa Y, Fujishiro M,
Okamura T, Fujio K, et al. Quantitative Measurement of GPCR Endocytosis via Pulse-Chase
Covalent Labeling. PloS one. 2015;10(5):e0129394.
15. Yagi H, Hatano M, Takeda N, Harada S, Suzuki

Y, Taniguchi Y, et al. Congenital Contractural
Arachnodactyly without FBN1 or FBN2 Gene
Mutations Complicated by Dilated Cardiomyopathy. Intern Med. 2015;54(10):1237-41.
16. Son BK, Sawaki D, Tomida S, Fujita D, Aizawa
K, Aoki H, et al. Granulocyte macrophagecolony-stimulating factor is required for aortic
dissection/intramural haematoma. Nature communications. 2015;6:6994.
17. Takahashi M, Miyazaki S, Myojo M, Sawaki D,
Iwata H, Kiyosue A, et al. Impact of the distancefrom the stent edge to the residual plaque on edge
restenosis following everolimus-eluting stentimplantation. PloS one. 2015;10(3):e0121079.
18. Fujino T, Yao A, Hatano M, Inaba T, Muraoka H,
Minatsuki S, et al. Targeted therapy is required
for management of pulmonary arterial hypertension after defect closure in adult patients withatrial septal defect and associated pulmonary
arterial hypertension. International heart journal.
2015;56(1):86-93.
19. Suzuki J, Aoyama N, Izumi Y, Isobe M, Komuro
I, Hirata Y. Effect of periodontitis on cardiovascular manifestations in Marfan syndrome.
Critical common role of TGF-beta. International
heart journal. 2015;56(2):121-4.
20. Minatsuki S, Miura I, Yao A, Abe H, Muraoka H,
Tanaka M, et al. Platelet-derived growth factor
receptor-tyrosine kinase inhibitor, imatinib, iseffective for treating pulmonary hypertension induced by pulmonary tumor thrombotic microangiopathy. International heart journal. 2015;
56(2):245-8.
21. Imamura T, Kinugawa K, Nitta D, Inaba T, Maki
H, Hatano M, et al. Novel scoring system using
cardiopulmonary exercise testing predicts prognosis in heart failure patients receiving guidelinedirected medical therapy. Circulation journal:
official journal of the Japanese Circulation
Society. 2015;79(5):1068-75.
22. Sumida T, Naito AT, Nomura S, Nakagawa A,
Higo T, Hashimoto A, et al. Complement C1qinduced activation of beta-catenin signallingcauses hypertensive arterial remodelling. Naturecommunications. 2015;6:6241.
23. Takeda N, Morita H, Fujita D, Inuzuka R,
Taniguchi Y, Nawata K, et al. A deleterious

118

MYH11 mutation causing familial thoracic aortic
dissection. Human genome variation. 2015;2:
15028.
24. 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. Circulation journal : official journalof the Japanese Circulation Society. 2016;80(2):332-9. Epub 2015/12/08.
25. Myojo M, Takahashi M, Tanaka T, Higashikuni Y,
Kiyosue A, Ando J, et al. Midterm follow-up after
retrievable inferior vena cava filter placement invenous thromboembolism patients with or without
malignancy. Clinical cardiology. 2015;38(4):21621.
26. Ko T, Higashitani M, Sato A, Uemura Y,
Norimatsu T, Mahara K, et al. Impact of Acute
Kidney Injury on Early to Long-Term Outcomesin Patients Who Underwent Surgery for Type A
Acute Aortic Dissection. The American journal of
cardiology. 2015;116(3):463-8.
27. 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. 2015:
1-7.
28. Fujita D, Takeda N, Morita H, Kato M, Nishimura
H, Inuzuka R, et al. A novel mutation of TGFBR2
causing Loeys-Dietz syndrome complicated withpregnancy-related fatal cervical arterial dissections. International journal of cardiology.
2015;201:288-90.
29. Sakamoto A, Ishizaka N, Imai Y, Uehara M,
Ando J, Nagai R, et al. Association between
serum IgG4 concentrations and the morphology of
the aorta in patients who undergo cardiac
computed tomography. Journal of cardiology.
2015;65(2):150-6.
30. Yokota J, Fujiu K, Tanimito H, Nebiya H,
Kashiwa K, Kinoshita O, et al. Electromagnetic
interference between continuous-flow left ventricular assist device and cardiac resynchronization
therapy defibrillator due to an unrecognizedmechanism. International journal of cardiology.
2015;179:510-3.
31. Okada K, Naito AT, Higo T, Nakagawa A,

Shibamoto M, Sakai T, et al. Wnt/beta-Catenin
Signaling Contributes to Skeletal Myopathy inHeart Failure via Direct Interaction With
Forkhead Box O. Circulation Heart failure. 2015;
8(4):799-808.
32. Suzuki J, Aoyama N, Aoki M, Tada Y,
Wakayama K, Akazawa H, et al. Incidence of
periodontitis in Japanese patients with cardiovascular diseases: a comparison between
abdominal aortic aneurysm and arrhythmia. Heartand vessels. 2015;30(4):498-502.
33. Ikeda Y, Takimoto E, Komuro I. SH2B1: a new
player in the regulation of cardiac hypertrophic
response in failing hearts. Cardiovascular research.
2015;107(2):197-9.
34. Kimura K, Morita H, Daimon M, Kawata T,
Nakao T, Lee SL, et al. Prognostic impact ofvenous thromboembolism in patients with
Duchenne muscular dystrophy: Prospective multicenter 5-year cohort study. International journalof cardiology. 2015;191:178-80.
35. Imamura T, Kinugawa K, Nitta D, Hatano M,
Komuro I. Should cardiac resynchronization
therapy be a rescue therapy for inotropedependent patients with advanced heart failure?
Journal of cardiac failure. 2015;21(6):535-8.
36. 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 andvessels. 2016;31(6):1016-9.
37. Kamo T, Akazawa H, Komuro I. Cardiac
nonmyocytes in the hub of cardiac hypertrophy.
Circulation research. 2015;117(1):89-98.
38. Yagi H, Amiya E, Shintani Y, Nitta D, Numakura
S, Hosoya Y, et al. A representative case ofhereditary transthyretin amyloidosis complicatedby intramyocardial hemorrhage. Amyloid : theinternational journal of experimental and clinicalinvestigation: the official journal of the International Society of Amyloidosis. 2015;22(1):70-2.
39. Hirokawa M, Morita H, Tajima T, Takahashi A,
Ashikawa K, Miya F, et al. A genome-wide
association study identifies PLCL2 and AP3D1DOT1L-SF3A2 as new susceptibility loci for
myocardial infarction in Japanese. European
journal of human genetics : EJHG. 2015;23(3):119374-80.
40. Takata M, Amiya E, Watanabe M, Ozeki A,
Watanabe A, Kawarasaki S, et al. Brachial arterydiameter has a predictive value in the improvement of flow-mediated dilation after aortic valve
replacement for aortic stenosis. Heart and vessels.
2015;30(2):218-26.
41. Nakayama A, Morita H, Hamamatsu A, Miyata T,
Hoshina K, Nagayama M, et al. Coronary
atherosclerotic lesions in patients with a ruptured
abdominal aortic aneurysm. Heart and vessels.
2015;30(3):304-8.
42. Fujita D, Takahashi M, Doi K, Abe M, Tazaki J,
Kiyosue A, et al. Response of urinary liver-type
fatty acid-binding protein to contrast media
administration has a potential to predict one-year
renal outcome in patients with ischemic heartdisease. Heart and vessels. 2015;30(3):296-303.
43. Nishimura S, Nagasaki M, Kunishima S,
Sawaguchi A, Sakata A, Sakaguchi H, et al.
IL-1alpha induces thrombopoiesis throughmegakaryocyte rupture in response to acuteplatelet needs. The Journal of cell biology. 2015;
209(3):453-66.
44. Kamo T, Akazawa H, Komuro I. Pleiotropic
Effects of Angiotensin II Receptor Signaling in
CardiovascularHomeostasis
andAging.
International heart journal. 2015;56(3):249-54.
45. Kimura K, Daimon M, Morita H, Kawata T,
Nakao T, Okano T, et al. Evaluation of rightventricle by speckle tracking and conventional
echocardiography in rats with right ventricular
heart failure. International heart journal. 2015;
56(3):349-53.
46. Morita H, Komuro I. Mendelian randomisation
study for statin treatment. Lancet. 2015;385(9981):1945-6.
47. Shimizu Y, Itoda Y, Higashikuni Y, Kadowaki Y,
Saito A, Fujita H, et al. Giant left atrial myxoma
that caused mitral valve obstruction andpulmonary hypertension. International journal of
cardiology. 2015;199:38-9.
48. 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 and vessels. 2015.
49. Takeda N, Morita H, Fujita D, Inuzuka R,
Taniguchi Y, Imai Y, et al. Congenital
contractural arachnodactyly complicated withaortic dilatation and dissection: Case report andreview of literature. American journal of medical
genetics Part A. 2015;167A(10):2382-7.
50. Takamura C, Suzuki JI, Ogawa M, Watanabe R,
Tada Y, Maejima Y, et al. Suppression of murine
autoimmune myocarditis achieved with direct
renin inhibition. Journal of cardiology. 2015.
51. Takahashi M, Myojo M, Watanabe A, Kiyosue A,
Kimura K, Ando J, et al. Effect of purified
eicosapentaenoic acid on red cell distribution
width in patients with ischemic heart disease.
Heart and vessels. 2015;30(5):587-94.
52. Suzuki J, Imai Y, Aoki M, Fujita D, Aoyama N,
Tada Y, et al. High incidence and severity of
periodontitis in patients with Marfan syndrome inJapan. Heart and vessels. 2015;30(5):692-5.
53. Sawaki D, Hou L, Tomida S, Sun J, Zhan H,
Aizawa K, et al. Modulation of cardiac fibrosis byKruppel-like factor 6 through transcriptional
control of thrombospondin 4 in cardiomyocytes.
Cardiovascular research. 2015;107(4):420-30.
54. Imai Y, Morita H, Takeda N, Miya F, Hyodo H,
Fujita D, et al. A deletion mutation in myosin
heavy chain 11 causing familial thoracic aortic
dissection in two Japanese pedigrees. International journal of cardiology. 2015;195:290-2.

120Department of Respiratory
Medicine
Professor
Takahide Nagase, M.D.,Ph.D.

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

Goh Tanaka, 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://www.m.u-tokyo.ac.jp/mcm/

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

121radiology 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 2015
1. Primary lung cancer
315
2. Abnormal chest X-ray
77
3. Respiratory Infection
47
4. Interstitial pneumonia
38
5. Malignancy other than
32
primary lung cancer
6. COPD
13
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
theme on respiratory diseases are also provided.
As for post-graduate education, respiratory physicians

122(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.

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 andremodeling, 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 GOLD National Leader.

References
1. Hasegawa W, Yamauchi Y, Yasunaga H, Sunohara
M, Jo T, Matsui H, Fushimi K, Takami K, Nagase
T. Clinical features of 280 hospitalized patientswith lymphangioleiomyomatosis in Japan. Respirology. 2015; 20(1): 160-165.
2. Horie M, Saito A, Yamaguchi Y, Ohshima M,
Nagase T. Three-dimensional Co-culture modelfor tumor-stromal interaction. J Vis Exp. 2015;
2(96).
3. Amano Y, Ishikawa R, Sakatani T, Ichinose J,
Sunohara M, Watanabe K, Kage H, Nakajima J,
Nagase T, Ohishi N, Takai D. Oncogenic TPM3ALK activation requires dimerization through thecoiled-coil structure of TPM3. Biochem Biophys
Res Commun. 2015; 457(3): 457-460.
4. Ishibashi F, Sunohara M, Kawagoe S.
Performance of severity scores for home carebased patients suffering from pneumonia. Geriatr
Gerontol Int. 2015; 15(3):311-7.
5. Hasegawa W, Yamauchi Y, Yasunaga H, Sunohara
M, Jo T, Matsui H, Fushimi K, Takami K, Nagase
T. Factors that predict in-hospital mortality ineosinophilic granulomatosis with polyangiitis.
Allergy. 2015; 70(5):585-90.
6. Yamauchi Y, Yasunaga H, Matsui H, Hasegawa W,
Jo T, Takami K, Fushimi K, Nagase T.
Comparison of in-hospital mortality in patientswith COPD, asthma and asthma-COPD overlap
exacerbations. Respirology. 2015; 20(6):940-6.
7. Yamauchi Y, Yasunaga H, Matsui H, Hasegawa W,
Jo T, Takami K, Fushimi K, Nagase T.
Comparison of clinical characteristics andoutcomes between aspiration pneumonia andcommunity-acquired pneumonia in patients with

123

chronic obstructive pulmonary disease. BMC
Pulm Med. 2015; 15: 69.
8. Watanabe K, Amano Y, Ishikawa R, Sunohara M,
Kage H, Ichinose J, Sano A, Nakajima J,
Fukayama M, Yatomi Y, Nagase T, Ohishi N,
Takai D. Histone methylation-mediated silencingof miR-139 enhances invasion of non-small-celllung cancer. Cancer Med. 2015; 4(10):1573-82.
9. Yoshida Y, Kage H, Murakawa T, Sato Y, Ota S,
Fukayama M, Nakajima J. Worse Prognosis forStage IA Lung Cancer Patients with Smoking
History and More Severe Chronic Obstructive
Pulmonary Disease. Ann Thorac Cardiovasc Surg.
2015; 21(3):194-200.
10. Urushiyama H, Terasaki Y, Nagasaka S, Terasaki
M, Kunugi S, Nagase T, Fukuda Y, Shimizu A.
Role of α1 and α2 chains of type IV collagen inearly fibrotic lesions of idiopathic interstitial
pneumonias and migration of lung fibroblasts.
Lab Invest. 2015; 95(8):872-85.
11. Saito A, Nagase T. Hippo and TGF-β interplay inthe lung field. Am J Physiol Lung Cell Mol
Physiol. 2015; 309(8):L756-67.
12. Matsuzaki H, Mikami Y, Makita K, Takeshima H,
Horie M, Noguchi S, Jo T, Narumoto O, Kohyama
T, Takizawa H, Nagase T, Yamauchi Y.
Interleukin-17A and Toll-like Receptor 3 Ligand
Poly(I:C) Synergistically Induced Neutrophil
Chemoattractant Production by Bronchial Epithelial Cells. PLoS One. 2015; 10(10):e0141746.

124

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

Associate Professor
Hiroyuki Isayama, 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.

Natsuyo Yamamoto, M.D., Ph.D.

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

Yuji Kondo, M.D., Ph.D.

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

Kazuyuki Hanajiri, 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.

Yotaro Kudo, M.D., Ph.D.

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

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

Suguru Mizuno, 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, an associate professor, 2lecturers, 22 associates, 13 fellows, 65 graduates andother visiting researchers including students fromabroad. A number of others are under a temporarytransfer in- and outside the country. The North andSouth wings on the 11th floor of Ward A haveprovided core hospital rooms for the department. At
present, fourth and fifth floors of Ward B also take
important part for providing rooms for inpatients.
Laboratories of the department are scattered in eachfloor, mainly of Clinical 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125

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 5,500 outpatients withvarious digestive diseases in a month. Professor’s
ward round is performed on Monday and Wednesday
mornings. Specialty and subspecialty clinical conferences are held on Monday evening.
Hepatocellular carcinoma is the most common
disease in patients who are admitted to the department(〜700 cases in 2015). 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
about 1000 cases each year. The cumulative number ofpatients treated for choledocholithiasis with endoscopic papillary balloon dilation method exceeds
1,300, which is possibly the largest in the world.
Recently, EST (endoscopic sphincterotomy) or
EPLBD (endoscopic papillary large balloon dilation)
was applied case by case, and more than 80 cases withcholedocholithiasis are annually treated. Endoscopic
placement of a metal stent is an effective palliative
care for malignant obstructive jaundice (about 80
procedures performed every year), and our group is apioneer of covered metal stents for biliary obstruction,and is one of the world’s largest centers using covered

metal stents. Pancreatic interventions such as
pancreatic stenting, cystic drainage, endoscopic stone
extraction and lithotripsy using ESWL (extracorporeal
shock-wave lithotripsy) are performed for many
challenging cases. We have also applied various
EUS-guided interventions to treat pancreato-biliary
diseases.
In the gastrointestinal field, ESD (endoscopic
submucosal dissection) is performed as a curativeendoscopic treatment for neoplasms in esophagus,
stomach or colon (320 patients a year). Non-exposedendoscopic wall-inversion surgery (news), which wasdeveloped with the Department of Gastrointestinal
Surgery, now expanded its clinical application fromthe resection of GIST to the treatment of gastriccancer. Double-balloon endoscopy and capsuleendoscopy which were introduced recently enabled
the examination of whole small intestines (300 casesin 2015). All those interventions are performed by themembers of the department, specially trained for eachtechnique. In addition, for the management strategy
against inoperative malignancies, we effectively
combine the interventional treatments with various
chemotherapy regimens using new moleculartargeting drugs.
On outpatient basis, ultrasonography is
performed on 12,500 patients. We do gastroduodenalendoscopy on 9,500 patients and colonoscopy on
6,000 patients each year, and diagnose about 790
cases of gastric cancer and 1300 cases of colorectal
tumor annually. About 50 % of them are treatedendoscopically. We further aim to perform basic
studies using specimen, and turn these efforts toclinical activities.

Educational Activities
Systematic and clinical lectures on gastroenterology are given regularly to undergraduate
medical students by staff members of the department.
In addition, several courses of practical teaching areprovided for the students. In particular, theDepartment of Gastroenterology makes much of theimportance of clinical clerkship for the fourth andfifth grade students, where each student is allotted to
an inpatient by joining the group of physicians andoffering the opportunity to learn digestive diseases

126

practically. The results are reported to the professor at
the end of the course in the style of oral examination.
Students are also required to summarize and outline
articles from world’s leading medical journals.
Residents of internal medicine join the Department of Gastroenterology for 1-4 months in rotation in
their first year as a doctor, where they learn therapeutics and diagnostics in gastroenterology together
with general internal medicine. Giving presentations
at the scientific meeting is highly encouraged. If they
are interested in gastroenterology in particular, they
can learn advanced techniques in gastroenterology inaffiliated hospitals for a few years. Usually, they will
come back to the department after that period, andimprove their clinical skills still further while at theeducation course. The majority of them also become
graduate student, and starts medical researches either
in a basic or clinical research area. Currently, thedepartment has 65 students, who were graduated from
more than 30 medical schools in Japan.

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.

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antagonism between hepatitis B viral mRNA andhost microRNA let-7. Sci Rep. 2016;6:23237.
2) Nagata N, Niikura R, Yamada A, et al. Acute
Middle Gastrointestinal Bleeding Risk Associatedwith NSAIDs, Antithrombotic Drugs, and PPIs: A
Multicenter Case-Control Study. PLoS One. 2016;
11:e0151332.
3) Takeuchi C, Yamamichi N, et al. Gastric polyps
diagnosed by double-contrast upper gastrointestinal barium X-ray radiography mostly arise
from the Helicobacter pylori-negative stomach
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weekend effect on outcomes of severe acutepancreatitis in Japan: data from the diagnosis
procedure combination database. J Gastroenterol.
2016 Feb 20. [Epub ahead of print]
5) Hamada T, Nakai Y, Isayama H, et al. Against
duodenobiliary reflux: implications from a randomized controlled trial. Gastrointest Endosc.
2016;83:673-4.
6) Hakuta R, Kogure H, Isayama H, et al. Electrohydraulic lithotripsy as a salvage option for stone
impaction during double-balloon endoscopeassisted ERCP. Gastrointest Endosc. 2016 Feb 6.
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7) Serizawa T, Hirata Y, Hayakawa Y, et al. Gastric127

Metaplasia Induced by Helicobacter pylori Is
Associated with Enhanced SOX9 Expression via
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8) Niimi K, Aikou S, Kodashima S, et al. Video ofthe Month: A Novel Endoscopic Full-Thickness
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expression levels of bile acid transporters areinversely correlated with the histological progression of nonalcoholic fatty liver disease. J
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12) Sakitani K, Hirata Y, Hikiba Y, et al. Inhibition of
autophagy exerts anti-colon cancer effects via
apoptosis induced by p53 activation and ER stress.
BMC Cancer. 2015;15:795.
13) Nakai Y, Isayama H, Tsujino T, et al. Cholecystectomy after endoscopic papillary balloon
dilation for bile duct stones reduced late biliarycomplications: a propensity score-based cohort
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14) Niikura R, Yamada A, Nagata N, et al. New
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15) Sakitani K, Hirata Y, Suzuki N, et al. Gastriccancer diagnosed after Helicobacter pylori
eradication in diabetes mellitus patients. BMC
Gastroenterol. 2015;15:143.
16) Yamamichi N, Hirano C, Ichinose M, et al.
Atrophic gastritis and enlarged gastric folds diagnosed by double-contrast upper gastrointestinal
barium X-ray radiography are useful to predict
future gastric cancer development based on the
3-year prospective observation. Gastric Cancer.

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Events during Bowel Preparation and Colonoscopy in Patients with Acute Lower Gastrointestinal Bleeding Compared with Elective NonGastrointestinal Bleeding. PLoS One. 2015;10:e0138000.
18) Kishikawa T, Otsuka M, Ohno M, et al.
Development of a screening method to identify
regulators of MICA shedding. Biochem Biophys
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19) Yamamichi N, Hirano C, Takahashi Y, et al.
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;19:670-5.
20) Yoshikawa T, Wu J, Otsuka M, et al. ROCK
inhibition enhances microRNA function bypromoting deadenylation of targeted mRNAs via
increasing PAIP2 expression. Nucleic Acids Res.
2015;43:7577-89.
21) Mizuno S, Hirano K, Isayama H, et al.
Prospective study of bezafibrate for the treatmentof primary sclerosing cholangitis. J Hepatobiliary
Pancreat Sci. 2015;22:766-70.
22) Hamada T, Yasunaga H, Nakai Y, et al. Bleeding
after endoscopic sphincterotomy or papillaryballoon dilation among users of antithrombotic
agents. Endoscopy. 2015;47:997-1004.
23) Yamada A, Niikura R, Kobayashi Y, et al. Risk
factors for small bowel angioectasia: The impactof visceral fat accumulation. World J Gastroenterol. 2015;21:7242-7.
24) Ohno M, Otsuka M, Kishikawa T, et al. Noveltherapeutic approaches for hepatitis B virus
covalently closed circular DNA. World J
Gastroenterol. 2015;21:7084-8.
25) Minami T, Tateishi R, Kondo M, et al. Serum
Alpha-Fetoprotein Has High Specificity for the
Early Detection of Hepatocellular Carcinoma
After Hepatitis C Virus Eradication in Patients.
Medicine (Baltimore). 2015;94:e901.
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oncoprotein. Sci Rep. 2015;5:10024.
27) Okushin K, Takahashi Y, Yamamichi N, et al.
Helicobacter pylori infection is not associatedwith fatty liver disease including non-alcoholic
fatty liver disease: a large-scale cross-sectional
study in Japan. BMC Gastroenterol. 2015;15:25.
28) Yamamichi N, Shimamoto T, Takahashi Y, et al.
Trend and risk factors of diverticulosis in Japan:
age, gender, and lifestyle/metabolic-related factors may cooperatively affect on the colorectal
diverticula formation. PLoS One. 2015;10:e0123688.
29) Watanabe T, Hirano K, Tada M, et al. Short-term
prognostic factors for primary sclerosing cholangitis. J Hepatobiliary Pancreat Sci. 2015;22:486-90.
30) Kishikawa T, Otsuka M, Tan PS, et al. Decreased
miR122 in hepatocellular carcinoma leads tochemoresistance with increased arginine. Oncotarget. 2015;6:8339-52.
31) Uchino K, Tateishi R, Fujiwara N, et al. Impact ofserum ferritin level on hepatocarcinogenesis inchronic hepatitis C patients. Hepatol Res. 2016;46:259-68.
32) Shichijo S, Hirata Y, Sakitani K, et al. Distribution of intestinal metaplasia as a predictor ofgastric cancer development. J Gastroenterol
Hepatol. 2015;30:1260-4.
33) Fujiwara N, Nakagawa H, Kudo Y, et al.
Sarcopenia, intramuscular fat deposition, andvisceral adiposity independently predict the outcomes of hepatocellular carcinoma. J Hepatol.
2015;63:131-40.
34) Takahara N, Isayama H, Nakai Y, et al. Pancreaticcancer with malignant ascites: clinical featuresand outcomes. Pancreas. 2015;44:380-5.
35) Sasahira N, Kawakami H, Isayama H, et al. Earlyuse of double-guidewire technique to facilitate
selective bile duct cannulation: the multicenter
randomized controlled EDUCATION trial. Endoscopy. 2015;47:421-9.
36) Ono S, Fujishiro M, Yoshida N, et al.
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of fecal occult blood on obscure gastrointestinal
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40) Nakai Y, Isayama H, Sasahira N, et al. Risk
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cannulation for therapeutic biliary ERCP. Gastrointest Endosc. 2015;81:119-26.
41) Tsuji Y, Fujishiro M, Kodashima S, et al.
Polyglycolic acid sheets and fibrin glue decrease
the risk of bleeding after endoscopic submucosal
dissection of gastric neoplasms (with video).
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42) Nakai Y, Isayama H, Sasaki T, et al. The
inhibition of renin-angiotensin system inadvanced pancreatic cancer: an exploratory
analysis in 349 patients. J Cancer Res Clin Oncol.
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43) Sakaguchi Y, Tsuji Y, Ono S, et al. Polyglycolicacid sheets with fibrin glue can prevent
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Internal Medicine
2. Medicine Ⅱ131Department of Nephrology and
Endocrinology
Professor
Masaomi Nangaku, M.D., Ph.D.

Associate Professor
Eisei Noiri, M.D., Ph.D.,

Norio Hanafusa, M.D., Ph.D.

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

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

Tetsuhiro Tanaka, M.D., Ph.D.(Oct.-),Takehiko Wada, M.D., Ph.D.(-Sep.)

Associate
Katsutoshi Takahashi, M.D.

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.,

Toshihisa Nakatani, M.D., Ph.D.,

Yuka Kinoshita, M.D., Ph.D.(July-),

Imari Mimura, M.D., Ph.D. (Nov.-),Manabu Taguchi, M.D., Ph.D.(-June),

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

Homepage

http://www.todai-jinnai.com

Introduction and Organization
The Department of Nephrology and Endocrinology
is one of the major divisions in the Department ofInternal Medicine of the University of Tokyo, which
covers nephrology, hypertension, and endocrinology,
and also renal diseases associated with diabetes
mellitus, cardiovascular diseases, collagen diseases
and so on. Usually we have up to 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.

Clinical activities
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

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patients with proteinuria and end-stage renal failure.
Each staff of our department also works at the
hemodialysis unit, thus we can manage patients inevery stage of renal diseases. In collaboration with
Department of Urology, we are conducting renaltransplantation and promoting peritoneal dialysis.
In the endocrine unit there is a variety of patients
having disorders in thyroid, parathyroid, pituitary,adrenal and gonadal glands. It is also our specialty todiagnose and treat secondary hypertension caused byprimary aldosteronism, Cushing’s syndrome, pheochromocytoma, renal artery stenosis and so on. We
often have consultation from other departments concerning disorders of water and mineral metabolism.

Education
We have responsibility for educating undergraduates, graduate students and residents. Our staffs
take part in several lectures for undergraduate andgraduate students. In addition, our members areactively involved in clinical clerkship forundergraduate students, and other clinical practice.
Particularly, we have put emphasis on participation of
the students in clinical practice including medical
investigations, diagnosis, and treatment.
In thewards, we are also educating residents during dailyclinical works and periodical lectures concerningkidney and endocrine diseases. Our department also
participates in Metabolism Research Course foreducating young clinical researchers and fellows incollaboration with Department of Diabetes andMetabolic Diseases, Department of Cardiology, andDepartment of Geriatric 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.

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Clinical activities
1. Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
2. Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does
not accept holiday dialysis.
3. Emergency hemodialysis and hemodiafiltration
for ICU patients.
4. Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.
5. DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
6. LDL apheresis for nephrotic syndrome and ASO
patients.
7. White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.
8. Cell-free and concentrated ascites reinfusion
therapy (CART) for refractory ascites.
9. Induction and maintenance of peritoneal dialysis
for ESRD.
Education
1. A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acuteand chronic renal failure including diabetic
nephropathy.
2. Technical development course for medical
engineers and nurses.
3. Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
4. Exposure in hemodialysis & apheresis course to
second year residents on request.
5. Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. “Apheresis Pocket Manual” hasbeen translated into Chinese and English, andthose translated versions have helped a number of
non-Japanese-speaking people to learn how to
perform apheresis.
6. Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.

Research
1. Prognostic analysis for post-liver transplantpatients who received plasma exchange therapy.
2. Development and application of a non-invasive
pulse hemoglobin meter.
3. Genome wide association study for Nephrotic
syndrome and those functional analyses.
4. Association between factors at the initiation ofrenal replacement therapy and prognosis.
5. Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
6. Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
7. AKI biomarkers and their clinical significance in
ICU/CCU.
8. Renal biomarker to determine clinical action
ability in CKD and type-2 DN.

Publications(1) Hirakawa Y, Yoshihara T, Kamiya M, Mimura I,
Fujikura D, Masuda T, Kikuchi R, Takahashi I,
Urano Y, Tobita S, Nangaku M. Quantitating
intracellular oxygen tension in vivo by phosphorescence lifetime measurement. Sci Rep. 2015
Dec 8;5:17838.
(2) Wada T, Nangaku M. A circulating permeability
factor in focal segmental glomerulosclerosis: thehunt continues. Clin Kidney J. 2015 Dec;8(6):708-15.
(3) Katagiri D, Hamasaki Y, Doi K, Negishi K,
Sugaya T, Nangaku M, Noiri E. Interstitial renal
fibrosis due to multiple cisplatin treatments isameliorated by semicarbazide-sensitive amineoxidase inhibition. Kidney Int. Available online
31 December 2015
(4) 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
factor-binding protein-1. Nephrology (Carlton).
2015 Oct 19.
(5) Mimura I, Tanaka T, Nangaku M. How theTarget Hemoglobin of Renal Anemia Should Be.
Nephron. 2015;131(3):202-9.
(6) Hirahashi J, Hanafusa N, Wada T, Arita M,
Hishikawa K, Hayashi M, Nangaku M. Aspirin

134

and Eicosapentaenoic Acid May Arrest Progressive IgA Nephropathy: A Potential Alternative to
Immunosuppression. Intern Med. 2015;54(18):2377-82.
(7) Takashi Y, Kinoshita Y, Makita N, Taguchi M,
Takahashi K, Nangaku M, Fukumoto S. Rapid
Recovery of Hypothalamic-Pituitary Axis after
Successful Resection of an ACTH-secreting
Neuroendocrine Tumor. Intern Med. 2015;54(17):2201-5.
(8) Bazzi C, Tagliabue E, Raimondi S, Rizza V,
Casellato D, Nangaku M. High (≥6.5)
Spontaneous and Persistent Urinary pH Is
Protective of Renal Function at Baseline andduring Disease Course in Idiopathic Membranous Nephropathy. Int J Nephrol. 2015;2015:
730234.
(9) 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. Epub 2015 Jul
4.
(10) Kato H, Ishida J, Matsusaka T, Ishimaru T,
Tanimoto K, Sugiyama F, Yagami K, Nangaku M,
Fukamizu A. Erythropoiesis and Blood Pressure
Are Regulated via AT1 Receptor by Distinctive
Pathways. PLoS One. 2015 Jun 24;10(6):e0129484.
(11) Imai E, Maruyama S, Nangaku M, Hirakata H,
Hayashi T, Narita I, Kono H, Nakatani E, Morita
S, Tsubakihara Y, Akizawa T. Rationale andstudy design of a randomized controlled trial toassess the effects of maintaining hemoglobin
levels using darbepoetin alfa on prevention ofdevelopment of end-stage kidney disease in
non-diabetic CKD patients (PREDICT Trial).
Clin Exp Nephrol. Epub 2015 Jun 17.
(12) Johnson
RJ,
NangakuM.
Endothelial
Dysfunction: The Secret Agent Driving Kidney
Disease. J Am Soc Nephrol. Epub 2015 Jun 2.
(13) Saito H, Hamasaki Y, Tojo A, Shintani Y,
Shimizu A, Nangaku M. Phospholipase A2
receptor positive membranous nephropathy longafter living donor kidney transplantation between identical twins. Nephrology (Carlton).
2015 Jul;20 Suppl 2:101-4.

(14) Okubo K, Ishibashi Y, Kume H, Hirahashi J,
Nangaku M. Successful management of a chest
exit site in a psoriasis patient. Perit Dial Int.
2015 May-Jun;35(3):372-3.
(15) 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. 2015
Jul;185(7):1889-98.
(16) Hishikawa K, Takase O, Yoshikawa M,
Tsujimura T, Nangaku M, Takato T. Adult
stem-like cells in kidney. World J Stem Cells.
2015 Mar 26;7(2):490-4.
(17) 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 anational administrative database. Nephrol Dial
Transplant. 2015 Jun;30(6):988-95.
(18) Tojo A, Hatakeyama S, Kinugasa S, Nangaku M.
Angiotensin receptor blocker telmisartan suppresses renal gluconeogenesis during starvation.
Diabetes Metab Syndr Obes. 2015 Feb 13;8:10313.
(19) Yamaguchi J, Tanaka T, Eto N, Nangaku M.
Inflammation and hypoxia linked to renal injury
by CCAAT/enhancer-binding protein δ. KidneyInt. 2015 Aug;88(2):262-75.
(20) Hayashi M, Uchida S, Kawamura T, Kuwahara
M, Nangaku M, Iino Y Prospective randomized
study of the tolerability and efficacy of
combination therapy for hypertensive chronic
kidney disease: results of the PROTECT-CKD
study. Clin Exp Nephrol. 2015 Oct;19(5):925-32.
(21) Higashijima Y, Tanaka T, Yamaguchi J, Tanaka S,
Nangaku M. Anti-inflammatory role of DPP-4
inhibitors in a nondiabetic model of glomerular
injury. Am J Physiol Renal Physiol. 2015 Apr 15;308(8):F878-87.
(22) 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. 2015 Oct;26(10):2378-87.

135(23) Shimizu K, Doi K, Imamura T, Noiri E, Yahagi
N, Nangaku M, Kinugawa K. 37. Ratio of urine
and blood urea nitrogen concentration predicts
the response of tolvaptan in congestive heart
failure. Nephrology (Carlton). 2015 Jun;20(6):405-12.
(24) Nangaku M, Inagi R, Mimura I, Tanaka T.
Epigenetic Changes Induced by HypoxiaInducible Factor: a Long Way Still To Go as aTarget for Therapy? J Am Soc Nephrol. 2015 Jul;
26(7):1478-80.
(25) Nangaku M, Mimura I, Yamaguchi J,
Higashijima Y, Wada T, Tanaka T. Role of uremic toxins in erythropoiesis-stimulating agent
resistance in chronic kidney disease and dialysis
patients. J Ren Nutr. 2015 Mar;25(2):160-3.
(26) Yamaguchi J, Tanaka T, Nangaku M. 40. Recent
advances in understanding of chronic kidneydisease. F1000Res. 2015 Nov 4;4. pii: F1000
Faculty Rev-1212.

136

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.,

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

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

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

Yoshihiko Izumida, M.D., Ph.D.,

Yusuke Hada, M.D., Ph.D.,

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

URL http://dm.umin.jp/
Introduction and Organization
In 1998 the Department of Internal Medicine at the
University of Tokyo was reorganized to the morefunctional units based on clinical specialties. The
physicians specialized in diabetes and metabolic
diseases from 3 former departments of Internal
Medicine were unified to the Department of Metabolic
Diseases. The Department of Diabetes and Metabolic
Diseases is one of the major divisions in the
Department of Internal Medicine at the University ofTokyo, and covers diabetes mellitus and metabolic
diseases including obesity disease and dyslipidemia.
Under the supervision and direction of the previous
professors Dr. Satoshi Kimura (1998-2003) 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 486 new inpatients per year.
Besides the staffs listed above, our division holds
faculties in branches, for example, Department of
Molecular Sciences on Diabetes (Project Professor, Dr.
Kohjiro Ueki and Project Assistant Professor, Dr.
Masatoshi Kobayashi), Department of ClinicalNutrition Therapy (Associate Professor Dr. Naoto
Kubota), Functional Regulation of Adipocytes(Project Associate Professor, Dr. Hironori Waki and
Project Lecturer, Dr.Takuya Sugiyama), Department
of Integrated Molecular Science on Metabolic
Diseases (Project Associate Professor, Dr. Masato
Iwabu and Project Lecturer, Dr. Miki Okada-Iwabu),
Department of Translational Systems Biology andMedicine Initiative (Project Assistant Professor, Dr.
Takayoshi Sasako), Division of Biophysics, Center for
Disease Biology and Integrative Medicine (Lecturer,

137

Dr. Noriko Takahashi), Ubiquitous Health Informatics(Project Associate Professor, Dr. Kayo Waki), Clinical
Epidemiology and Systems (Project AssistantProfessor, Dr. Mikio Takanashi), Division for HealthService Promotion, The University of Tokyo(Assistant Professor, Dr. Midori Kubota), 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 more than 20 students ofGraduate School in our division. With all these 65
members, we enthusiastically work on the research
activities, which lead to the outstanding contributionsin 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 more than 180 patients per day(total 43,883 patients per year). On the inpatient ward,
we not only take care of around 28 patients in ourdivision 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 day in the inpatient ward, and also give lectures
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.

1381) Molecular mechanisms of type 2 diabetes
We have been attempting to elucidate the mechanisms
underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, in
collaboration with RIKEN and several cohorts, we
explored the comprehensive catalog of genomic
variations
toidentify
variations
conferring
susceptibility to type 2 diabetes in the Japanese
population. We are also exploring the signaltransduction pathways and physiological roles of
insulin and adipokines in various tissues and themechanisms of insulin secretion under the normal or
pathological conditions, such as diabetes and obesity
disease, using a number of transgenic and knockout
animal models, in parallel with information obtainedby whole-genome analysis of human patients. In
particular, we are interested in the physiological andpathophysiological functions of adipokines secretedby adipocytes, including adiponectin, and the signaltransduction pathway of adiponectin through thereceptors, AdipoR1 and AdipoR2, that we discovered
and characterized. We have also identified“AdipoRon” as an adiponectin receptor agonist, which
will contribute to the development and optimization of
AdipoR-targeted therapeutics. In addition, we havebeen successfully unraveling the molecularmechanisms of β cell proliferation and inter-tissuecommunication of glucose metabolism in obesity
disease and type 2 diabetes. Recently, we areinvestigating brown and white adipocyte-specifictranscriptional and epigenetic regulations in obesity.
We believe that these findings and research activities
will lead to novel therapeutic strategies 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 anti-oxidative proteins on the lipid disorders andatherosclerosis. We are currently interested in thecholesterol and lipid absorption from the intestine andlipid 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)”, systematic
reviews and meta-analyses with a focus on important
issues such as metabolic syndrome, and investigatorinitiated clinical trials targeting for a new class ofanti-diabetic agents.

References
1. 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. Epub 2015 Dec 26.
2. 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. 2016. Epub 2015 Dec 29.
3. Kurano M, Dohi T, Nojiri T, Kobayashi T,
Hirowatari Y, Inoue A, Kano K, Matsumoto H,
Igarashi K, Nishikawa M, Miyauchi K, Daida H,
Ikeda H, Aoki J, Yatomi Y. Blood levels ofserotonin are specifically correlated with plasma
lysophosphatidylserine among the glycerolysophospholipids. BBA Clin. 2015;4:92-8.
4. Amemiya A, Noguchi H, Oe M, Ohashi Y,
Takehara K, Ueki K, Kadowaki T, Sanada H,
Mori T. Comparison of Gait Features Between
Feet With Callus or Corns and Normal Feet Using
Motion Sensors in People With Diabetes andPeople Without Diabetes. J Diabetes Sci Technol.
2015;10(2):614-5.
5. Okada-Iwabu M, Iwabu M, Ueki K, Yamauchi T,
Kadowaki T. Perspective of Small-Molecule

139

AdipoR Agonist for Type 2 Diabetes and Short
Life in Obesity. Diabetes Metab J. 2015;39(5):363-72.
6. 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;
JPHC Study Group. High hemoglobin A1c levels
within the non-diabetic range are associated withthe risk of all cancers. Int J Cancer. 2016;138(7):1741-53. Epub 2015 Dec 1.
7. Hara K, Kadowaki T, Odawara M. Genes
associated with diabetes: potential for novel
therapeutic targets? Expert Opin Ther Targets.
2016;20(3):255-67. Epub 2015 Oct 12.
8. Kurano M, Hara M, Nojiri T, Ikeda H, Tsukamoto
K, Yatomi Y. Resveratrol exerts a biphasic effecton apolipoprotein M. Br J Pharmacol. 2016;
173(1):222-33. Epub 2015 Nov 12.
9. Shibata S, Tada Y, Hau CS, Mitsui A, Kamata M,
Asano Y, Sugaya M, Kadono T, Masamoto Y,
Kurokawa M, Yamauchi T, Kubota N, Kadowaki
T, Sato S. Adiponectin regulates psoriasiform skininflammation by suppressing IL-17 production
from γδ-T cells. Nat Commun. 2015;6:7687.
10. Yamada T, Hara K, Shojima N, Yamauchi T,
Kadowaki T. Daytime Napping and the Risk of
Cardiovascular Disease and All-Cause Mortality:
A Prospective Study and Dose-Response MetaAnalysis. Sleep. 2015;38(12):1945-53.
11. Tokuhara Y, Kurano M, Shimamoto S, Igarashi K,
Nojiri T, Kobayashi T, Masuda A, Ikeda H,
Nagamatsu T, Fujii T, Aoki J, Yatomi Y. A New
Enzyme Immunoassay for the Quantitative
Determination of Classical Autotaxins (ATXα,ATXβ, and ATXγ) and Novel Autotaxins (ATXδ
and ATXε). PLoS One. 2015;10(6):e0130074.
12. Tsukube S, Ikeda Y, Kadowaki T, Odawara M.
Improved Treatment Satisfaction and Selfreported Health Status after Introduction of
Basal-Supported Oral Therapy Using Insulin
Glargine in Patients with Type 2 Diabetes:
Sub-Analysis of ALOHA2 Study. Diabetes Ther.
2015;6(2):153-71.
13. 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, Yanagisawa M.

Monitoring β-arrestin recruitment via β-lactamase
enzyme fragment complementation: purificationof peptide E as a low-affinity ligand for
mammalian bombesin receptors. PLoS One. 2015;10(6):e0127445.
14. 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 One.
2015;10(5):e0129394.
15. Nishimura S, Nagasaki M, Kunishima S,
Sawaguchi A, Sakata A, Sakaguchi H, Ohmori T,
Manabe I, Italiano JE Jr, Ryu T, Takayama N,
Komuro I, Kadowaki T, Eto K, Nagai R. IL-1αinduces thrombopoiesis through megakaryocyte
rupture in response to acute platelet needs. J Cell
Biol. 2015;209(3):453-66.
16. Moriyama M, Fujimoto Y, Rikimaru S, Ushikai M,
Kuroda E, Kawabe K, Takano K, Asakawa A, InuiA, Eto K, Kadowaki T, Sinasac DS, Okano Y,
Yazaki M, Ikeda S, Zhang C, Song YZ, Sakamoto
O, Kure S, Mitsubuchi H, Endo F, Horiuchi M,
Nakamura Y, Yamamura K, Saheki T. Mechanism
for increased hepatic glycerol synthesis in the
citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse: Urine
glycerol and glycerol 3-phosphate as potential
diagnostic markers of human citrin deficiency.
Biochim Biophys Acta. 2015;1852(9):1787-95.
17. Goto A, Noda M, Matsushita Y, Goto M, Kato M,
Isogawa A, Takahashi Y, Kurotani K, Oba S,
Nanri A, Mizoue T, Yamagishi K, Yatsuya H,
Saito I, Kokubo Y, Sawada N, Inoue M, Iso H,
Kadowaki T, Tsugane S; JPHC Study Group.
Hemoglobin a1c levels and the risk of cardiovascular disease in people without known
diabetes: a population-based cohort study in Japan.
Medicine (Baltimore). 2015;94(17):e785.
18. Shiomi Y, Yamauchi T, Iwabu M, Okada-Iwabu M,
Nakayama R, Orikawa Y, Yoshioka Y, Tanaka K,
Ueki K, Kadowaki T. A Novel Peroxisome
Proliferator-activated Receptor (PPAR)α Agonist
and PPARγ Antagonist, Z-551, Ameliorates
High-fat Diet-induced Obesity and Metabolic

140

Disorders in Mice. J Biol Chem. 2015;290(23):14567-81.
19. Waki K, Aizawa K, Kato S, Fujita H, Lee H,
Kobayashi H, Ogawa M, Mouri K, Kadowaki T,
Ohe K. DialBetics With a Multimedia Food
Recording Tool, FoodLog: Smartphone-Based
Self-Management for Type 2 Diabetes. J Diabetes
Sci Technol.2015;9(3):534-40.
20. Ohkawa R, Kurano M, Mishima Y, Nojiri T,
Tokuhara Y, Kishimoto T, Nakamura K, Okubo S,
Hosogaya S, Ozaki Y, Yokota H, Igarashi K, Ikeda
H, Tozuka M, Yatomi Y. Possible involvement of
sphingomyelin in the regulation of the plasma
sphingosine 1-phosphate level in human subjects.
Clin Biochem. 2015;48(10-11):690-7.
21. Kadowaki T, Marubayashi F, Yokota S, Katoh M,
Iijima H. Safety and efficacy of teneligliptin in
Japanese patients with type 2 diabetes mellitus: apooled analysis of two Phase III clinical studies.
Expert Opin Pharmacother. 2015;16(7):971-81.
22. Tanabe H, Fujii Y, Okada-Iwabu M, Iwabu M,
Nakamura Y, Hosaka T, Motoyama K, Ikeda M,
Wakiyama M, Terada T, Ohsawa N, Hato M,
Ogasawara S, Hino T, Murata T,
23. Iwata S, Hirata K, Kawano Y, Yamamoto M,
Kimura-Someya T, Shirouzu M, Yamauchi T,
Kadowaki T, Yokoyama S. Crystal structures of
the human adiponectin receptors. Nature. 2015;
520(7547):312-6.
24. Kadowaki T, Haneda M, Inagaki N, Terauchi Y,
Taniguchi A, Koiwai K, Rattunde H, Woerle HJ,
Broedl UC. Efficacy and safety of empagliflozin
monotherapy for 52 weeks in Japanese patientswith type 2 diabetes: a randomized, double-blind,parallel-group study. Adv Ther. 2015;32(4):306-18.
25. Takehara K, Amemiya A, Mugita Y, Tsunemi Y,
Seko Y, Ohashi Y, Ueki K, Kadowaki T, Oe M,
Nagase T, Ikeda M, Sanada H. Association
between Washing Residue on the Feet and Tinea
Pedis in Diabetic Patients. Nurs Res Pract. 2015
(doi: 10.1155/2015/872678).
26. Nagashima S, Yagyu H, Tozawa R, Tazoe F,
Takahashi M, Kitamine T, Yamamuro D, Sakai K,
Sekiya M, Okazaki H, Osuga J, Honda A,
Ishibashi S. Plasma cholesterol-lowering andtransient liver dysfunction in mice lacking

squalene synthase in the liver. J Lipid Res. 2015;
56(5):998-1005.
27. Nakatsu D, Horiuchi Y, Kano F, Noguchi Y,
Sugawara T, Takamoto I, Kubota N, Kadowaki T,
Murata M. L-cysteine reversibly inhibits glucoseinduced biphasic insulin secretion and ATP
production by inactivating PKM2. Proc Natl Acad
Sci U S A. 2015 ;112(10):E1067-76.
28. Kurano M, Hara M, Satoh H, Tsukamoto K.
Hepatic NPC1L1 overexpression ameliorates
glucose metabolism in diabetic mice via suppression of gluconeogenesis. Metabolism. 2015;64(5):588-96.
29. Tanabe H, Motoyama K, Ikeda M, Wakiyama M,
Terada T, Ohsawa N, Hosaka T, Hato M, Fujii Y,
Nakamura Y, Ogasawara S, Hino T, Murata T,
Iwata S, Okada-Iwabu M, Iwabu M, Hirata K,
Kawano Y, Yamamoto M, Kimura-Someya T,
Shirouzu M, Yamauchi T, Kadowaki T, Yokoyama
S. Expression, purification, crystallization, andpreliminary X-ray crystallographic studies of thehuman adiponectin receptors, AdipoR1 andAdipoR2. J Struct Funct Genomics. 2015;16(1):11-23.
30. Kurano M, Tsukamoto K, Hara M, Ohkawa R,
Ikeda H, Yatomi Y. LDL receptor and ApoE are
involved in the clearance of ApoM-associatedsphingosine 1-phosphate. J Biol Chem. 2015;
290(4):2477-88.
31. Nazare JA, Smith J, Borel AL, Aschner P, Barter P,
Van Gaal L, Tan CE, Wittchen HU, Matsuzawa Y,
Kadowaki T, Ross R, Brulle-Wohlhueter C,
Alméras N, Haffner SM, Balkau B, Després JP;
INSPIRE ME IAA Investigators. Usefulness ofmeasuring both body mass index and waist
circumference for the estimation of visceraladiposity and related cardiometabolic risk profile(from the INSPIRE ME IAA study). Am J Cardiol.
2015;115(3):307-15.
32. Odawara M, Kadowaki T, Naito Y. Effectivenessand safety of basal supported oral therapy withinsulin glargine, in Japanese insulin-naive, type 2
diabetes patients, with or without microvascularcomplications: subanalysis of the observational,
non-interventional, 24-week follow-up Add-on
Lantus® to Oral Hypoglycemic Agents (ALOHA)
study. J Diabetes Complications. 2015;29(1):141

127-33.
33. Nishikawa M, Kurano M, Ikeda H, Aoki J, Yatomi
Y. Lysophosphatidylserine has Bilateral Effects on
Macrophages in the Pathogenesis of Atherosclerosis. J Atheroscler Thromb. 2015;22(5):51826.
34. Kurano M, Suzuki A, Inoue A, Tokuhara Y, Kano
K, Matsumoto H, Igarashi K, Ohkawa R,
Nakamura K, Dohi T, Miyauchi K, Daida H,
Tsukamoto K, Ikeda H, Aoki J, Yatomi Y. Possible
involvement of minor lysophospholipids in theincrease in plasma lysophosphatidic acid in acutecoronary syndrome. Arterioscler Thromb Vasc
Biol. 2015 ;35(2):463-70.
35. Motonishi S, Nangaku M, Wada T, Ishimoto Y,
Ohse T, Matsusaka T, Kubota N, Shimizu A,
Kadowaki T, Tobe K, Inagi R. Sirtuin1 Maintains
Actin Cytoskeleton by Deacetylation of Cortactin
in Injured Podocytes. J Am Soc Nephrol. 2015;26(8):1939-59.
36. Yamada T, Hara K, Svensson AK, Shojima N,
Hosoe J, Iwasaki M, Yamauchi T, Kadowaki T.
Successfully achieving target weight loss influences subsequent maintenance of lower weightand dropout from treatment. Obesity (Silver
Spring). 2015;23(1):183-91.
37. Hashimoto S, Kubota N, Sato H, Sasaki M,
Takamoto I, Kubota T, Nakaya K, Noda M, Ueki
K, Kadowaki T. Insulin receptor substrate-2 (Irs2)
in endothelial cells plays a crucial role in insulin
secretion. Diabetes. 2015;64(3):876-86.
38. Hwang JY, Sim X, Wu Y, Liang J, Tabara Y, Hu C,
Hara K, Tam CH, Cai Q, Zhao Q, Jee S, Takeuchi
F, Go MJ, Ong RT, Ohkubo T, Kim YJ, Zhang R,
Yamauchi T, So WY, Long J, Gu D, Lee NR, Kim
S, Katsuya T, Oh JH, Liu J, Umemura S, Kim YJ,
Jiang F, Maeda S, Chan JC, Lu W, Hixson JE,
Adair LS, Jung KJ, Nabika T, Bae JB, Lee MH,
Seielstad M, Young TL, Teo YY, Kita Y,
Takashima N, Osawa H, Lee SH, Shin MH, Shin
DH, Choi BY, Shi J, Gao YT, Xiang YB, Zheng W,
Kato N, Yoon M, He J, Shu XO, Ma RC,
Kadowaki T, Jia W, Miki T, Qi L, Tai ES, Mohlke
KL, Han BG, Cho YS, Kim BJ. Genome-wide
association meta-analysis identifies novel variants
associated with fasting plasma glucose in East
Asians. Diabetes. 2015;64(1):291-8.

39. Hirokawa M, Morita H, Tajima T, Takahashi A,
Ashikawa K, Miya F, Shigemizu D,Ozaki K,
Sakata Y, Nakatani D, Suna S, Imai Y, Tanaka T,
Tsunoda T, Matsuda K, Kadowaki T, Nakamura Y,
Nagai R, Komuro I, Kubo M. A genome-wide
association study identifies PLCL2 and AP3D1DOT1L-SF3A2 as new susceptibility loci for
myocardial infarction in Japanese. Eur J Hum
Genet. 2015;23(3):374-80.

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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.

Takashi Kobayashi, 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, 60-70 patients with hematologicaldiseases are treated in the ward. Clinical facilities
include patient rooms with high-efficiency particulate

air filtration and filtrated water supply. Patients whoare eligible for the treatment with high-grade infection
prophylaxis are admitted to the facilities. Patient careis provided by team management. That is, three
doctors (a junior resident, a senior resident, and an
assistant professor) are assigned to a single patient.
Since clinical issues are highly related to hematopoietic stem cell transplantation especially for patientswith hematological diseases, a substantial portion of
our clinical conferences are shared with staff membersof the Department of Cell Therapy and Transplantation Medicine and the Department of Pediatrics(Hematology/Oncology). Many problems arising indaily clinical practice are discussed in the morning
clinical conference held thrice a week. Diagnostic andtherapeutic issues as well as pathological aspects ofindicative and/or educational cases are discussed inclinical conferences held twice a month.
Outpatient clinical services are provided from
Monday to Friday in the morning and afternoon using
three booths. Approximately 60-65 patients visit our
outpatient clinic every weekday. One of our ultimate

143

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.
Translational research to develop novel methods fordiagnosis and treatment based on basic research isalso performed. Every effort has been made to achieve
the highest quality in both clinical and basic medical
research. The ultimate aims of our research are theapplication of epoch-making discoveries in research
fields to the clinical hematology and oncology.
Representative publications from our departments
published in the past year are listed in the reference.

References
1. Hirokawa M, Sawada K, Fujishima N, Teramura M,
Bessho M, Dan K, Tsurumi H, Nakao S, Urabe A,
Fujisawa S, Yonemura Y, Kawano F, Oshimi K,
Sugimoto K, Matsuda A, Karasawa M, Arai A,
Komatsu N, Harigae H, Omine M, Ozawa K,
Kurokawa M; PRCA Collaborative Study Group.
Long-term outcome of patients with acquired

144

2.

3.

4.

5.

6.

7.

8.

9.

chronic pure red cell aplasia (PRCA) following
immunosuppressive therapy: a final report of thenationwide cohort study in 2004/2006 by the Japan
PRCA collaborative study group. Br J Haematol.
2015; 169:879-86.
Kogure Y, Yoshimi A, Ueda K, Nannya Y, Ichikawa
M, Nakamura F, Kurokawa M. Modified ESHAP
regimen for relapsed/refractory T cell lymphoma: aretrospective analysis. Ann Hematol. 2015; 94:98994.
Mishima Y, Tsuno NH, Matsuhashi M, Yoshizato T,
Sato T, Ikeda T, Watanabe-Okochi N, Nagura Y,
Sone S, Kurokawa M, Okazaki H. Effects ofuniversal vs bedside leukoreductions on the alloimmunization to platelets and the platelet transfusion refractoriness. Transfus Apher Sci. 2015; 52:
112-21.
Uni M, Kagoya Y, Nannya Y, Nakamura F,
Kurokawa M. Central nervous system relapse inpatients with diffuse large B-cell lymphoma:
analysis of incidence and prognostic factors. Leuk
Lymphoma. 2015; 56:1869-71.
Higo T, Miyagaki T, Nakamura F, Shinohara A,
Asano H, Abe H, Senda N, Yoshizaki A, Fukayama
M, Kurokawa M. Paraneoplastic pemphigus
occurring after bendamustine and rituximab therapy
for relapsed follicular lymphoma. Ann Hematol.
2015; 94:683-5.
Hangai S, Nannya Y, Kurokawa M. Role ofprocalcitonin and C-reactive protein for discrimination between tumor fever and infection in patientswith hematological diseases. Leuk Lymphoma.
2015; 56:910-4.
Higo T, Kobayashi T, Yamazaki S, Ando S, Gonoi W,
Ishida M, Okuma H, Nakamura F, Ushiku T,
Ohtomo K, Fukayama M, Kurokawa M. Cerebral
embolism through hematogenous dissemination of
pulmonary mucormycosis complicating relapsed
leukemia. Int J Clin Exp Pathol. 2015; 8:13639-42.
Shibata S, Tada Y, Hau CS, Mitsui A, Kamata M,
Asano Y, Sugaya M, Kadono T, Masamoto Y,
Kurokawa M, Yamauchi T, Kubota N, Kadowaki T,
Sato S. Adiponectin regulates psoriasiform skininflammation by suppressing IL-17 production fromγδ-T cells. Nat Commun. 2015; 6:7687.
Arai S, Miyauchi M, Kurokawa M. Modeling ofhematologic malignancies by iPS technology. Exp

Hematol. 2015; 43:654-60.
10. Iizuka H, Kagoya Y, Kataoka K, Yoshimi A,
Miyauchi M, Taoka K, Kumano K, Yamamoto T,
Hotta A, Arai S, Kurokawa M. Targeted genecorrection of RUNX1 in induced pluripotent stem
cells derived from familial platelet disorder withpropensity to myeloid malignancy restores normal
megakaryopoiesis. Exp Hematol. 2015; 43:849-57.
11. Uni M, Yoshimi A, Yamazaki S, Taoka K, Shinohara
A, Nannya Y, Nakamura F, Kurokawa M.
Comparison of garenoxacin with levofloxacin as
antimicrobial prophylaxis in acute myeloid leukemia.
Jpn J Clin Oncol. 2015; 45:745-8.
12. Wong WF, Kohu K, Nagashima T, Funayama R,
Matsumoto M, Movahed E, Tan GM, Yeow TC,
Looi CY, Kurokawa M, Osato M, Igarashi K,
Nakayama K, Satake M. The artificial loss of Runx1
reduces the expression of quiescence-associatedtranscription factors in CD4(+) T lymphocytes. Mol
Immunol. 2015; 68:223-33.
13. Kobayashi H, Kobayashi CI, Nakamura-Ishizu A,
Karigane D, Haeno H, Yamamoto KN, Sato T,
Ohteki T, Hayakawa Y, Barber GN, Kurokawa M,
Suda T, Takubo K. Bacterial c-di-GMP affects
hematopoietic stem/progenitors and their niches
through STING. Cell Rep. 2015; 11:71-84.

145

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)

Research Associate
Hirofumi Syoda、M.D., Ph.D. (Rheumatology)
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)

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 12 staffs mentioned above, who
preside over 5 medical staff, 21 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 Internal Medicine Research
Ward.

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.
For postgraduate education, internal medicine
trainees are accepted on rotation basis and trained as

146internist. 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) Analysis of regulatory T cells.
2) Analysis of the mechanisms of tolerance breakdown to systemic autoantigens using transgenicmice.
3) Analysis of antigen specific T cell clonalities in
immunological disorders.
4) Genetic analysis of rheumatoid arthritis and otherconnective tissue diseases.
5) Development of new gene therapies for immunological diseases.
6) Analysis of the mechanisms of oral tolerance.
7) Analysis of signal transduction mechanisms in
immunological disorders.
8) Mechanism of anti-nuclear antibodies production
in systemic autoimmune animal models.
9) Therapy of autoreactive B cell depletion using
modified self-antigen peptide tetramers in auto-

immune diseases.
10) Development and analysis of animal models of
bronchial asthma.
11) Exploration of the roles of protein prenylation in the
animal models of lung disease12) Analysis of cytokines and chemokines in thepathogenesis of allergic conditions.
13) Analysis of interstitial pneumonitis associatedwith connective tissue diseases,14) Mechanism of drug allergy

References

2015

1. Yamamoto K, Okada Y, Suzuki A, Kochi Y.
Genetic studies of rheumatoid arthritis. Proc Jpn
Acad Ser B Phys Biol Sci. 2015; 91(8):410-22
2. Terao C, Suzuki A, Ikari K, Kochi Y, Ohmura K,
Katayama M, Nakabo S, Yamamoto N, Suzuki T,
Iwamoto T, Yurugi K, Miura Y, Maekawa T,
Takasugi K, Kubo M, Saji H, Taniguchi A,
Momohara S, Yamamoto K, Yamanaka H, Mimori
T, Matsuda F. An association between amino acidposition 74 of HLA-DRB1 and anti-citrullinatedprotein antibody levels in Japanese patients with
anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol. 2015;67(8):2038-45.
3. AsanumaYF, Mimura T, Tsuboi H, Noma H,
Miyoshi F ,Yamamoto K ,T Sumida T. Nationwide epidemiological survey of 169 patients withadult Still ’ s disease in Japan. Mod Rheumatol.
2015;25(3):393-400
4. Yamamoto K, Okada Y, Suzuki A and Kochi Y.
Genetics of rheumatoid arthritis in Asia―present
and future. Nat.Rev.Rheumatol. 2015;11(6):3759.
5. Iwasaki Y, Fujio K, Okamura T, Yamamoto K.
Interleukin-27 in T cell immunity. Int J Mol Sci.
2015 Jan 27;16(2):2851-63.
6. Kato R, Sumitomo S, Kawahata K, Fujio K,
Yamamoto K. Successful treatment of cerebral
large vessel vasculitis in systemic lupus erythematosus with intravenous pulse cyclophosphamide.
Lupus. 2015 Jul;24(8):880-4.
7. Seri Y, Shoda H, Hanata N, Nagafuchi Y,
Sumitomo S, Fujio K, Yamamoto K. A case ofrefractory polyarteritis nodosa successfully

147

treated with rituximab. Mod Rheumatol. 2015
Mar 12:1-3
8. Sakaue S, Sumitomo S, Fujio K, Yamamoto K.
Unilateral proptosis in a woman with asthma.
BMJ Case Rep. 2015 Feb 12;2015.
9. Okamura T, Sumitomo S, Morita K, Iwasaki Y,
Inoue M, Nakachi S, Komai T, Shoda H,
Miyazaki J, Fujio K, Yamamoto K. TGF-β3expressing CD4+CD25(-)LAG3+ regulatory T
cells control humoral immune responses. Nat
Commun. 2015 Feb 19;6:6329.
10. Shoda H, Fujio K, Sakurai K, Ishigaki K,
Nagafuchi Y, Shibuya M, Sumitomo S, Okamura
T, Yamamoto K. Autoantigen BiP-Derived HLADR4 Epitopes Differentially Recognized by
Effector and Regulatory T Cells in Rheumatoid
Arthritis. Arthritis Rheumatol. 2015 May;67(5):1171-81.
11. Shibuya M, Fujio K, Shoda H, Okamura T,
Okamoto A, Sumitomo S, Yamamoto K. A new
T-cell activation mode for suboptimal doses ofantigen under the full activation of T cells withdifferent specificity. Eur J Immunol. 2015 Jun;45(6):1643-53.
12. 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 One.
2015 May 28;10(5):e0129394.
13. Ishigaki K, Shoda H, Kochi Y, Yasui T, Kadono Y,
Tanaka S, Fujio K, Yamamoto K. Quantitative andqualitative characterization of expanded CD4+ T
cell clones in rheumatoid arthritis patients. Sci
Rep. 2015 Aug 6;5:12937.
14. Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida
T, Fujio K, Yamamoto K. Peptidylarginine
deiminase type 4 deficiency reduced arthritis
severity in a glucose-6-phosphate isomeraseinduced arthritis model. Sci Rep. 2015 Aug 21;5:
13041.
15. Kubo K, Yamamoto K. IgG4-related disease. Int J
Rheum Dis. 2015 Aug 10. doi: 10.1111/1756185X.12586.
16. Tsuchida Y, Shibuya M, Shoda H, Sumitomo S,

Kubo K, Setoguchi K, Fujio K, Yamamoto K.
Characteristics of granulomatosis with polyangiitis patients in Japan. Mod Rheumatol. 2015
Mar;25(2):219-23.
17. Okamura T, Morita K, Iwasaki Y, Inoue M, Komai
T, Fujio K, Yamamoto K. Role of TGF-β3 in theregulation of immune responses. Clin Exp
Rheumatol. 2015 Jul-Aug;33(4 Suppl 92):S63-9.
18. Fujio K, Okamura T, Sumitomo S, Yamamoto K.
Therapeutic potential of regulatory cytokines thattarget B cells. Int Immunol. 2016 Apr;28(4):189-95. Epub 2015 Dec 8.
19. Tanaka Y, Takeuchi T, Miyasaka N, Sumida T,
Mimori T, Koike T, Endo K, Mashino N,
Yamamoto K. Efficacy and safety of rituximab inJapanese patients with systemic lupus erythematosus and lupus nephritis who are refractory toconventional therapy. Mod Rheumatol. 2016;
26(1):80-6. Epub 2015 Aug 19.
20. 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, vander Heijde D, Miyasaka N, Koike T. The first
double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive earlyrheumatoid arthritis patients with poor prognostic
factors, C-OPERA, shows inhibition of radiographic progression. Ann Rheum Dis 2016;75(1):75-83. Epub 2015 Jul 2.
21. Okada Y, Raj T, and Yamamoto K. Ethnicallyshared and heterogeneous impacts of molecularpathways suggested by the genome-wide metaanalysis of rheumatoid arthritis Rheumatology(Oxford). 2016;55(1):186-9. Epub 2015 Aug 28.

148

Department of Infectious
Diseases (Internal Medicine)
Associate Professor
Hiroshi Yotsuyanagi, M.D., Ph.D.

Research Associate
Yoshitaka Wakabayashi, M.D., Ph.D.

Homepage

http://infect.umin.jp/

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, a departmental library and a computer room as own properties.
In clinical and research activities, we are collaboratingwith the Department of Infection Control andPrevention. An associate professor, 6 guest lecturers,
an associate, 5 graduate students and full-time staff
members are all performing their own duties inclinical, 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, viral hepatitis, pneumonia, resistantbacteria infections such as MRSA, BLNAR or VRE,
tuberculosis, EBV infection, CMV infection, parasite
infection, etc. Every effort is made to give patients thebest care and best quality of life. Clinical associates,
full-time staff and residents take care of inpatients.
The case presentation by residents is held on a weekly
basis. Weekly clinical conference is held for
discussing about all cases, in particular, those withproblems difficult to be solved. Consultations are veryfrequent from other departments on the managementof infectious diseases. The general diagnostic,
therapeutic plans and decisions for each patient are
given at the Professor’s round.
Our department offers out-patient care everyday on
infectious diseases and general medicine. We are also
engaged in infection control and prevention of
emerging infectious diseases such dengue, MERS or
avian influenza virus, which appeared recently.

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
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

149

procedures on each case. The education of juniorresidents is performed as described in “Clinical
Activities”.

Research activities
Both clinical and basic researches are necessary to
improve the diagnosis and treatment. The members ofour department are doing best to obtain new findings
using highly sophisticated methodologies. A monthly
intramural research conference is held, in which twoto three members present their annual research
progresses to be discussed by all the department staff.
In addition, each laboratory holds its own conference
and/or journal club on a weekly or bi-weekly basis.
The research field covers wide areas of infectious
diseases including HIV infection, viral hepatitis andhepatocarcinogenesis, CMV infection and tuberculosis(Mycobacterium 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) Establishment of the criteria for prediction andearly diagnosis of CMV infection associated with
HIV infection.
(6) Innovation of new methods to control viral
hepatitis or prevent the development of hepatocellular carcinoma in chronic viral hepatitis.
(7) Establishment of the effective infection control
method of MRSA and other MDRO infection.

(8) Elucidating the mechanism and signal transduction of bacterial infection through toll-likereceptors.
(9) Establishment of new methods for practical
diagnosis and treatment of respiratory infection
including avian influenza.

Members
Hiroshi Yotsuyanagi, Takeya Tsutsumi, Shu
Okugawa, Shintaro Yanagimoto, Keita Tatsuno,
Mahoko Ikeda, Yoshitaka Wakabayashi, Daisuke
Jubishi, Ouko Ishii, Kaoru Miyashita

References
1) Hashimoto H, Hatakeyama S, Yotsuyanagi H.
Development of cryptococcal immune reconstitution inflammatory syndrome 41 months after the
initiation of antiretroviral therapy in an AIDS
patient. AIDS Res Ther 2015; 12:33.
2) Ogishi M, Yotsuyanagi H, Tsutsumi T, Gatanaga
H, Ode H, Sugiura W, et al. Deconvoluting thecomposition of low-frequency hepatitis C viralquasispecies: comparison of genotypes and NS3
resistance-associated variants between HCV/HIV
coinfected hemophiliacs and HCV monoinfectedpatients in Japan. PLoS One 2015; 10:e0119145.
3) Okushin K, Takahashi Y, Yamamichi N,
Shimamoto T, Enooku K, Fujinaga H, et al.
Helicobacter pylori infection is not associatedwith fatty liver disease including non-alcoholic
fatty liver disease: a large-scale cross-sectional
study in Japan. BMC Gastroenterol 2015; 15:25.
4) Okushin K, Tsutsumi T, Enooku K, Fujinaga H,
Kado A, Shibahara J, et al. The intrahepatic
expression levels of bile acid transporters areinversely correlated with the histological progression of nonalcoholic fatty liver disease. J
Gastroenterol 2015.
5) Saito M, Hatakeyama S, Wakabayashi Y,
Yanagimoto S, Takemura T, Yotsuyanagi H. A
pathologically proven case of adult-onset HIVrelated lymphocytic interstitial pneumonia withacute exacerbation treated with steroid andantiretroviral therapy. J Infect Chemother 2015;
21:868-872.
6) Sato M, Hikita H, Hagiwara S, Soroida Y, Suzuki

150

A, Gotoh H, et al. Potential associations between
perihepatic lymph node enlargement and liver
fibrosis, hepatocellular injury or hepatocarcinogenesis in chronic hepatitis B virus infection.
Hepatol Res 2015; 45:397-404.
7) Watanabe Y, Yamamoto H, Oikawa R, Toyota M,
Yamamoto M, Kokudo N, et al. DNA methylation
at hepatitis B viral integrants is associated withmethylation at flanking human genomic sequences. Genome Res 2015; 25:328-337.
8) Yotsuyanagi H, Fujinaga H, Okushin K. [Basic
diagnostic tests and diagnosis]. Nihon Rinsho
2015; 73 Suppl 9:481-486.
9) Yotsuyanagi H, Koike K. [Coinfection of HBVand HIV]. Nihon Rinsho 2015; 73 Suppl 9:555558.
10) Yotsuyanagi H, Koike K. [Coinfection of HCV
and HIV]. Nihon Rinsho 2015; 73 Suppl 9:300305.
11) Yotsuyanagi T, Yamauchi M, Yamashita K, Sugai
A, Gonda A, Kitada A, et al. Abnormality of
Auricular Muscles in Congenital Auricular
Deformities. Plast Reconstr Surg 2015; 136:78e88e.
12) Ikeda M, Yagihara Y, Tatsuno K, Okazaki M,
Okugawa S, Moriya K. Clinical characteristics
and antimicrobial susceptibility of Bacillus cereus
blood stream infections. Ann Clin Microbiol
Antimicrob 2015; 14:43.
13) Kato I, Fujimoto F, Higurashi Y, Yamaguchi R,
Takayama K, Suzuki M, et al. Antibiotic
Susceptibilities of Pseudomonas aeruginosa
Isolated from Blood Samples and Antibiotic
Utilization in a University Hospital in Japan.
Infect Dis Ther 2015; 4:213-218.
14) Yoshino Y, Okugawa S, Kimura S, Makita E, Seo
K, Koga I, et al. Infective endocarditis due toEnterobacter cloacae resistant to third- and fourthgeneration cephalosporins. J Microbiol Immunol
Infect 2015; 48:226-228.
15) Ishii K, Tabuchi F, Matsuo M, Tatsuno K, Sato T,
Okazaki M, et al. Phenotypic and genomic
comparisons of highly vancomycin-resistant
Staphylococcus aureus strains developed frommultiple clinical MRSA strains by in vitro
mutagenesis. Sci Rep 2015; 5:17092.
16) Shinya Y, Miyawaki S, Nakatomi H, Okano A,

Imai H, Shin M, et al. Recurrent cerebral
aneurysm formation and rupture within a shortperiod due to invasive aspergillosis of the nasal
sinus; pathological analysis of the catastrophic
clinical course. Int J Clin Exp Pathol 2015; 8:13510-13522.
17) Ito S, Hirabayashi K, Moriishi K, Matsui Y,
Moriya K, Koike K, et al. Novel sex-dependent
differentially methylated regions are demethylated
in adult male mouse livers. Biochem Biophys Res
Commun 2015; 462:332-338.
18) Minami T, Tateishi R, Kondo M, Nakagomi R,
Fujiwara N, Sato M, et al. Serum AlphaFetoprotein Has High Specificity for the Early
Detection of Hepatocellular Carcinoma After
Hepatitis C Virus Eradication in Patients.
Medicine (Baltimore) 2015; 94:e901.
19) Moriya K, Miyoshi H, Koike K. [Hepatocellular
carcinoma animal models]. Nihon Rinsho 2015;
73 Suppl 9:74-78.
20) Uchino K, Tateishi R, Fujiwara N, Minami T, Sato
M, Enooku K, et al. Impact of serum ferritin levelon hepatocarcinogenesis in chronic hepatitis C
patients. Hepatol Res 2016; 46:259-268.
21) Wada K, Yoshikawa T, Lee JJ, Mitsuda T,
Kidouchi K, Kurosu H, et al. Sharp injuries inJapanese operating theaters of HIV/AIDS referral
hospitals 2009-2011. Ind Health 2016; 54:224229.

151

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

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

Homepage

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

Introduction and Organization
The Department of Stress Science and Psychosomatic 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 chronic headache, irritable bowel syndrome, functional dyspepsia,
hypertension, diabetes mellitus, and hyperthyroidism.
Our teaching staff consists of one associate professor,
two associates, and 5 adjunct professors, and othermembers are 2 senior residents, 6 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 2015 January to 2015 December, overall 1,565
patients (59 individuals) were admitted to the ward,
many of whom were eating disorder patients.
Outpatient clinic is attended on every morning andafternoon in three consultation rooms by approximately fifteen physicians. During 2015 January to 2015
December, the numbers of the new outpatients and of

the overall outpatients in our department were 195 and3,335, respectively.

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

Research activities
Targeting stress-related diseases such as not only
those covered by our department but also otherlifestyle-related disease, and cancers, we are investigating their pathophysiology and psychopathology
through assessing bio-psycho-behavioral time-series152

data, various questionnaire data, and autonomic
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 stress-relateddiseases such as tension-type headache, eating
disorders, insomnia, and panic disorder using
portable computers for real-time assessment ofsubjective 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.
Six 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. Wada S, Shimizu K, Inoguchi H, Shimoda H,
Yoshiuchi K, Akechi T, Uchida M, Ogawa A,
Fujisawa D, Inoue S, Uchitomi Y, Matsushima E.
The association between depression and age incancer patients: a multicenter cross-sectional
study. Journal of Pain and Symptom Management50(6):768-777, 2015
2. Kikuchi H, Yoshiuchi K, Ando T, Yamamoto Y.
Influence of psychological factors on acuteexacerbation of tension-type headache: investiga-

3.

4.

5.

6.

7.

8.

tion by ecological momentary assessment. J
Psychosom Res 79:239-242, 2015
Kim J, Nakamura T, Kikuchi H, Yoshiuchi K,
Sasaki T, Yamamoto Y. Co-Variation of Depressive Mood and Spontaneous Physical Activity in
Major Depressive Disorder: Towards Continuous
Monitoring of Depressive Mood. IEEE Journal of
Biomedical and Health Informatics 19:1347-1355,
2015
Hashimoto T, Yoshiuchi K, Inada S, Shirakura K,
Wada N, Takeuchi 4, Matsushita M. Physicalactivity of elderly patients with rheumatoid
arthritis and healthy individuals: an actigraphy
study. Biopsychosoc Med 9:19, 2015
Shimizu K, Nakaya N, Saito-Nakaya K, Akechi T,
Fujimori M, Ogawa A, Fujisawa D, Sone T,
Yoshiuchi K, Ooshima Y, Inoguchi H, Goto K
Iwasaki M, Tsugane S, Uchitomi Y. Personality
traits and coping styles explain anxiety in lungcancer patients to a greater extent than otherfactors. Japanese Journal of Clinical Oncology
45:456-463, 2015
Odawara M, Hashizume M, Yoshiuchi K, Tsuboi
K. Real-time assessment of the effect of
biofeedback therapy in Japanese patients with
migraine: a pilot study. International Journal of
Behavioral Medicine 22:748-754, 2015
Kikuchi H, Yoshiuchi K, Inada S, Ando T,
Yamamoto Y. Development of an ecological momentary assessment scale for appetite. BioPsycho
Social Medicine 9:2, 2015
Matsuoka H, Yoshiuchi K, Koyama A, Otsuka M,
Nakagawa K. Chemotherapeutic drugs thatpenetrate the blood-brain barrier affect the development of hyperactive delirium in cancer patients.
Palliative & Supportive Care 13:859-864, 2015

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

154

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

Associate
Toshiyuki Ikeda, M.D., Yosuke Masamoto, M.D., Ph.D., Shunsaku Takayanagi, M.D., Ph.D.

Homepage

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

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

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

1551) 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.

156

References
1. Mishima Y,
Tsuno NH, Matsuhashi M,
Yoshizato T, Sato T, Ikeda T, Watanabe-Okochi
N, Nagura Y, Sone S, Kurokawa M, Okazaki H.
Effects of Universal vs Bedside Leukoreductions
on the Alloimmunization to Platelets and the
Platelet Transfusion Refractoriness. Transfus
Apher Sci 52:112-21, 2015
2. Hitomi Y, Kawashima M, Aiba Y, Nishida N,
Matsuhashi M, Okazaki H, Nakamura M,
Tokunaga K. Human primary biliary cirrhosis
susceptible allele of rs4979462 enhances
TNFSF15 expression by binding NF-1. Human
Genetics 134:737-47, 2015
3. Suzuki H, Aoki K, Chiba K, Sato Y, Shiozawa Y,
Shiraishi Y, Shimamura T, Niida A, Motomura K,
Ohka F, Yamamoto T, Tanahashi K, Ranjit M,
Wakabayashi T, Yoshizato T, Kataoka K,
Yoshida K, Nagata Y, Sato-Otsubo A, Tanaka H,
Sanada M, Kondo Y, Nakamura H, Mizoguchi M,
Abe T, Muragaki Y, Watanabe R, Ito I, Miyano S,
Natsume A, Ogawa S. Mutational landscape andclonal architecture in grade II and III gliomas.
Nat Genet 47:458-68, 2015.
4. Yoshizato T, Dumitriu B, Hosokawa K,
Makishima H, Yoshida K, Townsley D,
Sato-Otsubo A, Sato Y, Liu D, Suzuki H, Wu CO,
Shiraishi Y, Clemente MJ, Kataoka K, Shiozawa
Y, Okuno Y, Chiba K, Tanaka H, Nagata Y,
Katagiri T, Kon A, Sanada M, Scheinberg P,
Miyano S, Maciejewski JP, Nakao S, Young NS,
Ogawa S. Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med 373:
35-47, 2015
5. Morita K, Masamoto Y, Kataoka K, Koya J,
Kagoya Y, Yashiroda H, Sato T, Murata S,
Kurokawa M. BAALC potentiates oncogenic
ERK pathway through interactions with MEKK1and KLF4. Leukemia 29:2248-56, 2015
6. Shibata S, Tada Y, Hau CS, Mitsui A, Kamata M,
Asano Y, Sugaya M, Kadono T, Masamoto Y,
Kurokawa M, Yamauchi T, Kubota N, Kadowaki
T, Sato S. Adiponectin regulates psoriasiform skininflammation by suppressing IL-17 production
from γδ-T cells. Nat Commun 6:7687, 2015

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

158

Department of
Reproductive Endocrinology
Professor
Tomoyuki Fujii

Associate Professor
Kei Kawana
Osamu Hiraike
Kaori Koga

Lecturer
Yasushi Hirota
Tetsuya Hirata

Homepage http://plaza.umin.ac.jp/ivf/index.html
http://square.umin.ac.jp/tkyobgyn/
Organization
The Department of Reproductive Endocrinology isorganized by one professor, two associate professors
and one lecturers. All the staff members are taking
part in both clinical and research activities. For theclinical aspect, we are engaged with in-patient andout-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 ofendometriosis, 4) effect of ovarian steroid hormoneson bone metabolism, and 5) effects of endocrine
disrupters on the reproductive system.

159

References published in 2015
(1) Fujimoto A, et. al. Elective single-embryo transfer
improves cumulative pregnancy outcome in young
patients but not in women of advanced reproductive
age. J Assist Reprod Genet. 2015 Dec; 32(12):1773-9.
(2) Takamura M, et al. Simultaneous Detection and
Evaluation of Four Subsets of CD4+ T Lymphocyte
in Lesions and Peripheral Blood in Endometriosis.
Am J Reprod Immunol. 2015 Dec; 74(6): 480-6.
(3) Koga K, et al. Prevention of the recurrence ofsymptom and lesions after conservative surgery forendometriosis. Fertil Steril. 2015 Oct; 104(4): 793801.
(4) Harada M, et al. Evidence of the activation of
unfolded protein response in granulosa and cumulus
cells during follicular growth and maturation.
Gynecol Endocrinol. 2015 Oct; 31(10): 783-7.
(5) Hirata T, et al. Four Cases of Postoperative
Pneumothorax among 2814 Consecutive Laparoscopic Gynecologic Surgeries: A Possible Correlation between Postoperative Pneumothorax andEndometriosis. J Minim Invasive Gynecol. 2015
Sep-Oct; 22(6): 980-4.
(6) Miyashita M, et al. Drospirenone induces decidualization in human eutopic endometrial stromal cells
and reduces DNA synthesis of human endometriotic
stromal cells. Fertil Steril. 2015 Jul; 104(1): 21724.e2.
(7) Harada M, et al. Laparoscopic excision of ovarian
endometrioma does not exert a qualitative effect on
ovarian function: insights from in vitro fertilizationand single embryo transfer cycles. J Assist Reprod
Genet. 2015 May; 32(5): 685-9.
(8) Sakurabashi A, et al. CCAR2 negatively regulates
nuclear receptor LXRα by competing with SIRT1
deacetylase. J Steroid Biochem Mol Biol. 2015
May; 149: 80-8.
(9) Izumi G, et al. Cyclic stretch augments productionof neutrophil chemokines, matrix metalloproteinases, and activin a in human endometrial
stromal cells. Am J Reprod Immunol. 2015 Jun;73(6): 501-6.
(10) Yamamoto N, et al. Temporary balloon occlusion of
the uterine arteries to control hemorrhage during
hysterectomy in a case of uterine arteriovenous

fistula. J Obstet Gynaecol Res. 2015 Feb; 41(2):314-8.
(11) Samejima T, et al. Identifying patients who can
improve fertility with myomectomy. Eur J Obstet
Gynecol Reprod Biol. 2015 Feb; 185: 28-32.
(12) Miyasaka A, et al. A coexistence case of right tubal
adenomyoma and ectopic pregnancy. J Minim
Invasive Gynecol. 2015 Jan; 22(1): 6.
(13) Fukuda T, et al. HAND2-mediated proteolysis
negatively regulates the function of estrogen receptor α. Mol Med Rep. 2015 Oct; 12(4): 5538-44.

160

Department of
Gynecologic Oncology
Professor
Yutaka Osuga

Associate Professor
Kei Kawana
Katsutoshi Oda

Lecturer
Takahide Arimoto

Homepage

http://go.umin.jp/index.html

Organization
The Department of Gynecologic Oncology isorganized by one professor and two associate
professors, being directed practically by Professor
Tomoyuki Fujii, the Chairman of the Department of
Obstetrics and Gynecology. The staff members aretaking part in both clinical and research activities, aswell as teaching activities, with 19 associates of the
University of Tokyo 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.
For example, to identify the risk factors for cervicalintraepithelial neoplasia (CIN), we reanalysed the datafrom our previous case-control study by adjusting forhuman papillomavirus (HPV) antibodies. Unlike ourprevious study based only on HPV DNA, smoking andChlamydia trachomatis infection were revealed as
significant risk factors for CIN after adjustment for
HPV antibodies. The enhanced oncogenicity ofparticular human papillomavirus type 16 (HPV16) E6variants is population-dependent, implying the in-volvement of additional genetic cofactors. This study
was designed to investigate the association between
E6 variants and human leukocyte antigen (HLA)polymorphism within a Japanese population. Fiftyseven women with HPV16-positive cervical cancer
were analyzed for E6 sequence variation and its
relationship to HLA class II alleles. Compared withlocal controls (n = 138) and published controls (n =916), DRB1*1501 and DQB1*0602 frequencies weresignificantly increased among patients with HPV16
E6 prototype (n = 11). Additionally, DRB1*1502 waspositively associated with a particular E6 variant
designated D25E (n = 25), although we could not finda significant association between HLA class II alleles
and L83V variants (n = 16). Our observations suggestthat a specific match between E6 variant proteins andHLA types may contribute to HPV16-related cervicalcarcinogenesis.
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-161

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
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 a broadspectrum prophylactic vaccine against genital HPV.
In endometrial cancer, we identified novel
mutations in PIK3CA and AKT1, and reported thattargeting the Phosphatidylinositol 3-kinase (PI3K) /Akt Pathway may serve as a novel molecular-targeted
therapy. We also investigated molecular biomarkers to
predict the prognosis and/or drug sensitivity inendometrial cancer, using genome-wide analyses inclinical samples. Of note, extensive chromosomal
instability was an independent poor prognostic factor
in endometrial cancer.
In ovarian cancer, we also investigated genomewide analyses, including whole-exome sequencing
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 thattargeting the PI3K pathway is also promising against
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 singleinstitution analyses in clinical setting. For example, toevaluate the efficacy and toxicity of systematic
lymphadenectomy and postoperative radiotherapy(PORT) in the treatment of endometrial cancer (EC), a
total of 256 patients with EC between 2000 and 2008
were retrospectively analyzed. Surgery included
systematic pelvic and aortic lymphadenectomy,
whereas pelvic lymphadenectomy alone was
performed to preoperative stage I patients withsuperficial myometrial invasion and G1 endometrioid
adenocarcinoma. PORT was administered to 67
patients with positive lymph nodes, deep myometrial
invasion, or adnexal/peritoneal metastases. Prior to
PORT, 37 patients with adnexal/peritoneal involvement or aortic node metastases were treated withchemotherapy. Surgery was undergone in 247 patients,
including with 215 pelvic lymphadenectomy and 126

162

aortic lymphadenectomy. Five-year survival was
97.0% for stage I, 83.3% for stage II, 84.1% for stage
III, and 45.2% for stage IV. In PORT group, 13 (19%)
were recurred including one (1.5%) intrapelvic
recurrence, and five-year survival was 96.7% forintermediate-risk group and 85.3% for high-risk group.
Among the patients who had received lymphadenectomy, 19 (8.8%) experienced severe (more thangrade 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 associated with good prognosis but increased
rates of ileus in patients with EC. PORT subsequent tolymphadenectomy should limit to relatively high-riskpatients.

References published in 2015
(1) Nagasaka K, et al. Positive peritoneal cytology atinterval surgery is a poor prognostic factor inpatients with stage T3c advanced ovariancarcinoma: A retrospective study. J Obstet Gynaecol
Res. 2015 May; 41(5): 755-62.
(2) Taguchi A, et al. Characterization of noveltranscripts of human papillomavirus type 16 using
cap analysis gene expression technology. J Virol.
2015 Feb; 89(4): 2448-52.
(3) Fukuda T, et al. The anti-malarial chloroquine
suppresses proliferation and overcomes cisplatin
resistance of endometrial cancer cells via autophagy
inhibition. Gynecol Oncol. 2015 Jun; 137(3): 53845.
(4) Seiki T, et al. HPV-16 impairs the subcellular
distribution and levels of expression of protein
phosphatase 1γ in cervical malignancy. BMC
Cancer. 2015 Apr 7; 15: 230.
(5) Miyasaka A, et al. PI3K/mTOR pathway inhibition
overcomes radioresistance via suppression of the
HIF1-α/VEGF pathway in endometrial cancer.
Gynecol Oncol. 2015 Jul; 138(1): 174-80.
(6) Inaba K, et al. Antitumor activity of a combinationof dual PI3K/mTOR inhibitor SAR245409 andselective MEK1/2 inhibitor pimasertib in endo-

metrial carcinomas. Gynecol Oncol. 2015 Aug;138(2): 323-31.
(7) Uehara Y, et al. Integrated copy number andexpression analysis identifies profiles of whole-arm
chromosomal alterations and subgroups withfavorable outcome in ovarian clear cell carcinomas.
PLoS One. 2015 Jun 4;10(6):e0128066.
(8) Fukuda T, et al. Putative tumor suppression functionof SIRT6 in endometrial cancer. FEBS Lett. 2015
Aug 4; 589(17): 2274-81.
(9) Ikeda Y, et al. Prognostic importance of CDK4/6specific activity as a predictive marker forrecurrence in patients with endometrial cancer, withor without adjuvant chemotherapy. Br J Cancer.
2015 Nov 17; 113(10): 1477-83.

163

Department of Perinatal Medicine
Professor
Tomoyuki Fujii

LecturerTakeshi Nagamatsu

Homepage

http://www.iiosan.umin.jp/index.htm

Organization
The Department of Perinatal Medicine is organized
by one professor and one lecturer, being directed
practically by Professor Tomoyuki Fujii, the chairmanof the Department of Obstetrics and Gynecology. All
the staff members are taking part in both the clinicaland research activities, as well as the teachingactivities, with 19 associates of the University ofTokyo Hospital. For the clinical aspect, they are
engaged with in-patient and out-patient care including
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 20152016
1: 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
2: Taguchi A, Yamashita A, Kawana K, Nagamatsu T,

164

3:

4:

5:

6:

Furuya H, Inoue E, Osuga Y, Fujii T. Recent
Progress in Therapeutics for InflammationAssociated Preterm Birth: A Review. Reprod Sci.
2015 Dec 1.
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
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.
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
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

165

Department of Molecular andCellular Reproductive Medicine
Professor
Yutaka Osuga

Associate Professor
Kaori Koga
Osamu Hiraike

Lecturer
Yasushi Hirota
Tetsuya Hirata

Homepage http://plaza.umin.ac.jp/ivf/index.html
http://square.umin.ac.jp/tkyobgyn/
Organization
The Department of Reproductive Endocrinology isorganized by one professor and one associate
professor.

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases andgenetic counseling. We also perform minimal accesssurgery for endometriosis, uterine fibroid, benign
tumor and so on.
In the field of gynecological surgery, we have been
constantly trying to minimize surgical invasion topatients as much as possible. With both of wellequipped instruments and well-trained expertise, morethan 90% of surgery cases for benign gynecologicaldisorders are operated endoscopically. These endoscopic surgeries include laparoscopic or laparoscopicallyassisted cystectomy or salpingo-oophorectomy, laparoscopic hysterectomy or laparoscopically assisted
vaginal hysterectomy, laparoscopic or laparoscopically assisted myomectomy, diagnostic laparoscopy
for infertility, laparoscopic surgery for ectopic

pregnancy, hysteroscopic surgery and so on, whichmake a total of about 400 cases per year.
Primary care for peri/post-menopausal women is
becoming more important. We have alreadyestablished the primary care system for womenfocusing on climacteric syndrome and osteoporosis.
Hormone replacement therapy (HRT) is employed forthe purpose.
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 ofendometriosis, 4) effect of ovarian steroid hormoneson bone metabolism, and 5) effects of endocrine
disrupters on the reproductive system.

References published in 2015
(1) Fujimoto A, et al. Elective single-embryo transfer
improves cumulative pregnancy outcome in young
patients but not in women of advanced reproductive
age. J Assist Reprod Genet. 2015 Dec; 32(12):1773-9.

166(2) Takamura M, et al. Simultaneous Detection and
Evaluation of Four Subsets of CD4+ T Lymphocyte
in Lesions and Peripheral Blood in Endometriosis.
Am J Reprod Immunol. 2015 Dec; 74(6): 480-6.
(3) Koga K, et al. Prevention of the recurrence ofsymptom and lesions after conservative surgery forendometriosis. Fertil Steril. 2015 Oct; 104(4): 793801.
(4) Harada M, et al. Evidence of the activation of
unfolded protein response in granulosa and cumulus
cells during follicular growth and maturation.
Gynecol Endocrinol. 2015 Oct; 31(10): 783-7.
(5) Hirata T, et al. Four Cases of Postoperative
Pneumothorax Among 2814 Consecutive Laparoscopic Gynecologic Surgeries: A Possible Correlation Between Postoperative Pneumothorax andEndometriosis. J Minim Invasive Gynecol. 2015
Sep-Oct; 22(6): 980-4.
(6) Miyashita M, et al. Drospirenone induces decidualization in human eutopic endometrial stromal cells
and reduces DNA synthesis of human endometriotic
stromal cells. Fertil Steril. 2015 Jul; 104(1): 21724.e2.
(7) Harada M, et al. Laparoscopic excision of ovarian
endometrioma does not exert a qualitative effect on
ovarian function: insights from in vitro fertilizationand single embryo transfer cycles. J Assist Reprod
Genet. 2015 May; 32(5): 685-9.
(8) Sakurabashi A, et al. CCAR2 negatively regulates
nuclear receptor LXRα by competing with SIRT1
deacetylase. J Steroid Biochem Mol Biol. 2015
May; 149: 80-8.
(9) Izumi G, et al. Cyclic stretch augments productionof neutrophil chemokines, matrix metalloproteinases, and activin a in human endometrial
stromal cells. Am J Reprod Immunol. 2015 Jun;73(6): 501-6.
(10) Yamamoto N, et al. Temporary balloon occlusion of
the uterine arteries to control hemorrhage during
hysterectomy in a case of uterine arteriovenous
fistula. J Obstet Gynaecol Res. 2015 Feb; 41(2):314-8.
(11) Samejima T, et al. Identifying patients who can
improve fertility with myomectomy. Eur J Obstet
Gynecol Reprod Biol. 2015 Feb; 185: 28-32.
(12) Miyasaka A, et al. A coexistence case of right tubal
adenomyoma and ectopic pregnancy. J Minim

Invasive Gynecol. 2015 Jan; 22(1): 6.
(13) Fukuda T, et al. HAND2-mediated proteolysis
negatively regulates the function of estrogen
receptor α. Mol Med Rep. 2015 Oct; 12(4): 553844.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

168

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
Nobutaka Shimizu, M.D., Ph.D., Sho-ichirou Kanda, M.D., Ph.D., Riki Nishimura,
M.D.,Ph.D., Hiroko Asakai, M.D., Satsuki Kakiuchi, M.D.,Ph.D., Hiroki Yasudo M.D.,
Ph.D., Tsuyoshi Isojima, M.D., Takahiro Shindo,M.D., Kousuke Tanaka. M.D., Atsushi
Satou, M.D., Ph.D., Konomi Shimoda, M.D., Mayumi Hangai, M.D., Yoko Mizuno, M.D.,
Sayaka Ohta, M.D., Yousuke Furukawa, M.D., Takanobu Inoue, M.D., Yasuo Kubota, M.D.,
Katsutoshi Nakano, M.D, Masahiro Sekigucho, M.D., Takuya Ohshima, M.D., Takahira
Kasagami, M.D., Ph.D.,(As of March 31, 2016)

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 the169

second, third and fourth floors of the Research
Building of Internal Medicine and on the second andthird floors of the East Research Building.

Clinical activities
We have specialized outpatient clinics covering allpediatric fields in addition to general pediatrics. In
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, Ewing sarcoma, osteosarcoma, 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),
endocrinologicaldisorders,metabolic disorders and psychosomatic diseases areadmitted in the wards. Approximately 10 patients
received hematopoietic stem cell transplantation every
year. There are patients with severe combined
immunodeficiency, aplastic anemia-myelodysplastic
syndrome, acute lymphocytic leukemia with high-riskfeatures, acute myelogenous leukemia, non-Hodgkin
lymphomas, disseminated neuroblastoma and brain
tumors.
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.

Teaching activities
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 solid tumors,
we performed target capture sequencing andgenome-wide methylation analysis in rhabdomyosarcoma and neuroblastoma using next-generation
sequencing and array based technologies.
Subsequently, we found 4 distinct molecularsubgroups based on the methylation patterns in
rhabdomyosarcoma. In addition, abnormal lities of
epigenetic related genes were observed inapproximately 30% of neuroblastoma specimens.
Methylation subgroups detected in rhabdomyosarcoma were associated with pathogenetic

170

findings, clinical information, and gene mutations,indicating that this classification would be usefulfor therapeutic strategy. Moreover, epigenetic
dysregulation could be involved in the pathogenesis of neuroblastoma.
② Nephrology group: Our aim is to reveal themolecular mechanism of proteinuria. We analyzed
circulating factors and genes which is involved innephrotic syndrome. We also analyzed pathological changes in glomerulonephritis, and foundseveral new molecules which is involved in thephenotypical changes of mesangial cells.
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 genetic basis ofcongenital CNS anomalies is investigated.
Molecular and clinical analyses of mitochondrial
disorders and the neuropathological studies ofperinatal brain damage are also performed.
⑥ Neonatology group: Neonatal brain function has
been investigated using near infra-red spectroscopy (NIRS) with researchers of Department of
Education. A clinical trial of formula suppliedwith biotin has been conducted with groups of theother Universities. Cytokine profiles have been
investigated in order to elucidate pathophysiologyof several diseases in perinatal period.
⑦ Immunology group: Research area of interest
includes refractory Kawasaki disease and epidemiology of childhood infectious disease.

Referencess
1. Akamatsu T, Dai H, Mizuguchi M, Goto Y, Oka A,
Itoh M: LOX-1 is a novel therapeutic target inneonatal hypoxic-ischemic encephalopathy. Am J
Pathol 184: 1843-1852, 2014
2. Fujita D, Takeda N, Imai Y, Inuzuka R, Komuro I,
Hirata Y: Pathophysiology and Japanese clinicalcharacteristics in Marfan syndrome. Pediatr Int
56: 484-491, 2014
3. Hangai M, Kimura Y, Mori H, Yasui K, Tsuchida
S, Takahashi N: Computed tomography findingsof an ongoing subgaleal hemorrhage. Pediatr Int
56: 623-626, 2014
4. Hangai M, Watanabe K, Shiozawa R, Hiwatari M,
Ida K, Takita J: Relapsed Acute Lymphoblastic
Leukemia with Unusual Multiple Bone Invasions:
A case report. Oncol Lett 7: 991-993, 2014
5. Harita Y, Ishizuka K, Tanego A, Sugawara N,
Chikamoto H, Akioka Y, Tsurumi H, Miura K,
Gotoh Y, Tsujita M, Yamamoto T, Horike K,
Takeda A, Oka A, Igarashi T, Hattori M:
Decreased glomerular filtration as the primaryfactor of elevated circulating suPAR levels in
focal segmental glomerulosclerosis. Pediatr
Nephrol 29: 1553-1560, 2014
6. Hayashi T, Inuzuka R, Shindo T, Hirata Y,
Shimizu N, Oka A: Serum Hyaluronic Acid
Concentration in Fontan Circulation: Correlation
With Hepatic Function and Portal Vein Hemodynamics. Pediatr Cardiol 35: 608-615, 2014
7. Hoshino H, Kubota M: Canavan disease: clinicalfeatures and recent advances in research. Pediatr
Int 56: 477-483, 2014
8. Imai M, Watanabe H, Yasui K, Kimura Y, Shitara
Y, Tsuchida S, Takahashi N, Taga G: Functional
connectivity of the cortex of term and preterm
infants and infants with Down's syndrome.
Neuroimage 85: 272-278, 2014
9. Isojima T, Harita Y, Furuyama M, Sugawara N,
Ishizuka K, Horita S, Kajiho Y, Miura K, Igarashi
T, Hattori M, Kitanaka S: LMX1B mutation withresidual transcriptional activity as a cause ofisolated glomerulopathy. Nephrol Dial Transplant
29: 81-88, 2014
10. Isojima T, Doi K, Mitsui J, Oda Y, Tokuhiro E,
Yasoda A, Yorifuji T, Horikawa R, Yoshimura J,
Ishiura H, Morishita S, Tsuji S, Kitanaka S: A
recurrent de novo FAM111A mutation causes
Kenny-Caffey syndrome type2. J Bone Miner Res
29: 992- 998, 2014

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11. Kato M, Manabe A, Koh K, Inukai T, Kiyokawa
N, Fukushima T, Goto H, Hasegawa D, Ogawa C,
Koike K, Ota S, Noguchi Y, Kikuchi A, Tsuchida
M, Ohara A: Treatment outcomes of adolescentacute lymphoblastic leukemia treated on Tokyo
Children’s Cancer Study Group (TCCSG) clinical
trials. Int J Hematol 100: 180-187, 2014
12. Kato M, Koh K, Manabe A, Saito T, Hasegawa D,
Isoyama K, Kinoshita A, Maeda M, Okimoto Y,
Kajiwara M, Kaneko T, Sugita K, Kikuchi A,
Tsuchida M, Ohara A: No impact of high-dose
cytarabine and asparaginase as early intensification with intermediate-risk pediatric acutelymphoblastic leukemia: Results of Randomized
Trial TCCSG study L99-15. Br J Haematol 164:376-383, 2014
13. Kato M, Imamura T, Manabe A, Hashii Y, Koh K,
Sato A, Takahashi H, Hori H, Taki T, Inoue M,
Hayashi Y, Horibe K, Tsuchida M, Kojima S, Oda
M, Ohara A: Prognostic impact of gained chromosomes in high-hyperdiploid childhood acutelymphoblastic leukemia: a collaborative retrospective study of the Tokyo Children’s Cancer
Study Group (TCCSG) and Japan Association ofChildhood Leukemia Study (JACLS). Br J
Haematol 166: 295-298, 2014
14. Kato M, Shiozawa R, Koh K, Nagatoshi Y, Takita
J, Ida K, Kikuchi A, Hanada R: The effect of theorder of total body irradiation and chemotherapy
on graft-versus-host disease. J Pediatr Hematol
Oncol 36: e9-12, 2014
15. Kato M, Yoshida N, Inagaki J, Maeba H, Kudo K,
Cho Y, Kurosawa H, Okimoto Y, Tauchi H, Yabe
H, Sawada A, Kato K, Atsuta Y, Watanabe K:
Salvage allogeneic stem cell transplantation inpatients with pediatric myelodysplastic syndrome
and myeloproliferative neoplasms. Pediatr Blood
Cancer 61:1860-1866, 2014
16. Kawamata R, Suzuki Y, Yada Y, Koike Y, Kono Y,
Yada T, Takahashi N: Gut hormone profiles inpreterm and term infants during the first 2 monthsof life. Journal of Pediatric Endocrinology andMetabolism 27: 717-723, 2014
17. Morisaki N, Belfort MB, Mori R, Kusuda S,
Fujimura M: Brief Parenteral Nutrition Accelerates Weight Gain, Head Growth even in Healthy
VLBWs. PLoS ONE 9: e88392, 2014

18. Morisaki N, Ganchimeg T, Ota E, Vogel J, Souza
JP, Mori R, Gulmezoglu A: Maternal andinstitutional characteristics associated with theadministration of prophylactic antibiotics for
caesarean section: Secondary analysis of the
WHO multi-country survey on maternal andnewborn health. British Journal of Obstetrics andGynecology 121 Suppl 1: 66-75, 2014
19. Morisaki N, Ganchimeg T, Vogel J, Cecatti J,
Barrett J, Jayaratne K, Mittal S, Ortiz-Panozo E,
Souza JP, Crowther C, Ota E, Mori R: Mode andtiming of twin delivery and perinatal outcomes inlow- and middle-income countries: Secondary
analysis of the WHO multi- country survey onmaternal and newborn health. British Journal of
Obstetrics and Gynecology 121 Suppl 1: 89-100,
2014
20. Morisaki N, Ganchimeg T, Ota E, Vogel J, Souza
JP, Hogue C, Jayaratne K, Mori R: Risk factors
for spontaneous and provider-initiated preterm
delivery in high and low Human Development
Index countries: Secondary analysis of the WHO
multi-country survey on maternal and newborn
health. British Journal of Obstetrics andGynecology 121 Suppl 1: 101-109, 2014
21. Seki M, Yoshida K, Shiraishi Y, Shimamura T,
Sato Y, Nishimura R, Okuno Y, Chiba K, Tanaka
H, Kato K, Kato M, Hanada R, Nomura Y, Park
MJ, Ishida T, Oka A, Igarashi T, Miyano S,
Hayashi Y, Ogawa S, Takita J: Biallelic DICER1
mutations in sporadic pleuropulmonary blastoma.
Cancer Res 74: 2742-2749, 201422. Sekine T, Komoda F, Miura K, Takita J, Shimadzu
M, Matsuyama T, Ashida A, Igarashi T: Japanese
Dent disease has a wider clinical spectrum than
Dent disease in Europe/USA: genetic and clinicalstudies of 86 unrelated patients with lowmolecular-weight proteinuria. Nephrol Dial
Transplant 29: 376-384, 201423. Shiozawa Y, Takita J, Kato M, Sotomatsu M, Koh
K, Ida K, Hayashi Y: Prognostic significance of
leukopenia in childhood acute lymphoblastic
leukemia. Oncol Lett 7: 1169-1174, 2014
24. Takita J, Chen Y, Kato M, Ohki K, Sato Y, Ohta S,
Sugita K, Nishimura R, Hoshino N, Seki M,
Sanada M, Oka A, Hayashi Y, Ogaw S: Genomewide approach to identify second gene targets for

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malignant rhabdoid tumors using high-density
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25. Tsurumi H, Harita Y, Kurihara H, Kosako H,
Hayashi K, Matsunaga A, Kajiho Y, Kanda S,
Miura K, Sekine T, Oka A, Ishizuka K, Horita S,
Hattori M, Hattori S, Igarashi T: Epithelial protein
lost in neoplasm modulates platelet-derived
growth factor-mediated adhesion and motility ofmesangial cells. Kidney Int 86: 548-557, 2014
26. Yasudo H, Ando T, Takeuchi M, Nakano H,
Itonaga T, Takehara H, Isojima T, Miura K, Harita
Y, Takita J, Oka A: Systemic lupus erythematosus
complicated with liver cirrhosis in a patient with
Papillon-Lefèvre syndrome. Lupus 23: 1523-1527,
2014

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

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

Research Associate
Masahiko Sugiyama, M.D.

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

Kaori Sato, M.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, by Professor Kimoto.
In 1971, it was authorized as the first clinical department of Pediatric Surgery in a National University.
A pediatric intensive care unit was founded with Prof.
Ishida in 1973, and a ward which could accommodate
mainly pediatric surgical patients was completed.
Assistant Prof. Saito assumed office as the first
Director of this Pediatric Surgery clinical department.
Dr. Sumio Saito became Professor of PediatricSurgery in 1983. Professor Saito had enthusiastically
performed clinical studies such as operation techniques and the use of biliary atresia.
Dr. Nakajo took office as a professor in 1985. Prof.
Nakajo had developed original operative procedures
such as a radical operation for umbilical hernia and ananti-reflex valve for biliary atresia. These original
operative procedures have been inherited by pediatricsurgeons as Nakajo methods.
Our department was authorized as the Department ofPediatric Surgery in 1989 after Kyusyu University by
the Ministry of Education.
Dr. Yoshiaki Tsuchida assumed the role of Professor in1990 and published many highly regarded articles,

mainly concerning neuroblastoma and Wilm’s tumor
from research and clinical work.
In 1995, the department was reorganized as the
Reproductive, Developmental and Aging Science,
Pediatric Science and Pediatric Surgery, due to the
University policy for the Graduate School.
In 1997, Dr Hashizume became Professor in the
Department of Pediatric Surgery. He started livingrelated 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 the clinical and research
activity on the pediatric minimally invasive surgery
and retired in 2015.
The present staffs are 1 associate professor and chief,
1 lecturer, and 3 research associates. More than 20
members of our department shoulder the clinical workas pediatric surgeons.

Clinical activities
Staffs higher than research associate level take chargeof the out-patient clinic from Monday through Friday.
The pediatric surgical outpatient clinic takes place inthe same location as the pediatric outpatient clinic andwe closely cooperate with pediatricians to diagnose
and treat patients. We also have specialized outpatient
clinics, liver and biliary tract clinics and a tumor clinic.

174

Recently, a second-opinion clinic has opened withcareful detailed explanations and this has received afavorable reception.
Our ward is on the second floor south of the hospital A
wing. Other pediatric surgical patients are also
admitted to this ward. We have 16 beds in the ward
and about 400 patients a year are hospitalized. Most
operation cases are inguinal hernia, but we have othercases such as respiratory surgery disease, neonatal
digestive organ obstructions, infant malignant tumors
such as Wilms' tumor and neuroblastoma, biliary tract
diseases such as biliary tract dilatation and biliaryatresia, respiratory anomalies such as trachea stenosis
and lung cysts, gastrointestinal anomalies, andurological disorders including hydronephrosis andvesicoureteral reflux.
We compare positively with Pediatric Surgery at otherinstitutions that perform endoscopic surgery(laparoscopic surgery/thorascopic surgery). We havedeveloped an endoscopic surgery technique forpediatric diseases not covered by insurance to apply toadvanced medical care. Furthermore, we surgicallymanage seriously ill mentally and physicallyhandicapped infants and nervous system intractabledisease patients to improve their quality of life, andwe cooperate with pediatricians (neonatologists) totreat patients with prenatal diagnosis

Education
We expose 1st and 2nd year students to our dailyclinical work as well as research work during “Free
Quarter” and “Research Lab Visit” courses. Thesestudents are guided to be concerned with clinical areas
and are in charge of part of the research project. The
students hold a results announcement party at the endof training. For M2 students, general pediatric surgery
and neonatal surgery instruction is given by theprofessor and the lecturer.
An education program is also provided for M3 and M4
students for 5 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, pediatrichepatobiliary surgery, and pediatric emergency
medicine which include the practice of cardiac

massage and intra-tracheal intubation using
mannequins for practice.
We take charge of the core surgical curriculum in the“super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge about pediatric surgical disease andsurgery, and hemodynamic and respiratory evaluation
as well as basic surgical techniques and patientmanagement.

Research activities
Professor Iwanaka has established a low invasive
operation study group and developed experiments forendscopic surgery using white rabbits in the animal
resources research facilities. This study group tries todevelop endoscopic surgery for infants. Prof. Iwanaka
also provides a training program for infant endscopic
surgery for members of our department. In addition,
he has started the project of robotic surgery to perform
radical operation with laparoscopic surgery techniquefor biliary atresia. This group creates multiple
functional forceps 3 mm in a diameter for robotic
surgery system at first. And they are developing
radical operation for long gap esophageal atresia byusing the latest technique of NOTES (Natural OrificeTransluminal Endoscopic Surgery).
The regenerative medicine study group focused on
the research on regeneration of trachea. A newlaboratory in the Department of Tissue Engineering
was founded to perform not only conventional animal
experiments but also human experiments to fabricate a
trachea in the clinical course.
The researches on development of animal models.
The tumor study group analyzes the genes related totumor development and suppression. Further more,
new tumor marker is studying by using tumor tissues
and blood samples.

References(1) Otani Y, Komura M, Komura H, Ishimaru T,
Konishi K, Komuro H, Hoshi K, Takato T, Tabata
Y, Iwanaka T. Optimal amount of basic fibroblast
growth factor (b-FGF) in gelatin sponges
incorporating β-tricalcium phosphate (TCP) withchondrocytes. Tissue Eng Part A 21(3-4), 2015.
PMID: 25287675

175(2) Takazawa S, Ishimaru T, Harada K, Tsukuda Y,
Sugita N, Mitsuishi M,Iwanaka T.. Video-Based
Skill Assessment of Endoscopic Suturing in a
Pediatric Chest Model and a Box Trainer. J
Laparoendosc Adv Surg Tech A. 25(5) 2015.
PMID: 25423170(3) Nagata K, Usui N, Terui K, Takayasu H, Goishi K,
Hayakawa M, Tazuke Y, Yokoi A, Okuyama H,
Taguchi T.. Risk factors for the recurrence of thecongenital diaphragmatic hernia-report from thelong-term follow-up study of Japanese CDH
study group. Eur J Pediatr Surg. 2015, 25(1):9-14.. PMID: 25526606(4) Fujishiro J, Ishimaru T, Sugiyama M, Arai M,
Uotani T, Yoshida M, Miyakawa K, Kakihara T,
Iwanaka T. Thoracoscopic plication for diaphragmatic eventration after surgery for congenital
heart disease in children. J Laparoendosc Adv
Surg Tech A. 2015; 25(4): 348-51. PMID:
25536425(5) Okuyama H, Koga H, Ishimaru T, Kawashima H,
Yamataka A, Urushihara N, Segawa O, Uchida H,
Iwanaka T.. Current Practice and Outcomes ofThoracoscopic Esophageal Atresia and Tracheoesophageal Fistula Repair: A Multi-institutional
Analysis in Japan. J Laparoendosc Adv Surg
Tech A. 25(5): 441-4, 2015. PMID: 25594776(6) Harada K, Takazawa S, Tsukuda Y, Ishimaru T,
Sugita N,Iwanaka T, Mitsuishi M.. Quantitative
pediatric surgical skill assessment using a
rapid-prototyped chest model. Minim Invasive
Ther Allied Technol
24(4): 226-32, 2015.
PMID: 25600864(7) Ishimaru T, Komura M, Sugiyma M, Komura H,
Arai M, Fujishiro J, Uotani C, Miyakawa K,
Kakihara T, Hoshi K, Takato T, Tabata Y, Komuro
H, Iwanaka T. Slow release of basic fibroblast
growth factor (b-FGF) enhances mechanicalproperties of rat trachea. J Pediatr Surg 50(2):255-9, 2015. PMID: 25638613(8) Tanaka Y, Uchida H, Kawashima H, Sato K,
Takazawa S, Deie K, Masuko T, Kanno K,
Shimizu M. Influence of surgical intervention onneurodevelopmental outcome in infants withfocal intestinal perforation Pediatrics International, 57(4):687-9, 2015. PMID: 25676146(9) Komura M, Komura H, Otani Y, Suzuki K, Satake

R, Kodaka T, Terawaki K, Yonekawa H,
Ikebukuro K, Hoshi K, Takato T, Tabata Y,
Komuro H, Iwanaka T.. Tracheoplasty withcartilage-engineered esophagus environments. J
Pediatr Surg. 50(7): 1093-8, 2015.
PMID:
25783340(10) Takayasu H, Masumoto K, Hagiwara K, Sasaki T,
Ono K, Jimbo T, Uesugi T, Gotoh C, Urita Y,
Shinkai T, Tanaka H.. Increased pulmonary RhoA
expression in the nitrofen-induced congenital
diaphragmatic hernia rat model. J Pediatr Surg.
2015 Sep;50(9):1467-71. PMID: 25783350(11) Takazawa S, Uchida H, Kawashima H, Tanaka Y,
Sato K, Jimbo T, Iwanaka T.. Laparoscopic partial
gastrectomy of a huge gastric duplication cyst in
an infant. Nagoya J Med Sci. 77(1-2):291-6,
2015. PMID: 25797994(12) Amano H, Uchida H, Kawashima H, Deie K,
Murase N, Makita S, Yokota K, Tanaka Y. The
umbilical Benz incision for reduced port surgery
in pediatric patients. Journal of the Society of
Laparoendoscopic Surgeons / Society of Laparoendoscopic Surgeons, 19(1), 2015.
PMID:
25848185(13) Takayasu H, Masumoto K, Jimbo T, Sakamoto N,
Sasaki T, Uesugi T, Gotoh C, Urita Y, Shinkai T..
Analysis of risk factors of long-term complications in congenital diaphragmatic hernia: A
single institution's experience. Asian J Surg.
2015 Apr 30.. PMID: 25937583(14) Takeyama E, Tanaka M, Fujishiro J, Kitagawa N,
Iwanaka T, Tanaka Y. A case of alphafetoprotein-producing gastric cancer in a childpresenting with rupture of multiple liver metastases. Pediatr Surg Int. 2015 Sep;31(9):885-8.
PMID: 26081312(15) Tanaka Y, Uchida H, Kawashima H, Fujiogi M,
Takazawa S, Deie K, Amano H. Long-term
outcomes of operative versus nonoperative treatment for uncomplicated appendicitis. J Pediatr
Surg. 50(11):1893-7, 2015. PMID: 26259556(16) Fujiogi M, Tanaka Y, Kawashima H, Toma M,
Suzuki K, Amano H, Morita K, Uchida H,
Iwanaka T. An Easy and Safe Technique for
Laparoscopic Pyloromyotomy: Using a Vascular
Clamp for Stabilization of the Pylorus.
J
Laparoendosc Adv Surg Tech A. 25(12):1036-9,

176

2015.. PMID: 26262762(17) 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 of Growth Retardation in Congenital
Diaphragmatic Hernia: A Long-Term Follow-Up
Study from the Japanese Congenital Diaphragmatic Hernia Study Group. Eur J Pediatr Surg.
2015 Oct 28.. PMID: 26509310(18) 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 ashort tip and small shaft for pediatric laparoscopic surgery: in vivo assessment of multidirectional suturing on the vertical plane of theliver in rabbits. Surg Endosc. 2015 Oct 28.
[Epub ahead of print]. PMID: 26511118(19) Iwanaka T, Yamataka A, Uemura S, Okuyama H,
Segawa O, Nio M, Yoshizawa J, Yagi M, Ieiri S,
Uchida H, Koga H, Sato M, Soh H, Take H,
Hirose R, Fukuzawa H, Mizuno M, Watanabe T.
Pediatric Surgery. Asian J Endosc Surg. 8(4):390-407, 2015. PMID: 26708583(20) Fujishiro J, Ishimaru T, Sugiyama M, Arai M,
Suzuki K, Kawashima H, Iwanaka T. Minimallyinvasive surgery for diaphragmatic diseases inneonates and infants Surg Today. 2015, in press.
PMID: 27246508(21) Ishimaru T, Komura M, Sugiyama M, Komura H,
Arai M, Fujishiro J, Uotani C, Miyakawa K,
Kakihara T, Hoshi K, Takato T, Tabata Y, Komuro
H, Iwanaka T. . Slow release of basic fibroblast
growth factor (b-FGF) enhances mechanicalproperties of rat trachea. J Pediatr Surg. 2015,50(2):255-9. PMID: 25638613(22) Komura M, Komura H, Otani Y, Suzuki K, Satake
R, Kodaka T, Terawaki K, Yonekawa H,
Ikebukuro K, Hoshi K, Takato T, Tabata Y,
Komuro H, Iwanaka T.. Tracheoplasty withcartilage-engineered esophagus environments. J
Pediatr Surg. 2015; 50(7):1093-8..
PMID:
25783340

Reproductive, Developmental andAging Sciences
3. Aging Sciences

178

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.

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.

179

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
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. Azuma K, Shiba S, Hasegawa T, Ikeda K, Urano
T, Horie-Inoue K, Ouchi Y, Amizuka N, Inoue
S: Osteoblast-specific γ-glutamyl carboxylasedeficient mice display enhanced bone formation
with aberrant mineralization. J Bone Miner Res
30(7):1245-1254, 2015.
3. Ebihara S, Izukura H, Miyagi M, Okuni I, Sekiya
H, Ebihara T: Chemical Senses Affecting Coughand Swallowing. Curr Pharm Des, 2016. [Epubahead of print] PMID: 26881438
4. Ebihara S, Sekiya H, Miyagi M, Ebihara T,
Okazaki T: Dysphagia, dystussia, and aspiration
pneumonia in elderly people. J Thorac Dis
8:632-9, 2016. doi: 10.21037/jtd.2016.02.60.
5. Ebihara T: Aromatic innovations in geriatriccare: preventing aspiration pneumonia. (Invited
Edotrial Interview) Intern J Clin Aromatherapy
10:15-20, 2015.
6. Fujimura T, Takahashi S, Kume H, Urano T,
Takayama K, Yamada Y, Suzuki M, Fukuhara H,
Nakagawa T, Inoue S, Homma Y: Toremifene, aselective
estrogen
receptormodulator,
significantly improved biochemical recurrence inbone metastatic prostate cancer: a randomized
controlled phase II a trial. BMC Cancer 15:836,
2015.
7. Htun NC, Ishikawa-Takata K, Kuroda A, Tanaka
T, Kikutani T, Obuchi SP, Hirano H, Iijima K:
Screening for malnutrition in community
dwelling older Japanese: preliminary development and evaluation of the Japanese Nutritional

180

Risk Screening Tool (NRST). J Nutr Health
Aging 20(2):114-120, 2016.
8. Ikeda K, Horie-Inoue K, Ueno T, Suzuki T, Sato
W, Shigekawa T, Osaki A, Saeki T, Berezikov E,
Mano H, Inoue S: miR-378a-3p modulates
tamoxifen sensitivity in breast cancer MCF-7
cells through targeting GOLT1A. Sci Rep 5:13170, 2015.
9. Ishii S, Ogawa S, Akishita M: The State of
Health in Older Adults in Japan: Trends in
Disability, Chronic Medical Conditions andMortality. PLoS One 10(10):e0139639, 2015.
10. Ishiki A, Okinaga S, Tomita N, Kawahara R,
Tsuji I, Nagatomi R, Taki Y, Takahashi T,
Kuzuya M, Morimoto S, Iijima K, Koseki T,
Arai H, Furukawa K: Changes in Cognitive
Functions in the Elderly Living in Temporary
Housing after the Great East Japan Earthquake.
PLoS One 13:0147025, 2016.
11. Iwamoto J, Okano H, Furuya T, Urano T,
Hasegawa M, Hirabayashi H, Kumakubo T,
Makita K: Patient preference for monthly
bisphosphonate versus weekly bisphosphonate ina cluster-randomized, open-label, crossover trial:
Minodroate Alendronate/Risedronate Trial in
Osteoporosis (MARTO). J Bone Miner Metab
34:201-8, 2016.
12. Izumi G, Koga K, Nagai M, Urata Y, Takamura
M, Harada M, Hirata T, Hirota Y, Ogawa K,
Inoue S, Fujii T, Osuga Y: Cyclic stretch
augments production of neutrophil chemokines,
matrix metalloproteinases, and Activin A in
human endometrial stromal cells. Am J Reprod
Immunol 73(6):501-506, 2015.
13. Kuroda A, Tanaka T, Hirano H, Ohara Y,
Kikutani T, Furuya H, Obuchi SP, Kawai H,
Ishii S, Akishita M, Tsuji T, Iijima K: Eating
Alone as Social Disengagement is Strongly
Associated With Depressive Symptoms inJapanese Community-Dwelling Older Adults. J
Am Med Dir Assoc 16(7):578-85, 2015.
14. Matsushita S, Suzuki K, Ogino Y, Hino S, SatoT, Suyama M, Matsumoto T, Omori A, Inoue S,
Yamada G: Androgen regulates Mafb expression
through its 3’UTR during mouse urethral masculinization. Endocrinology 157(2):844-857, 2016.

15. Miyazaki T, Ikeda K, Sato W, Horie-Inoue K,
Okamoto K, Inoue S: MicroRNA library-based
functional screening identified androgensensitive miR-216a as a player in bicalutamide
resistance in prostate cancer. J Clin Med 4(10):1853-1865, 2015.
16. Mori T, Ishii S, Greendale GA, Cauley JA,
Ruppert K, Crandall CJ, Karlamangla AS: Parity,
Lactation, Bone Strength, and 16-year Fracture
Risk in Adult Women: Findings From the Studyof Women's Health Across the Nation (SWAN).
Bone 73:160-6, 2015.
17. Nakajima Y, Osakabe A, Waku T, Suzuki T,
Akaogi K, Fujimura T, Homma Y, Inoue S,
Yanagisawa J: Estrogen exhibits a biphasic
effect on prostate tumor growth through the
ERβ-KLF5 pathway. Mol Cell Biol 36(1):144156, 2015.
18. Nihei M1, Okazaki T, Ebihara S, Kobayashi M,
Niu K, Gui P, Tamai T, Nukiwa T, Yamaya M,
Kikuchi T, Nagatomi R, Ebihara T, Ichinose M:
Chronic inflammation, lymphangiogenesis, andeffect of an anti-VEGFR therapy in a mousemodel and in human patients with aspiration
pneumonia. J Pathol 235:632-45, 2015. doi: 10.
1002/path.4473, Epub, 2015.
19. 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.
20. Ota H, Ogawa S, Ouchi Y, Akishita M:
Protective effects of NMDA receptor antagonist,memantine, against senescence of PC12 cells: apossible role of nNOS and combined effects with
donepezil. Exp Gerontol 72:109-116, 2015.
21. Saito-Kanatani M, Urano T, Hiroi H, Momoeda
M, Ito M, Fujii T, Inoue S: Identification of
TRIM22 as a progesterone-responsive gene in
Ishikawa endometrial cancer cells. J Steroid
Biochem Mol Biol 154:217-225, 2015.
22. Sawaki D, Hou L, Tomida S, Sun J, Zhan H,
Aizawa K, Son BK, Kariya T, Takimoto E, Otsu
K, Conway SJ, Manabe I, Komuro I, Friedman
SL, Nagai R, Suzuki T: Modulation of Cardiac

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Fibrosis by Krüppel-like Factor 6 throughTranscriptional Control of Thrombospondin 4 in
Cardiomyocytes. Cardiovasc Res 107(4):420-30,
2015
23. Seino S, Shinkai S, Iijima K, Obuchi S, Fujiwara
Y, Yoshida H, Kawai H, Nishi M, Murayama H,
Taniguchi Y, Amano H, Takahashi R: Reference
Values and Age Differences in Body Composition of Community-Dwelling Older Japanese
Men and Women: A Pooled Analysis of Four
Cohort Studies. PLoS One 10(7):e0131975,
2015.
24. Shibasaki K, Ogawa S, Yamada S, Iijima K, Eto
M, Kozaki K, Toba K, Ouchi Y, Akishita M:
Favorable Effect of Sympathetic Nervous
Activity on Rehabilitation Outcomes in Frail
Elderly. J Am Med Dir Assoc 16, 799, e7-799,
e12, 2015.
25. Son BK, Sawaki D, Tomida S, Fujita D, Aizawa
K, Aoki H, Akishita M, Manabe I, Komuro I,
Friedman SL, Nagai R, Suzuki T: Granulocyte
macrophage colony-stimulating factor is required
for aortic dissection/intramural haematoma. Nat
Commun. 29, 6, 6994. doi: 10.1038/ncomms
7994, 2015.
26. Takayama K, Misawa A, Suzuki T, Takagi K,
Hayashizaki Y, Fujimura T, Homma Y,
Takahashi S, Urano T, Inoue S: TET2 repression
by androgen hormone regulates global hydroxymethylation status and prostate cancer progression. Nat Commun 6, 8219, 2015.
27. Tamiya H, Miyakawa M, Takeshita A, Miura D,
Takeuchi Y: Ultrasonographic evaluation ofparathyroid hyperplasia in multiple endocrine
neoplasia type 1: Positive correlation between
parathyroid volume and circulating parathyroid
hormone concentration. J Bone Miner Metab
(Springer) 33:523-9, 2015. 査読あり.
28. Tamiya H, Yasunaga H, Matusi H, Fushimi K,
Akishita M, Ogawa S: Comparison of short-term
mortality and morbidity between parenteral andenteral nutrition for adults without cancer: apropensity-matched analysis using a national
inpatient database. Am J Clin Nutr (American
Society for Nutrition) 102:1222-1228, 2015.
29. Tamiya H, Yasunaga H, Matusi H, Fushimi K,
Ogawa S, Akishita M: Hypnotics and theoccurrence of bone fractures in hospitalized
dementia patients: a matched case-control study
using a national inpatient database. PLoS ONE(Public Library of Science) 10(6):e0129366,
2015.
30. Tsuda Y, Yasunaga H, Horiguchi H, Ogawa S,
Kawano H, Tanaka S: Association between
dementia and postoperative complications after
hip fracture surgery in the elderly: analysis of
87,654 patients using a national administrative
database. Arch. Orthop. Trauma Surg. 135:15111517, 2015.
31. Urano T, Shiraki M, Sasaki N, Ouchi Y, Inoue S:
SLC25A24 as a novel susceptibility gene for low
fat mass in humans and mice. J Clin Endocrinol
Metab 100(4):E655-E663, 2015.
32. Yakabe M, Ogawa S, Ota H, Iijima K, Eto M,
Ouchi Y, Akishita M: Beta-hydroxy-betamethylbutyrate Inhibits Lipopolysaccharideinduced Interleukin-6 Expression by Increasing
Protein Phosphatase-1α Expression. RNA andTranscription 1(1):1-5, 2015.
33. Yamada Y, Eto M, Ito Y, Mochizuki S, Son BK,
Ogawa S, Iijima K, Kaneki M, Kozaki K, Toba
K, Akishita M, Ouchi Y: Suppressive Role of
PPARγ-Regulated Endothelial Nitric Oxide
Synthase in Adipocyte Lipolysis. PLoS One 10:
e0136597, 2015.
34. Yamaguchi Y, Hibi S, Ishii M, Hanaoka Y,
Yamamoto H, Ouchi Y, Akishita M: Removal of
the CPAP Therapy Device During Sleep and Its
Association With Body Position Changes andOxygen Desaturations. Respir Care 60:658-665,
2015.
35. Zhang P, Elabd S, Hammer S, Solozobova V,
Yan H, Barte F, Inoue S, Heinrich T, Wittbrodt J,
Loosli F, Davidson G, Blattner C: TRIM25 has adual function in the p53/Mdm2 circuit.
Oncogene 34(46):5729-5738, 2015.
英文短報
1. Hashizume T, Tokumaru AM, Harada K: Small
intestine perforation due to accidental pressthrough package ingestion in an elderly patientwith Lewy body dementia and recurrent
cardiopulmonary arrest. BMJ Case Rep. pii:
bcr2015212723, 2015.

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2. Ishii S, Tanaka T, Akishita M, Iijima K: Re:
Growing research on sarcopenia in Asia.
Geriatr Gerontol Int 15:238-9, 2015.
3. Ishii S, Tanaka T, Ouchi Y, Akishita M, Iijima
K: Development of conversion formulae
between 4-m, 5-m and 6-m gait speed. Geriatr
Gerontol Int 15:233-4, 2015
4. Nanao M, Kojima T, Yamaguchi Y, Ogawa S,
Akishita M: An elderly man with rapidly
progressive depression and activities of dailyliving decline: Case report of late-onset hypogonadism syndrome. Geriatr Gerontol Int. 15(8):1098-9, 2015.
5. Noguchi M, Yamada Y, Sakakura K, Katayama
T, Momomura S, Ako J. Coronary thrombus
aspiration revealed tumorous embolism of
myxofibrosarcoma from the left atrium.
Cardiovasc Interv Ther 31(1):75-8, 2016.
英文総説
1. Misawa A, Inoue S: Estrogen-related receptors
in breast cancer and prostate cancer. Front
Endocrinol (Lausanne) 6:83, 2015.
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 (in press)
3. Urano T, Inoue S: Recent genetic discoveries inosteoporosis, sarcopenia and obesity. Endocr J
62(6):475-484, 2015.
4. Yakabe M, Ogawa S, Akishita M: Clinicalmanifestations and pathophysiology of sarcopenia. RNA and Transcription 1:10-17, 2015.

Surgical Sciences
1. Surgery

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Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Sato, Masaaki
Anraku, Masaki

StaffsNitadori, 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.

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Clinical activities
Six staffs (Nakajima J, Sato M, Anraku M, Nitadori
J, Nagayama K, and Kuwano H), who are certificatedas members of the Japanese Board of General
Thoracic Surgery, are in charge of the Department ofThoracic Surgery, University of Tokyo Hospital. They
specialize in surgical treatment for diseases of therespiratory and the mediastinal organs and the chest
wall, except for diseases of the esophagus andmammary glands.
Lung cancer is the leading cause of cancer death inour country: Ministry of Health, Labour and Welfare
documented that number of deaths from malignant
neoplasms in 2014 was approximately 380 thousandout of 1.27 million total deaths in Japan. Of them, 73
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 thoracoscopy
for the diagnosis and treatment of the thoracic disease
with less surgical invasiveness since 1992 for safer
treatment of older patients with cardiovascular and/or
respiratory complications. We currently conduct a
standard surgery for clinical stage IA/IB NSCLC, i.e.
lobectomy
andlymphadenectomy
through
thoracoscopy: In 2015, more than 90% of patientswith NSCLC was the candidate for thoracoscopic
surgery in our department. Researches on
less-invasiveness, oncological advantage of thethoracoscopic surgery are thus actively done.
We also treat patients with advanced, unresectable
NSCLC and those with recurrent NSCLC
postoperatively by an immunotherapy. We 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 paraneoplastic syndromes, such as the myasthenia gravis
and the pure red cell aplasia. Although they are
relatively rare diseases, we sought to establish thestrategies on diagnosis and treatment of these diseases,
which are still yet to be determined, from our clinicalexperiences of more than 200 cases with the diseases
in our department. We 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 is certified as a lung transplant centers
in March 2014. We started to register patients who
were eligible for lung transplantation. We successfully
performed the first case in Tokyo of living donor lungtransplantation 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 a patient who had
suffered from the pulmonary hypertension.
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

186

Academic education

Selected publications

Medical students in the fifth grade have two-weeks’program on the clinical training of the thoracic and the
cardiovascular surgery. They are able to participate theclinical clerkship of the thoracic surgery, an elective
course for 4 weeks. We also conduct a further researchtraining for medical students who like to study
thoracic surgery. The Department of Thoracic Surgery
also offers the 4-year postgraduate program for
qualified surgeons who are willing to specialize in thethoracic surgery. We have a training program forsurgeons who wish to be a board-certified thoracic
surgeon after 4-year residency.

1. Qiang G, Nakajima J. Simultaneous Stapling of
Pulmonary Vein and Bronchus in Video-Assisted
Thoracic Surgery Lobectomy. Ann Thorac
Cardiovasc Surg. 2015; 21(1):78-80
2. Murakawa T, Karasaki T, Kitano K, Nagayama K,
Nitadori JI, Anraku M, Nakajima J. Invasive
thymoma disseminated into the pleural cavity:
mid-term results of surgical resection. Eur J
Cardiothorac Surg. 2015; 47(3):567-72
3. Sato T, Kondo H, Watanabe A, Nakajima J, Niwa
H, Horio H, Okami J, Okumura N, Sugio K,
Teramukai S, Kishi K, Ebina M, Sugiyama Y,
Kondo T, Date H. A simple risk scoring systemfor predicting acute exacerbation of interstitial
pneumonia after pulmonary resection in lungcancer patients. Gen Thorac Cardiovasc Surg.
2015; 63(3):164-72.
4. Murakawa T, Ichinose J, Hino H, Kitano K,
Konoeda C, Nakajima J. Long-Term Outcomes ofOpen and Video-Assisted Thoracoscopic Lung
Lobectomy for the Treatment of Early Stage
Non-small Cell Lung Cancer are Similar: A
Propensity-Matched Study. World J Surg. 2015;39(5):1084-91
5. Amano Y, Ishikawa R, Sakatani T, Ichinose J,
Sunohara M, Watanabe K, Kage H, Nakajima J,
Nagase T, Ohishi N, Takai D. Oncogenic
TPM3-ALK activation requires dimerization
through the coiled-coil structure of TPM3.
Biochem Biophys Res Commun. 2015;
457(3):457-60
6. Huang H, Kitano K, Nagayama K, Nitadori J,
Anraku M, Murakawa T, Nakajima J. Results ofbony chest wall reconstruction with expanded
polytetrafluoroethylene soft tissue patch. Ann
Thorac Cardiovasc Surg. 2015; 21(2):119-24.
7. Konoeda C, Nakajima J, Murakawa T. Fibroblastsof recipient origin contribute to airway fibrosis inmurine tracheal transplantations. Transpl Int.
2015; 28(6):761-3.
8. Hino H, Murakawa T, Ichinose J, Nagayama K,
Nitadori J, Anraku M, Nakajima J. Results ofLung Cancer Surgery for Octogenarians. Ann
Thorac Cardiovasc Surg. 2015; 21(3):209-16

Current researches
Main subjects of current research at present include
basic and clinical studies on the malignant neoplasmsin the thorax, and transplantation of the thoracic
organs. Recently we conducted clinical studies on the
immunotherapy with adopted gammadelta- T-cell forthe treatment of the patients with unresectable orrecurrent NSCLC.
The following are the major themes under research:(1) Minimally invasive surgeries for thoracic
malignant neoplasms.
(2) Image analysis of the lung cancer focusing on its
degree of malignancy.
(3) Global analysis of oncogenes and suppressor
genes associated with lung cancer.
(4) Application of new fluorescent agents fordiagnosis of lung cancer.
(5) Immunotherapy for lung cancer and malignant
mesothelioma.
(6) Single and multi-institutional studies on thymic
epithelial malignant neoplasms.
(7) Single and multi-institutional studies on surgicaltherapeutics for pulmonary metastasis.
(8) Analysis on mechanisms of acute or chronic
rejection of the allogeneic lung and trachea after
allogeneic transplantation.
(9) Research on donor lung preservation.

187

9. Shiono S, Matsutani N, Okumura S, Nakajima J,
Horio H, Kohno M, Ikeda N, Kawamura M; The
Metastatic Lung Tumor Study Group of Japan.
The prognostic impact of lymph-node dissection
on lobectomy for pulmonary metastasis. Eur J
Cardiothorac Surg. 2015; 48(4):616-21
10. Yoshida Y, Kage H, Murakawa T, Sato Y, Ota S,
Fukayama M, Nakajima J. Worse Prognosis forStage IA Lung Cancer Patients with Smoking
History and More Severe Chronic Obstructive
Pulmonary Disease. Ann Thorac Cardiovasc Surg.
21 (3): 194-200, 2015
11. Yamada Y, Yoshino I, Nakajima J, Miyoshi S,
Ohnuki T, Suzuki M, Nagayasu T, Iwasaki A,
Okumura M; Japanese Association for Researchof the Thymus. Surgical outcomes of patients with
Stage III thymoma in the Japanese Nationwide
Database. Ann Thorac Surg. 2015; 100(3):961-7.
12. Miyai M, Eikawa S, Hosoi A, Iino T, Matsushita
H, Isobe M, Uenaka A, Udono H, Nakajima J,
Nakayama E, Kakimi K. Detection and Tracking
of NY-ESO-1-Specific CD8+ T Cells by
High-Throughput T Cell Receptor β (TCRB)
Gene Rearrangements Sequencing in a
Peptide-Vaccinated Patient. PLoS One. 2015 Aug
20; 10(8):e0136086. doi: 10.1371/journal.pone.
136086. eCollection 2015. PMID: 26291626
13. Matsumiya R, Hosono O, Yoshikawa N, Uehara
M, Kobayashi H, Oda A, Matsubara E, Tanada S,
Shintani Y, Nagayama K, Nakajima J, Tanaka H.
Elevated Serum IgG4 Complicated by Pericardial
Involvement with a Patchy (18)F-FDG Uptake in
PET/CT: Atypical Presentation of IgG4-relatedDisease. Intern Med. 2015; 54(18):2337-41.
14. Kawashima M, Murakawa T, Shinozaki T,
Ichinose J, Hino H, Konoeda C, Tsuchiya T,
Murayama T, Nagayama K, Nitadori JI, Anraku M,
Nakajima J. Significance of the Glasgow
Prognostic Score as a prognostic indicator forlung cancer surgery. Interact Cardiovasc Thorac
Surg. 2015; 21(5):637-43
15. Watanabe K, Amano Y, Ishikawa R, Sunohara M,
Kage H, Ichinose J, Sano A, Nakajima J,
Fukayama M, Yatomi Y, Nagase T, Ohishi N,
Takai D. Histone methylation-mediated silencingof miR-139 enhances invasion of non-small-celllung cancer. Cancer Med. 2015 Oct; 4(10):157382.
16. Nozawa H, Tanaka J, Nishikawa T, Tanaka T,
Kiyomatsu T, Kawai K, Hata K, Kazama S,
Yamaguchi H, Ishihara S, Sunami E, Kitayama J,
Nakajima J, Kokudo N, Watanabe T. Predictors
and outcome of complete removal of colorectal
cancer with synchronous lung metastases. Mol
Clin Oncol. 2015; 3(5):1041-1047.
17. Tajima S, Yanagiya M, Sato M, Nakajima J,
Fukayama M. Metaplastic thymoma withmyasthenia gravis presumably caused by anaccumulation of intratumoral immature T cells: acase report. Int J Clin Exp Pathol. 2015; 8(11):15375-80, PMID: 26823897

188

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.
He also started implantation of alcohol-preserved
aortic homograft for abdominal aortic aneurysm in
1952, and closed commissurotomy for mitral valve
stenosis in 1954. The first open heart surgery (atrial
septal defect closure) was performed in 1955, using
selective brain perfusion cooling method that wasdeveloped in the Department.
Establishment of Department of Thoracic Surgery
in the University of Tokyo Hospital was approved by
the government first in Japan December 15, 1964.
Under the leadership of Professor Kimoto excellent
research works were created especially on pacemakerand artificial heart, and many opinion leaders were
produced. Dr. Masahiro Saigusa, the second Professor,
endeavored to make open heart surgery safer byintroducing new- generation heart-lung machines tothe Department. Dr. Kenichi Asano, the third
Professor, started posterior-leaflet preserving mitralvalve replacement first in Japan. He also dramatically
improved surgical results of Tetralogy of Fallot. Dr.
Akira Furuse, the fourth Professor, modernizedmanagement of extremely busy clinical works. During
this time, the Department was divided into two
Divisions, Cardiovascular and General thoracic, due
to the University policy of Graduate-school.
Dr. Shinichi Takamoto assumed the fifth Professor
in June 1997. He rearranged clinical teams into threegroups (adult cardiac disease, thoracic aortic diseaseand congenital heart disease) to adapt the rapid
progress of cardiovascular surgery. Dr. Minoru Ono
was elected as the sixth Professor in November 2009.
Additional clinical team of treatment of advanced
heart failure was established to cope with anincreasing number of patients who require ventricularassist device treatment. Present staffs are one Chief
Professor, one Associate Professor and three Lecturer
and eight Associates.

189

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 thefollow-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 ofextended thoracic aortic aneurysm and repair ofcomplex congenital heart diseases, such as Jatene,
Fontan and Norwood operations. Transcatheter aortic
valve replacement was initiated in 2015. Several
high-risk very old patients with aortic valve stenosis
were successfully treated.
The University of Tokyo Tissue Bank was founded
in 1997, based on the Department of Cardiovascular
Surgery. The Bank has been actively promoting
procurement, preservation and shipping of humanvalve and blood vessel allograft in Japan. We take thelead in surgical treatment using allograft for severe
active endocarditis or infection of aortic aneurysm or
vascular prosthesis. Surgical treatment using allograft
was approved as advanced medical technology by theGovernment in 2006. As of March 2015, 67 cases ofheart transplantation and more than 210 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 inclinical practice on diagnosis of cardiovasculardisease in the autumn term at the 2nd grade. We expose
the students to daily clinical works as well as researchworks during the course of “Free Quarter” and“Research Lab Visit”, which are scheduled in thesummer and spring vacations at 1st and 2nd grade. Joint
lectures with the Cardiology Department arescheduled 3rd through 4th grades. Each student is
assigned one or two cardiovascular surgical cases in
the Regular Clinical Clerkship, in which he/she isrequired to learn preoperative patient evaluation andmanagement, surgical treatment and postoperative
care, based on participatory practice. There are also
fifteen small key-lectures on cardiovascular surgery.
Hands-on practice is provided during the Advanced
Clinical Clerkship one-month course in the lastmonths 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
protocols of left ventricular assist device, 2) basic andclinical research on cryopreserved allograft, 3)application of regenerative medicine to end-stage
heart failure, 4) mechanism analysis of right heart

190

failure and development of effective pharmacologicaltherapy, 5) development of versatile suture device, 6)
clinical research for new drug for spinal cord ischemia,7) clinical research to test the safety and efficacy ofartificial pancreas during open heart surgery.

References
1. Takata M, Amiya E, Watanabe M, Ozeki A,
Watanabe A, Kawarasaki S, Nakao T, Hosoya Y,
Uno K, Saito A, Murasawa T, Ono M, Nagai R,
Komuro I: Brachial artery diameter has a
predictive value in the improvement of flowmediated dilation after aortic valve replacement
for aortic stenosis. Heart Vessels. 2015; 30: 218-26.
2. Yokota J, Fujiu K, Tanimito H, Nebiya H,
Kashiwa K, Kinoshita O, Nawata K, Kimura M,
Satsu T, Chou K, Sumitani M, Ono M, Komuro I:
Electromagnetic interference between continuousflow left ventricular assist device and cardiac
resynchronization therapy defibrillator due to an
unrecognized mechanism. Int J Cardiol. 2015;
179: 510-3.
3. Imamura T, Kinugawa K, Fujino T, Inaba T, Maki
H, Hatano M, Kinoshita O, Nawata K, Kyo S,
Ono M. Aortic Insufficiency in Patients With
Sustained Left Ventricular Systolic Dysfunction
After Axial Flow Assist Device Implantation. Circ
J. 2015; 79: 104-11.
4. Panthee N, Ono M. Spinal cord injury following
thoracic and thoracoabdominal aortic repairs.
Asian Cardiovasc Thorac Ann. 2015; 23: 235-46.
5. Kimura M, Kinoshita O, Nawata K, Nishimura T,
Hatano M, Imamura T, Endo M, Kagami Y, Kubo
H, Kashiwa K, Kinugawa K, Kyo S, Komuro I,
Ono M. Midterm outcome of implantable left
ventricular assist devices as a bridge to transplantation: Single-center experience in Japan. J
Cardiol. 2015; 65: 383-9
6. Komae H, Sekine H, Dobashi I, Matsuura K, Ono
M, Okano T, Shimizu T: Three-dimensional
functional human myocardial tissues fabricatedfrom induced pluripotent stem cells. J Tissue Eng
Regen Med. 2015 Jan 28. doi: 10.1002/term.1995.
7. Imamura T, Kinugawa K, Nitta D, Inaba T, Maki
H, Hatano M, Kinoshita O, Nawata K, Kyo S,

Ono M: Readmission due to driveline infection
can be predicted by new score by using serum
albumin and body mass index during long-term
left ventricular assist device support. J Artif
Organs. 2015 Jun; 18(2): 120-7.
8. Kikuchi R, Ono M, Kinugawa K, Endo M, Mizuta
K, Urahashi T, Ihara Y, Yoshida S, Ito S, andKamibeppu K: Health-related quality of life inparents of pediatric solid organ transplant
recipients in Japan. Pediatr Transplant. 2015 May;
19(3): 332-41.
9. Imamura T, Kinugawa K, Nitta D, Fujino T, Inaba
T, Maki H, Hatano M, Kinoshita O, Nawata K,
Kyo S, Ono M: A Novel Scoring System using
Post-operative Cardiopulmonary Exercise Testing
Predict Future Explantation of Left Ventricular
Assist Device. Circ J. 2015; 79(3): 560-6.
10. Imamura T, Kinugawa K, Nitta D, Hatano M,
Kinoshita O, Nawata K, Ono M: Perioperative
Hypoalbuminemia Affects Improvement in
Exercise Tolerance After Left Ventricular Assist
Device Implantation. Circ J 2015; 79(9): 1970-5.
11. Imamura T, Kinugawa K, Nitta D, Hatano M,
Kinoshita O, Nawata K, Kyo S, Ono M:
Prophylactic Intra-Aortic Balloon Pump Before
Ventricular Assist Device Implantation Reduces
Perioperative Medical Expenses and Improves
Postoperative Clinical Course in INTERMACS
Profile 2 Patients. Circ J. 2015; 79(9): 1963-9.
12. Imamura T, Kinugawa K, Nitta D, Hatano M, Ono
M: Opening of Aortic Valve during Exercise is
Key to Preventing Development of Aortic
Insufficiency during Ventricular Assist Device
Treatment. ASAIO J. 2015 Sep-Oct; 61(5): 514-9.
13. Sawa Y, Yoshikawa Y, Toda K, Fukushima S,
Yamazaki K, Ono M, Sakata Y, Hagiwara N,
Kinugawa K, Miyagawa S: Safety and Efficacy ofAutologous
Skeletal
Myoblast
Sheets(TCD-51073) for the Treatment of Severe Chronic
Heart Failure Due to Ischemic Heart Disease. Circ
J. 2015; 79(5): 991-9.
14. Imamura T, Kinugawa K, Nitta D, Inaba T, Maki
H, Hatano M, Kinoshita O, Nawata K, Kyo S,
Ono M: Opening of native aortic valve
accomplished after left ventricular assist device
implantation in patients with insufficient pre-

191

operative Beta-blocker treatment. Int Heart J.
2015 May 13; 56(3): 303-8.
15. Imamura T, Kinugawa K, Nitta D, Hatano M,
Kinoshita O, Nawata K, Ono M: Biventricular
failure with low pulmonary vascular resistance
was managed by left ventricular assist device
alone without right-sided mechanical support. J
Artif Organs. 2015 Sep; 18(3):272-5.
16. Fujino T, Yao A, Hatano M, Inaba T, Muraoka H,
Minatsuki S, Imamura T, Maki H, Kinugawa K,
Ono M, Nagai R, Komuro I: Targeted therapy isrequired for management of pulmonary arterial
hypertension after defect closure in adult patientswith atrial septal defect and associated pulmonary
arterial hypertension. Int Heart J. 2015; 56(1):86-93.
17. Imamura T, Kinugawa K, Okada I, Kato N, Fujino
T, Inaba T, Maki H, Hatano M, Kinoshita O,
awata K, Kyo S, Ono M: Parasympathetic
reinnervation accompanied by improved postexercise heart rate recovery and quality of life inheart transplant recipients. Int Heart J. 2015;
56(2): 180-5.
18. Imamura T, Kinugawa K, Nitta D, Fujino T, Inaba
T, Maki H, Hatano M, Kinoshita O, Nawata K,
Yao A, Kyo S, Ono M: Late rejection occurred inrecipients who experienced acute cellular rejection within the first year after heart transplantation.
Int Heart J. 2015; 56(2): 174-9.
19. Imamura T, Kinugawa K, Nitta D, Hatano M,
Kinoshita O, Nawata K, Ono M.: Advantage ofPulsatility in Left Ventricular Reverse Remodeling and Aortic Insufficiency Prevention
During Left Ventricular Assist Device Treatment.
Circ J. 2015; 79(9): 1994-9.
20. Shimizu Y, Itoda Y, Higashikuni Y, Kadowaki Y,
Saito A, Fujita H, Yamashita H, Watanabe M,
Ono M, Komuro I.: Giant left atrial myxoma thatcaused mitral valve obstruction and pulmonary
hypertension. Int J Cardiol. 2015 Nov; 199: 38-9.
21. Kato NP, Okada I, Imamura T, Kagami Y, Endo
M, Nitta D, Fujino T, Muraoka H, Minatsuki S,
Maki H, Inaba T, Kinoshita O, Nawata K, Hatano
M, Yao A, Kyo S, Ono M, Jaarsma T, Kinugawa
K.: Quality of Life and Influential Factors inPatients Implanted With a Left Ventricular Assist
Device. Circ J. 2015; 79(10): 2186-92.

22. Kimura M, Nawata K, Kinoshita O, Hatano M,
Imamura T, Kinugawa K, Ono M.: Successful
Treatment of Intractable Fluid Retention Using
Tolvaptan After Treatment for Postoperative
Mediastinitis in a Patient With a Left Ventricular
Assist Device. Int Heart J. 2015; 56(5): 574-7.
23. 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. 2015; 56(6): 676-8.
24. Ando M, Yamauchi H, Morota T, Taketani T,
Shimada S, Nawata K, Umeki A, Ono M: Longterm outcome after the original and simple
modified technique of valve-sparing aortic root
reimplantation in Marfan-based population, David
V University of Tokyo modification. J Cardiol.
2016 Jan; 67(1) : 86-91.
25. Nakatani T, Fukushima N, Ono M, Saiki Y,
Matsuda H, Nunoda S, Sawa Y, Isobe M.: The
Registry Report of Heart Transplantation in Japan(1999-2014). Circ J. 2016 Jan; 80(1): 44-50.
26. Imamura T, Kinugawa K, Nitta D, Kinoshita O,
Nawata K, Ono M.: Preoperative iodine-123
meta-iodobenzylguanidine imaging is a novel
predictor of left ventricular reverse remodeling
during treatment with a left ventricular assist
device. J Artif Organs. 2016 Mar; 19(1): 29-36.
27. Takura T, Kyo S, Ono M, Tominaga R, Miyagawa
S, Tanoue Y, Sawa Y.: Preliminary report on thecost effectiveness of ventricular assist devices. J
Artif Organs. 2016 Mar; 19(1): 37-43.
28. Imamura T, Kinugawa K, Sakata Y, Miyagawa S,
Sawa Y, Yamazaki K, Ono M.: Improved clinicalcourse of autologous skeletal myoblast sheet(TCD-51073) transplantation when compared to apropensity score-matched cardiac resynchronization therapy population. J Artif Organs. 2016 Mar;19(1): 80-6.
29. Imamura T, Kinugawa K, Kinoshita O, Nawata K,
Ono M.: High pulmonary vascular resistance inaddition to low right ventricular stroke work
index effectively predicts biventricular assist
device requirement. J Artif Organs. 2016 Mar;19(1): 44-53.
30. Hasumi E, Fujiu K, Imamura T, Iwata H, Sawaki
D, Hosoya Y, Ando J, Kojima T, Shimizu Y,192

Oguri G, Matsubara T, Hatano M, Akazawa H,
Watanabe M, Ono M, Komuro I.: Cardiac Arrest
Triggered by Subepicardial Aneurysm Without
Cardiac Rupture. Circ J. 2016 Jan; 80(2): 538-40.
31. 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. 2016 Jan;80(2): 387-94.
32. Itoda Y, Panthee N, Tanaka T, Ando T, Sakuma I,
Ono M.: Novel Anastomotic Device for Distal
Coronary Anastomosis: Preclinical Results From
Swine Off-Pump Coronary Artery Bypass Model.
Ann Thorac Surg. 2016 Feb; 101(2): 736-41.
33. Panthee N, Okada JI, Washio T, Mochizuki Y,
Suzuki R, Koyama H, Ono M, Hisada T, Sugiura
S. Tailor-made heart simulation predicts the effectof cardiac resynchronization therapy in a canine
model of heart failure. Med Image Anal. 2016
Feb; 31: 46-62.
34. Imamura T, Kinugawa K, Nitta D, Kinoshita O,
Nawata K, Ono M.: Everolimus Attenuates
Myocardial Hypertrophy and Improves Diastolic
Function in Heart Transplant Recipients. Int HeartJ. 2016 Mar; 57(2): 204-10.

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Department of
Gastrointestinal Surgery
Professor
Yasuyuki Seto MD. PhD.

Associate Professor
Sachiyo Nomura MD. PhD.

Lectuler
Hiroharu Yamashita MD. PhD.

Associates
Masato Nishida MD. PhD.

Susumu Aikou MD. PhD.

Koichi Yagi MD. PhD.

Takashi Mitsui MD. Ph.D.

Yoshimi Yasukawa MD.

Kotaro Sugawara MD.

Raito Asaoka MD.

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. Okumura Y, Aikou S, Onoyama H, Jinbo K,
Yamagata Y, Mori K, Yamashita H, Nomura S,
Takahashi M, Koyama K, Momose T, Abe H,
Matsusaka K, Ushiku T, Fukayama M, Seto Y.
Evaluation of 18F-FDG uptake for detecting
lymph node metastasis of gastric cancer: aprospective pilot study for one-to-one comparison

195

2.

3.

4.

5.

6.

7.

8.

of radiation dose and pathological findings. WorldJ Surg Oncol. 2015 Dec 2;13:327.
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
Yamagata K, Uno K, Mori K, Seto Y. Unusual U
wave induced by reconstructed retrosternal esophagus. Clin Case Rep. 2015 Nov;3(11):949-51.
Hirano K, Hosoi A, Matsushita H, Iino T, Ueha S,
Matsushima K, Seto Y, Kakimi K. The nitricoxide radical scavenger carboxy-PTIO reduces theimmunosuppressive activity of myeloid-derived
suppressor cells and potentiates the antitumor
activity of adoptive cytotoxic T lymphocyte
immunotherapy. Oncoimmunology. 2015 Apr 1;
4(8):e1019195. eCollection 2015 Aug.
Ikemura M, Kunita A, Miwa Y, Jimbo K, Mori K,
Seto Y, Fukayama M. Gut wall replacing type ofgastrointestinal stromal tumor presenting as aperforation of the ileal diverticulum. Pathol Res
Pract. 2015 Nov;211(11):892-5.
Ri M, Miyata H, Aikou S, Seto Y, Akazawa K,
Takeuchi M, Matsui Y, Konno H, Gotoh M, Mori
M, Motomura N, Takamoto S, Sawa Y, Kuwano H,
Kokudo N. Effects of body mass index (BMI) on
surgical outcomes: a nationwide survey using a
Japanese web-based database. Surg Today. 2015
Oct;45(10):1271-9.
Urabe M, Yamagata Y, Aikou S, Mori K,
Yamashita H, Nomura S, Shibahara J, Fukayama
M, Seto Y. Solitary fibrous tumor of the greater
omentum, mimicking gastrointestinal stromal
tumor of the small intestine: a case report. Int
Surg. 2015 May;100(5):836-40.
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. 2015 Apr 15;13:147

196

Hepato-biliary-Pancreatic Surgery
Division and Artificial Organ
and Transplantation Division
Professor
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/

1. 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.

2. 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, 60 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.

3. 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

197

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

4. 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.

5. Publications (2015)
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.

198

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199

limitations. 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
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44. Yamashita S, Aoki T, Inoue Y, Kaneko J,
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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.
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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,
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colorectal liver metastases with portal vein
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262(1):105-11.
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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
Yukio Homma, M.D., Ph.D.

Associate Professor
Hiroshi Fukuhara, M.D., Ph.D.,

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

Lecturer
Tohru Nakagawa, M.D., Ph.D.,

Hideyo Miyazaki, M.D., Ph.D.,

Akihiko Matsumoto, M.D., Ph.D.

Associate
Sayuri Takahashi, M.D., Ph.D.,

Jinpei Kumagai, M.D., Ph.D.,

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

Aya Niimi, M.D.,

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

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

Yuta Yamada, M.D.,

Shigenori Kakutani, M.D., Ph.D.,

Atsushi Kanatani, M.D., Ph.D.,

Daijin Watanabe, M.D.,

Kaori Endoh, 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 1,200 from January 2015 to December 2015.
Elective operations are performed on Tuesday,

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Wednesday and Thursday. 1,466 operations were
performed in 2015. The numbers of main operations
are adrenalectomy 21, nephrectomy 41, partial
nephrectomy 36, nephroureterectomy 35, radical
cystectomy 21, radical prostatectomy 138, transurethral resection of the bladder tumor (TUR-Bt) 140,transurethral resection of the prostate (TUR-P) 17,
laparoscopic surgery 66, and Robot assisted surgery
143 (radical prostatectomy 138, partial nephrectomy
5).
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 24,000 patientdays from January 2015 to December 2015.

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. Aizawa, N., Homma, Y., Igawa, Y.: Effects of
L-arginine, mirabegron, and oxybutynin on the
primary bladder afferent nerve activities
synchronized with reflexic, rhythmic bladdercontractions in the rat. Neurourol Urodyn, 34: 368,
2015
2. Aizawa, N., Ito, H., Sugiyama, R. et al.: Selective
inhibitory effect of imidafenacin and 5-hydroxymethyl tolterodine on capsaicin sensitive C fibersof the primary bladder mechanosensitive afferent
nerves in the rat. J Urol, 193: 1423, 2015
3. Aizawa, N., Ogawa, S., Sugiyama, R. et al.:Influence of urethane-anesthesia on the effect ofresiniferatoxin treatment on bladder function inrats with spinal cord injury. Neurourol Urodyn,
34: 274, 2015
4. Akiyama, Y., Nomiya, A., Niimi, A. et al.:Botulinum toxin type A injection for refractoryinterstitial cystitis: A randomized comparative
study and predictors of treatment response. Int J
Urol, 22: 835, 2015
5. Amemiya, T., Honma, M., Kariya, Y. et al.:Elucidation of the molecular mechanisms underlying adverse reactions associated with a kinase
inhibitor using systems toxicology. Systems
Biology and Applications, 1: 15005, 2015
6. Azuma, T., Nagase, Y., Oshi, M.: Pyuria predicts
poor prognosis in patients with non-muscleinvasive bladder cancer treated with bacillus
Calmette-Guérin. Mol Clin Oncol, 3: 1113, 2015
7. Fujimura, T., Yamada, Y., Sugihara, T. et al.:Nocturia in men is a chaotic condition dominatedby nocturnal polyuria. Int J Urol, 22: 496, 2015
8. Fujimura, T., Takahashi, S., Kume, H. et al.:Toremifene, a selective estrogen receptor
modulator, significantly improved biochemical

203

recurrence in bone metastatic prostate cancer: arandomized controlled phase II a trial. BMC
cancer, 15: 836, 2015
9. Fukuhara, H., Todo, T.: New generation of
oncolytic herpes virus. Current Cancer Therapy
Reviews, 11: 163, 2015
10. Hakimi, A. A., Tickoo, S. K., Jacobsen, A. et al.:TCEB1-mutated renal cell carcinoma: a distinct
genomic and morphological subtype. Mod Pathol,
28: 845, 2015
11. Ito, H., Aizawa, N., Fujita, Y. et al.: Long-Term
Caloric Restriction in Rats may Prevent Age
Related Impairment of In Vitro Bladder Function.
J Urol, 193: 2123, 2015
12. Iwamoto, H., Zhang, Y., Seki, T. et al.: PlGFinduced VEGFR1-dependent vascular remodelingdetermines opposing antitumor effects and drug
resistance to Dll4-Notch inhibitors. Sci Adv, 1:e1400244, 201513. Jensen, L. D., Nakamura, M., Bräutigam, L. et al.:VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular andneuronal development in zebrafish. Proc Natl
Acad Sci U S A, 112: E5944, 2015
14. Kakutani, S., Fukuhara, H., Taguchi, S. et al.:Combination of docetaxel, ifosfamide andcisplatin (DIP) as a potential salvage chemotherapy for metastatic urothelial carcinoma. Jpn J
Clin Oncol, 45: 281, 2015
15. Kamei, J., Furuta, A., Akiyama, Y. et al.:Video-urodynamic effects of mirabegron, a beta3-adrenoceptor agonist, in patients with lowcompliance bladder. Int J Urol, 22: 956, 2015
16. Kanatani, A., Nakagawa, T., Kawai, T. et al.:Adjuvant chemotherapy is possibly beneficial for
locally advanced or node-positive bladder cancer.
Clin Genitourin Cancer, 13: e107, 2015
17. Kanayama, H. O., Fukumori, T., Fujimoto, H. etal.: Clinicopathological characteristics andoncological outcomes in patients with renal cell
carcinoma registered in 2007: The first large-scale
multicenter study from the Cancer Registration
Committee of the Japanese Urological Association.
Int J Urol, 22: S1, 2015
18. Kawai, T, Suzuki, M, Otsuka, M. et al.:Hypertensive crisis during hemostasis of adrenal
bleeding using a soft-coagulation device. Int J

Urol, 22: 799, 2015
19. Kume, H., Kawai, T., Nagata, M. et al.:Intermittent docetaxel chemotherapy is feasible
for castration-resistant prostate cancer. Mol Clin
Oncol, 3: 303, 2015
20. Maeda, D., Akiyama, Y., Morikawa, T. et al.:Hunner-Type (Classic) Interstitial Cystitis: A
Distinct Inflammatory Disorder Characterized byPancystitis, with Frequent Expansion of Clonal
B-Cells and Epithelial Denudation. PLoS One,
10: e0143316, 2015
21. Maekawa, S., Nagata, M., Watanabe, H. et al.:Resection of bulky chromophobe renal cell
carcinoma resolved severe idiopathic thrombocytopenic purpura: A case report. Int J Urol, 22:1167, 201522. Makino, K., Kume, H., Morikawa, T. et al.:Adenocarcinoma at Anastomotic Site of Ureterosigmoidostomy Potentially of Urothelial Origin
Spreading to the Upper Urinary Tract. Case Rep
Urol, 564082, 201523. Makise, N., Morikawa, T., Kawai, T. et al.:Squamous differentiation and prognosis in upper
urinary tract urothelial carcinoma. Int J Clin Exp
Pathol, 8: 7203, 201524. Makise, N., Morikawa, T., Takeshima Y. et al.:Urinary bladder urothelial carcinoma with concurrent plasmacytoid and micropapillary differentiations: A report of two cases with an emphasis
on serum carbohydrate antigen 19-9. Pathol Int,
65: 495, 2015
25. Matsumoto, S., Matsumoto, S., Homma, Y.:
Measurement of oxyhemoglobin concentration
changes in interstitial cystitis female patients: A
near-infrared spectroscopy study. Int J Urol, 22:689, 2015
26. Michel, M., Igawa Y.: Therapeutic targets foroveractive bladder other than smooth muscle.
Exper Opin Ther Targets, 5: 687, 201527. Miyama, Y., Morikawa, T., Nakagawa, T. et al.:Lipid Cell and Micropapillary Variants ofUrothelial Carcinoma of the Ureter. Case Rep
Oncol, 8: 515, 201528. Nakajima, Y., Osakabe, A., Waku, T. et al.:Estrogen Exhibits a Biphasic Effect on Prostate
Tumor Growth through the Estrogen Receptor
beta-KLF5 Pathway. Mol Cell Biol, 36: 144, 2015

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29. Nakamura, M., Satoh, N., Suzuki, M. et al.:Stimulatory effect of insulin on renal proximal
tubule sodium transport is preserved in type 2
diabetes with nephropathy. Biochem Biophys Res
Commun, 461: 154, 201530. Nakamura, M., Yamazaki, O., Shirai, A. et al.:Preserved Na/HCO3 cotransporter sensitivity toinsulin may promote hypertension in metabolic
syndrome. Kidney Int, 87: 535, 2015
31. Nishimatsu, H., Suzuki, E., Saito, Y. et al.:Senescent Cells Impair Erectile Function throughInduction of Endothelial Dysfunction and Nerve
Injury in Mice. PLoS One, 10: e0124129, 201532. Nishimatsu, H., Suzuki, E., Saito, Y. et al.:Neuromedin B Restores Erectile Function byProtecting the Cavernous Body and the Nitrergic
Nerves from Injury in a Diabetic Rat Model.
PLoS One, 10: e0133874, 2015
33. Otsuka, M., Nagata, M., Suzuki, M. et al.:Primary Retroperitoneal Tumor with Unexpected
Gingival Involvement. Intern Med, 54: 1787,
2015
34. Sugihara, T., Yasunaga, H., Yu, C. et al.:Perioperative Outcome Comparisons Between
Open and Laparoscopic Nephroureterectomy
Among a Population-Based Cohort from 2010 to2012. J Endourol, 29: 770, 201535. Suzuki, E., Fujita, D., Takahashi, M. et al.:Adipose tissue-derived stem cells as a therapeutic
tool for cardiovascular disease. World J Cardiol,
26: 454, 2015
36. Tabata, M., Ikeda, M., Urakami, S. et al.: Impactof adjuvant chemotherapy on patients withpathological stage T3b and/or lymph nodemetastatic bladder cancer after radical cystectomy.
Jpn J Clin Oncol, 45: 963, 2015
37. Taguchi, S., Fukuhara, H., Shiraishi, K. et al.:
Radical Prostatectomy versus External BeamRadiotherapy for cT1-4N0M0 Prostate Cancer:
Comparison of Patient Outcomes Including
Mortality. PLoS One, 10: e0141123, 2015
38. Taguchi, S., Nakagawa, T., Matsumoto, A. et al.:Pretreatment neutrophil-to- lymphocyte ratio as
an independent predictor of survival in patientswith metastatic urothelial carcinoma: A multiinstitutional study. Int J Urol, 22: 638, 2015
39. Taguchi, S., Kishida, Y, Tamura, K. et al.:Intrapelvic Bulky Tumor as an Unusual
Presentation of Erdheim-Chester Disease. InternMed, 54: 3241, 2015
40. Takahashi, M., Kume, H., Koyama, K. et al.:Preoperative Evaluation of Renal Cell Carcinoma
by Using 18F-FDG PET/CT. Clin Nucl Med, 40:936, 2015
41. Takahashi, S., Shiraishi, T., Miles, N. et al.:Nanowire analysis of cancer-testis antigens asbiomarkers of aggressive prostate cancer. Urology,
85: 704 .e1, 2015
42. Takahashi, S., Aruga, S., Yamamoto, Y. et al.:Urinary Oxalate Excretion Decreased in Androgen
Receptor-Knockout Mice by Suppressing Oxalate
Synthesis in The Liver. Open Journal of Urology,
5: 123, 2015
43. Takayama, K., Misawa, A., Suzuki, T. et al.:Corrigendum: TET2 repression by androgen
hormone regulates global hydroxymethylation
status and prostate cancer progression. Nat
Commun, 6: 8219, 2015
44. Takayama, K., Suzuki, T., Tsutsumi, S. et al.:
RUNX1, an androgen- and EZH2- regulated gene,has differential roles in AR-dependent and-independent prostate cancer. Oncotarget, 6: 2263,
2015
45. Wang, J., Cao, Z., Zhang, X. M. et al.: Novelmechanism of macrophage-mediated metastasis
revealed in a zebrafish model of tumor development. Cancer Res, 75: 306, 201546. Yamada, Y., Nomiya, A., Niimi, A. et al.: A survey
on clinical practice of interstitial cystitis in Japan.
Transl Androl Urol, 4: 486, 2015
47. Yamaguchi, O., Kakizaki, H., Homma, Y. et al.:Safety and efficacy of mirabegron as 'add-on'
therapy in patients with overactive bladder treatedwith solifenacin: a post-marketing, open-label
study in Japan (MILAI study). BJU Int, 116: 612,
2015
48. Yamaguchi, O., Marui, E., Igawa, Y. et al.:Efficacy and Safety of the Selective β3-Adrenoceptor Agonist Mirabegron in JapanesePatients with Overactive Bladder: A Randomized,
Double-Blind, Placebo-Controlled, Dose-Finding
Study. Low Urin Tract Symptoms, 7: 84, 201549. Yamamoto, S., Yoshida, K., Tsumura, K. et al.:Xanthogranulomatous cystitis treated by trans-

205

urethral resection. Urol Case Rep, 3: 143, 2015
50. Yokoyama, O., Igawa, Y., Takeda, M.: Tadalafil
for lower urinary tract symptoms secondary tobenign prostatic hyperplasia: a review of clinicaldata in Asian men and an update on the mechanism of action. Ther Adv Urol, 7: 249, 2015
51. Zaitsu, M., Toyokawa, S., Tonooka, A. et al.: Sex
differences in bladder cancer pathology andsurvival: analysis of a population-based cancer
registry. Cancer Med, 4: 363, 2015

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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., Ph.D.

Koji Murono, 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 eight
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 483
surgically treated inpatients in the year of 2015. 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.
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.

207

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

References
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Tanaka T, Tanaka J, Hata K, Kawai K, Yamaguchi H,
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Tanaka T, Tanaka J, Kiyomatsu T, Kawai K,
Nozawa H, Kazama S, Yamaguchi H, Ishihara S,
Sunami E, Kitayama J, Watanabe T. Clinicalpatterns and progression of ulcerative proctitis in theJapanese population: A retrospective study ofincidence and risk factors influencing progression.
Colorectal Disease. 2015.
Emoto S, Kitayama J, Ishigami H, Yamaguchi H,
Watanabe T. Clinical significance of cytologicalstatus of peritoneal lavage fluid during intraperitoneal chemotherapy for gastric cancer withovert peritoneal dissemination. Annals of Surgical
Oncology. 22(3): 780-6. 2015.
Ernst J. Kuipers, William M. Grady, David
Lieberman, Thomas Seufferlein, Joseph J. Sung,
Petra G. Boelens, Cornelis J. H. van de Velde andToshiaki Watanabe. Colorectal cacer. Nature
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Fujii M, Matano M, Nanki K, Sato T. Efficient
genetic engineering of human intestinal organoids
using electroporation. Nature Protocols. 10(10):1474-1485. 2015.
Hata K, Ishihara S, Watanabe T. Successful
Surveillance Colonoscopy for Patients with
Ulcerative Colitis After Ileorectal Anastomosis. J
Crohns Colitis. 9(10). 937-8. 2015.
Hata K, Kazama S, Nozawa H, Kawai K,
Kiyomatsu T, Tanaka J, Tanaka T, Nishikawa T,
Yamaguchi H, Ishihara S, Sunami E, Kitayama J,
Watanabe T. Laparoscopic Surgery for Ulcerative
Colitis: review of the literature. Surgery Today.
45(8). 933-8. 2015.
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. Surveillance colonoscopy
for colitis-associated dysplasia and cancer inulcerative colitis patients. Dig Endosc. Epub ahead.
2015.
Hata K, Yamamoto Y, Kiyomatsu T, Tanaka T,
Kazama S, Nozawa H, Kawai K, Tanaka J,
Nishikawa T, Otani K, Yasuda K, Kishikawa J,

Anzai H, Shinagawa T, Arakawa K, Yamaguchi H,
Ishihara S, Sunami E, Kitayama J, Watanabe T.
Hereditary gastrointestinal cancer. Surgery Today. inpress. 2015.
10. Hiyoshi M, Kawai K, Shibuya M, Ozawa T,
Kishikawa J, Nirei T, Tanaka T, Tanaka J,
Kiyomatsu T, Tada T, Kanazawa T, Kazama S,
Shoda H, Sumitomo S, Kubo K, Ymaguchi H,
Ishihara S, Sunami E, Kitayama J, Yamamoto K,
Watanabe T. A case of tracheobronchitis withdyspnea in ulcerative colitis. Internal Medicine.
54(7): 749-53. 2015.
11. Hongo K, Kazama S, Tsuno NH, Ishihara S, Sunami
E, Kitayama J, Watanabe T. Immunohistochemical
detection of high-mobility group box 1 correlateswith resistance of preoperative chemoradiotherapy
for lower rectal cancer: a retrospective study. World
journal of surgical oncology. 13(1): 7. 2015.
12. Iida Y, Sunami E, Yamashita H, Hiyoshi M,
Ishihara S, Yamaguchi H, Inoue A, Makide K,
Tsuno NH, Aoki J, Kitayama J, Watanabe T.
Phosphatidylserine-specificphospholipase
A1(PS-PLA1) expression in colorectal cancer
correlates with tumor invasion and hematogenous
metastasis. Anticancer Research. 35(3): 1459-64.
2015.
13. Ishihara S, Otani K, Yasuda K, Nishikawa T, Tanaka
J, Tanaka T, Kiyomatsu T, Hata K, Kawai K,
Nozawa H, Kazama S, Yamaguchi H, Sunami E,
Kitayama J, Watanabe T. Recent advances in robotic
surgery for rectal cancer. International Journal of
Clinical Oncology. 20(4): 633-640. 2015.
14. Ishihara S, 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. Benefit of primary tumor resection instage IV colorectal cancer with unresectablemetastasis: a multicenter retrospective study using apropensity score analysis. International Journal of
Colorectal Disease. 30(6): 807-812. 2015.
15. Ishihara S, Matsuda K, Tanaka T, Tanaka J,
Kiyomatsu T, Kawai K, Nozawa H, Kazama S,
Kanazawa T, Yamaguchi H, Sunami E, Kitayama J,
Hashiguchi Y, Watanabe T. Patient factors
predisposing to complications following laparoscopic surgery for colorectal cancers. Surgical Laparoscopy, Endoscopy & Percutaneous Techniques.

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25(2): 168-172. 2015.
16. Ishihara S, Matsusaka S, Kondo K, Horie H, Uehara
K, Oguchi M, Murofushi K, Ueno M, Mizunuma N,
Shinbo T, Kato D, Okuda J, Hashiguchi Y,
Nakazawa M, Sunami E, Kawai K, Yamashita H,
Okada T, Ishikawa Y, Nakajima T, Watanabe T. A
phase I dose escalation study of oxaliplatin plus oral
S-1 and pelvic radiation in patients with locallyadvanced rectal cancer (SHOGUN trial). Radiation
Onoclogy. 10(24): online journal. 2015.
17. Ishii H. Comparison of Functional Outcomes ofPatients Who Underwent Hand-sewn or Stapled
Ileal Pouch-Anal Anastomosis for Ulcerative Colitis.
Intarnational Surgery. 100(7-8): 1169-76.2015.
18. Kaneko K, Kawai K, Tsuno NH, Ishihara S,
Yamaguchi H, Sunami E, Watanabe T. Perioperative
Allogeneic Blood Transfusion Is Associated With
Surgical Site Infection After Abdominoperineal
Resection-a Space for the Implementation of Patient
Blood Management Strategies. International Surgery.
100(5): 797-804. 2015.
19. Kaneko M, Sasaki S, Ishimaru K, Terai E,
Nakayama H, Watanabe T. The impact of perioperative allogeneic blood transfusion on survival in
the aged patients with colorectal cancer. Anticancer
Res. 35: 3553-3558. 2015.
20. Kawai K, Sunami E, Yamaguchi H, Ishihara S,
Kazama S, Nozawa H, Hata K, Kiyomatsu T,
Tanaka J, Tanaka T, Nishikawa T, Kitayama J,
Watanabe T. Nomograms for colorectal cancer: A
systematic review. World Journal of Gastroenterology. 21(41):11877-11886. 2015.
21. Kawai K, Sunami E, Tanaka J, Tanaka T, Kiyomatsu
T, Nozawa H, Kazama S, Kanazawa T, Hosaka A,
Ishihara S, Yamaguchi H, Shigematsu K, Watanabe
T. Synchronous colorectal malignancy and abdominal aortic aneurysm treated with endovascularaneurysm repair followed by laparoscopic colectomy. International Surgery. 100(4): 600-603. 2015.
22. Kawai K, Ishihara S, Yamaguchi H, Sunami E,
Kitayama J, Miyata H, Watanabe T. Nomogram
prediction of metachronous colorectal neoplasms inpatients with colorectal cancer. Annals of Surgery.
261(5): 926-932. 2015.
23. Kawai K, Ishihara S, Yamaguchi H, Sunami E,
Kitayama J, Miyata H, Sugihara K, Watanabe T.
Nomograms for predicting the prognosis of stage IV

colorectal cancer after curative resection: amulticenter retrospective study. European Journal of
Surgical Oncology. 41(4): 457-465. 2015.
24. Kazama S, Kitayama J, Hiyoshi M, Taketomi Y,
Murakami M, Nishikawa T, Tanaka T, Tanaka J,
Kiyomatsu T, Kawai K, Hata K, Yamaguchi H,
Nozawa H, Ishihara S, Sunami E, Watanabe T.
Phospholipase A2 Group III and Group X Have
Opposing Associations with Prognosis in Colorectal
Cancer. Anticancer Res. 35(5): 2983-90. 2015.
25. Kishikawa J, Kawai K, Tsuno NH, Ishihara S,
Yamaguchi H, Sunami E, Watanabe T.
Characteristics and prognosis of colorectal cancer
associated with rheumatic disease. International
Surgery. 100(5): 783-789. 2015.
26. Kitayama J,Emoto S,Yamaguchi H,Ishigami
H,Onoyama H,Yamashita H,Seto Y,Matsuzaki K,
Watanabe. Flow cytometric quantidication of
intraperitoneal free tumour cells is a usefulbiomarker in gastric cancer patients with peritoneal
metastasis. Ann Surg Oncol. 22(7): 2336-42.2015.
27. Kiyomatsu H, Kawai K, Ishihara S, Sunami E,
Watanabe T. "Mesalazine-induced pleuropericarditis
in a patient with Crohn’s disease" Internal Medicine.
54(13): 1605-1608. 2015.
28. Kotaka M, Yoshino T, Oba K, Shinozaki K,
Touyama T, Manaka D, Matsui T, Ishigure K,
Hasegawa J, Inoue K, Goto K, Sakamoto J, Saji S,
Ohtsu A, Watanabe T. Initial safety report on thetolerability of modified FOLFOX6 as adjuvant
therapy in patients with curatively resected stage II
or III colon cancer (JFMC41-1001-C2: JOIN trial).
Cancer Chemotherapy and Pharmacology. 76(1):75-84. 2015.
29. Matano M, Date S, Shimokawa M, Takano A, Fujii
M, Ohta Y, Watanabe T, Kanai T, Sato T. Modelingcolorectal cancer using CRISPR-Cas9-mediatedengineering of human intestinal organoids. Nature
Medicine. 21(3): 256-262. 2015.
30. Nagai Y, Yamamoto Y, Yasuhara T, Hata K,
Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T,
Kawai K, Nozawa H, Kazama S, Yamaguchi H,
Ishihara S, Sunami E, Yamanaka T, Miyagawa K,
Watanabe T. High RAD54B expression: an
independent predictor of postoperative distantrecurrence in colorectal cancer patients. Oncotarget.
6(25): 21064-73. 2015.

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31. Nagata H, Yamaguchi H, Watanabe T. Peritoneal
metastasis of pancreas cancer mimicking the local
recurrence of colon cancer after laparoscopic
colectomy. ANZ Surgery. Epub ahead of print. 2015.
32. Nishikawa T, Sunami E, Tanaka T, Tanaka J,
Kiyomatsu T, Kawai K, Hata K, Kazama S, Nozawa
H, Ishihara S, Watanabe T. Incidence and prognostic
significance of positive peritoneal lavage in colorectal cancer. Surg Today. 45(9): 1073-1081. 2015.
33. Nozawa H, Nishikawa T, Tanaka T, Tanaka J,
Kiyomatsu T, Kawai K, Hata K, Kazama S,
Yamaguchi H, Sunami E, Kitayama J, Watanabe T.
‘Deepness of Response' is associated with overall
survival in standard systemic chemotherapy formetastatic colorectal cancer. Chemotherapy. 60(5-6):
360-367. 2015.
34. Nozawa H, Tanaka J, Nishikawa T, Tanaka T,
Kiyomatsu T, Kawai K, Hata K, Kazama S,
Yamaguchi H, Ishihara S, Sunami E, Kitayama J,
Nakamura J, Kokudo N, Watanabe T. Predictors andoutcome of complete removal of colorectal cancer
with synchronous lung metastases. Mol Clin Onc. 3:1041-1047. 2015.
35. Nozawa H, Nishikawa T, Tanaka T, Tanaka J,
Kiyomatsu T, Kawai K, Hata K, Kazama S,
Yamaguchi H, Ishihara S, Sunami E, Kitayama J,
Watanabe T. Large colorectal carcinoma ispredictive of recurrence after adjuvant chemotherapy using oxaliplatin. Anticancer Res. 35(9):5073-5078. 2015.
36. Nozawa H, Ishihara S, Morikawa T, Tanaka J,
Yasuda K, Ohtani K, Nishikawa T, Tanaka T,
Kiyomatsu T, Kawai K, Hata K, Kazama S,
Yamaguchi
H, Sunami
E, Kitayama
J,
Fukayama M, Watanabe T. Metachronous tubulovillous and tubular adenomas of the anal canal.
Diagn Pathology. 10: 139. 2015.
37. Nozawa H, Ishihara S, Fujishiro M, Kodashima S,
Ohtani K, Yasuda K, Nishikawa T, Tanaka T, TanakaJ, Kiyomatsu T, Kawai K, Hata K, Kazama S,
Sunami E, Kitayama J, Watanabe T. Outcome ofsalvage surgery for colorectal cancer initially treatedby upfront endoscopic therapy. Surgery. 2015.
38. Ohta K, Hoshino H, Wang J, Ono S, Iida Y, Hata K,
Huang SK, Colquhoun S, Hoon DS. MicroRNA-93
activates c-Met/PI3K/Akt pathway activity inhepatocellular carcinoma by directly inhibiting

PTEN and CDKN1A. Oncotarget. 6(5): 3211-24.
2015.
39. Oka S, Tanaka S, Saito Y, Iishi H, Kudo SE,
Ikematsu H, Igarashi M, Saitoh Y, Inoue Y,
Kobayashi K, Hisabe T, Tsuruta O, Sano Y, Yamano
H, Shimizu S, Yahagi N, Watanabe T, Nakamura H,
Fujii T, Ishikawa H, Sugihara K; Colorectal
Endoscopic Resection Standardization Implementation Working Group of the Japanese Society forCancer of the Colon and Rectum, Tokyo, Japan.
Local recurrence after endoscopic resection for large
colorectal neoplasia: a multicenter prospective study
in Japan. The American journal of gastroenterology.
110(5): 697-707. 2015.
40. Oki E, Ando K, Kasagi Y, Zaitsu Y, Sugiyama M,
Nakashima Y, Sonoda H, Ohgaki K, Saeki H,
Maehara Y. Recent advances in multidisciplinary
approach for rectal cancer. International Journal of
Clinical Oncology. 20(4): 641-9. 2015.
41. Ozawa T, Ishihara S, Nishikawa T, Tanaka T, TanakaJ, Kiyomatsu T, Hata K, Kawai K, Nozawa H,
Kanazawa T, Kazama S, Yamaguchi H, Sunami E,
Kitayama J, Watanabe T. Prognostic significance ofthe lymph node ratio in stage IV colorectal cancer
patients who have undergone curative resection. Ann
Surg Oncol. 22(5): 1513-9. 2015.
42. Ozawa T, Yamaguchi H, Kiyomatsu T, Saito S,
Ishihara S, Sunami E, Kitayama J, Watanabe T. A
case report of idiopathic systemic capillary leak
syndrome that occurred during the postoperative
period of abdominoperineal resection for colorectal
cancer. Int Surg. 100(1): 58-62. 2015.
43. Ozawa T, Ishihara S, Sunami E, Kitayama J,
Watanabe T. Log odds of positive lymph nodes as
a prognostic indicator in stage IV colorectal cancer
patients undergoing curative resection. J Surg Oncol.
111(4): 465-71. 2015.
44. Ozawa T, Saito S, Matsuura S, Kishi H, Maeda M,
Watanabe T. Thyroid gland metastasis of rectal
cancer. J Surg Case Rep. 2015(5): pii: rjv053. 2015.
45. Ozawa T, Ishihara S, Nishikawa T, Tanaka T, TanakaJ, Kiyomatsu T, Hata K, Kawai K, Nozawa H,
Kazama S, Yamaguchi H, Sunami E, Kitayama J,
Watanabe T. The preoperative platelet to lymphocyte
ratio is a prognostic marker in patients with stage II
colorectal cancer. Int J Colorectal Dis. 30(9): 116571. 2015.

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46. Ozawa T, Ishihara S, Kawai K, Kazama S,
Yamaguchi H, Sunami E, Kitayama J, Watanabe T.
Impact of a lymphocyte to monocyte ratio in stage
IV colorectal cancer. J Surg Res. 199(2): 386-92.
2015.
47. Park SY, Choi GS, Park JS, Kim HJ, Sakai Y,
Hasegawa S, Watanabe T, Kim SH. Distinctive
oncological features of stage IIIA colorectal cancer:
Analysis of prognostic factors for selective adjuvant
chemotherapy. Journal of Surgical Oncology.
111(7): 882-90. 2015.
48. Sasaki K, Kawasaki H, Abe H, Nagai H, Yoshimi F.
Retrocecal hernia successfully treated withlaparoscopic surgery: a case report and literature
review of 15 cases in Japan. International Journal ofSurgery Case Reports Online. 2015.
49. Shibata J, Kawai K, Nishikawa T, Tanaka T, TanakaJ, Kiyomatsu T, Hata K, Nozawa H, Kazama S,
Yamaguchi H, Ishihara S, Sunami E, Kitayama J,
Sugihara K, and Watanabe T. Prognostic Impact ofHistologic Type in Curatively Resected Stage IV
Colorectal Cancer: A Japanese Multicenter
Retrospective Study. Annals of Surgical Oncology.
22 (Suppl 3): 621-9. 2015.
50. Shibata J, Ishihara S, Tada N, Kawai K, Tsuno N.H.,
Yamaguchi H, Sunami E, Kitayama J, Watanabe T.
Surgical stress response after colorectal resection: acomparison of robotic, laparoscopic, and open
surgery. Techniques in Coloproctology. 19(5): 27580. 2015.
51. Shida D, Tagawa K, Inada K, Nasu K, Seyama Y,
Maeshiro T, Miyamoto S, Inoue S, Umekita N.
Enhanced recovery after surgery (ERAS) protocols
for colorectal cancer in Japan. BMC Surg. 15(90):001-006. 2015.
52. Shida D, Wakamatsu K, Tanaka Y, Yoshimura A,
Kawaguchi M, Miyamoto S, Tagawa K. The
postoperative patient-reported quality of recovery incolorectal cancer patients under enhanced recovery
after surgery using QoR-40. BMC Cancer. 15(799):
001-006. 2015.
53. Shinagawa T, Hata K, Watanabe T. Hepatic Portal
Venous Gas After Colonoscopy for Ulcerative
Colitis: A Case Report. Journal of Crohn's andColitis. 9(11): 1058-9. 2015.

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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.,

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 three
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. Akagi D, Chen M, Toy R, Chatterjee A, Conte MS.
Systemic delivery of proresolving lipid mediators
resolvin D2 and maresin 1 attenuates intimal
hyperplasia in mice. FASEB J. 29(6): 2504-13.
2015.
2. Akai T, Hoshina K, Yamamoto S, Takeuchi H,
Nemoto Y, Ohshima M, Yamauchi H, Ono M,
Watanabe T. Biomechanical analysis of an aortic
aneurysm model and its clinical application tothoracic aortic aneurysms for defining "saccular"
aneurysms. J Am Heart Assoc. 4: e001547. 2015.
3. Haga M, Hoshina K, Shigematsu K, Watanabe T.
Feasibility of perioperative strategy for abdominal
aortic aneurysm in patients with pre-existing
chronic renal insufficiency at a single institute.
Surg Today. in press. 2015.
4. 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. 7-Mar: pii: S0741-5214(15)00067-1. 2015.

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5. Hashimoto T, Shibasaki F. Hypoxia-inducible
factor as an angiogenic master switch. Frontiers in
Pediatrics. 24(3): 33. 2015.
6. Hashimoto T, Yamamoto K, Foster T, Bai H,
Shigematsu K, Dardik A. Intraluminal drugdelivery to the arteriovenous fistula endothelium.
Journal of Visualized Experiments. in press. 2015.
7. Kobayashi M, Hoshina K, Yamamoto S, Nemoto
Y, Akai T, Shigematsu K, Watanabe T, Ohshima
M. Development of an Image-Based Modeling
System to Investigate Evolutional Geometric
Changes of a Stent Graft in an Abdominal Aortic
Aneurysm. Circulation Journal. 79(7): 1534-41.
2015.
8. Matsukura M, Hoshina K, Shigematsu K, Miyata
T, Watanabe T. Paramalleolar Bollinger score in
the era of diabetes and end-stage renal disease: its
usefulness for predicting operative outcome ofcritical limb ischemia patients. Circ J. in press.
2015.
9. Miyahara T, Shigematsu K, Nishiyama A,
Hashimoto T, Hoshina K, Watanabe T. Long-term
results of combined aortoiliac and infrainguinalarterial reconstruction for the treatment of criticallimb ischemia. Annals of Vascular Diseases. 8(1):14-20. 2015.
10. Miyahara T, Suhara M, Nemoto Y, Shirasu T,
Haga M, Mochizuki Y, Matsukura M, Akai T,
Taniguchi R, Nemoto M, Yamamoto S, Nishiyama
A, Hosaka A, Hoshina K, Okamoto H,
Shigematsu K, Miyata T, Watanabe T. Long-term
results of treatment for critcal limb ischemia. Ann
Vasc Dis. 8: 192-197.2015.
11. Mochizuki Y, Hoshina K, Shigematsu K, Miyata T,
Watanabe T. Distal bypass to a critically ischemic
foot increases the skin perfusion pressure at the
opposite site of the distal anastomosis. Vascular.
Epub ahead of print. 2015.
12. Nemoto M , Koyama H, Nishiyama A,
Shigematsu K, Miyata T, Watanabe T. Adequate
selection of a therapeutic site enables efficientdevelopment of collateral vessels in angiogenic
treatment with bone marrow mononuclear cells. J
Am Heart Assoc. 4(9): e002287. 2015.
13. 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. J Vasc Surg. Epub ahead ofprint. 2015.
14. Shirasu T, Hoshina K, Yamamoto S, Shigematsu
K, Miyata T, Watanabe T. Poor Prognosis in
Critical Limb Ischemia Without Pre-Onset
Intermittent Claudication. Circ J. 79(7): 1618-23.
2015.
15. Shirasu T, Miyata T, Nishiyama A, Miyahara T,
Hoshina K, Shigematsu K, Watanabe T. Usefulpredictors for critical limb ischemia in severely
ischemic limbs. Int Angiol. Epub ahead of print.
2015.
16. Tajima K, Hoshina K, Oushik T, Shigematsu K,
Fukayama M. Intimal sarcoma of the abdominal
aorta and common iliac arteries presenting asepithelioid angiosarcoma of the skin: a case report.
Int J Clin Exp Pathol. 8: 5856-62. 2015.
17. Takayama T, Shi X, Wang B, Franco S, Zhou Y,
DiRenzo D, Kent A, Hartig P, Zent J, Guo LW. A
Murine Model of Arterial Restenosis: TechnicalAspects of Femoral Wire Injury. J Vis Exp.
10-Mar: 97. 2015.
18. Urabe G, Hoshina K, Deguchi J, Miyata T.
Structural analysis of adventitial collagen tofeature aging and aneurysm formation in humanaorta. J Vasc Surg. Epub ahead of print. 2015.
19. Urabe Y, Tanaka S, Saito Y, Igarashi M, WatanabeT, Sugihara K. Impact of revisions of the JSCCR
guidelines on the treatment of T1 colorectal
carcinomas in Japan. Zeitschrift für Gastroenterologie. 53(4): 291-301. 2015.
20. Yamamoto K, Protack CD, Kuwahara G, Tsuneki
M, Hashimoto T, Hall MR, Assi R, Brownson KE,
Foster TR, Bai H, Wang M, Madri JA, Dardik A.
Disturbed shear stress reduces Klf2 expression inarterial-venous fistulae in vivo. Physiol Report.
3(3): e12348. 2015.

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Department of Metabolic Careand Endocrine Surgery
Professor
Yasuyuki Seto MD. PhD.

Associate Professor
Keiichiro Tada MD. PhD.

Associates
Kotoe Nishioka MD. PhD

Yasuko Kikuchi MD. PhD

Takayoshi Niwa MD. PhD

Takako Wakeda MD. PhD

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.

2162) 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. 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.
2. 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 and preoperative
treatment decision. World J Surg Oncol;11:217,
2013.
3. 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.
4. 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.
5. 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.
6. 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.
7. Terada K, Okochi-Takada E, Akashi-Tanaka S,
Miyamoto K, Taniyama K, Tsuda H, Asada K,
Kaminishi M, Ushijima T. Association between
frequent CpG island methylation and HER2
amplification in human breast cancers. Carcinogenesis; 30(3):466-71,2009.
8. Niwa T, Saito H, Imajoh-ohmi S, Kaminishi M,
Seto Y, Miki Y, Nakanishi A. BRCA2 interacts
with the cytoskeletal linker protein plectin to form
a complex controlling centrosome localization.
Cancer Sci;100(11):2115-25,2009.

Surgical Sciences
2. Sensory and Motor System Medicine

218

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

Associate Professor
Makoto Sugaya, M.D., Ph.D.

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.

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

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

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

Jun Omatsu, M.D.

Arisa Ito, 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, two 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.

219

In addition to series of lectures, clinical education isprovided for fifth- and sixth- grade medical students,
which aims at giving a general introduction for how tomake dermatological approaches for diagnosis andtreatment, with a stress on learning how to observeand describe a variety of skin eruptions. Actually thestudents are supposed to see patients in outpatient
clinic every day for an entire week, as well as toparticipate in the inpatient clinic.

Research
Each specialized outpatient service reflects its own
research field in a disease-oriented manner. However,those specialized groups performing their own clinicaland research activities are never exclusive, and there
are increasing communications with other departments
such as internal medicine and blood transfusion
service as well as intergroup communications. Recent
advanced techniques in cellular, molecular biology
and our newly established laboratories, will enable us
to organize optimal research conditions.

Publications
1.

2.

3.

4.

Higo T, Miyagaki T, Nakamura F, Shinohara A,
Asano H, Abe H, Senda N, Yoshizaki A,
Fukayama M, Kurokawa M: Paraneoplastic
pemphigus occurring after bendamustine andrituximab therapy for relapsed follicular lymphoma. Ann Hematol. 2015;94(4):683-5.
Saigusa R, Asano Y, Taniguchi T, Yamashita T,
Takahashi T, Ichimura Y, Toyama T, Tamaki Z,
Tada Y, Sugaya M, Kadono T, Sato S: A possible
contribution of endothelial CCN1 downregulation
due to Fli1 deficiency to the development ofdigital ulcers in systemic sclerosis. Exp Dermatol.
2015;24(2):127-32.
Asano Y, Sato S: New criteria improverecognition of early systemic sclerosis. Nat Rev
Rheumatol. 2015;11(1):3-4.
Taniguchi T, Asano Y, Akamata K, Noda S,
Takahashi T, Ichimura Y, Toyama T, Trojanowska
M, Sato S: Fli1 haploinsufficiency induces
fibrosis, vascular activation and immune abnormalities resembling systemic sclerosis inbleomycin- treated mice. Arthritis Rheumatol.
2015;67(5): 1335-44.

5.

Mitsui A, Tada Y, Shibata S, Kamata M, Hau C,
Asahina A, Sato S: Deficiency of both L-selectin
and ICAM-1 exacerbates imiquimod-induced
psoriasis-like skin inflammation through increased infiltration of antigen presenting cells.
Clin Immunol. 2015;157(1):43-55.
6. Saigusa R, Asano Y, Nakamura K, Miura S,
Ichimura Y, Takahashi T, Toyama T, Taniguchi T,
Noda S, Aozasa N, Akamata K, Sumida H,
Miyazaki M, Tamaki Z, Yanaba K, Kuwano Y,
Sato S: The association of anti-RNA polymerase
III antibody and malignancy in Japanese patientswith systemic sclerosis. J Dermatol. 2015;42(5):524-7.
7. Miura S, Asano Y, Saigusa R, Yamashita T,
Taniguchi T, Takahashi T, Ichimura Y, Toyama T,
Tamaki Z, Tada Y, Sugaya M, Sato S, Kadono T:
Serum vaspin levels: a possible correlation withdigital ulcers in patients with systemic sclerosis. J
Dermatol. 2015;42(5): 528-31.
8. Miura S, Asano Y, Saigusa R, Yamashita T,
Taniguchi T, Takahashi T, Ichimura Y, Toyama T,
Tamaki Z, Tada Y, Sugaya M, Sato S, Kadono T:
Serum omentin levels: a possible contribution tovascular involvement in patients with systemicsclerosis. J Dermatol. 2015;42(5):461-6.
9. Akamata K, Asano Y, Yamashita T, Noda S,
Taniguchi T, Takahashi T, Ichimura Y, Toyama T,
Trojanowska M, Sato S: Endothelin receptor
blockade ameliorates vascular fragility inendothelial cell-specific Fli1 knockout mice byincreasing Fli1 DNA-binding ability. Arthritis
Rheumatol. 2015;67(5):1335-44.
10. Watanabe R, Gehad A, Yang C, Campbell L,
Teague JE, Schlapbach C, Elco C, Huang V,
Matos TR, Kupper TS, Clark RA: Human skin is
protected by four functionally and phenotypicallydiscrete populations of resident and recirculating
memory T cells. Sci Transl Med. 2015;7(279):
279ra39.
11. Yoshizaki A, Sato S: Abnormal B lymphocyte
activation and function in systemic sclerosis. Ann
Dermatol.2015;27(1):1-9.
12. Noda S, Krueger JG, Guttman-Yassky E: Thetranslational revolution and use of biologics inpatients with inflammatory skin diseases. J
Allergy Clin Immunol. 2015;135(2):324-36.

220

13. Wu CY, Asano Y, Taniguchi T, Sato S, Yu HS:Serum heparanase levels: a protective marker
against digital ulcers in patients with systemicsclerosis. J Dermatol. 2015;42(6):625-8.
14. Miyagaki T, Sugaya M: Recent advances in atopic
dermatitis and psoriasis: genetic background,barrier function, and therapeutic targets. J
Dermatol Sci. 2015;78(2):89-94.
15. Kimura T, Tse K, Sette A, Ley K; Vaccination tomodulate atherosclerosis. Autoimmunity. 2015;
48(3):152-60.
16. Saeki H, Imafuku S, Abe M, Shintani Y, Onozuka
D, Hagihara A, Katoh N, Murota H, Takeuchi S,
Sugaya M, Tanioka M, Kaneko S, Masuda K,
Hiragun T, Inomata N, Kitami Y, Tsunemi Y, Abe
S, Kobayashi M, Morisky DE, Furue M: Poor
adherence to medication as assessed by theMorisky Medication Adherence Scale-8 and low
satisfaction with treatment in 237 psoriasis
patients. J Dermatol. 2015;42(4):367-72.
17. Nakajima R, Miyagaki T, Oka T, Nakao M,
Kawaguchi M, Suga H, Morimura S, Kai H,
Asano Y, Tada Y, Kadono T, Sato S, Sugaya M:
Elevated serum galectin-9 levels in patients withatopic dermatitis. J Dermatol. 2015; 42(7):723-6.
18. Kimura T, Sugaya M, Oka T, Blauvelt A, Okochi
H, Sato S: Lymphatic dysfunction attenuatestumor immunity through impaired antigen
presentation. Oncotarget. 2015;6(20): 18081-93.
19. Shibata S, Tada Y, Hau CSY, Mitsui A, Kamata M,
Asano Y, Sugaya M, Kadono T, Masamoto Y,
Kurokawa M, Yamauchi T, Kubota N, Kadowaki
T, Sato S: Adiponectin regulates psoriasiform skininflammation by suppressing IL-17 production
from γδ T cells. Nat Commun. 2015;6:7687.
20. Ichimura Y, Asano Y, Akamata K, Noda S,
Taniguchi T, Takahashi T, Toyama T, Tada Y,
Sugaya M, Sato S, Kadono T. Progranulin
overproduction due to Fli1 deficiency contributes
to the resistance of dermal fibroblasts to tumor
necrosis factor alpha in systemic sclerosis.
Arthritis Rheumatol. 2015 Dec;67(12):3245-55.
21. Sugaya M: Chemokines and skin diseases. Arch
Immunol Ther Exp. 2015;63(2): 109-115.
22. Furue M, Onozuka D, Takeuchi S, Murota H,
Sugaya M, Masuda K, Hiragun T, Kaneko S,
Saeki H, Shintani Y, Tsunemi Y, Abe S,

Kobayashi M, Kitami Y, Tanioka M, Imafuku S,
Abe M, Inomata N, Morisky DE, Katoh N: Poor
adherence to oral and topical medication in 3096
dermatological patients as assessed by Morisky
Medication Adherence Scale-8. Br J Dermatol.
2015;172(1):272-275.
23. Sugaya M, Morimura S, Suga H, Kawaguchi M,
Miyagaki T, Ohmatsu H, Fujita H, Sato S:CCR4
is expressed on infiltrating cells in lesional skin ofearly mycosis fungoides and atopic dermatitis. J
Dermatol. 2015; 42(6):613-615.
24. Kaneko S, Masuda K, Hiragun T, Inomata N,
Furue M, Onozuka D, Takeuchi S, Murota H,
Sugaya M, Saeki H, Shintani Y, Tsunemi Y, Abe
S, Kobayashi M, Tanioka M, Kitami Y, Imafuku
S, Abe M, Hagihara A, Morisky D, Katoh
N:Transient improvement of urticaria induces
poor adherence as assessed by Morisky Medication Adherence Scale-8. J Dermatol. 2015;
42(11):1078-1082.
25. Murota H, Takeuchi S, Sugaya M, Tanioka M,
Onozuka D, Hagihara A, Saeki H, Imafuku S,
Abe M, Shintani Y, Kaneko S, Masuda K,
Hiragun T, Inomata N, Kitami Y, Tsunemi Y,
Abe S, Kobayashi M, Donald E. Morisky DE,
Furue M, Katoh N:Characterization of socioeconomic status of Japanese patients with atopic
dermatitis showing poor medical adherence andreasons for drug discontinuation. J Dermatol Sci.
2015;79(3):279-287.
26. Tsunemi Y, Abe S, Kobayashi M, Kitami Y,
Onozuka D, Hagihara A, Takeuchi S, Murota H,
Sugaya M, Masuda K, Hiragun T, Kaneko S,
Saeki H, Shintani Y, Tanioka M, Imafuku S, Abe
M, Inomata N, Morisky DE, Furue M, Katoh N:
Adherence to oral and topical medication in 445
patients with tinea pedis as assessed by theMorisky Medication Adherence Scale-8. Eur J
Dermatol. 2015; 25(6):570-577.
27. Kitadate A, Ikeda S, Teshima K, Ito M, Toyota I,
Hasunuma N, Takahshi N, Miyagaki T, Sugaya M,
Tagawa H: MicroRNA-16 mediates the regulationof a senescence- apoptosis switch in cutaneous Tcell and other non-Hodgkin lymphomas.
Oncogene. 2015 Dec 7. doi:10.1038/onc. 2015.
435.

221

28. Higo T, Miyagaki T, Nakamura F, Shinohara A,
Asano H, Abe H, Senda N, Yoshizaki A,
Fukayama M, Kurokawa M: Paraneoplastic
pemphigus occurring after bendamustine andrituximab therapy for relapsed follicularlymphoma. Ann Hematol. 2015;94:683-685.
29. Miyagaki T, Sugaya M: Recent advances in atopic
dermatitis and psoriasis: genetic background,barrier function, and therapeutic targets. J
Dermatol Sci. 2015;78:89-94.
30. Miyagaki T, Sugaya M, Oka T, Fujita H, Sato S:
Serum chemokine levels differentially regulated
by vorinostat in a Sézary syndrome patient. Br J
Dermatol. 2015;173:620-622.
31. Miyagaki T, Fujimoto M, Sato S: Regulatory B
cells in human inflammatory and autoimmune
diseases: from mouse models to clinical research.
Int Immunol. 2015;27: 495-504.
32. Takahashi T, Asano Y, Noda S, Aozasa N,
Akamata K, Taniguchi T, Ichimura Y, Toyama T,
Sumida H, Kuwano Y, Tada Y, Sugaya M, Kadono
T, Sato S: A possible contribution of lipocalin-2 tothe development of dermal fibrosis, pulmonary
vascular involvement, and renal dysfunction insystemic sclerosis. Br J Dermatol. 2015 Sep;
173(3):681-9.
33. Nakamura K, Asano Y, Shibata S, Nakao M,
Shida R, Takahashi T, Mitsui A, Araki M, Yamada
A, Sato S: A case of psoriasis vulgaris developing
ulcerative colitis during adalimumab treatment. J
Dermatol. 2015 Oct;42(10):1029-30.
34. Nakajima R, Komine M, Miyamoto Y, Fusumae T,
Fujita Y, Maekawa T, Murata S, Ohtsuki M:
Sarcomatoid carcinoma arising in the congenital
pigmented nevus after treatment with carbon
dioxide snow freezing method. J Dermatol. 2015
Nov;42(11):1083-6.
35. Takahashi N, Noda S, Taniguchi T, Adachi M:
Efficacy comparison of ustekinumab between
anti-TNF-a drug naïve and anti-TNF-a drug
resistant Japanese psoriasis cases. Int J Dermatol.
2015 Oct;54(10):1194-8.
36. Saigusa R, Asano Y, Taniguchi T, Yamashita T,
Ichimura Y, Takahashi T, Toyama T, Yoshizaki A,
Sugawara K, Tsuruta D, Taniguchi T, Sato S:
Multi-facet contribution of the TLR4-activated
IRF5 transcription factor in systemic sclerosis.

Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15136-41.
37. Nakamura K: Case of psoriasis vulgaris
developing ulcerative colitis during adalimumab
treatment. J Dermatol. 2015 Oct;42(10):1029-30.
38. Yoshizaki A, Sato S: Abnormal B lymphocyte
activation and function in systemic sclerosis. Ann
Dermatol. 2015;27(1):1-9.
39. Yokoyama T, Yoshizaki A, Simon KL, Kirby MR,
Anderson SM, Candotti F: Age- Dependent
Defects of Regulatory B Cells in Wiskott-Aldrich
Syndrome Gene Knockout Mice. PLoS One.
2015;10(10).
40. Miyagawa T, Kadono T, Taniguchi T, Nakamura
K, Saigusa R, Yoshizaki A, Miyagaki T, Yamada
D, Masui Y, Sato S: Cutaneous apocrine
carcinoma of the scrotum: A case with widespreadsubcutaneous induration. J Dermatol. 2015;42(8):815-817.
41. Takahashi T, Asano Y, Shibata S, Nakamura K,
Nakao M, Shida R, Mitsui A, Araki M, Watanabe
R, Fujita H, Tada Y, Sato S: Arthritis possibly
induced and exacerbated by TNF antagonist in apatient with psoriasis vulgaris. Br J Dermatol.
2015;172(5): 1458-60.

222

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. Each week, theprofessor goes the round of inpatients on Tuesday
evening. Preoperative and postoperative conferences
and seminar that all members of the department
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,
hand surgery, craniomaxillofacial surgery, burn andtrauma, cosmetic surgery, and regenerative medicine.
In the bed side practice the students have the223

opportunity 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 and dermal papilla 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.

References (2013)
出版物等(2015)
1: 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. PubMed PMID: 26152884.
2: Ogata F, Fujiu K, Matsumoto S, Nakayama Y,
Shibata M, Oike Y, Koshima I, Watabe T, Nagai R,
Manabe I. Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4(+) T
Cells Drives the Pathogenesis of Lymphedema. J
Invest Dermatol. 2016 Mar;136(3):706-14. doi:
10.1016/j.jid.2015.12.001. Epub 2015 Dec 10.
PubMed PMID: 27015456.
3: 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. PubMed PMID: 26732295.
4: 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. PubMed PMID: 26644082.
5: 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):254-258. doi: 10.
1002/micr.22525. Epub 2015 Oct 29. PubMed
PMID: 26510923.
6: Yamamoto T, Yoshimatsu H, Hayashi A. A
method of continuous indirect aspiration for field

224

clearance in lymphatic supermicrosurgery.
Microsurgery. 2016 Feb;36(2):175. doi: 10.1002/
micr.22426. Epub 2015 May 19. PubMed PMID:
25989528.
7: Yamashita S, Hayashi D, Nakano A, Hayashi Y,
Hirama M. Total synthesis of avermectin B1arevisited. J Antibiot (Tokyo). 2016 Jan;69(1):31-50. doi: 10.1038/ja.2015.47. Epub 2015 Sep 9.
PubMed PMID: 26350782.
8: 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.
Epub 2015 Oct 9. PubMed PMID: 26481925.
9: Fuse Y, Yamamoto T. Half notching method forsupermicrosurgical lambda-shaped lymphaticovenular anastomosis. J Plast Reconstr Aesthet
Surg. 2016 Jan;69(1):e13-4. doi: 10.1016/j.bjps.
2015.08.039. Epub 2015 Sep 5. PubMed PMID:
26371424.
10: 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. PubMed PMID: 26299828.
11: 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.
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12: 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. PubMed PMID:
26258914.
13: Fuse Y, Yamamoto T. Diamond-shaped anastomosisforsupermicrosurgicalside-to-side
lymphaticovenular anastomosis. J Plast Reconstr
Aesthet Surg. 2015 Dec;68(12): e209-10. doi:

10.1016/j.bjps.2015.08.033. Epub 2015 Sep 5.
PubMed PMID: 26363810.
14: Mineda K, Feng J, Ishimine H, Takada H, Doi K,
Kuno S, Kinoshita K, Kanayama K, Kato H,
Mashiko T, Hashimoto I, Nakanishi H, Kurisaki A,
Yoshimura K. Therapeutic Potential of Human
Adipose-Derived Stem/Stromal Cell Microspheroids Prepared by Three-Dimensional Culture
in Non-Cross-Linked Hyaluronic Acid Gel. StemCells Transl Med. 2015 Dec;4(12):1511-22. doi:
10.5966/sctm.2015-0037. Epub 2015 Oct 22.
PubMed PMID: 26494781; PubMed Central
PMCID: PMC4675504.
15: Uda H, Tomioka YK, Sarukawa S, Sunaga A,
Sugawara Y. Comparison of abdominal wall
morbidity between medial and lateral row-based
deep inferior epigastric perforator flap. J Plast
Reconstr Aesthet Surg. 2015 Nov;68(11):1550-5.
doi:10.1016/j.bjps.2015.06.028. Epub 2015 Jul 17.
PubMed PMID: 26248491.
16: Ito T, Saito T, Ishiura R, Yamamoto T. Diagnosisof trauma-induced lymphedema using indocyanine green lymphography. J Plast Reconstr
Aesthet Surg. 2015 Nov;68(11):e177-8. doi:
10.1016/j.bjps.2015.07.013. Epub 2015 Jul 26.
PubMed PMID: 26239376.
17: Hayashi N, Yamamoto T, Hayashi A, Yoshimatsu
H. Correlation between indocyanine green (ICG)
patterns and real-time elastography images inlower extremity lymphedema patients. J Plast
Reconstr Aesthet Surg. 2015 Nov;68(11):1592-9.
doi: 10.1016/j.bjps.2015.06.027. Epub 2015 Jul 6.
PubMed PMID:26239375.
18: Todokoro T, Hara H, Yamamoto T, Koshima I. A
threader technique using an 11-0 loop needle forsupermicrosurgery. Microsurgery. 2015 Nov;
35(8):672-3. doi:10.1002/micr.22365. Epub 2014
Dec 20. PubMed PMID: 25529110.
19: Seki Y, Yamamoto T, Yoshimatsu H, Hayashi A,
Kurazono A, Mori M, Kato Y, Koshima I. The
Superior-Edge-of-the-Knee Incision Method in
Lymphaticovenular Anastomosis for Lower
Extremity Lymphedema. Plast Reconstr Surg.
2015 Nov; 136(5): 665e-75e. doi: 10.1097/PRS.
0000000000001715. PubMed PMID: 26505724.
20: Mashiko T, Kinoshita K, Kanayama K, Feng J,
Yoshimura K. Perpendicular Strut Injection of

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Hyaluronic Acid Filler for Deep Wrinkles. Plast
Reconstr Surg Glob Open. 2015 Dec 9; 3(11):e567. doi: 10.1097/GOX.0000000000000552.
eCollection 2015 Nov. PubMed PMID: 26893992;
PubMed Central PMCID: PMC4727719.
21: Yoshimatsu H, Yamamoto T, Hayashi N, Kato M,
Iida T, Koshima I. Reconstruction of the ankle
complex wound with a fabricated superficial
circumflex iliac artery chimeric flap including thesartorius muscle: A case report. Microsurgery.
2015 Oct 29. doi: 10.1002/micr.22518. [Epubahead of print] PubMed PMID: 26513645.
22: Yamamoto T, Yoshimatsu H, Hayashi A, Koshima
I. Parallel pocket incision: Less invasive surgicalintervention for the treatment of intractablepressure ulcer with wound edge undermining. J
Plast Reconstr Aesthet Surg. 2015 Oct;68(10):1432-7. doi: 10.1016/j.bjps.2015.06.004. Epub2015 Jun 17. PubMed PMID: 26159471.
23: Yoshimatsu H, Yamamoto T, Iida T. Deep branchof the superficial circumflex iliac artery for
backup. J Plast Reconstr Aesthet Surg. 2015 Oct;68(10):1478-9. doi: 10.1016/j.bjps.2015.05.041.
Epub 2015 Jun 18. PubMed PMID: 26113280.
24: Yoshino Y, Yamamoto T, Fujisawa K, Saito T,
Ishiura R, Iida T. Inguinal seroma prevention after
superficial circumflex iliac artery perforator flap
harvest using non-microsurgical lympho-venous
shunt. J Plast Reconstr Aesthet Surg. 2015 Oct;68(10):1479-81. doi: 10.1016/j.bjps.2015.06.007.
Epub 2015 Jun 12. PubMed PMID: 26113273.
25: Saito T, Yoshimatsu H, Yamamoto T, Narushima
M. Precise measurement using a new backgroundsheet with crack scales for super microsurgicalanastomosis. J Plast Reconstr Aesthet Surg. 2015
Oct; 68(10):1476-7. doi: 10.1016/j.bjps.2015.05.
030. Epub 2015 May 30. PubMed PMID:
26072122.
26: Yamamoto T, Mito D, Hayashi A, Narushima M.
Multiple-in-one concept for lymphatic supermicrosurgery. Microsurgery. 2015 Oct; 35(7):588-9. doi:10.1002/micr.22345. Epub 2014 Oct 28.
PubMed PMID: 25350401.
27: Hara H, Mihara M, Ohtsu H, Narushima M, Iida T,
Koshima I. Indication of Lymphaticovenous Anastomosis for Lower Limb Primary Lymphedema.
Plast Reconstr Surg. 2015 Oct;136(4):883-93. doi:

10.1097/PRS.0000000000001631.
PubMedPMID:26086382.
28: Yamamoto T, Yoshimatsu H, Yamamoto N,
Yokoyama A, Numahata T, Koshima I. Multisite
Lymphaticovenular Anastomosis Using Vein Graftfor Uterine Cancer-Related Lymphedema After
Pelvic Lymphadenectomy. Vasc EndovascularSurg. 2015 Oct;49(7):195-200. doi: 10.1177/
1538574415614402. Epub 2015 Oct 29. PubMed
PMID: 26516190.
29: Mashiko T, Akizuki T, Watanabe Y, Sasaki R,
Yokoyama M, Yoshimura K, Mineda K. Clinicopathologic Assessment of Myositis Ossificans
Circumscripta of the Masseter Muscles. J
Craniofac Surg. 2015 Sep;26(6):2025-6. doi: 10.
1097/SCS.0000000000001908. PubMed PMID:
26147032.
30: Yoshimatsu H, Yamamoto T, Iwamoto T, Haragi
M, Narushima M, Iida T, Koshima I. Pedicle-ina-trench technique for lower extremity
reconstruction. J Plast Reconstr Aesthet Surg.
2015 Sep; 68(9):1318-9. doi: 10.1016/j.bjps.2015.
05.002. Epub 2015 May 22. PubMed PMID:
26037221.
31: Ishiura R, Yoshimatsu H, Yamamoto T, Iida T.
Near-infrared fluorescent angiography fordemarcation of infected ulcer debridement. J Plast
Reconstr Aesthet Surg. 2015 Sep;68(9):1315-7.
doi: 10.1016/j.bjps.2015.04.017. Epub 2015 Apr
30. PubMed PMID: 25971416.
32: Yoshimatsu H, Yamamoto T, Iida T. Indocyanine
green angiography for prediction of thrombosis in
the internal jugular vein. Microsurgery. 2015 Sep;
35(6):469-73. doi: 10.1002/micr.22460. Epub2015 Sep 2. PubMed PMID: 26331715.
33: Yamamoto T, Fujita M, Ishiura R, Yoshimatsu H,
Narushima M. Trans-flap anchoring suturetechnique for tension-free skin flap interposition.
Microsurgery. 2015 Sep;35(6):494-5. doi: 10.
1002/micr.22337. Epub 2014 Oct 3. PubMed
PMID: 25277072.
34: Fujisawa K, Yamamoto T, Saito T, Ishiura R, Iida
T. Inguinal seroma prevention by reverse mapping
using
inodocyanine
green
lymphography.
Microsurgery. 2015 Aug 25. doi: 10.1002/micr.
22468. [Epub ahead of print] PubMed PMID:
26303783.

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35: Mihara M, Hara H, Shibasaki J, Seki Y, Hayashi A,
Iida T, Adachi S, Uchida Y, Kaneko H, Haragi M,
Murakami A. Indocyanine green lymphography
and lymphaticovenous anastomosis for generalized lymphatic dysplasia with pleural effusion andascites in neonates. Ann Vasc Surg. 2015 Aug;29(6):1111-22. doi: 10.1016/j.avsg.2015.02.013.
Epub 2015 May 27. PubMed PMID: 26025477.

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

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

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

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

Madoka Sugiyama, D.D.S.

Yuki Kanno, D.D.S.

Kazumichi Yonenaga, M.D., D.D.S.

Ryoko Inaki, 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 and malocclusionin patients with cleft lip/palate
2) Research on facial growth in patients withcraniofacial anomalies
3) Reconstruction of oral and maxillofacial area bycustom-made artificial bone (CT bone) (clinical
trial)
4) Transplantation of implant-type tissue-engineered
cartilage for cleft lip-nose patients (clinical study)5) Management of occlusion in patients withfibrodysplasia ossificans progressiva (FOP)2296) QOL study of oral health care system inpreoperative cancer patients
7) Clinical study of antifungal susceptibility inpatients with oral candidiasis
Basic and experimental research:
1) Regeneration of bone and cartilage with tissueengineering approach2) Development of intelligent artificial bone with theability of bone induction3) Development of micro-tetrapod bone implant4) Molecular biology of cartilage repair and its
application to cartilage regenerative medicine
5) Cartilage regenerative medicine using iPS cells6) Development of novel scaffolds for cartilage andbone regeneration
7) In vivo evaluation of tissue-engineered cartilage
and bone8) Study on the control of mesenchymal celldifferentiation
9) Elucidation of epigenetic abnormalities in oral
cancers and oral premalignant lesions
10) Elucidation of sphingosine-1-phosphate signaling
and its role in multistage oral cancer11) Functional analysis of microRNAs in humandental pulp stem cells

Publications
1. Suenaga H, Saijo H, Hoshi K, Mori Y, Takato T.
Diclofenac sodium induced Stevens-Johnson
Syndrome in a hospitalized patient during
treatment of splenic injury and mandibular
fracture. J Oral Maxillofac Surg Med Pathol. 2015
Jan; 27(1): 2932.
2. Abe M, Inaki R, Kanno Y, Hoshi K, Takato T.
Molecular analysis of a mammary analogue
secretory carcinoma in the upper lip - Novelsearch for genetic and epigenetic abnormalities in
MASC. Int J of Surg Case Rep. 2015 Feb; 9: 8-11.
3. Ishimaru T, Komura M, Sugiyama M, Komura H,
Arai M, Fujishiro J, Uotani C,Miyakawa K,
Kakihara T, Hoshi K, Takato T, Tabata Y, Komuro
H, Iwanaka T. Slow release of basic fibroblast
growth factor (b-FGF) enhances mechanicalproperties of rat trachea: J Pediatr Surg. 2015 Feb;
50(2): 255-9.

4. Otani Y, Komura M, Komura H, Ishimaru T,
Konishi K, Komuro H, Hoshi K, Takato T, Tabata
Y, Iwanaka T. Optimal amount of basic fibroblast
growth factor in gelatin sponges incorporating β-tricalcium phosphate with chondrocytes. Tissue
Eng Part A. 2015 Feb; 21(3-4): 627-36.
5. Sugita S, Hosaka Y, Okada K, Mori D, Yano F,
Kobayashi 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 developmentincooperation
withcalcium/calmodulin-dependent protein kinase 2. Proc Natl Acad Sci U
S A. 2015 Mar; 112(10): 3080-5.
6. Wang J, Suenaga H, Liao H, Hoshi K, Yang L,
Kobayashi
E,
SakumaI.
Real-timecomputer-generated integral imaging and 3D
image calibration for augmented reality surgicalnavigation. Comput Med Imaging Graph. 2015
Mar; 40: 147-59.
7. Komatsu N, Suenaga H, Sugiyama M, Hoshi K,
Takato T. Inflammatory internal carotid aneurysm
detected in a patient withbenign fibro-osseous
lesion in the maxillary sinus: A rare case report. J
Oral Maxillofac Surg Med Pathol. 2015 Apr; 402
8. Mikoya T, Shibukawa T, Susami T, Sato Y,
Tengan T, Katashima H, Oyama A, Matsuzawa Y,
Itoh Y, Funayama E. Dental Arch Relationship
Outcomes in One- and Two-Stage Palatoplasty forJapanese Patients with Complete Unilateral Cleft
Lip and Palate. Cleft Palate Craniofac J. 2015
May; 52(3): 277-286.
9. Nakayachi M, Ito J, Hayashida C, Ohyama Y,
Kakino A, Okayasu M, Sato T, Ogasawara T,
Kaneda T, Suda N, Sawamura T, Hakeda Y.
Lectin-like oxidized low-density lipoprotein
receptor-1 abrogation causes resistance toinflammatory bone destruction in mice, despite
promoting osteoclastogenesis in the steady state.
Bone. 2015 Jun; 75: 170-82
10. Saito T, Ohba S, Yano F, Seto I, Yonehara Y,
Takato T, Ogasawara T. Runx1 and Runx3 Are
Downstream Effectors of Nanog in Promoting
Osteogenic Differentiation of the Mouse Mesenchymal Cell Line C3H10T1/2. Cell Reprogram.
2015 Jun; 17(3): 227-34.

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11. Komura M, Komura H, Otani Y, Suzuki K, Satake
R, Kodaka T, Terawaki K,Yonekawa H, Ikebukuro
K, Hoshi K, Takato T, Tabata Y, Komuro H,
Iwanaka T. Tracheoplasty with cartilageengineered esophagus environments.J Pediatr
Surg. 2015 Jul; 50(7): 1093-8.
12. Yoshitake T, Takeda A, Ohki K, Inoue Y,
Yamawaki T, Otsuka S, Akimoto M,Nemoto M,
Shimakura Y, Sato A. Five-year efficacy offinasteride in 801 Japanese men with androgenetic
alopecia. J Dermatol. 2015 Jul; 42(7): 735-8.
13. Misawa M, Nitta N, Shirasaki Y, Hayashi K,
Kosaka R, Hyodo K, Numano T, Homma K,
Kuribayashi S, Fujihara Y, Hoshi K.
Characteristic X-ray absorptiometry applied to theassessment of tissue-engineered cartilage development. J Xray Sci Technol. 2015; 23(4): 489-502.
14. Sato T, Suenaga H, Igarashi M, Hoshi K, Takato T.
Rare case of external dental fistula of thesubmental region misdiagnosed as inverted
follicular keratosis and thyroglossal duct cyst. Int
J Surg Case Rep. 2015 Sep; 16:39-43.
15. Kawase-Koga Y, Mori Y, Kanno Y, Hoshi K,
Takato T. Short Lingual Osteotomy Using a
Piezosurgery Ultrasonic Bone-Cutting Device
During Sagittal Split Ramus Osteotomy. J
Craniofac Surg. 2015 Oct; 26(7): e567-8.
16. Kishi Y, Fujihara H, Kawaguchi K, Yamada H,
Nakayama R, Yamamoto N, Fujihara Y, Hamada Y,
Satomura K, Masutani M. PARP Inhibitor PJ34
Suppresses Osteogenic Differentiation in Mouse
Mesenchymal Stem Cells by Modulating BMP-2
Signaling Pathway. Int J Mol Sci. 2015 Oct 19;
16(10): 24820-38.
17. Wang J, Suenaga H, Yang L, Liao H, Ando T,
Kobayashi E, Sakuma I. 3D Surgical Overlay with
Markerless Image Registration Using a Single
Camera. Lecture Notes in Computer Science.
2015 Oct; 9365: 124-133.
18. 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 tissue membranes(biosheets). J Pediatr Surg. 2015 Nov 5.
19. Suenaga H, Furukawa KS, Suzuki Y, Takato T,
Ushida T. Bone regeneration in calvarial defects

in a rat model by implantation of human bonemarrow-derived mesenchymal stromal cellspheroids. J Mater Sci Mater Med. 2015 Nov;
26(11): 254.
20. Suenaga H, Hosokawa R, Saijo H, Hoshi K,
Takato T. Nasolabial cyst in a patient with cleft lip
and alveolus: a case report. J Oral Maxillofac
Surg Med Pathol. 2015 Nov; 27(6): 839-842.
21. Suenaga H, Tran HH, Liao H, Masamune K, Dohi
T, Hoshi K, Takato T. Vision-based Markerless
Registration Using Stereo Vision and an
Augmented Reality Surgical Navigation System:
A Pilot Study. BMC Med Imaging. 2015 Nov 2;
15(1): 51.
22. 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
UI, Tanaka S, Saito T. Comparison of mouse andhuman ankles and establishment of mouse ankle
osteoarthritis models by surgically-induced
instability. Osteoarthritis Cartilage. 2015 Nov 17.
pii: S1063-4584(15)01389-8.
23. Kobayashi R, Tsunoda K, Ueha R, Fujimaki Y,
Saijo H, Itoh K, Yamasoba T.Effect of a nasal clip
on inhaling a sufficient cortico steroid powder
dose. Ann Allergy Asthma Immunol. 2015 Dec;
115(6): 525-6.
24. Okuma T, Hirata M, Yano F, Mori D, Kawaguchi
H, Chung UI, Tanaka S, Saito T. Regulation ofmouse chondrocyte differentiation by CCAAT/
enhancer-binding proteins. Biomed Res. 2015;
36(1): 21-9.
25. Saito T, Yano F, Mori D, Kawata M, Hoshi K,
Takato T, Masaki H, Otsu M, Eto K, Nakauchi H,
Chung UI, Tanaka S. Hyaline cartilage formationand tumorigenesis of implanted tissues derived
from human induced pluripotent stem cells.
Biomed Res. 2015; 36(3): 179-86.
26. Kawase-Koga Y, Mori Y, Fujii Y, Kanno Y,
Chikazu D, Susami T, Takato T． Complications
after intraoral vertical ramus osteotomy:
relationship to the shapes of osteotomy line. Int J
Oral Maxillofac Surg. (in press)
27. 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

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Ridge augmentation with Particulate Cancellous
Bone and Marrow．Implant Dentistry. (in press）
28. Sato T, Suenaga H, Sugiyama M, Hoshi K, Takato
T. Rare case report of huge Inflammatory
Pseudotumor of the Mandible. J Oral Maxillofac
Surg Med Pathol. (in press)
29. 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.
(in press)

232

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

Associate Professors
Hirotaka Chikuda, M.D., Ph.D.

Yuho Kadono, M.D., Ph.D.

Lecturers
Taku Saito, 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.

Takumi Matsumoto, M.D., Ph.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.

Naohiro Izawa, M.D., Ph.D.

Hideaki Miyamoto, M.D.

Masato Oshina, M.D.

Keitaro Tahara, M.D.

Shuhei Murase, M.D.

Taizo Kaneko, M.D.

Masachika Ikegami, 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

233(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, two associate professors, 3 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 17 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, a ten-year
course has been adopted with clinical and researchtraining taking place either in the University of Tokyo
Hospital or in our 50 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 37,886 patients
visited the outpatient clinic in 2015.
The ward has approximately 55 to 65 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 professor
on Tuesday. Post- and preoperative case conferences
are held on Monday evening, Tuesday morning andThursday evening.
1,268 operations were performed in 2016. These
include 252 spine surgeries, 62 surgeries forrheumatoid arthritis patients, 132 hip surgeries, 252knee surgeries (including 40 computer-assisted ACL
reconstructions, 68 computer-assisted TKA, 38 UKA),
251 hand surgeries, 48 foot and ankle surgeries, 17234

pediatric surgeries, 90 surgeries for bone and soft
tissue tumor, and 183 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235

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. Oichi T, Chikuda H, Morikawa T, Mori H,
Kitamura D, Higuchi J, Taniguchi Y,
Matsubayashi Y, Oshima Y, Tanaka S. Concurrent
spinal schwannoma and meningioma mimicking asingle cervical dumbbell-shaped tumor: casereport. J Neurosurg Spine. 2015 Dec;23(6):784-7.
2. Oichi T, Oshima Y, Takeshita K, Chikuda H,
Tanaka S. Evaluation of Comorbidity Indices for a
Study of Patient Outcomes Following Cervical
Decompression Surgery: A Retrospective Cohort
Study. Spine (Phila Pa 1976). 2015 Dec; 40(24):1941-7.
3. Tsuda Y, Yasunaga H, Horiguchi H, Ogawa S,
Kawano H, Tanaka S. Association between
dementia and postoperative complications after
hip fracture surgery in the elderly: analysis of
87,654 patients using a national administrative
database. Arch Orthop Trauma Surg. 2015 Nov;
135(11):1511-7.
4. Muraki S, Akune T, Teraguchi M, Kagotani R,
Asai Y, Yoshida M, Tokimura F, Tanaka S, Oka H,
Kawaguchi H, Nakamura K, Yoshimura N.
Quadriceps muscle strength, radiographic knee

osteoarthritis and knee pain: the ROAD study.
BMC Musculoskelet Disord. 2015 Oct 16;16:305.
5. Ohya J, Chikuda H, Oichi T, Horiguchi H,
Takeshita K, Tanaka S, Yasunaga H. Perioperative
stroke in patients undergoing elective spinal surgery: a retrospective analysis using the Japanesediagnosis procedure combination database. BMC
Musculoskelet Disord. 2015 Oct 2;16:276.
6. Sugita S, Murakami H, Demura S, Kato S,
Yoshioka K, Yokogawa N, Tanaka S, Tsuchiya H.
Repeated total en bloc spondylectomy for spinal
metastases at different sites in one patient. Eur
Spine J. 2015 Oct;24(10):2196-200.
7. Kato S, Chikuda H, Ohya J, Hayakawa K,
Takeshita K, Tanaka S, Ogata T. Phosphorylated
neurofilament subunit levels in the serum of
cervical compressive myelopathy patients. J Clin
Neurosci. 2015 Oct;22(10):1638-42.
8. Ando Y, Yasui T, Isawa K, Tanaka S, Tanaka Y,
Takakura Y. Total Talar Replacement for
Idiopathic Necrosis of the Talus: A Case Report. J
Foot Ankle Surg. 2015 Sep 17.[Epub ahead ofprint]
9. Kyomoto M, Shobuike T, Moro T, Yamane S,
Takatori Y, Tanaka S, Miyamoto H, Ishihara K.
Prevention of bacterial adhesion and biofilm
formation on a vitamin E-blended, cross-linked
polyethylene
surfacewithapoly (2methacryloyloxyethyl phosphorylcholine) layer.
Acta Biomater. 2015 Sep;24:24-34.
10. Muraki S, Akune T, Nagata K, Ishimoto Y,
Yoshida M, Tokimura F, Tanaka S, Kawaguchi H,
Nakamura K, Oka H, Yoshimura N. Does
osteophytosis at the knee predict health-related
quality of life decline? A 3-year follow-up of the
ROAD study. Clin Rheumatol. 2015 Sep;34(9):1589-97.
11. Yoshimura N, Muraki S, Oka H, Tanaka S, Ogata
T, Kawaguchi H, Akune T, Nakamura K. Erratum
to: Association between new indices in thelocomotive syndrome risk test and decline inmobility: third survey of the ROAD study. J
Orthop Sci. 2015 Sep;20(5):906.
12. Yoshimura N, Muraki S, Oka H, Tanaka S, Ogata
T, Kawaguchi H, Akune T, Nakamura K.
Association between new indices in thelocomotive syndrome risk test and decline in236

mobility: third survey of the ROAD study. J
Orthop Sci. 2015 Sep;20(5):896-905.
13. Ishigaki K, Shoda H, Kochi Y, Yasui T, Kadono Y,
Tanaka S, Fujio K, Yamamoto K. Quantitative andqualitative characterization of expanded CD4+ T
cell clones in rheumatoid arthritis patients. Sci
Rep. 2015 Aug 6;5:12937.
14. Moro T, Takatori Y, Kyomoto M, Ishihara K,
Kawaguchi H, Hashimoto M, Tanaka 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 Jul;33(7):1103-10.
15. Taketomi S, Inui H, Nakamura K, Yamagami R,
Tahara K, Sanada T, Masuda H, Tanaka S,
Nakagawa T. Secure fixation of femoral bone plugwith a suspensory button in anatomical anterior
cruciate ligament reconstruction with bonepatellar tendon-bone graft. Joints. 2016 Jan 28;
3(3):102-8.
16. Shoda N, Yasunaga H, Horiguchi H, Fushimi K,
Matsuda S, Kadono Y, Tanaka S. Prophylactic
effect of fondaparinux and enoxaparin forpreventing pulmonary embolism after total hip or
knee arthroplasty: A retrospective observational
study using the Japanese Diagnosis Procedure
Combination database. Mod Rheumatol. 2015 Jul;
25(4):625-9.
17. Mure K, Yoshimura N, Hashimoto M, Muraki S,
Oka H, Tanaka S, Kawaguchi H, Nakamura K,
Akune T, Takeshita T. Urinary 8-iso-prostaglandin
F2α as a marker of metabolic risks in the general
Japanese population: The ROAD study. Obesity(Silver Spring). 2015 Jul;23(7):1517-24.
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
Jul;229(7):506-14.
19. Ohya J, Chikuda H, Kato S, Hayakawa K, Oka H,
Takeshita K, Tanaka S, Ogata T. Elevated levelsof phosphorylated neurofilament heavy subunit in
the cerebrospinal fluid of patients with lumbar
spinal stenosis: preliminary findings. Spine J.
2015 Jul 1;15(7):1587-92.
20. 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. Genomewide
comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKLinduced osteoclastogenesis. J Bone Miner Res.
2015 May;30(5):869-77.
21. Yoshimura N, Muraki S, Oka H, Tanaka S,
Kawaguchi H, Nakamura K, Akune T. Mutual
associations among musculoskeletal diseases andmetabolic syndrome components: A 3-year
follow-up of the ROAD study. Mod Rheumatol.
2015 May;25(3):438-48.
22. Teraguchi M, Yoshimura N, Hashizume H,
Muraki S, Yamada H, Oka H, Minamide A,
Nakagawa H, Ishimoto Y, Nagata K, Kagotani R,
Tanaka S, Kawaguchi H, Nakamura K, Akune T,
Yoshida M. The association of combination ofdisc degeneration, end plate signal change, andSchmorl node with low back pain in a large
population study: the Wakayama Spine Study.
Spine J. 2015 Apr 1;15(4):622-8.
23. Ohya J, Chikuda H, Kato S, Horiguchi H,
Takeshita K, Tanaka S, Yasunaga H. Risks of
in-hospital death and complications after fusion
surgery in patients with atlantoaxial subluxation:
analysis of 1090 patients using the JapaneseDiagnosis Procedure Combination database.
World Neurosurg. 2015 Apr;83(4):603-7.
24. Sugita S, Hosaka Y, Okada K, Mori D, Yano F,
Kobayashi 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 developmentincooperation
withcalcium/calmodulindependent protein kinase 2. Proc Natl Acad Sci
USA. 2015 Mar 10; 112(10):3080-5.
25. 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 Mar;473(3):942-51.
26. Ito H, Takatori Y, Moro T, Oshima H, Oka H,
Tanaka S. Total hip arthroplasty after rotational

237

acetabular osteotomy. J Arthroplasty. 2015 Mar;30(3):403-6.
27. Kagotani R, Yoshida M, Muraki S, Oka H,
Hashizume H, Yamada H, Enyo Y, Nagata K,
Ishimoto Y, Teraguchi M, Tanaka S, Nakamura K,
Kawaguchi H, Akune T, Yoshimura N. Prevalenceof diffuse idiopathic skeletal hyperostosis (DISH)
of the whole spine and its association with lumbar
spondylosis and knee osteoarthritis: the ROAD
study. J Bone Miner Metab. 2015 Mar;33(2):221-9.
28. Takatori Y, Moro T, Ishihara K, Kamogawa M,
Oda H, Umeyama T, Kim YT, Ito H, Kyomoto M,
Tanaka T, Kawaguchi H, Tanaka S. Clinical andradiographic outcomes of total hip replacementwith poly (2-methacryloyloxyethyl phosphorylcholine)-grafted highly cross-linked polyethylene
liners: three-year results of a prospective consecutive series. Mod Rheumatol. 2015 Mar; 25(2):286-91.
29. Hayakawa K, Uchida S, Ogata T, Tanaka S,
Kataoka K, Itaka K. Intrathecal injection of atherapeutic gene-containing polyplex to treat
spinal cord injury. J Control Release. 2015 Jan
10;197:1-9.
30. Saito T, Yano F, Mori D, Kawata M, Hoshi K,
Takato T, Masaki H, Otsu M, Eto K, Nakauchi H,
Chung UI, Tanaka S. Hyaline cartilage formationand tumorigenesis of implanted tissues derived
from human induced pluripotent stem cells.
Biomed Res. 2015;36(3):179-86.
31. Okuma T, Hirata M, Yano F, Mori D, Kawaguchi
H, Chung UI, Tanaka S, Saito T. Regulation ofmouse chondrocyte differentiation by CCAAT/
enhancer-binding proteins. Biomed Res. 2015;
36(1):21-9.
32. Oshima Y, Miyoshi K, Mikami Y, Nakamoto H,
Tanaka S. Long-Term Outcomes of CervicalLaminoplasty in the Elderly. Biomed Res Int.
2015; 2015:713952.
33. Watanabe K, Kyomoto M, Saiga K, Taketomi S,
Inui H, Kadono Y, Takatori Y, Tanaka S, Ishihara
K, Moro T. Effects of Surface Modification andBulk Geometry on the Biotribological Behavior of
Cross-Linked Polyethylene: Wear Testing and
Finite Element Analysis. Biomed Res Int. 2015;
2015:435432.

34. Ogihara S, Yamazaki T, Maruyama T, Oka H,
Miyoshi K, Azuma S, Yamada T, Murakami M,
Kawamura N, Hara N, Terayama S, Morii J, Kato
S, Tanaka S. Prospective multicenter surveillance
and risk factor analysis of deep surgical site
infection after posterior thoracic and/or lumbar
spinal surgery in adults. J Orthop Sci. 2015 Jan;20(1):71-7.
35. Ohya J, Oshima Y, Takeshita K, Oka H, Chikuda
H, Taniguchi Y, Matsubayashi Y, Tanaka S.
Patient satisfaction with double-door laminoplasty
for cervical compression myelopathy. J Orthop
Sci. 2015 Jan; 20(1):64-70.
36. Matsubayashi Y, Takeshita K, Sumitani M,
Oshima Y, Tonosu J, Kato S, Ohya J, Oichi T,
Okamoto N, Tanaka S. Psychometric Validation of
the Japanese Version of the Neuropathic Pain
Symptom Inventory. PLoS One. 2015 Nov 24;
10(11):e0143350.
37. Oka H, Matsudaira K, Fujii T, Okazaki H, Shinkai
Y, Tsuji Y, Tanaka S, Kato R. Risk Factors for
Prolonged Treatment of Whiplash-AssociatedDisorders. PLoS One. 2015 Jul 6; 10(7):e0132191.
38. Kato S, Oshima Y, Oka H, Chikuda H, Takeshita Y,
Miyoshi K, Kawamura N, Masuda K, Kunogi J,
Okazaki R, Azuma S, Hara N, Tanaka S, Takeshita
K. Comparison of the Japanese Orthopaedic
Association (JOA) score and modified JOA(mJOA) score for the assessment of cervicalmyelopathy: a multicenter observational study.
PLoS One. 2015 Apr 2;10(4): e0123022.

238

Department of Ophthalmology
Professor
Makoto Aihara, M.D., Ph.D.

Associate Professor
Satoshi Kato, M.D., Ph.D. Satoru Yamagami, M.D., Ph.D

Lecturer
Toshikatsu Kaburaki, M.D., Ph.D., Tomohiko Usui, M.D., Ph.D.,
Megumi Honjyo, M.D., Ph.D., Chihiro Mayama,M.D.,Ph.D., Ryo Obata, M.D., Ph.D.

Research Associate
Muneyuki Takao, M.D., Ryo Asaoka, M.D., Ph.D., Hiroshi Murata, M.D.,
Tomoyasu Shiraya, M.D., Hiroyo Hirasawa,M.D.,Ph.D., Tatsuya Inoue, M.D.,Ph.D.,
Hiromasa Sawamura, M.D., Ph.D., Takashi Ueta,M.D., Ph.D., Kazuyoshi Otomo, M.D.,
Taku Toyama, M.D., Keiko Azuma, M.D., Fumiyuki Araki, M.D., Ph.D., Rie Tanaka, M.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 subspecialities such as
cornea, glaucoma, retina, uveitis, neuro-ophthal-mology, orthoptics, diabetic retinopathy, and genetic
and color blindness problems. The staff members
supervise the ambulatory and special services
depending on each one’s speciality.
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
transplantation. In addition, we are engaged inpractical training for medical students on ophthalmological examinations at the outpatient clinic. As a239

postgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

Research activities
Research topics in our department cover a variety offields in ophthalmology; e.g. ocular pharmacology,
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. Analysis with laser-speckle method of vascularflow in retina and iris
2. Clinical investigation of normal tension glaucoma
3. Drug effect on glaucoma
4. Screening method of glaucoma
5. Tissue engineering of the cornea
6. Molecular analysis of corneal neovascularization
7. Gene therapy for corneal dystrophies
8. Analysis of Meibomian gland with Mibography
9. Analysis of safety of topical eye drops using
human corneal epithelial cell sheets
10. Molecular analysis of retinal degenerative diseases
11. Color blindness and visual function
12. Electrophysiological analysis of the effect ofdrugs on the retina
13. Pathophysiology of age-related macular degeneration
14. Molecular analysis of retinal neovascularization
15. Immuno-hereditary analysis of Harada’s disease
and Bechet’s disease
16. Immunosuppressive reagents on Bechet’s disease
17. Pathophysiology and molecular mechanisms of
diabetic retinopahty

References
1. Aihara M, Adachi M, Hamada N, Honda N,
Koseki N, Matsuo H, Miyata K, Otani S, Unoki
K: Effects of Switching from Timolol to
Brimonidine in Prostaglandin Analog and Timolol
Combination Therapy. J ocul Pharmacol Ther 31:
482-486, 2015
2. Aihara M, Ikeda Y, Mizoue S, Arakaki Y, Kita N,

Kobayashi S, Group NES: Effect of Switching to
Travoprost Preserved With SofZia in Glaucoma
Patients With Chronic Superficial Punctate Keratitis While Receiving BAK-preserved Latanoprost.
Journal of glaucoma May 2, 2015
3. Akiyama-Fukuda R, Usui T, Yamagami S :Diagnosis of dry eye by tear meniscus measurements using anteriro segment swept source opticalcoherence tomography. Cornea 11:S115-20, 2015
4. Ando W, Yamamoto K, Atsumi T, Tamaoki S,
Oinuma K, Shiratsuchi H, Tokunaga H, Inaba Y,
Kobayashi N, Aihara M, Ohzono K: Comparison
between component designs with different
femoral head size in metal-on-metal total hip
arthroplasty; multicenter randomized prospective
study. Journal of orthopaedics 12: 228-36,2015
5. Aoki A, Tan X, Yamagishi R, Shinkai S, Obata R,
Miyaji T, Yamaguchi T, Numaga J, Ito H, Yanagi
Y: Risk Factors for Age-Related Macular
Degeneration in an Elderly Japanese Population:
The Hatoyama Study. Invest Ophthalmol Vis Sci
5:2580-5, 2015
6. Aoyama Y, Murata H, Aihara M: Targeting a
low-teen intraocular pressure by trabeculectomy
with a fornix-based conjunctival flap: continuous
Japanese case series by a single surgeon. Journalof glaucoma 24: 225-32, 2015
7. Arita R, Mori N, Shirakawa R, Asai K, Imanaka
T, Fukano Y, Nakamura M, Amano S:Meibum
Color and Free Fatty Acid Composition in
Patients With Meibomian Gland Dysfunction.
Invest Ophthalmol Vis Sci 56:4403-4412,2015
8. Arita R, Morishige N, Shirakawa R, Sato Y,
Amano S:Effects of Eyelid Warming Devices on
Tear Film Parameters in Normal Subjects andPatients withMeibomian Gland Dysfunction. Ocul
Surf. 13:321-330,2015
9. Arita R, Morishige N, Koh S, Shirakawa R,
Kawashima M, Sakimoto T, Suzuki T, Tsubota K:
Increased Tear Fluid Production as a Compensatory Response to Meibomian Gland Loss: A
Multicenter Cross-sectional Study. Ophthalmology 122:925-933,2015
10. Asaoka R, Nakakura S, Tabuchi H, Murata H,
Nakao Y, Ihara N, Rimayanti U, Aihara M,
Kiuchi Y. The relationship between Corvis ST
tonometry measured corneal parameters and240

intraocular pressure, corneal thickness and corneal
curvature. PloSOne 20;10(10):e0140385, 2015.
doi: 10.1371/journal.pone.0140385. eCollection,
2015
11. Aung T, Ozaki M, Mizoguchi T, Allingham RR,
Li Z, Haripriya A, Nakano S, Uebe S, Harder JM,
Chan AS, Lee MC, Burdon KP, Astakhov YS,
Abu-Amero KK,Zenteno JC, Nilgün Y,
Zarnowski T, Pakravan M, Safieh LA, Jia L,
Wang YX, Williams S, Paoli D, Schlottmann PG,
Huang L, Sim KS, Foo JN, Nakano M, Ikeda Y,
Kumar RS, Ueno M, Manabe S, Hayashi K,
Kazama S, Ideta R: A common variant mapping to
CACNA1A is associated with susceptibility to
exfoliation syndrome. Nat Genet 47:387-92, 2015
12. Fujino Y, Murata H, Mayama C, Asaoka R.
Applying 'Lasso' regression to predict future
visual field progression in glaucoma patients.
Invest Ophthalmol Vis Sci 1;56(4):2334-9, 2015
13. Fujiwara T, Fujiwara M, Numoto K, Ogura K,
Yoshida A, Yonemoto T, Suzuki S, Kawai A.
Second primary osteosarcomas in patients withretinoblastoma. Jpn J Clin Oncol 45:1139-1145,
2015
14. Hernández R, Burr JM, Vale L, Azuara-Blanco A,
Cook JA, Banister K, Tuulonen A, Ryan M:
Surveillance of Ocular Hypertension Study group(Asaoka R). Monitoring ocular hypertension, howmuch and how often? A cost-effectivenessperspective. Br J Ophthalmol 11: 306757, 201515. Hirasawa K, Murata H, Asaoka R. Revalidating
the usefulness of a ‘sector-wise regression’approach to predict glaucomatous visual function
progression. Invest Ophthalmol Vis Sci 56:43324335, 201516. Hirasawa H, Mayama C, Tomidokoro A, Araie M,
Iwase A, Sugiyama K, Kishi S, Maeda N,
Yoshimura N: Diagnostic performance andreproducibility of circumpapillary retinal nerve
fiber layer thickness measurement in 10-degree
sectors in early stage glaucoma. Jpn J Ophthalmol
59:86-93, 2015
17. Ishiyama Y, Murata H, Hirasawa H, Asaoka R:
Estimating the usefulness of Humphrey Perimetry
gaze tracking for evaluating structure-function
relationship in glaucoma. Invest Ophthalmol Vis
Sci 56:7801-7805, 2015

18. Ishiyama Y, Murata H, Asaoka R: The usefulnessof gaze tracking as an index of visual fieldreliability
inglaucomapatients.
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Fujii N: Immunohistochemical localization ofd-β-aspartic acid-containing proteins in pterygium.
J Pharm Biomed Anal 116: 86-89, 2015.
22. Kongkaew S, Yotmanee P, Rungrotmongkol T,
Kaiyawet N, Meeprasert A, Kaburaki T, Noguchi
H, Takeuchi F, Kungwan N, Hannongbua S.
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Selective Binding of Human Leukocyte Antigen
Alleles Associated with Behçet’s Disease. PLoS
One.10:e0135575, 201523. Masuda A, Hara T, Miyata K, Matsuo H, Murata
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values accurately estimate glaucomatous visual
field damage in eyes with glaucoma and cataract?.
Br J Ophthalmol 99: 1240-1244, 201524. Matsuura M, Hirasawa K, Murata H, Asaoka R:
The relationship between visual acuity and the
reproducibility of visual field measurements inglaucoma patients. Invest Ophthalmol Vis Sci 56:
5630-5635, 2015
25. Mayama C, Saito H, Hirasawa H, Tomidokoro A,
Araie M, Iwase A, Ohkubo S, Sugiyama K,
Hangai M, Yoshimura N: Diagnosis of EarlyStage Glaucoma by Grid-Wise Macular Inner
Retinal Layer Thickness Measurement and Effectof Compensation of Disc-Fovea Inclination.
Invest Ophthalmol Vis Sci 56:5681-5690, 2015
26. Minami K, Miyata K, Nagai N, Sasaki H: Use of a
warmed ophthalmic viscoelastic device toaccelerate the unfolding of 1-piece intraocularlenses in the capsular bag. J Cataract Refract Surg
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Refract Surg 41: 2444-2449, 201528. Miyata K, Honbo M, Nejima R, Minami K,
Amano S: Long-term Effect of surface lightscattering in a foldable acrylic intraocular lens. J
Cataract Refract Surg 41: 1205-1209, 2015.
29. Namba K, Goto H, Kaburaki T, Kitaichi N,
Mizuki N, Asukata Y, Fujino Y, Meguro A,
Sakamoto S, Shibuya E, Yokoi K, Ohno S. A
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Behçet's Disease in Japan. Ocul Immunol
Inflamm 23 Suppl 1:S1-S23, 201530. Nejima R, Terada Y, Mori Y, Ogata M, Minami K,
Miyata K: Clinical utlity of femtosecond
laser-assisted astigmatic keratotomy after cataract
surgery. Jpn J Ophthalmol 59: 209-215, 2015.
31. Nejima R, Masuda A, Minami K, Mori Y,
Hasegawa Y, Miyata K: Topographic Changes
After Excision Surgery of Primary Pterygia andthe Effect of Pterygium Size on Topograpic
Restoration. Eye Contact Lens 41: 58-63, 2015
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Outcomes of Late-Onset Bleb-Related Endophthalmitis Treated with Pars Plana Vitrectomy. J
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34. Ono T, Yuki K, Asaoka R, Kouyama K, Abe T,
Tanabe S, Fukagawa K, Uchino M, Shimoyama
M, Ozawa Y, Ozeki N, Shiba D, and Tsubota K.
Glaucomatous Visual Field Defect Severity and
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Department ofOtorhinolaryngology andHead & Neck Surgery
Professor
Tatsuya Yamasoba, M.D., Ph.D.

Associate Professor
Takahiro Asakage, M.D., Ph.D.

Shin-ichi Iwasaki, MD.,Ph.D

Akinobu Kakigi, M.D., Ph.D.

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

Takashi Sakamoto, M.D., Ph.D.

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

Shotaro Karino, M.D., Ph.D．

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

Research Associate
Naoya Egami, M.D.

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

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

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

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

Sayaka Suzuki, M.D.

Chisato Fujimoto, M.D, Ph.D

Rumi Ueha, M.D.

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

Hironobu Nishijima, M.D.

Makoto Kinoshita, 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 inJapan. Our department covers all otorhinolaryngological diseases and associated systemic
diseases, and has specialized clinics in middle ear andinner ear diseases, hearing impaired infant andchildren, adult and elderly patients, facial paresis,
vertigo and balance disorders, olfactory disorders andparanasal diseases, voice and speech disorders, taste

and swallowing respiratory disorders, aphasia, central
auditory disorders and head & neck cancers.
A professor, associate professors, lecturers(assistant professors) and associates participate insurgery, out-patient and in-patient care as well as
research and educational 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

244club is held to introduce current research papers.

Clinical activities
In the out-patient clinic, general and special
services are provided to approximately 150 outpatients on a daily basis in all areas ofotorhinolaryngology and related specialties, andapproximately 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,
the professor’s and associate professor’s rounds.
Approximately 800 operations are performed
annually.
Cochlear implant surgery over 300 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
with neighboring tissues and reconstruct upper
respiratory and swallowing functions at one stage
operation cooperating with plastic surgeons.
Reconstructive surgery of microtia and atresia toreconstruct external ear is routinely performed withplastic 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 theprofessor 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

245

development in deaf children.
13) Physiology bone conduction innovation of bone
conduction hearing and bilateral hearing.
14) Embryology of middle, inner ear and central
auditory system.
Various clinical and basic researches are conductedby staffs, residents, and graduate students as well as
doctors at affiliated hospitals.

References
1. Akashi K, Ebihara Y, Omura G, Saito Y, Yoshida
M, Ando M, Asakage T, Yamasoba T, Murakami
Y. Frequent Copy Gain of the MET Gene in
Hypopharyngeal and Laryngeal Cancer in theJapanese Population.Journal of Cancer Therapy6:1093,2015
2. Ando M, Saito Y, Morikawa T, Omura G,
Kobayashi K, Akashi K, Yoshida M, Ebihara Y,
Fujimoto C, Fukayama M, Yamasoba T, Asakage
T:Maxillary carcinosarcoma Identification of anovel MET mutation in both carcinomatous andsarcomatous components through next generation
sequencing. Head Neck 37:E179-E185,2015
3. Baba M, Itaka K, Kondo K, Yamasoba T, Kataoka
K :Treatment of neurological disorders byintroducing mRNA in vivo using polyplex nanomicelles. Journal of Controlled Release 201:41-48,
2015
4. Baba S, Kagoya R, Kondo K, Suzukawa K, Ohta
K, Yamasoba T: T-cell phenotypes in chronicrhinosinusitis with nasal polyps in Japanesepatients. Allergy, Asthma & Clinical Immunology
11:33, 2015
5. Egami N, Kakigi A, Takeda T, Yamasoba
T:Dehydration effects of V2 antagonist on
endolymphatic hydrops in guinea pigs. Hearing
Research 332:151-159,2015
6. Fujimaki Y, Nito T, Yamasoba T, Tayama N,
Makiyama K, Murofushi T, Tsunoda A, Ohshima
K, Nishiyama K, Kano S, Niimi S:Patients'
perceptions of vocal problems: results from asurvey in the Tokyo area. Acta Otolaryngol
135(6):532-535,2015
7. Fujimoto C, Egami N, Kinoshita M, Sugasawa K,
Yamasoba T, Iwasaki S:Idiopathic latent vesti-bulopathy: a clinical entity as a cause of chronic
postural instability. Eur Arch otorhinolaryngol
272: 43-49,2015
8. Fujimoto C, Egami N, Kinoshita M, Sugasawa K,
Yamasoba T, Iwasaki S:Involvement of vestibularorgans in idiopathic sudden hearing loss withvertigo: an analysis using oVEMP and cVEMP
testing. Clin Neurophysiol 126:1033-1038,2015
9. Fujimoto C, Egami N, Demura S, Yamasoba T,
Iwasaki S:The effect of aging on the center-ofpressure power spectrum in foam posturography.
Neurosci Lett 585:92-97,2015
10. Igarashi K, Matsumoto Y, Kakigi A:Acupressure
Bead in the Eustachian Tube. J AcupunctMeridian Stud 8(4):200-2,2015
11. Iwasaki S, Fujimoto C, Kinoshita M,
Kamogashira T, Egami N, Yamasoba T:Clinicalcharacteristics of patients with abnormal ocular/cervical vestibular evoked myogenic potentials in
the presence of normal caloric responses.Ann Otol
Rhinol Laryngol 124:458-465,2015
12. Iwasaki S, Yamasoba T: Dizziness and imbalancein the elderly: age-related decline in the vestibular
system.Aging and disease 6 (1):38,2015
13. Kagoya R, Kondo K, Baba S, Toma-Hirano M,
Nishijima H, Suzukawa K, Kikuta S, Yamasoba
T: Correlation of basophil infiltration in nasal
polyps with the severity of chronic rhinosinusitis.
Annals of Allergy, Asthma & Immunology 1:
30-35,2015
14. Kamogashira T, Fujimoto C, Yamasoba T:
Reactive oxygen species, apoptosis, and mitochondrial dysfunction in hearing loss. Biomed Res
Int 2015:617207,2015
15. Kashio A, Sakamoto T, Karino S, Kakigi A,
Iwasaki S, Yamasoba T: Predicting round window
niche visibility via the facial recess using highresolution computed tomography. Otology&
Neurotology 36:e18-e23, 2015
16. Kikuta S, Sakamoto T, Nagayama S, Kanaya K,
Kinoshita M, Kondo K, Tsunoda K, Mori K,
Yamasoba T: Sensory Deprivation Disrupts
Homeostatic Regeneration of Newly Generated
Olfactory Sensory Neurons after Injury in Adult
Mice.The Journal of Neuroscience 35:2657-2673,
2015
17. Kinoshita M, Kikkawa Y S, Sakamoto T, Kondo

246

K, Ishihara K, Konno T, Pawsey N, Yamasoba T :Safety, reliability, and operability of cochlear
implant electrode arrays coated with biocompatible polymer. Acta oto-laryngologica 135:
320-327,2015
18. Kobayashi K, Ando M, Saito Y, Kondo K, Omura
G, Shinozaki-Ushiku A, Fukayama M, Asakage T,
Yamasoba T: Nerve Growth Factor Signals as
Possible Pathogenic Biomarkers for Perineural
Invasion in Adenoid Cystic Carcinoma. Otolaryngology Head and Neck Surgery 153:218-24,
2015
19. Nomura T, Ushio M, Kondo K, Yamasoba
T:Effects of nasal septum perforation repair
surgery on three-dimensional airflow: anevaluation using computational fluid dynamics.
Eur Arch. Otorhinolaryngol. 272:3327-33, 2015
20. Okada K, Sato S, Sato A, Mandelboim O,
Yamasoba T, Kiyono H. Identification andAnalysis of Natural Killer Cells in Murine Nasal
Passages. PloS one10 (11):e0142920,2015
21. Omura G, Ando M, Saito Y, Kobayashi K,
Yamasoba T, Asakage T: Disease control andclinicopathological prognostic factors of totalpharyngolaryngectomyforhypopharyngeal
cancer: a single-center study. International journalof clinical oncology 20 (2):290-297,2015
22. Kobayashi R, Tsunoda K, Ueha R, Fujimaki Y,
Saijo H, Itoh K, Yamasoba T: Effect of a nasal
clip on inhaling a sufficient cortico steroid
powder dose. Ann Allergy Asthma Immunol 115:525-6,2015
23. Saito Y, Yoshida M, Omura G, Kobayashi K,
Fujimoto C, Ando M, Sakamoto T, Asakage T,
Yamasoba T: Prognostic value of p16 expression
irrespective of human papillomavirus status inpatients with oropharyngeal carcinoma. Jpn J Clin
Oncol. 45:828-36, 201524. Sakamoto T, Yamasoba T: Current Concepts of
the Mechanisms in Age-Related Hearing Loss.J
Clin Exp Pathol 5 :250,2015
25. Sakamoto T, Kikuta S, Kikkawa YS,
Tsutsumiuchi K, Kanaya K, Fujimaki Y, Ueha R,
Saito Y, Yamasoba T: Differences in Postoperative Hearing Outcomes and Vertigo inPatients with Otosclerosis Treated with LaserAssisted Stapedotomy versus Stapedectomy.ORL

77:287-293,2015
26. Saito Y, Yoshida M, Omura G, Kobayashi K,
Fujimoto C, Ando M, Sakamoto T, Asakage T,
Yamasoba T: Prognostic value of p16 expression irrespective of human papillomavirus status
in patients with oropharyngeal carcinoma. Jpn J
Clin Oncol. 45:828-836,2015
27. Suzuki S, Yasunaga H, Matsui H, Fushimi K,
Kondo K, Yamasoba T :Complication rates after
functional endoscopic sinus surgery: Analysis of
50,734 Japanese patients. Laryngoscope 125(8):1785-91, 201528. Suzuki S, Yasunaga H, Matsui H, Horiguchi H,
Fushimi K, Yamasoba T: haryngocutaneous
fistula and delay in free oral feeding after
pharyngolaryngectomy for hypopharyngeal cancer.
Head Neck,2015
29. 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,2015
30. Takeda T, Takeda S, Okada T, Kakigi A,
Yamasoba T: Experimental Studies on the
Recovery Processes From Severe Facial Palsy andthe Development of Its Sequelae.Otology &Neurotology 36:896-903,2015
31. Takei Y, Kikkawa YS, Atapour N, Hensch TK,
Hirokawa N: Defects in Synaptic Plasticity,
Reduced NMDA-Receptor Transport, and Instability of Postsynaptic Density Proteins in Mice
Lacking Microtubule-Associated Protein 1A. J
Neurosci 35:15539-54,2015
32. Tokunaga T, Sakashita M, Haruna T, Asaka D,
Takeno S, Ikeda H, Nakayama T, Seki N, Ito S,
Murata J, Sakuma Y, Yoshida N, Terada T,
Morikura I, Sakaida H, Kondo K, Yamada K,
Okano M, Ohtori N, Yoshikawa M, Hirakawa K,
Haruna S, Himi T, Ikeda K, Ishitoya J, Iino Y,
Kawata R, Kawauchi H, Kobayashi M, Yamasoba
T, Miwa T, Urashima M, Tamari M, Noguchi E,
Ninomiya T, Imoto Y, Morikawa T, Tomita K,
Takabayashi T, Fujieda S:Novel scoring system
and algorithm for classifying chronic rhinosinusitis: The JESREC Study. Allergy 70:9951003,2015

247

33. Ueha R, Nito T, Sakamoto T, Fujimaki Y,
Yamauchi A, Yamasoba T: Supra-thyroid alar
cartilage approach for the complete resection oflaryngeal submucosal tumors and postoperative
voice quality. European Archives of Oto-RhinoLaryngology 272 (10):2907-2913, 2015
34. Ueha R, Nito T, Sakamoto T, Yamauchi A,
Tsunoda Koichi, Yamasoba T: Postoperative
swallowing in multiple system atrophy. European
Journal of Neurology23(2): 393-400, 201535. Yamasoba T: Interventions to Prevent AgeRelated Hearing Loss Josef Mille, Colleen G Le
Prell, Leonard Rybak (Eds) Free Radicals in ENT
Pathology. Springer International Publishing:335-349,2015
36. Yamauchi A, Yokonishi H, Imagawa H,
Sakakibara K, Nito T, Tayama N, Yamasoba
T :Vocal Fold Vibration in Vocal Fold Atrophy:
Quantitative Analysis With High-Speed Digital
Imaging.. Journal of Voice 29(6):755-62,2015
37. Yamauchi A, Yokonishi H, Imagawa H,
Sakakibara K, Nito T, Tayama N, Yamasoba T:
Quantitative analysis of digital videokymography:
a preliminary study on age-and gender-relateddifference of vocal fold vibration in normal
speakers. Journal of Voice 29:109-119,2015
38. Yasuda T, Fukumura K, Uchida Y, Koshi H, Iida
H, Masamune K, Yamasoba T, Sato Y, Nakajima
T Effects of Low-Load, Elastic Band ResistanceTraining Combined With Blood Flow Restriction
on Muscle Size and Arterial Stiffness in Older
Adults.J Gerontol A Biol Sci Med Sci 70:950-8,
2015
39. Yoshimoto R, Iwasaki S, Takago H, Nakajima T,
Sahara Y, Kitamura K: Developmental increase in
hyperpolarization-activated current regulates
intrinsic firing properties in rat vestibular
ganglion cells. Neuroscience 284:632-642,2015

248

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 2013, 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249

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.

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) Motion analysis of patients with joint disorders in
the lower extremities
2) Motion analysis of motor development in children
3) Early detection, diagnosis, and progression prevention of musculoskeletal disorders in the elderly
4) Rehabilitation approaches for patients withhemophilia
5) Rehabilitation approaches for patients with spina
bifida6) Treatment and rehabilitation for patients withcongenital limb deficiencies
7) Disabilities and handicaps in patients with skeletal
dysplasias
8) Analysis of musculo-skeletal involvement incongenital insensitivity to pain

References
1. Goto M, Takedani H, Nitta O, Kawama K: Joint
function and arthropathy severity in patients withhemophilia. J Jpn Phys Ther Assoc 18: 15-22,
2015
2. Inokuchi H, Tojima M, Mano H, Ishikawa Y,
Ogata N, Haga N: Neck range of motion
measurements using a new three-dimensionalmotion analysis system: validity and repeatability.
Eur Spine J 24(12): 2807-2815, 2015
3. Kaneoka A, Krisciunas GP, Walsh K, Raade AS,
Langmore SE: A comparison of 2 methods ofendoscopic laryngeal sensory testing: A
preliminary study. Ann Otol Rhinol Laryngol
124(3): 187-193, 2015
4. Kaneoka A, Pisegna JM, Miloro KV, Lo M, Saito
H, Riquelme LF, LaValley MP, Langmore SE:
Prevention of healthcare-associated pneumonia
with oral care in individuals without mechanicalventilation: A systematic review and metaanalysis of randomized controlled trials. InfectControl Hosp Epidemiol, 36(8): 899-906, 2015
5. Nagata E, Haga N, Fujisawa Y, Fukami M,
Nishimura G, Ogata T: Femoral-tibial-digital
malformations in a boy with the Japanese founder
triplication of BHLHA9. Am J Med Genet Part A
167A(12): 3226-3228, 2015
6. Haga N, Kubota M, Miwa Z: Hereditary sensory
and autonomic neuropathy types IV and V in
Japan. Pediatr Int 57: 30-36, 2015
7. Nakahara Y, Suzuki R, Katagiri T, Toguchida J,
Haga N: Phenotypic differences of patients withfibrodysplasia ossificans progressiva due top.Arg258Ser variants of ACVR1. Human Genome
Variation 2; 15055, 2015

Surgical Sciences
3. Vital Care Medicine

251

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
Ryo Orii, M.D., Ph.D.

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.,

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

Jun Ninagawa, M.D.,

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

Miho Asahara, M.D., Ph.D.

Masaaki Asamoto, M.D., Yoshiomi Kusakabe, M.D., Ph.D., Kanae Nagatomo, M.D.,
Taro Kariya, M.D., Ph.D., Michiko Ushio, M.D.,

Yuriko Tashiro, M.D.,

Kazuhito Mietani, M.D.,

Atsuko Kato, M.D.,

Yuko Araki, M.D.,

Takuma Hiraiwa, M.D.,

Kayo Hirose, M.D., Ph.D.,

Miki Shinokawa, M.D.,

Yasuko Okagami, M.D.,

Takuya Ohata, 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 29 faculty staffs, 3 part time clinical staffs, 9graduate students and 13 residents. We introduce theactivities about Teaching, Research and Clinical workof 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 a252

daily basis in all areas of diseases accompanied with
pain. From April 2015 to March 2016, 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 hemorrhagic
shock

253

18) Mechanisms of chemotherapy-induced neuronal
dysfunction

Publications(1) Akasaka K, Tanaka T, Maruyama T, Kitamura N,
Hashimoto A, Ito Y, Watanabe H, Wakayama T,
Arai T, Hayashi M, Moriyama H, Uchida K,
Ohkouchi S, Tazawa R, Takada T, Yamaguchi E,
Ichiwata T, Hirose M, Arai T, Inoue Y, Kobayashi
H, Nakata K. A mathematical model to predict
protein wash out kinetics during whole-lunglavage in autoimmune pulmonary alveolar
proteinosis. Am J Physiol Lung Cell Mol Physiol.
2015 Jan 15;308(2):L105-17.
(2) Asahara M, Ito N, Yokomizo T, Nakamura M,
Shimizu T, Yamada Y. The absence of theleukotriene B4 receptor BLT1 attenuates
peripheral inflammation and spinal nociceptive
processing following intraplantar formalin injury.
Molecular Pain 2015 Mar 12;11:11(3) Kariya T, Ito N, Kitamura T, Yamada Y. Recovery
from Extreme Hemodilution (Hemoglobin Levelof 0.6 g/dl) in Cadaveric Liver Transplantation
Anesthesia and Analgesia Case report 2015 May
15;4(10):132-6.
(4) Obuchi M, Sumitani M, Shin M, Ishii K, Kogure
T, Miyauchi S, Yamada Y. Spinal cord stimulation
ameliorates neuropathic pain-related sleep
disorders: a case series. Neuromodulation 2015;
18: 191-3(5) Natori A, Ogata T, Sumitani M, Kogure T,
Yamauchi T, Yamauchi H. Potential role ofpNF-H, a biomarker of axonal damage in thecentral nervous system, as a predictive marker ofchemotherapy-induced cognitive impairment Clin
Caner Res 2015; 21: 1348-52(6) Suka M, Odajima T, Okamoto M, Sumitani M,
Igarashi A, Ishikawa H, Kusama M, Yamamoto M,
Nakayama T, Sugimori H. Relationship between
health literacy, health information access healthbehavior and health status in Japanese people.
Patient Education Counsel 2015; 98: 660-8(7) Yokota J, Fujiu K, Tanimoto H, Nebiya H,
Kashiwa K, Kinoshita O, Nawata K, Kimura M,
Stasu T, Chou K, Sumitani M, Ono M, Komuro I.
Electromagnetic
interference
betweencontinuous-flow left ventricular assist device andcardiac resynchronization therapy defibrillator
due to an unrecognized mechanism. Intl J Cardiol
2015; 179: 510-3(8) Sumitani M, Misaki M, Kumagaya S, Yozu A,
Otake Y, Osumi M, Miyauchi S. Internallyrepresented space and its mirror-reveresed imageof the visuospatial representation: a possible
association. Medical Hypotheses 2015; 85: 500-5(9) Osumi M, Sumitani M, Wake N, Sano Y, Ichinose
A, Kumagaya S, Kuniyoshi Y, Morioka S.
Structured movement representations of aphantom limb associated with phantom limb pain.
Neuroscience Letters 2015; 605: 7-11
(10) Matsubayashi Y, Takeshita K, Sumitani M,
Oshima Y, Tonosu J, Kato S, Ohya J, Oichi T,
Okamoto N, Tanaka S. Psychometric validationof the Japanese version of the Neuropathic Pain
Symptom Inventory. Plos One 2015; 10:e0143350

254

Department of Emergency andCritical Care Medicine
Professor
Naoki Yahagi, M.D.

Associate Professor
Susumu Nakajima, M.D.

Yoichi Kitsuta, M.D.

LecturerTakeshi Ishii, M.D.
Takehiro Matsubara,

Masataka Gunshin, M.D.
Yoshihiro Ueda, M.D.

M.D.Kent Doi, M.D.

Rei Ito, M.D.
Shota Den, M.D.
Ichiro Hirayama, M.D.

Akihide Kanazawa, M.D.
Miyuki Yamamoto, M.D.
Kohei Yoshimoto,M.D.

Yohei Komaru, M.D.
Takuya Sato, M.D.
Yoshihisa Miyamoto, M.D.

Keisuke Nyuunoya, M.D.
Masafumi Kaiume, M.D.

Associate
Takahiro Hiruma, M.D.
Motoko Hattori , M.D.
Tomohiro Sonoo, M.D.
Akinori Maeda, M.D.

Staff
Satoshi Iwai, M.D.
Hiromu Naraba, M.D.
Masaki Mochizuki, 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 Facilitiesof the University of Tokyo Hospital and at the sametime as the intensive care service for in-hospitalpatients, it became a tertiary emergency care andcritical care center in the metropolitan Tokyo and also
became the principal teaching facility of the
University of Tokyo. It is a designated Level I Trauma
Center, and also the home 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 andfull monitoring and resuscitation equipment. There are

9 treatment spaces including space for orthpedics,
gynecology, and Optho-ENT evaluations.
10overnight-stay monitored beds, X-ray, rapid spiral CT,
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
beds, high care unit (ICU2) of 24 beds, pediatricintensive care unit (PICU) of 6 beds and neonatal
intensive care unit (NICU) of 6 beds.
The Emergency Care Center and the Critical Care
Center see an excellent mix of multiple trauma,
high-acuity medical, surgical, pediatric, and gynecologic patients. The Life Flight service provides another255

opportunity for exposure to critically ill patients.
Consult services are available from all of the clinicaldepartments of the Medical School. The university ofTokyo hospital was officially designated as emergency
medical care center in December 2010.

Clinical activities
Our clinical activities are divided into four
categories as follows:
1) Emergency medicine
Our department is responsible for not only
tertiary emergency but also primary and secondary
emergency care on 24-hour-a-day basis. In the 2015,
we had about 5,126 ambulance patients out of total
16,400 ER outpatients.
The new ER, four times the size of the present
ER was built in November, 2006. The facility has 5
consultation rooms, 4 specialized consultation
rooms for dentistry, ophthalmology, otorhinolaryngology and gynecology, 2 resuscitation bays, 1
operating room and 4 observation beds.
2) Intensive care
Staff members specialized in internal medicine,cardiovascular medicine, orthopedic surgery,
surgery, neurosurgery or anesthesiology create “thesemi-closed ICU” model. We are responsible for theentire care of the critically ill patients (i.e. patientswith respiratory insufficiency such as ARDS, withsepsis, with MOF, with shock), post-operative
patients, and tertiary emergency patients, placing anemphasis on evidence-based medical therapy. We
had 2,300 ICU/CCU patients in the 2015. In 2007,
the number of beds in ICU/CCU increased to 16
and the facility included the 24 beds for the highcare ICU2.
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 areallocated to three types of wards, that is, generalward, ICU2 and ICU/CCU in accordance with theircritical condition. 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 andout-hospital disasters. In regard to in-hospital risk
management, including “code blue emergency”, weare responsible for patient safety on 24-hour/365day basis. And in regard to out-hospital risk
management, our hospital has been authorized by
the Tokyo Metropolitan Government as a disasterbase hospital, and also the Government hasrequested the formation of Disaster Medical
Assistant Team (DMAT) from us. We are now
proceeding with a drastic revision of in-hospitalmanual for disaster control, holding seminars on
disaster medicine, and enforcing the disastertraining. We have oxygen and medical suction
equipment on the passageways in the new ER since2006 fiscal year in case treating the large number ofdisaster patients.

Teaching activities
1) Six hours of lecture for the 2nd year medical
student, the topics include the prehospitalemergency care, the initial evaluation of emergency
patients, disaster medicine, serious infections
disease, and medical equipment. Four hours ofsimulation training of Basic Life Support.
2) One month of elective clinical clerkship for the 3rdyear. ACLS Basic course (ICLS) and 1 day Hospital
MIMMS (Major Incident Medical Management andSupport) course are held for the participants in theclinical clerkship program, and successful
completion of each course will enable students to becertified as the provider .
3) 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
learning a ACLS course, students experience thereal practice of emergency medicine as fellow
passengers in the ambulance and as 2.5-day trainees
in affiliated hospitals’ emergency centers.
In conformity with the guideline by Ministry of
Health, Labour and Welfare, all residents learn andpractice emergency medicine and primary care at
every level, primary, secondary and tertiary. The
residents are trained in the ACLS Basic (ICLS)
during resident year to obtain the knowledge andskills in CPR.

256

Junior residents are also assigned to ICU services
to gain the knowledge of intensive care from
pathophysiological and internal medicine’s point ofview.
In the senior resident program in 2006, we willtrain the new residents to be skilled in advanced
critical care medicine including primary caretrauma, MOF, shock, and equipment support.
As medical aspects of disaster management, we
provide the residents with lectures based on
MIMMS (Major Incident Medical Management andSupport) program, triage training, and risk
communication techniques using wireless network.
In addition, we produce the seminar for nurses suchas medical support in the big earthquake.

Research activities
We investigate the pathophysiology of sepsis andsepsis-related conditions including ARDS by using
several different animal models (cecal lingation andpuncture, histone injection, etc).
Several clinical studies that evaluated the utility of
new biomarkers in ICU population have been
conducted. In addition, we performed health care cost
analysis on out-of-hospital cardiopulmonary arrest byusing the Japanese Diagnosis Procedure Combination
database, which is the largest clinical database inJapan.

References
1. Wada T, Yasunaga H, Inokuchi R, Horiguchi H,
Fushimi K, Matsubara T, Nakajima S, Yahagi N.
Relationship between hospital volume and earlyoutcomes in acute ischemic stroke patients treatedwith recombinant tissue plasminogen activator.
Int J Stroke 2015 Jan; 10(1): 73-8. doi: 10.1111/ijs.
12311. Epub 2014 Jul 18.
2. Fujita D, Takahashi M, Doi K, Abe M, Tazaki J,
Kiyosue A, Myojo M, Ando J, Fujita H, Noiri E,
Sugaya T, Hirata Y, Komuro I. Response ofurinary liver-type fatty acid-binding protein tocontrast media administration has a potential topredict one-year renal outcome in patients withischemic heart disease. Heart Vessels 2015 May;30(3): 296-303. doi:10.1007/s00380-014-0484-9.
Epub 2014 Feb 20

3. Fukuda K, Doi K, Yahagi N. Effective pre-hospitalcare for out-of-hospital cardiac arrest caused byrespiratory disease. Heart, Lung and Circulation
2015 March; 24 (3): 241-249. doi: 10.1016/j.hlc.
2014.09.004. Epub 2014 Sep 28.
4. Fukuda T, Nakamura K, Fukuda-Ohashi N, Yahagi
N. How long should resuscitative efforts becontinued in adult out-of-hospital cardiac arrest?
Can J Cardiol 2015 Mar; 31(3): 364.e1-2. doi:
10.1016/j.cjca.2014.11. 028. Epub 2014 Dec 3.
5. 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 2015 April; 30 (2): 381-385.
doi:10.1016/j.jcrc.2014.11.003.
6. Ebisawa K, Fukuda T, Inokuchi R, Nakamura K.
Recombinant thrombomodulin monotherapy forsecondary thrombotic thrombocytopenic purpura.
Am J Emerg Med 2015 Apr; 33(4):599.e1-3. doi:
10.1016/j.ajem.2014.08.076. Epub 2014 Sep 6.
Review.
7. Imamura T, Kinugawa K, Doi K, Hatano M, Fujino
T, Kinoshita O, Nawata K, Noiri E, Kyo S, Ono M.
Plasma neutrophil gelatinase-associated lipocalin
and worsening renal function during everolimus
therapy after heart transplantation. Int Heart J
2015; 56(1): 73-9. doi: 10.1536/ihj.14-179. Epub
2014 Dec 24.
8. Inokuchi R, Ohashi N, Nakamura K, Wada T,
Gunshin M, Kitsuta Y, Nakajima S, Yahagi N.
Comparison of intranasal and intravenous
diazepam on status epilepticus in elderly stroke
patients: a retrospective cohort study. Medicine
2015 Feb; 94 (7): e555. doi: 10.1097/MD.0000000
000000555.
9. 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 Transplant2015 Mar 19. pii: gfv069. [Epub ahead of print]
10. Shimizu K, Doi K, Imamura T, Noiri E, Yahagi N,
Nangaku M, Kinugawa K. Ratio of urine and bloodurea nitrogen concentration predicts the response

257

of tolvaptan in congestive heart failure.
Nephrology (Carlton) 2015 Jun; 20(6): 405-12.
doi: 10.1111/nep.12406.
11. Ohashi-Fukuda N, Inokuchi R, Sato H, Nakamura
K, Iwagami M, Wada T, Jona M, Hisasue T,
Nakajima S, Yahagi N. Poorer prognosis with
ethylenediaminetetraacetic acid-dependent pseudothrombocytopenia: a single-center cohort study.
Medicine 2015 Apr; 94(15): e674. doi: 10.1097/
MD. 0000000000000674.
12. 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. 2015
Feb 2. pii: JASN.2014080750. [Epub ahead ofprint]
13. Fukuda T, Ohashi N, Matsubara T, Yahagi N. The
contributions of emergency physicians to out-ofhospital cardiopulmonary arrest: an analysis of thenational Utstein Registry data. J Emerg Med 2015
Apr; 48(4):e81-92. doi: 10.1016/j.jemermed.2014.
09.053. Epub 2015 Jan 22.
14. Inokuchi R, Ueda Y, Sonoo T, Yahagi N. Toxic
shock syndrome. BMJ Case Rep 2015 Apr 15;
2015. pii: bcr2015209635. doi: 10.1136/bcr-2015209635.
15. Inokuchi R, Hatano T, Fukuda N, Yamaguchi T,
Nakajima S, Yahagi N. Noninfectious funiculitis.
J Emer Med 2015; 49:e33-4. 2015 Apr 21. pii:
S0736- 4679(15)00128-6. doi: 10.1016/ j.
jemermed. 2015.02.001. [Epub ahead of print].
16. Inokuchi R, Ohashi-Fukuda N, Nakamura K, Wada
T, Gunshin M, Kitsuta Y, Nakajima S, Yahagi N.
Comparison of intranasal and intravenous
diazepam on status epilepticus in stroke patients.
Medicine 2015 Feb; 94(7): e555. doi:10.1097/MD.
0000000000000555.
17. Kishino F, Inokuchi R, Komaru Y, Takaya N,
Yamamoto M, Nakajima S, Yahagi N. A healthy
young woman with massive hemorrhagic ascites.
Am J Emer Med 2015 April 24: http://dx.doi.org/
10.1016/j.ajem. 2015.04.039
18. Ono Y, Ishida T, Iwasaki Y, Kawakami Y,
Inokuchi R, Tase C, Shinohara K. The off-hour
effect on trauma patients requiring subspecialty
intervention at a community hospital in Japan: aretrospective cohort study. Scand J Trauma Resus
Emerg Med 2015 Feb 10; 23:20. doi: 10.1186/
s13049-015-0095-1.
19. Inokuchi R, Ohshima K, Yamamoto M, Fukuda T,
Nakamura K. Crowned dens syndrome. Spine J
2015 Jun 1; 15(6): 1499-500. doi: 10.1016/ j.
spinee.2015.03. 022. Epub 2015 Mar 20.
20. Ono Y, Okubo Y, Hashimoto K, Inokuchi R,
Odajima H, Tase C, Shinohara K. Massive
subcutaneous emphysema, bilateral pneumothorax,
pneumomediastinum,
pneumoperitoneum,
pneumoretroperitoneum, and pneumoscrotum
after multiple direct laryngoscopies: an autopsy
case report. J Anesth 2015 Mar 18. [Epub ahead ofprint]
21. Yasuda M, Inokuchi R, Ohshima K, Yamamoto M,
Tokunaga K, Fukuda T, Nakamura K. Linezolid isa novel and effective treatment for septic
pulmonary embolism. Am J Emerg Med 2015 Jul;33(7):988.e3-4. doi: 10.1016/j.ajem. 2014.12.035.
Epub 2015 Jan 6.
22. Sonoo T, Nakamura K, Ando T, Sen K, Maeda A,
Kobayashi E, Sakuma I, Doi K, Nakajima S,
Yahagi N. Prospective analysis of cardiac
collapsibility of inferior vena cava (IVC) using
ultrasonography. J Crit Care 2015 May 10. pii:
S0883-9441(15)00272-5. doi: 10.1016/ j.jcrc.2015.
04.124. [Epub ahead of print]
23. 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 2015 Jun; 20(6):405-12. doi: 10.1111/
nep.12406
24. 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
gelatinase-associated lipocalin predicts major
adverse cardiovascular events after cardiac careunit discharge. J Cardiol 2015 Jul 27. pii:
S0914-5087(15)00160-4. doi: 10.1016/j.jjcc.2015.
05.010. [Epub ahead of print]
25. Shigemura J, Harada N, Tanichi M, Nagamine M,
Shimizu K, Katsuda Y, Tokuno S, Tsumatori G,
Yoshino A. Rumor-Related and Exclusive
Behavior Coverage in Internet News Reports
Following the 2009 H1N1 Influenza Outbreak in258Japan. Disaster Med Public Health Prep 2015 Aug;9(4): 459-63. doi: 10.1017/ dmp.2015.57.
26. Hamaya R, Ono Y, Chida Y, Inokuchi R,
Kikuchi K, Tameda T, Tase C, Shinohara K.
Polytetrafluoroethylene fume-induced pulmonary
edema: a case report and review of the literature. J
Med Case Rep 2015, 9:111.
27. Asada T, Aoki Y, Sugiyama T, Yamamoto M, Ishii
T, Kitsuta Y, Nakajima S, Yahagi N, Doi K. Organsystem network disruption in non-survivor of
critically ill patients. Crit Care Med 2015 Oct 22.
[Epub ahead of print], 2015. 2016 Jan; 44 (1):83-90.
28. Inokuchi R, Sato H, Iwagami M, Komaru Y, Iwai S,
Gunshin M, Nakamura K, Shinohara K, Kitsuta Y,
Nakajima S, Yahagi N. Impact of a new medical
record system for emergency departments designed
to accelerate clinical documentation: a crossoverstudy. Medicine 2015; 94:e856.
29. Wada T, Yasunaga H, Inokuchi R, Matsui H,
Horiguchi H, Fushimi K, Matsubara T, Nakajima S,
Yahagi N. Effectiveness of surgical rib fixation on
prolonged mechanical ventilation in patients withtraumatic rib fractures: A propensity-score matchedanalysis. J Crit Care 2015; 30(6):1227-31.
30. Sonoo T, Inokuchi R, Yamamoto M, Nakamura K,
Nakajima S, Yahagi N. Severe hemorrhage fromcervical cancer managed successfully by Foley
catheter balloon tamponade. West J Emerg Med2015 Sep; 16:793-4.
31. 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) 2015 Oct
19. doi: 10.1111/nep.12656. [Epub ahead of print]
32. Wada T, Nakahara S, Bounta B, Phommahaxay K,
Phonelervong V, Phommachanh S, Mayxay M,
Manivong T, Phoutsavath P, Ichikawa M, Kimura
A. Road traffic injury among child motorcyclists in
Vientiane Capital, Laos: a cross-sectional study
using a hospital-based injury surveillance database.
Intern J Injury Cont Safety Prom 2015 Sep 01. Doi:
10.1080/17457300.2015.1080728.
33. Fukuda T, Ohashi-Fukuda N, Matsubara T, Doi K,
Kitsuta Y, Nakajima S, Yahagi N. Trends inoutcomes for out-of-hospital cardiac arrest by age

in Japan: an observational study. Medicine 2015
Dec; 94(49): e2049. Doi: 10.1097/MD. 000000000
0002049.
34. 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 2015 Published online
before print December 15, 2015, doi: 10.1161/
STROKEAHA.115.011250.

Health Sciences and Nursing
1. Health Sciences

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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, 9 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.

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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., 2015)
1. GBD 2013 DALYs and HALE Collaborators.
Global, regional, and national disability-adjusted
life years (DALYs) for 306 diseases and injuries
and healthy life expectancy (HALE) for 188
countries, 1990-2013: quantifying the epidemiological transition. Lancet. 2015 Aug 27. [Epubahead of print].
2. GBD 2013 Mortality and Causes of Death
Collaborators. Global, regional, and national
age-sex specific all-cause and cause-specificmortality for 240 causes of death, 1990-2013: asystematic analysis for the Global Burden of
Disease Study 2013. Lancet. 2015 Jan 10;385(9963):117-71. Epub 2014 Dec 18.
3. GBD 2013 Risk Factors Collaborators. Global,
regional, and national comparative risk
assessment of 79 behavioural, environmental andoccupational, and metabolic risks or clusters ofrisks in 188 countries, 1990-2013: a systematic
analysis for the Global Burden of Disease Study
2013. Lancet. 2015 Sep 10. [Epub ahead of print].
4. Global Burden of Disease Study 2013
Collaborators. Global, regional, and national
incidence, prevalence, and years lived withdisability for 301 acute and chronic diseases andinjuries in 188 countries, 1990-2013: a systematic
analysis for the Global Burden of Disease Study
2013. Lancet. 2015 Jun 7. [Epub ahead of print].
5. Hayasaka Y, Furukawa TA, Sozu T, Imai H,
Kawakami N, Horikoshi M. Enthusiasm forhomework and improvement in subthresholddepression during behavior therapy: Secondary

analysis of data from a randomized controlled
trial. BMC Psychiatry. 2015; 15: 302.
6. 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. 2015 Dec
1. [Epub ahead of print].
7. Imamura K, Kawakami N, Furukawa T,
Matsuyama Y, Shimazu A, Umanodan R, et al.
Effects of an Internet-Based Cognitive Behavioral
Therapy Intervention on Improving WorkEngagement and Other Work-Related Outcomes:
An Analysis of Secondary Outcomes of a
Randomized Controlled Trial. J Occup Environ
Med. 2015; 57(5): 578-84 .
8. Imamura K, Kawakami N, Furukawa TA,
Matsuyama Y, Shimazu A, Kasai K. Effects of aninternet-based cognitive behavioural therapy
intervention on preventing major depressive
episodes among workers: a protocol for arandomised controlled trial. BMJ Open. 2015; 5:e007590.
9. Imamura K, Kawakami N, Furukawa TA,
Matsuyama Y, Shimazu A, Umanodan R, et al.
Does Internet-based cognitive behavioral therapy(iCBT) prevent major depressive episode forworkers? A 12-month follow-up of a randomized
controlled trial. Psychological medicine. 2015;45(9): 1907-17.
10. Imamura K, Kawakami N, Naganuma Y, Igarashi
Y. Development of Screening Inventories for
Bipolar Disorder at Workplace: a diagnostic
accuracy study. J Affect Disord. 2015; 178: 32–8.
11. Inoue A, Kawakami N, Eguchi H, Miyaki K,
Tsutsumi A. Organizational Justice andPhysiological Coronary Heart Disease Risk
Factors in Japanese Employees: a Cross-Sectional
Study. Int J Behav Med. 2015; 22(6): 775-85.
12. Ishikawa H, Kawakami N, Kessler RC; World
Mental Health Japan Survey Collaborators.
Lifetime and 12-month prevalence, severity andunmet need for treatment of common mental
disorders in Japan: results from the final dataset ofWorld Mental Health Japan Survey. Epidemiol
Psychiatr Sci. 2015 Jul 7:1-13. [Epub ahead ofprint].

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13. 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. 2015 Nov 19. pii: bjp.bp.114.156265.
[Epub ahead of print].
14. Kan C, Kawakami N, Umeda M, Miller E; World
MentalHealthJapan
SurveyGroup
2002?2006.Childhood adversities and adult use of
potentially injurious physical discipline in Japan.
J Fam Violence. 2015; 30(4): 515-527.
15. Kanehara A, Umeda M, Kawakami N; World
Mental Health Japan Survey Group. Barriers tomental health care in Japan: Results from theWorld Mental Health Japan Survey. Psychiatry
Clin Neurosci. 2015; 69(9): 523-33.
16. Kawasaki S, Nishimura Y, Takizawa R, Koike S,
Kinoshita A, Satomura Y, Sakakibara E, Sakurada
H, Yamagishi M, Nishimura F, Yoshikawa A, Inai
A, Nishioka M, Eriguchi Y, Kakiuchi C, Araki T,
Kan C, Umeda M, Shimazu A, Hashimoto H,
Kawakami N, Kasai K. Using social epidemiology
and neuroscience to explore the relationshipbetween job stress and frontotemporal cortex
activity among workers. Soc Neurosci. 2015;10(3): 230-42.
17. Kitayama S, Park J, Boylan JM, Miyamoto Y,
Levine CS, Markus HR, Karasawa M, Coe CL,
Kawakami N, Love GD, Ryff CD. Expression ofanger and ill health in two cultures: an
examination of inflammation and cardiovascularrisk. Psychol Sci. 2015; 26(2): 211-20.
18. Miki T, Kochi T, Eguchi M, Kuwahara K,
Tsuruoka H, Kurotani K, Ito R, Akter S, Kashino I,
Pham NM, Kabe I, Kawakami N, Mizoue T, Nanri
A. Dietary intake of minerals in relation todepressive symptoms in Japanese employees: the
Furukawa Nutrition and Health Study. Nutrition.
2015; 31(5): 686-90
19. Miki T, Kochi T, Kuwahara K, Eguchi M,
Kurotani K, Tsuruoka H, et al. Dietary patterns
derived by reduced rank regression (RRR) anddepressive symptoms in Japanese employees: the
Furukawa Nutrition and Health Study. Psychiatry
Research. 2015; 229(1-2): 214-9.

20. Miyaki K, Song Y, Suzuki T, Eguchi H,
Kawakami N, Takahashi M, Shimazu A, Inoue A,
Kurioka S, Kan C, Tsutsumi A. DNA Methylation
Status of the Methylenetetrahydrofolate Reductase Gene is associated with Depressive
Symptoms in Japanese Workers: A CrossSectional Study. Journal of Neurology and Neurological Disorders. 2015.
21. Nakagawa Y, Inoue A, Kawakami N, Tsuno K,
Tomioka K, Nakanishi M, et al. Change inorganizational justice and job performance inJapanese employees: a prospective cohort study. J
Occup Health. 2015;57(4):388-93.
22. Ryff CD, Miyamoto Y, Boylan JM, Coe CL,
Karasawa M, Kawakami N, Kan C, Love GD,
Levine C, Markus HR, Park J, Kitayama S.
Culture, inequality, and health: evidence from the
MIDUS and MIDJA comparison. Cult Brain.
2015; 3(1): 1-20.
23. Shimazu A, Schaufeli W, Kamiyama K,
Kawakami N. Workaholism vs. Work Engagement: the Two Different Predictors of Future
Well-being and Performance. IntJ Behav Med.
2015; 22(1): 18-23.
24. Stickley A, Koyanagi A, Kawakami N; WHO
World Mental Health Japan Survey Group.
Childhood adversities and adult-onset chronic
pain: Results from the World Mental Health
Survey, Japan. Eur J Pain. 2015; 19(10): 1418-27.
25. Suzuki T, Miyaki K, Song Y, Tsutsumi A,
Kawakami N, Shimazu A, Takahashi M, Inoue A,
Kurioka S. Relationship between sicknesspresenteeism (WHO-HPQ) with depression andsickness absence due to mental disease in a cohortof Japanese workers. J Affect Disord. 2015; 180:
14-20.
26. Takano A, Miyamoto Y, Kawakami N, Matsumoto
T. A study of therapeutic attitudes towards
working with drug abusers: Reliability andvalidity of the Japanese version of the Drug andDrug Problems Perception Questionnaire.
Archives of Psychiatric Nursing. 2015; 29(5):302–308.
27. Tsuno K, Kawakami N. Multifactor leadershipstyles and new exposure to workplace bullying: a
six-month prospective study. Industrial health.
2015; 53(2): 139-51.

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28. Tsuno K, Kawakami N, Tsutsumi A, Shimazu A,
Inoue A, Odagiri Y, et al. Socioeconomic
determinants of bullying in the workplace: anational representative sample in Japan. PloS one.
2015; 10(3): e0119435.
29. Umeda M, Kawakami N, Kessler RC, Miller E;
World Mental Health Japan Survey Group
2002–2006. Childhood adversities and adult useof potentially injurious physical discipline inJapan. J Fam Violence. 2015; 30(4): 515-527.
30. Umeda M, McMunn A, Cable N, Hashimoto H,
Kawakami N, Marmot M. Does an advantageous
occupational position make women happier incontemporary Japan? Findings from the JapaneseStudy of Health, Occupation, and Psychosocial
Factors Related Equity (J-HOPE). SSM Population Health. 2015; 1: 8-15.
31. Watanabe K, Otsuka Y, Inoue A, Sakurai K, Ui A,
Nakata A. Interrelationships between job
resources, vigor, exercise habit, and serum lipids
in Japanese employees: a multiple group pathanalysis using medical checkup data. Int J Behav
Med. 2015; Oct 16.[Epub ahead of print].

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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
Kosuke Kashiwabara, M.S., Tomohiro Shinozaki, M.P.H.

Project Research Associate
Akiko Harada, Ph.D.

Homepage

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

Introduction and Organization
The Department of Epidemiology and Biostatistics
changed the name from “Epidemiology” in 1992 andhas responsibility for providing educational courses
on epidemiology and biostatistics to undergraduate
students as well as graduate ones. As compared to thesituation in the United States, the education ofbiostatistics and methodological aspects of epidemiology is poor in Japanese universities and graduate
schools, although the necessity for collaboration withbiostatisticians in clinical research (especially clinical
trials) is recently being to be claimed by clinicalresearchers and pharmaceutical industry. One missionof our educational courses is to provide detailed
knowledge and experiences in biostatistics/
epidemiology to students who are expected to takepart in clinical/epidemiological research as experts
and the other mission is to provide basic principles ofbiostatistics/epidemiology to students who will workin many health-related fields including nursing. Our
main research project is the development ofmethodology for clinical/epidemiological research andit requires keeping touch with real clinical/

epidemiological problems. For these purposes andresearch coordination, a non-profit organization titled‘The Japan Clinical Research Support Unit’ wasestablished by the faculty members in 2001, and theorganization is providing research support in design,
data management and statistical analysis in many
projects inside/outside the university.
The faculty of the department provided lecturesin a series of educational courses organized by ‘The
Clinical Bioinformatics Research Unit’ in 2002-2007.

Teaching activities
1. Undergraduate Courses
1) Epidemiology and Biostatistics (2 credits)
2) Applied Mathematics (2 credits)
3) Statistical Methods and Information Processing(2 credits, practice)4) Design and Analysis of EpidemiologicalResearch (2+1 credits, 1 practice)5) Medical Data Analysis (2 credits)
6) Biostatistics(2 credits; for the School of Medicine)
2. School of Public Health

2651) Statistical Analysis of Medical Research(2 credits)
2) Practice of Biostatistics (2 credits)3) Design of Medical Research (2 credits)
3. Graduate Courses
1) Biostatistics (4 credits)
2) Epidemiology and Preventive Health Sciences(4 credits)
3) Introduction to Medical Statistics(2 credits; for the School of Medicine)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 have been supporting some of the above
collaborative clinical/epidemiologic studies throughthe Japan Clinical Research Support Unit, a non-profit
organization which aims to support investigatorinitiated studies and to provide education toresearchers and support staffs.
We are also officially conducting a consultation
for design and analysis of clinical trials assisted by theClinical Research Support Center of the University ofTokyo Hospital.

References
1. Fukushima A, Kinugawa S, Homma T, Masaki Y,
Furihata T, Yokota T, Matsushima S, Takada S,
Kadoguchi T, Oba K, Okita K, Tsutsui H. Serum
Brain-Derived Neurotrophic Factor Level Predicts
Adverse Clinical Outcomes in Patients with Heart
Failure. J Card Fail 2015; 21(4):300-6..
2. Kobayashi Y, Komatsu Y, Yuki S, Fukushima H,
Sasaki T, Iwanaga I, Uebayashi M, Okuda H,
Kusumi T, Miyagishima T, Sogabe S, Tateyama M,
Hatanaka K, Tsuji Y, Nakamura M, Konno J,
Yamamoto F, Onodera M, Iwai K, Sakata Y, Abe
R, Oba K, Sakamoto N. Randomized controlled
trial on the skin toxicity of panitumumab inJapanese patients with metastatic colorectal
cancer: HGCSG1001 study; J-STEPP. Future
Oncol 2015;11:617-27.
3. Shinohara N, Obara W, Tatsugami K, Naito S,
Kamba T, Takahashi M, Murai S, Abe T, Oba K,
Naito S. Prognosis of Japanese patients withpreviously untreated metastatic renal cell
carcinoma in the era of molecular-targeted therapy.
Cancer Sci. 2015 Feb 25. doi: 10.1111/cas.12646.
4. Murai K, Akagi T, Shimosegawa K, Sugawara T,
Ishizawa K, Ito S, Murai K, Motegi M, Yokoyama
H, Noji H, Tajima K, Kimura J, Chou T, Ogawa K,
Harigae H, Kubo K, Oba K, Sakamoto J, Ishida Y.
A prospective analysis of clinical efficacy andsafety in chronic myeloid leukemia-chronic phasepatients with imatinib resistance or intolerance asevaluated using European LeukemiaNet 2013
criteria. Eur J Haematol. 2015 Feb 19. doi: 10.
1111/ejh.12536.
5. Buyse M, Molenberghs G, Paoletti X, Oba K,
Alonso A, Van der Elst W, Burzykowski T.
Statistical evaluation of surrogate endpoints with
examples from cancer clinical trials. Biom J. 2015
Feb 12. doi: 10.1002/bimj.201400049.
6. Komatsu Y, Okita K, Yuki S, Furuhata T,
Fukushima H, Masuko H, Kawamoto Y, Isobe H,
Miyagishima T, Sasaki K, Nakamura M, Ohsaki Y,
Nakajima J, Tateyama M, Eto K, Minami S,
Yokoyama R, Iwanaga I, Shibuya H, Kudo M,
Oba K, Takahashi Y. An open-label, randomized,

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comparative, phase III study on effects ofreducing steroid use in combination with
Palonosetron. Cancer Sci 2015;106:891-5.
7. Iwamoto S, Takahashi T, Tamagawa H, Nakamura
M, Munemoto Y, Kato T, Hata T, Denda T, Morita
Y, Inukai M, Kunieda K, Nagata N, Kurachi K,
Ina K, Ooshiro M, Shimoyama T, Baba H, Oba K,
Sakamoto J, Mishima H. FOLFIRI plus
bevacizumab as second-line therapy in patientswith metastatic colorectal cancer after first-line
bevacizumab plus oxaliplatin-based therapy: therandomized phase III EAGLE study. Ann Oncol
2015 Apr 23.
8. Sakuhara Y, Nishio S, Morita K, Abo D,
Hasegawa Y, Yuasa N, Mochizuki T, Soyama T,
Oba K, Shirato H, Kudo K. Transcatheter Arterial
Embolization with Ethanol Injection in
Symptomatic Patients with Enlarged Polycystic
Kidneys. Radiology 2015:141637.
9. Jinnouchi H, Kuramitsu S, Shinozaki T,
Kobayashi Y, Hiromasa T, Morinaga T, Mazaki T,
Sakakura K, Soga Y, Hyodo M, Shirai S, Ando K.
Two-year clinical outcomes of newer-generation
drug-eluting
stent
implantation
followingrotational atherectomy for heavily calcified
lesions. Circ J. 2015;79(9):1938-43.
10. Abe Y, Kawakami H, Oba K, Hayashi T, Yasuda I,
Mukai T, Isayama H, Ishiwatari H, Doi S,
Nakashima M, Yamamoto N, Kuwatani M,
Mitsuhashi T, Hasegawa T, Hirose Y, Yamada T,
Tanaka M, Sakamoto N; Japan EUS-FNA Stylet
Study Group. Effect of a stylet on a histological
specimen in EUS-guided fine-needle tissue
acquisition by using 22-gauge needles: amulticenter, prospective, randomized, controlled
trial. Gastrointest Endosc 2015;82:837-844.
11. Kotaka M, Yoshino T, Oba K, Shinozaki K,
Touyama T, Manaka D, Matsui T, Ishigure K,
Hasegawa J, Inoue K, Goto K, Sakamoto J, Saji S,
Ohtsu A, Watanabe T. Initial safety report on thetolerability of modified FOLFOX6 as adjuvant
therapy in patients with curatively resected stage
II or III colon cancer (JFMC41-1001-C2: JOIN
trial). Cancer Chemother Pharmacol 2015;76:7584.
12. Matsushima M, Yabe I, Oba K, Sakushima K,
Mito Y, Takei A, Houzen H, Tsuzaka K, Yoshida

K, Maruo Y, Sasaki H. Comparison of Different
Symptom Assessment Scales for Multiple System
Atrophy. Cerebellum. 2015 Jun 21.
13. Tada N, Kawai K, Tsuno NH, Ishihara S,
Yamaguchi H, Sunami E, Kitayama J, Oba K,
Watanabe T. Prediction of the preoperative
chemoradiotherapy response for rectal cancer by
peripheral blood lymphocyte subsets. World J
Surg Oncol 2015;13:30
14. Kuramitsu S, Hiromasa T, Enomoto S, Shinozaki
T, Iwabuchi M, Mazaki T, Domei T, Yamaji K,
Soga Y, Hyodo M, Shirai S, Ando K. Incidence
and clinical impact of stent fracture after the
PROMUS
element
platinum
chromium
everolimus-eluting stent implantation. JACC
Cardiovasc Interv. 2015;8(9):1180-8.
15. Sugimoto T, Umeda M, Shinozaki T, Naruse T,
Miyamoto Y. Sources of perceived social support
associated with reduced psychological distress at
one year after the Great East Japan Earthquake: A
nationwide cross-sectional survey in 2012.
Psychiatry Clin Neurosci. 2015; 69(9):580–586.
16. Taniguchi Y, Fujiwara Y, Nofuji Y, Nishi M,
Murayama H, Seino S, Tajima R, Matsuyama Y,
Shinkai S. Prospective Study of Arterial Stiffness
and Subsequent Cognitive Decline Among
Community-Dwelling
Older
Japanese.
J
Epidemiol. 2015 Aug 1 [cited 2015 August 3].
Availablefrom:https://www.jstage.jst.go.jp/
article/jea/advpub/0/advpub_JE20140250/_article[Epub ahead of print].
17. Kawashima M, Murakawa T, Shinozaki T,
Ichinose J, Hino H, Konoeda C, Tsuchiya T,
Murayama T, Nagayama K, Nitadori JI, Anraku M,
Nakajima J. Significance of the Glasgow
Prognostic Score as a prognostic indicator forlung cancer surgery. Interact Cardiovasc Thorac
Surg. 2015;21(5):637-43.
18. Shinozaki T, Matsuyama Y. Doubly robust
estimation of standardized risk difference andratio in the exposed population. Epidemiology.
2015;26(6):873-7.
19. Fujimoto S, Kondo T, Kumamaru KK, Shinozaki
T, Takamura K, Kawaguchi Y, Matsumori R, Hiki
M, Miyauchi K, Daida H, Rybicki FJ. Prognostic
value of coronary computed tomography (CT)angiography and coronary artery calcium score

267

performed before revascularization. J Am Heart
Assoc. 2015;4(8);e002264.
20. Saitoh A, Saitoh A, Sato I, Shinozaki T, Nagata S.
Current practices and needs regarding perinatal
childhood immunization education for Japanesemothers. Vaccine. 2015;33(45):6128-33.
21. Fujimoto S, Kondo T, Takamura K, Baber U,
Shinozaki T, Nishizaki Y, Kawaguchi Y,
Matsumori R, Hiki M, Miyauchi K, Daida H,
Hecht H, Stone GW, Narula J. Incremental
prognostic value of coronary computed tomographic angiography high-risk plaque characteristics in newly symptomatic patients. J Cardiol.
2016; 67:538-44.
22. Utsunomiya T, Shimada M, Kudo M, Ichida T,
Matsui O, Izumi N, Matsuyama Y, Sakamoto M,
Nakashima O, Ku Y, Takayama T, Kokudo N;
Liver Cancer Study Group of Japan. A comparisonof the surgical outcomes among patients with
HBV-positive, HCV-positive, and non-B non-C
hepatocellular carcinoma: a nationwide study of
11,950 patients. Annals of Surgery 2015; 261(3):513-520.
23. Imamura K, Kawakami N, Furukawa TA,
Matsuyama Y, Shimazu A, Umanodan R,
Kawakami S, Kasai K. Effects of an internetbased cognitive behavioral therapy intervention
on improving work engagement and otherwork-related outcomes: an analysis of secondary
outcomes of a randomized controlled trial. Journalof Occupational and Environmental Medicine
2015; 57(5): 578-584.
24. Kimura T, Deshpande GA, Urayama KY, Masuda
K, Fukui T, Matsuyama Y. Association of weightgain since age 20 with non-alcoholic fatty liverdisease in normal weight individuals. Journal of
Gastroenterology and Hepatology 2015; 30(5):909-917.
25. Kokudo N, Hasegawa K, Akahane M, Igaki H,
Izumi N, Ichida T, Uemoto S, Kaneko S,
Kawasaki S, Ku Y, Kudo M, Kubo S, Takayama T,
Tateishi R, Fukuda T, Matsui O, Matsuyama Y,
Murakami T, Arii S, Okazaki M, Makuuchi M.
Evidence-based Clinical Practice Guidelines for
Hepatocellular Carcinoma: The Japan Society of
Hepatology 2013 update (3rd JSH-HCC
Guidelines). Hepatology Research 2015; 45(2):123-127.
26. 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, Matsuyama
Y, Nanto S; J-DESsERT investigators. Outcomesof the largest multi-center trial stratified by thepresence of diabetes mellitus comparing
sirolimus-eluting stents (SES) and paclitaxeleluting stents (PES) in patients with coronary
artery disease. The Japan drug-eluting stents
evaluation: a randomized trial (J-DESsERT).
Cardiovascular Intervention and Therapeutics
2015; 30(2): 103-114.
27. Imamura K, Kawakami N, Furukawa TA,
Matsuyama Y, Shimazu A, Kasai K. Effects of aninternet-based cognitive behavioural therapy
intervention on preventing major depressive
episodes among workers: a protocol for arandomised controlled trial. BMJ Open 2015;
5(5): e007590.
28. Takao T, Kimura K, Suka M, Yanagisawa H,
Kikuchi M, Kawazu S, Matsuyama Y.
Relationships between the risk of cardiovasculardisease in type 2 diabetes patients and both
visit-to-visit variability and time-to-effectdifferences in blood pressure. Journal of Diabetes
and Its Complications 2015; 29(5): 699-706.
29. Ng CF, Matsuyama Y, and Ohashi Y. Case-only
method to estimate the relative incidence ofadverse events for comparison of two treatments:
Application in disseminated intravascular
coagulation patients. Japanese Journal of
Biometrics 2015; 36: 13-24.
30. Gotoda T, Ishikawa H, Ohnishi H, Sugano K,
Kusano C, Yokoi C, Matsuyama Y, Moriyasu F.
Randomized controlled trial comparing gastriccancer screening by gastrointestinal X-ray withserology for Helicobacter pylori and pepsinogens
followed by gastrointestinal endoscopy. Gastric
Cancer 2015; 18(3): 605-611.
31. Zhu Y, Matsuyama Y, Ohashi Y, and Setoguchi S.
When to conduct probabilistic linkage vs.
deterministic linkage? : A simulation study.
Journal of Biomedical Informatics 2015; 56:
80-86.

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32. Kokudo T, Hasegawa K, Uldry E, Matsuyama Y,
Kaneko J, Akamatsu N, Aoki T, Sakamoto Y,
Demartines N, Sugawara Y, Kokudo N, Halkic N.
A new formula for calculating standard liver
volume for living donor liver transplantation
without using body weight. Journal of Hepatology
2015; 63(4): 848-854.
33. Ishiguro N, Koseki N, Kaiho M, Kikuta H,
Togashi T, Oba K, Morita K, Nagano N,
Nakanishi M, Hazama K, Watanabe T, Sasaki S,
Horino A, Kenri T, Ariga T; Hokkaido PediatricRespiratory Infection Study Group. Regional
Differences in Rates of Macrolide-Resistant
Mycoplasma pneumoniae in Hokkaido, Japan. Jpn
J Infect Dis. 2015 Jul 10. [Epub ahead of print]
34. Nomoto H, Miyoshi H, Furumoto T, Oba K,
Tsutsui H, Miyoshi A, Kondo T, Tsuchida K,
Atsumi T, Manda N, Kurihara Y, Aoki S; SAIS
Study Group. A Comparison of the Effects of the
GLP-1 Analogue Liraglutide and Insulin Glargine
on Endothelial Function and Metabolic
Parameters: A Randomized, Controlled Trial
Sapporo Athero-Incretin Study 2 (SAIS2). PLoS
One. 2015 Aug 18;10(8):e0135854.
35. Asakawa N, Sakakibara M, Noguchi K, Kamiya K,
Yamada S, Yoshitani T, Ono K, Oba K, Tsutsui H.
Adaptive Servo-Ventilation Has More Favorable
Acute Effects on Hemodynamics Than
Continuous Positive Airway Pressure in Patients
With Heart Failure. Int Heart J 2015;56:527-32.
36. Soda H, Maeda H, Hasegawa J, Takahashi T,
Hazama S, Fukunaga M, Kono E, Kotaka M,
Sakamoto J, Nagata N, Oba K, Mishima H.
Multicenter Phase II study of FOLFOX or
biweekly XELOX and Erbitux (cetuximab) as
first-line therapy in patients with wild-type
KRAS/BRAF metastatic colorectal cancer: The
FLEET study. BMC Cancer 2015;15:695.
37. Matsuda C, Honda M, Tanaka C, Fukunaga M,
Ishibashi K, Munemoto Y, Hata T, Bando H,
Oshiro M, Kobayashi M, Tokunaga Y, Fujii A,
Nagata N, Oba K, Mishima H. Multicenter
randomized phase II clinical trial of oxaliplatin
reintroduction as a third- or later-line therapy formetastatic colorectal cancer-biweekly versus
standard triweekly XELOX (The ORION Study).
Int J Clin Oncol. 2015 Oct 16. [Epub ahead ofprint]
38. Munemoto Y, Kanda M, Ishibashi K, Hata T,
Kobayashi M, Hasegawa J, Fukunaga M,
Takagane A, Otsuji T, Miyake Y, Nagase M,
Sakamoto J, Matsuoka M, Oba K, Mishima H.
Capecitabine and oxaliplatin combined with
bevacizumab are feasible for treating selected
Japanese patients at least 75 years of age withmetastatic colorectal cancer. BMC Cancer 2015;
15:786.
39. Oba K. Statistical challenges for central
monitoring in clinical trials: a review. Int J Clin
Oncol 2016;21(1):28-37.
40. Yamaguchi R, Makino Y, Chiba F, Torimitsu S,
Yajima D, Shinozaki T, Iwase H. Fluid-fluid leveland pericardial hyperdense ring appearance
findings on unenhanced postmortem CT candifferentiate between postmortem and antemortem
pericardial hemorrhage. AJR Am J Roentgenol.
2015;205(6):W568-77.
41. Jinnouchi H, Kuramitsu S, Shinozaki T, Hiromasa
T, Kobayashi Y, Morinaga T, Yamaji K, Soga Y,
Shirai S, Ando K. Two-year clinical outcomes of
the NOBORI biolimus-eluting stents versus
XIENCE/PROMUS everolimus-eluting stents insmall vessel disease. Catheter Cardiovasc Interv.
2016, available online.
42. Shimada H, Fukagawa T, Haga Y, Oba K. Does
remnant gastric cancer really differ from primary
gastric cancer? A systematic review of theliterature by the Task Force of Japanese Gastric
Cancer Association. Gastric Cancer 2016; 19(2):339-49.
43. Tabuchi T, Fujiwara T, Shinozaki T. Tobacco
price increase and smoking behaviour changes invarious subgroups: a nationwide longitudinal
7-year follow-up study among a middle-aged
Japanese population. Tob Control. 2016, available
online.
44. Takao T, Matsuyama Y, Suka M, Yanagisawa H,
Iwamoto Y. The combined effect of visit-to-visit
variability in HbA1c and systolic blood pressure
on the incidence of cardiovascular events inpatients with type 2 diabetes. BMJ Open Diabetes
Res Care 2015 Nov 13;3(1):e000129.
45. Omichi K, Shindoh J, Yamamoto S, Matsuyama Y,
Akamatsu N, Arita J, Kaneko J, Sakamoto Y,

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Hasegawa K, Kokudo N. Postoperative outcomesfor patients with non-B non-C hepatocellular
carcinoma: A subgroup analysis of patients with ahistory of hepatitis B infection. Annals of Surgical
Oncology 2015; 22(Suppl 3): 1034-1040.
46. 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(1): 61-70.
47. 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 patientswith hepatocellular carcinoma. Journal of
Hepatology 2016; 64(3): 594-600.
48. 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
in a randomized controlled study stratified by thepresence of diabetes mellitus: J-DEsSERT trial.
International Journal of Cardiology 2016; 208:
4-12.
49. Hiromasa T, Kuramitsu S, Shinozaki T, Jinnouchi
H, Morinaga T, Kobayashi Y, Domei T, Soga Y,
Shirai S, Ando K. Impact of total stent length after
cobalt chromium everolimus-eluting stent implantation on 3-year clinical outcomes. Catheter
Cardiovasc Interv. 2016, available online.
50. 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: left ventricular diastolic
dysfunction or clinical factors? J Cardiol. 2016,
available online.
51. Kashiwabara K, Matsuyama Y, Uehara R,
Murakami Y. [Association between medical insti-

tution characteristics and patients' dissatisfaction
based on the Patient's Behavior Survey in Japan].
Nihon Koshu Eisei Zasshi. 2015;62(10):587-95.
Japanese.

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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 nine graduate lecturers fromother organizations, and eight visiting researchers
contribute to department teaching and research
activities.
We have eleven department graduate students.

271

Seven of them are doctoral program students.
In this annual report, the organization andteaching activities are reviewed followed by an
explanation of research activities.

mentation, and evaluation of health promotion
programs for the prevention of lifestyle-relateddisease in the community and workplace.

Research activities
Teaching activities
Our departments highly prioritize the teaching andguidance of graduate students and their research
activities. Sixteen bachelor theses, twenty mastertheses, and ten doctoral dissertations were completed
between April 2004 and March 2016. Our departments’ staff members are also responsible for thefollowing 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-

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

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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.
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
healthReferences
1. Chen AZ, Hayashi K, Lee JS, Takagi H, Ideno Y,
Suzuki S. Associations between lifestyle patterns
and working women’s characteristics: Analyses
from the Japan Nurses’ Health Study. The
Kitakanto Medical Journal 65(1): 21-28.

2. Kobayashi A, Miyazaki Y, Lee JS, Matsumura Y,
Suzuki R, Hayashi K. Evaluation of a short-formof the food frequency questionnaire for Japaneseworking women. The Kitakanto Medical Journal
65(1): 29-38.
3. Lee JS, Mishra G, Hayashi K, Watanabe E, MoriK, Kawakubo K. Combined eating behaviors andoverweight: Eating quickly, late evening meals,
and skipping breakfast. Eating Behaviors 21:
84-88.
4. Mishra GD, Lee JS, Hayashi K, Watanabe E, MoriK, Kawakubo K. How do health behaviors relate
to dietary practice patterns among Japanese
adults? APJCN (in press).
5. 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 (in press).
6. Tamate S. External Norms and SystematicallyObserved Norms. Japanese Economic Review
66(2): 247-259.
7. Yasui T, Hayashi K, Mizunuma H, Kubota T, Lee
JS, Suzuki S. Risk profiles for endometriosis inJapanese women --- Results from a repeatedsurvey of self reports. Journal of Epidemiology
25(3): 194-203.
8. Nakazawa E, Takimoto Y, Akabayashi A. Social
framework surrounding the development ofregenerative medicine in Japan. Cambridge
Quarterly of Healthcare Ethics (in press).
9. Katsui K. Kunihiko HASHIDA’s Theory of “I-JIN”,“I-GYO” and “KAKU-I”. Kampo Medicine 67:
75-84 [in Japanese].
10. Hino K, Ishii N, Asami Y, Lee JS. Step Counts ofParticipants in Yokohama Walking Point Program:
Data analysis between November 2014 and June
2015. Reports of the City Planning Institute of Japan
14: 300-305 [in Japanese].
11. Yoshida, S. The problem of the natural goodness inEmile. Ethica 8: 91-110 [in Japanese].
12. Ozeki R. Various cases of the decision making
support 3: The case when the patient has no person
who agrees to be a surrogate. Palliative Care25(3):197-201 [in Japanese]
13. Katsui K. The seminar of History of Kampo
Medicine at Faculty of Letters, the University of273Tokyo. Journal of Kampo Medicine 62: 633-639 [inJapanese].
14. Shibayama O, Horie T, Higuchi Y, Otani M,
Ishizawa T, Kayano M, Takimoto Y, Yoshiuchi K. A
Case Report of Eating Disorder Not Otherwise
Specified Whose Main Morbidity was ObsessiveCompulsive Disorder and in Which a Combined
Therapy of SSRI and Cognitive-Behavioral Therapy
Succeeded．Jpn J Psychosom Med 55(5): 432-438[in Japanese].
15. Takimoto Y, Kanai Y, Kaitsu M. Answers of Ethics
vol.4: Telling predictable prognosis to patients withunstable both physical and mental condition. The
Japanese Journal of Hospice and Palliative Care25(3): 246-251 [in Japanese].
16. Takimoto Y, Kanai Y, Kaitsu M. Answers of Ethics
vol. 5: Pneumonia treatments for patients withdementia. The Japanese Journal of Hospice andPalliative Care 25(4): 330-334 [in Japanese].
17. Takimoto Y, Kanai Y, Kaitsu M. Answers of Ethics
vol. 6: I am worried about this sedation is ethicallyvalid? The Japanese Journal of Hospice andPalliative Care 25(5): 440-443 [in Japanese].
18. Takimoto Y. Narrative Approach in Clinical Ethics 2(<Series> Clinical Ethics for Psychosomatic
Medicine: Its Basics and Applications). Jpn J
Psychosom Med 55(5): 439-441 [in Japanese].
19. Takimoto Y. Narrative Approach in Clinical Ethics 3(<Series> Clinical Ethics for Psychosomatic
Medicine: Its Basics and Applications). Jpn J
Psychosom Med 55(8): 975-977.
20. Takimoto Y. Clinical Ethics: Refusal of Treatment(<Series>Clinical Ethics for Psychosomatic
Medicine: Its Basics and Applications). Jpn J
Psychosom Med 55(11): 1267-1269.
21. Furusawa Y. Rethinking of spiritual care: From thetheoretical and practical viewpoint. Chizan Journal
74:6-14 [in Japanese].

Health Sciences and Nursing
2. Preventive and Administrative Nursing

275

Department of
Nursing Administration /Advanced Clinical Nursing
Associate Professor
Yukie Takemura, Ph.D., R.N.

Assistant Professor
Mari Ikeda, Ph.D., R.N.
Kimie Takehara, Ph.D., R.N.
Kazunori Komagata, M.S.N., R.N.

Homepage

http://nurs-adm.umin.jp/

Introduction and Organization

Teaching activities

The Department of Nursing Administration/
Advanced Clinical Nursing has 60 years of history andtradition. It was firstly established as Department ofFundamental Nursing in School of Health Care andNursing in 1954. The School of Health Care andNursing composed of two basic medical departments
and six nursing departments. When the School of
Health Care and Nursing was reorganized as the
School of Health Sciences in 1965, only one nursing
department remained so the department was re-named
as Department of Nursing, responsible for total
nursing education. In 1992, as School of Health
Sciences became The School of Health Sciences andNursing, two new departments of nursing wasestablished, so the Department of Nursing became
once again Department of Fundamental Nursing. As
the result of shift to the chair system of the Graduate
School of Medicine in 1996, two departments were
established, Department of Nursing Administration
and Department of Advanced Clinical Nursing. Our
department is responsible for the Fundamental
Nursing education for undergraduate students. This
year, Dr. Yukie Takemura was appointed as the
Associate Professor.

Undergraduate Courses
In the undergraduate program our department is incharge of the lectures and clinical practicums for
Fundamental Nursing I, Fundamental Nursing II,
Fundamental Nursing III, Nursing Administration andFirst Aid & CPR.
Fundamental Nursing 1 (2 credits, Lectures)This course offers fundamental knowledge ofnursing, such as history and theory in nursing,concepts of professional nursing practice, nursing
service and care delivery systems, nursing administration, and nursing education. We invite nursing
professions who success various places for learning
clinical application of these knowledge and discussion
about various roles and activities of nursing.
Fundamental Nursing 2 (2 credits, Lectures)This course offers fundamentals in understanding
interpersonal relationships and assessing clients'
health. Students will learn; 1) theory and practice incommunication, 2) physical examination skills
essential to health assessment.

276

Fundamental Nursing 3(4 credits, Lectures and laboratory practicum)This course provides theory and practice offundamental nursing skills, which are essential toproviding nursing care with physiological andpsychosocial integrity. Students learn nursing process
and clients’ needs with case discussion in groups.
Clinical Practicum in Fundamental Nursing(2 credits, Practicum)
Under instructors' supervision, students haveopportunity to apply their fundamental knowledge andskills of nursing in a variety of settings. Students willassess clients' health and needs through application ofnursing process.
Nursing Administration (1 credit, Lectures)This course prepares students for nurse
administrators/managers of all types of health caresettings such as institutions, organizations, communityand politics. Students will learn fundamental theory
and practice in nursing administration/management
through analyzing current issues in health care andnursing.
Nursing Administration Practicum(1 credit, Practicum)
Students have nursing administrative practicum inunits or divisions in hospitals. Students will learn caredelivery systems such as staffing and patientclassification systems, nursing informatics, andbudgetary issues including cost effectiveness andquality improvement.
First Aid & CPR (1 credit, Lectures & practicum)
Students will understand the emergency medical
system and learn how to act in emergency situations.
The practicum includes following subjects; 1)
observation and measurement of vital signs, 2) firstaid to the victim with bleeding, intoxication, or burn,3) how to carry an injured person, and 4) CPR(cardiopulmonary resuscitation), AED (automatedexternal defibrillator).

Graduate courses
In the graduate program our department is incharge of the lectures for Nursing Administration andAdvance Clinical Nursing.
Nursing Administration I, II (2 credits each)This course offers critical analysis of theories innursing administration related to quality assurance/
improvement and cost effectiveness/efficient caredelivery systems. Also exploration of political andadministrative functional role in nursing are discussed.
Advance Clinical Nursing I (2 credits)
This course offers an overview of advanced
clinical practice, research, and education and theirfoundations. Students learn the expertise of nurses andtheir legal responsibility.
We have the department seminar in collaboration
every week, where members provide the actual plans
for their own research and discuss the topic.

Research activities
Issues of Nursing Administration
We have been examining administrative issues incontemporary nursing. Our main research topic is
developing new administration model which focuseson the organizational mission and staff’s empowerment.
Development of Nursing Care Skills to Improve
Patient Care Environment
We have been examining self-management support
for patients with chronic disease, nursing care systemin outpatient and long-term facilities for older adults,
and development of innovative nursing care skills. We
also examined nursing practice and nursing education
to clarify the current status and issues in order tobetter understand the state of individual patient.

References
1. Kaitani T, Nakagami G, Sugama J, Tachi M,
Matsuyama Y, Miyachi Y, Nagase T, Takemura Y,
Sanada H. Evaluation of an advanced pressure
ulcer management protocol followed by trained
wound, ostomy, and continence nurses: a
non-randomized controlled trial. Chronic Wound
Care Management and Research .2015; 2: 39-51.
2. Kaitani T, Nakagami G, Iizaka S, Fukuda T, Oe
M, Igarashi A, Mori T, Takemura Y, Mizokami Y,
Sugama J, Sanada H. Cost-utility analysis of anadvanced pressure ulcer management protocol
followed by trained wound, ostomy, and conti-

277

nence nurses. Wound Repair and Regeneration.2015;23(6):915-921.
3. Yamamoto-Mitani N, Igarashi A, Watanabe M,
Takemura Y, Suzuki M. Factors of “goodcollaboration” in home-based end-of-life care: aquestionnaire survey of Japanese homecare nurses,
home helpers, and care managers. Care Management Journals 2015; 16(3): 129-140.
4. Takemura Y. Clarification of the organizationalroutine learning process: comparison of novice
and experienced nurses newly assigned to a ward.
Journal of Society of Nursing Practice 2015;27(2):19-30.
5. Noguchi H, Oe M, Takehara K, Mori T, Sanada H,
Reliability and validity of an on-site measurement
and visualization system to measure plantarpressure and shear force in footwear for theeducation of diabetic patients, J. Jpn WOCM.,
2015;19(3):327-335.
6. Oe M, Nagai S. Ikeda M, Oya M, Ohashi Y,
Otomo E, Murayama R, Ueki K, Kadowaki T,
Komiyama C, Sanada H. Difficulties of theintroduction of self-monitoring of blood glucose
in elderly diabetic patients.Journal of Nursing
Science and Engineering, 2015;2(3):164-173.
7. Takehara K, Amemiya A, Mugita Y, Tsunemi Y,
Seko Y, Ohashi Y, Ueki K, Kadowaki T, Oe M,
Nagase T, Ikeda M, Sanada H. Association
between Washing Residue on the Feet and Tinea
Pedis in Diabetic Patients. Nursing Research andPractice, vol. 2015, Article ID 872678, 7 pages,
2015. doi:10.1155/2015/872678
8. Tsunemi Y, Takehara K, Miura Y, Nakagami G,
Sanada H, Kawashima M. Diagnosis of tinea
pedis by dermatophyte test strip. Br J Dermatol.
2015;173(5):1323-1324.
9. Iizaka S, Takehara K, Sanada H. Validation of a
portable device for measuring stratum corneum
hydration. J.Jpn.WOCM. 2015.19(1):33-39.
10. Oe M, Takehara K, Ohashi Y, Mugita Y,
Murayama R, Komiyama C, Ueki K, Kadowaki T,
Sanada H. Incidence of foot ulcers in patientswith diabetes at a university hospital in Tokyo
over a 5-year period. Diabetol Int. 2015;6(1):55-59.
11. Tsunemi Y, Takehara K, Oe M, Sanada H,
Kawashima M. Diagnostic accuracy of tinea

unguium based on clinical observation. J
Dermatol. 2015;42(2):221-22.
12. Suetsugu Y, Honjyo S, Ikeda M, Kamibeppu K.
The Japanese version of the Postpartum Bonding
Questionnaire: Examination of the reliability,
validity, and scale structure. J Psychosom Res.
2015;79(1):55-61.

278

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, 9 master’s
students, 5 research students, 26 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. Late effects of treatment, posttraumatic stressdisorder, posttraumatic growth, and supports forschool reentry in children with cancer;
4. Impact of opening a sick-child day care on
work-life balance in female workers;
5. Caregiving burden and utilization of respite careservices in families of severely disabled children;
6. Support for dying patients and their families(QOL and family functioning);
7. Livelihood supports for families of elderly people
with dementia.
8. Transition in patients with child chronic diseases.
Studies on “Late effects in pediatric cancer
survivors” and “Supporting pediatric cancer survivors’
reentry to school” have been ongoing, in collaboration
with pediatric cancer researchers and a variety of

Education
1. Graduate Courses, School of Health Sciences andNursing (credit hours)
Advanced Family Nursing I (2)Advanced Family Nursing II (2)Nursing Consulation(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)279family 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.
Additionally, based on the department’s richcollective research experiences, we founded theCenter for Quality of Life Research in April 2012 to
study QOL across wide developmental stages andhealth conditions. Using this platform, we aim to
accumulate, integrate, and disseminate scientificresearch and knowledge on QOL in a more systematicmanner.
Most recently, newly initiated research studies bydepartment members are exploring the various
experiences of children with cancer and their families
who were extensively affected by the Tohoku
Earthquake of 2011.
In 2015, studies focusing on transition such as“transferring into adult health care” and“independence and autonomy” in patients with childchronic diseases have begun. We conducted
self-questionnaire surveys for both doctors and nurses,,
and were committed to prepare to establish atransition outpatient clinic in the University of Tokyo
Hospital. The transition outpatient clinic will open in
June, 2016. Furthermore, we have been developing
newly check lists to evaluate long-term follow ups inpatients after hematopoietic stem cell transplantation,and supports for school reentry in pediatric cancer
survivors. Those studies and activities have beenongoing in interdisciplinary collaboration with healthprofessionals 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, Sato I, Hoshi Y. The experience ofJapanese adolescents and young adults afterlosing siblings to childhood cancer; three types ofnarrative. Journal of Pediatric Oncology Nursing.
2015 May-Jun; 32(3): 165-77.
2. Kamibeppu K, Murayama S, Ozono S, Sakamoto
N, Iwai T, Asami K, et al.. Predictors of posttraumatic stress symptoms among adolescent andyoung adult survivors of childhood cancer:
importance of monitoring survivors’ experiencesof family functioning. Journal of Family Nursing.
2015 Nov; 21(4): 529-50.
3. Ikeda M, Hayashi M, Kamibeppu K. The
experience of postpartum depression among
mothers with withdrawn attachment style during
pregnancy and the first postnatal month. Journalof Depression. 2015 Dec; 4(4): 61-8.
4. Sato I, Higuchi A, Yanagisawa T, Mukasa A, Ida
K, Sawamura Y, et al. Parent’s perceived
provision of information regarding diagnosis tochildren with brain tumors. Open Journal of
Nursing. 2015 May; 5(5): 451-64.
5. Kageyama M, Yokoyama K, Nagata S, Kita S,
Nakamura Y, Kobayashi S, et al. Rate of family
violence among patients with schizophrenia inJapan. Asia-Pacific Journal of Public Health. 2015
Sep; 27(6): 652-60.
6. Soejima T, Sato I, Takita J, Koh K, Maeda M, Ida
K, et al. Support for school reentry and relationships among children with cancer, peers, andteachers. Pediatrics International. 2015 Dec; 57(6):1101-7.
7. Ohtsuka-Ono H, Sato I, Ikeda M, Kamibeppu K.
Premenstrual distress among Japanese high school
students: self-care strategies and associatedphysical and psychosocial factors. Women &Health. 2015 Jun; 55(8): 859-82.
8. Suetsugu Y, Honjo S, Ikeda M, Kamibeppu K.
The Japanese version of the Postpartum Bonding
Questionnaire: Examination of the reliability,
validity, and scale structure. Journal of Psychosomatic Research. 2015 Jul; 79(1): 55-61.
9. Kikuchi R, Kamibeppu K. Parents’ quality of lifeand family functioning in pediatric organtransplantation. Journal of Pediatric Nursing.

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2015 May-Jun; 30: 463-77.
10. Kikuchi R, Ono M, Kinugawa K, Endo M, Mizuta
K, Urahashi T, et al. Health-related quality of life
in parents of pediatric solid organ transplant
recipients in Japan. Pediatric Transplantation.
2015 May-Jun; 19(3): 332-41.
11. Kikuchi R, Ono M, Kikugawa K, Endo M, Mizuta
K, Urahachi T, et al. Perceived burden of
nurturing in pediatric organ transplantation in
Japan. Japanese Journal of Transplantation. 2015
Aug; 50(2-3), 203-10.
12. Komachi M, Kamibeppu K. Acute stresssymptoms in families of patients admitted to theintensive care unit during the first 24 hours
following admission in Japan. Open Journal of
Nursing. 2015 Apr; 5(4): 325-35.
13. Fujioka H, Wakimizu R, Tanaka R, Ohto T,
Ieshima A, Yoneyama A, Kamibeppu K.
Empirical study on the empowerment of families
raising children with severe motor and intellectual
disabilities in Japan: The association with positive
feelings towards child rearing. Health. 2015 Dec;
7: 1725-40.
14. Hiraga K, Nonaka R, Soejima T, Toju K, Sato I,
Takeda T, et al. Primary influencing factors to thestructure of role awareness in special support
education coordinator for children with cancer.
Ikuryo. 2015 Nov; 58: 45-51.
15. Ono M, Kamibeppu K. Support for Children
Living with Mothers Having Severe mental
Illness: A Qualitative Analysis Based on
Interviews with Mental Health Personnel In
Psychiatric Institutions. Japanese Journal of
Research in Family Nursing. 2015 Sep; 21(1):
2-13.

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Department ofCommunity Health Nursing /Public Health Nursing
Associate Professor
Satoko Nagata, Ph.D., R.N., P.H.N.

Research Associate
Takashi Naruse, Ph.D., R.N., P.H.N.
Masako Kageyama, Ph.D., R.N., P.H.N.
Naoko Mikoshiba, Ph.D., R.N., P.H.N.
Shinji Iizaka, 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 five faculty members introduced above and
16 graduate course students (9 in master course, 7 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 thehome care patients and the medical, health andwelfare system. Students learn the basics of caremanagement, home health care service, and healthcare system.

2) Community Health Nursing (2 credits, lectures)
In this class, students learn the methodology andbasic theory of health promotion, disease
prevention and resilience toward society for
individuals, families, and groups in community.
3) Community Health Nursing Practice (2 credits,
practice)This program is intended to understand the systemof health promotion and prevention by attending
the actual community health nursing activities athealth center. Students are expected to realize theprinciple and the common technique ofcommunity health nursing activities by observing
the activities of public health nurses.
4) 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.
5) Health Assistance Practice (1 credit, practice)In this program, students will comprehend

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multilaterally how characteristics of the residents,
health resources and environment of thecommunity effects health and discuss on the healthmatters of the overall community. In addition,
students will visit various working sites for nurses
to deepen their knowledge of multiple healthrelated resources, and learn the actual skills of
health guidance towards individuals/ families/
groups through experience.
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)This 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 of

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community 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
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 the elderly to support favorable living conditions for thispopulation. Our research includes (1) identification ofservice needs among frail elderly persons in community dwellings, (2) evaluation of community care services’ impact on the elderly and their family caregivers, and (3) the development of an approach aimed atproviding care for the terminally ill in community 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) Satoko Nagata, Atsushi Matsunaga, Chie Teramoto. Follow-up study of the general and mental
health of people living in temporary housing at 10
and 20 months after the Great East Japan Earthquake. Japan Journal of Nursing Science, 12(2),162-165, 2015.
(2) Satoko Nagata, Kaoru Ogawa, Atsuko Taguchi,
Takashi Naruse, Sachiyo Murashima, Joan Kathy
Magilvy. Promoting the use of visiting nurse services for patients discharged from hospital:
Evaluation of a Japanese municipality’s model
project. Home Health Care Management & Practice, 27, 47-53, 2015.
(3) Takashi Naruse, Mahiro Sakai, Hiroshige
Matsumoto, Satoko Nagata. Diseases that precededisability among latter-stage elderly individuals

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in Japan. BioScience Trends, 9(4), 270-274, 2015.
(4) Takashi Naruse, Rumiko Tsuchiya, Natsuki
Yamamoto, Satoko Nagata. Identifying Characteristics of Adults Absent from a Metabolic
Syndrome Checkup in Japan Using CHAID
Dendrograms and Insurance Claim Data. Health,7, 1841-1846, 2015.
(5) Masako Kageyama, Keiko Yokoyama, Satoko
Nagata, Sachiko Kita, Yukako Nakamura, Sayaka
Kobayashi, Phyllis Solomon. Rate of family
violence among patients with schizophrenia inJapan. Asia-Pacific Journal of Public Health,27(6), 652-660, 2015.
(6) Masako Kageyama, Keiko Yokoyama, Yukako
Nakamura, Sayaka Kobayashi. Changes inFamilies’ Caregiving Experiences throughInvolvement as Participants then Facilitators in a
Family Peer-Education Program for Mental
Disorders in Japan. Family Process, Epub aheadof print 2 NOV 2015, DOI: 10.1111/famp.12194.
(7) Naoko Mikoshiba, Noriko Yamamoto-Mitani,
Kazuki Sato, Yoshinari Asaoka, Takafumi Ohki,
Misato Ohata, Mitsunori Miyashita. Validation of
the Japanese version of HFS-14, a diseasespecific quality of life scale for patients sufferingfrom hand-foot syndrome. Support Care Cancer,
23(9), 2739-2745, 2015.
(8) Aya Saitoh, Akihiko Saitoh, Isamu Sato, Tomohiro
Shinozaki, Satoko Nagata. Current practices andneeds regarding perinatal childhood immunization education for Japanese mothers. Vaccine,
33(45), 6128-6133, 2015.
(9) Mahiro Sakai, Hiroki Yanase, Atsuko Taguchi,
Takashi Naruse, Satoko Nagata. Community
residents’ confidence in spending end-of-life at
home: a cross sectional study. Japanese Journal of
Health and Human Ecology, 81(4), 122-133,
2015.
(10) Chie Teramoto, Satoko Nagata, Reiko Okamoto,
Ruriko Suzuki, Emiko Kishi, Michie Nomura,
Noriko Jojima, Masumi Nishida, Keiko Koide,
Emiko Kusano, Saori Iwamoto, Sachiyo Murashima.
Identifying Residents’ Health Issues Six Weeks after
the Great East Japan Earthquake. Public HealthNursing, 32(6), 654-661, 2015.
(11) Chie Teramoto, Atsushi Matsunaga, Satoko
Nagata. Cross-sectional study of social support

and psychological distress among displaced
earthquake survivors in Japan. Japan Journal of
Nursing Science, 12(4), 320-329, 2015.
(12) Hiroshige Matsumoto, Takashi Naruse, Mahiro
Sakai, Satoko Nagata. Who prefers to age inplace? Cross-sectional survey of middle-aged
people in Japan. Geriatrics and Gerontology
International, published online DOI: 10.1111/ggi.
12503, 2015.
(13) Masako Kageyama, Iwao Oshima, Yukako
Nakamura, Keiko Yokoyama, Sayaka Kobayashi.
Scale development for promoting protocol
adherence to a family peer-education program on
mental disorders: A fidelity scale. Japanese
Journal of Public Health, 62(4), 198-208, 2015.
(14) Masako Kageyama, Keiko Yokoyama, Sayaka
Kobayashi, Yukako Nakamura. Qualitative
Evaluation of a Family Peer-Education Programon Mental Disorders: An Analysis of FreeResponse Descriptions at Post-Test of theProgram. Journal of Japan Academy of Nursing
Science, 35, 43-52, 2015.
(15) Masako Kageyama, Keiko Yokoyama, Yukako
Nakamura. Benefits for Families of People with
Mental Disorders Who Continuously Implement a
Family Peer-education Program: A Program
Post-test. Japan Academy of Community HealthNursing, 18(1), 28-37, 2015.
(16) Masako Kageyama, Iwao Oshima, Yukako
Nakamura, Keiko Yokoyama. Subjective evaluation of "Omotenashi-Family Experiences Learning Program" on mental disorders : A post-test
evaluation for family participants and family
facilitators. Japanese journal of psychiatricrehabilitation, 19(2), 194-202, 2015.

Health Sciences and Nursing
3. Clinical Nursing

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Department of Adult HealthNursing/Palliative Care Nursing
Professor
Noriko Yamamoto-Mitani, Ph.D., R.N.

Assistant Professor (Senior)
Yukari Takai, Ph.D., R.N.

Assistant Professor (Junior)
Ayumi Igarashi, Ph.D., R.N.
Maiko Noguchi-Watanabe. Ph.D., R.N.

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. Noriko
Yamamoto-Mitani has been responsible for administration 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.
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.

Research
Faculty members conduct studies on various topics
in the field of adult and gerontological nursing.
1) Quality assurance and improvement for long-termcare for the elderly

287

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 homecare 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) Standardization and diffusion of care for chronic
pain
Pain is a common symptom among older people,
and we have conducted studies aiming to develop anddisseminate nursing care of chronic pain. We explore
reality of the situation for older people with chronic
pain. We aim to improve quality of care for chronic
pain in the long-term care facilities, by developing an

educational material regarding care for chronic pain.
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.
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.
The listed below are main research projects that we
conducted in 2015. Details of our publications andfunding are shown in our department website andannual report.
A) Developing a program for care quality improvement at long-term care facilities for older people
In this project, it has been aimed to improve quality
in care of chronic pain in long term care hospitals. The
following studies are to be conducted: developing acare protocol for chronic pain in long-term carefacilities in Japan, elucidating barriers to quality
improvement and searching for effective ways toovercoming these barriers, and developing an
educational program for nurses working at long-termcare facilities and mini-trial.
This year we have conducted a nationwide survey
to long-term care hospitals for older people. We havecaptured quantitatively the current level of care quality,
practice of quality improvement, problems eachprofessional faced, and barriers to solve the problems.
From the survey we have learned elevating caredemands in those hospitals with the introduction ofcommunity integrated care system, high staff (i.e.,licensed nurses, nursing aides) burn-out and low
work-engagement. As a pilot for quality improvement
intervention, we have started a case conference in acare mix hospital in Tokyo. We are going to present
findings of the study at Annual Scientific Meeting ofJapan Academy of Nursing Sciences, GerontologicalSociety of America Annual Meeting, or Japan
Association of Medical and Care Facilities Annual
Scientific Meeting. The papers were currently underreview/ in preparation.

288B) 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.
C) 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.

Publications
1. Mikoshiba N, Yamamoto-Mitani N, Sato K,
Asaoka Y, Ohki T, Ohata M, Miyashita M.
Validation of the Japanese version of HFS-14, adisease-specific quality of life scale for patients

2.

3.

4.

5.

6.

7.

8.

suffering from hand-foot syndrome. Support Care
Cancer. 2015; 23(9): 2739-45. doi: 10. 1007/
s00520-015-2638-4.
Igarashi A, Kurinobu T, Ko A, Okamoto Y,
Matsuura S, Feng M, Yamamoto-Mitani N.
Factors related to the provision of home-based
end-of-life care among home-care nursing, homehelp, and care management agencies in Japan.
BMC Res Notes. 2015; 12(8): 434. doi:10.1186/
s13104-015-1418-z.
Yamamoto-Mitani N, Igarashi A, NoguchiWatanabe M, Takemura Y, Suzuki M. Factors ofGood Collaboration in Home-Based End-of-Life
Care: A Questionnaire Survey of Japanese Home
Care Nurses, Home Helpers,and Care Managers.
Care Manag J. 2015; 16(3):129-40. doi:10.1891/
1521-0987.16.3.129.
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.
Gastroenterol Nurs. 2016; 39(1):42-7. doi:10.
1097/SGA.0000000000000201.
Takai Y, Yamamoto-Mitani N, Abe Y, Suzuki M.
Literature review of pain management for people
with chronic pain, Japan Journal of Nursing
Science, 2015; 12(3):167–83. doi:10.1111/jjns.
12065.
Torimoto-Sasai Y, Igarashi A, Wada T, Ogata Y,
Yamamoto-Mitani N. Female family caregivers
face a higher risk of hypertension and lowered
estimated glomerular filtration rates: A crosssectional, comparative study. BMC Public Health.
2015; 15:177. doi: 10.1186/s12889-015-1519-6.
Mikoshiba N, Yamamoto-Mitani N, Sato K,
Asaoka Y, Ohki T, Ohata M, Miyashita
M. Validation of the Japanese version of HFS-14,
a disease-specific quality of life scale for patients
suffering from hand-foot syndrome. Support Care
Cancer. 2015; 23(9): 2739-45. doi: 10.1007/
s00520-015-2638-4.
Kinoshita H, Maeda I, Morita T, Miyashita M,
Yamagishi A, Shirahige Y, Takebayashi T,
Yamaguchi T, Igarashi A, Eguchi K. Place ofdeath and the differences in patient quality ofdeath and dying and caregiver burden. J Clin

289

Oncol. 2015; 33(4): 357-67. doi: 10.1200/JCO.
2014.55.7355.
9. Sakai S, Yamamoto-Mitani N, Takai Y,Fukahori
H, Ogata Y. Developing an instrument to selfevaluate the Discharge Planning of Ward Nurses.
Nursing Open.21 SEP 2015. DOI: 10.1002/nop2.
31.
10. Mikoshiba N, Yamamoto-Mitani N, Sato K, Yaju
Y, Miyashita M. Relationship between Self-Careand Hand Foot Syndrome Specific Quality of Lifein Cancer Patients. Open Journal of Nursing 2016;
6, 100-109. doi:10.4236/ojn.2016.62011.
11. Suzuki M, Deno M, Myers M, Asakage T,
Takahashi K, Saito K, Mori Y,Saito H, Ichikawa
Y, Yamamoto-Mitani N, Miyashita M. Anxiety
and depression in patients after surgery for headand neck cancer in Japan. Palliative andSupportive Care. 2015. doi:http://dx.doi.org/10.
1017/S1478951515000930.

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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.,

Homepage

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

Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
Currently, it has 3 faculty members introduced above
and 15 graduate students (9 in master course, 6 indoctoral course) and 3 visiting researchers.

Teaching activities
We have graduate and undergraduate courses for
midwifery and maternal care, and women's health.
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 focus on maternal and childhealth with emphasis on the promotion of women's
health and their quality of life at every stage of theirlives.
We conduct the following research projects.
1. Collecting evidence for health guidance during
pregnancy• Adequate maternal nutrition and weight
management
This study examines maternal body composition,
lipid metabolic biomarkers and nutritional intake tooptimize weight management and a healthy
lifestyle during pregnancy to prevent low birth291

weight. Based on our investigations into the
optimal maternal nutritional status and gestational
weight gain, we propose health guidance that canhelp pregnant women lower the risk of pregnancy
complications and adverse birth outcomes.
• The effect of exercise during pregnancy
This study investigates the effect of exercise on
mental and physical health among pregnant
women.
• Lifestyle factors and oxidative stress markers
during pregnancy
This study investigates the potential relationships
between lifestyle factors and oxidative stressmarkers during pregnancy, and to establish optimal
oxidative stress markers for predicting a healthy
lifestyle for pregnant women.
• Development of effective skin care intervention toprevent neonatal skin trouble.
This study investigates the effect of moisturizing
skin care on improvement of skin barrier functions
among healthy neonates.
2. Development of a self-managing support system
for the body after childbirth• Urinary and rectal incontinence after childbirthThis study investigates the prevalence and risk
factors of urinary and rectal incontinence among
women within five years after childbirth• Development of effective postpartum pelvic floor
muscle training
This study examine the effect of postpartum pelvic
floor muscle training with ultrasound biofeedback
on recovery of pelvic floor muscle function: arandomized controlled trial• Promotion of women's healthcare after delivery
This study examines the relationship between
maternal body composition and lifestyle factors
among postpartum women, including breastfeeding.
3. Development of a support system for women's
mental health during the perinatal period• "Fear of childbirth" and psychosocial factors
among pregnant Japanese womenThis study aims to identify the psychosocial risk
factors of intense fear of childbirth.
• 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.

Publications
1. Sasagawa, E., Aiga, H., Corado Soriano, EY.,
Cuyuch Marroquín, BL., Hernández Ramírez, MA.,
& Guevara de Aguilar, AV., et al. (2015).
Mother-to-Child Transmission of Chagas Disease in
El Salvador. American Journal of Tropical Medicine
and Hygiene, 93(2), 326-333.
2. Shiraishi, M., Matsuzaki, M., Yatsuki, Y., Murayama,
R., Severinsson, E., & Haruna, M. (2015).
Associations of dietary intake and plasma concentrations of eicosapentaenoic and docosahexaenoic acidwith prenatal depressive symptoms in Japan.
Nursing Health Science, 17(2), 257-62.
3. Shiraishi, M., Haruna, M., Matsuzaki, M.,
Murayama, R., & Sasaki, S. (2015). The biomarkerbased validity of a brief-type diet history questionnaire for estimating eicosapentaenoic acid anddocosahexaenoic acid intakes in pregnant Japanesewomen. Asia Pac J Clin Nutr, 24(2), 316-22.
4. Kita, S., Haruna, M., Matsuzaki, M., & Kamibeppu,
K. (2015). Associations between intimate partner
violence (IPV) during pregnancy, mother-to-infantbonding failure, and postnatal depressive symptoms.
Achieves of Women's Mental Health (in press).
5. Kageyama, M., Yokoyama K., Nagata, S., Kita, S.,
Nakamura, Y., Kobayashi, S., & Solomon, P. (2015).
Rate of family violence among patients withschizophrenia in Japan. Asia-Pacific Journal of
Public Health, 27(6), 652-660.
6. Takegata, M., Haruna, M., & Kitamura, T. (2015).
Continuous education for perinatal mental healthamong clinical midwives: Necessity and a literature
review. International Journal of Nursing and Health
Science, 2(6), 73-77.
7. Ohashi,Y., Takegata, M., Haruna, M., Kitamura, T.,292

Takaura, F., & Tada, K. (2015). Association of
specific negative life events with depression severity
one month after childbirth in community-dwellingmothers. International Journal of Nursing and
Health Science, 2(2),13-20.
8. Severinsson, E., Haruna, M., Rönnerhag, M., &Berggren, I. (2015). Patient Safety, Adverse
Healthcare Events and Near-Misses in Obstetric
Care —A Systematic Literature Review. Open
Journal of nursing, 5(12), 1110-1122.
9. Takehara, K., Dagvadorj, A., Hikita, N., Sumaya, N.,
Ganhuyag, S., Bavuusuren, B., Ota, E., Haruna, M.,
Yoshida, M., Kita, S., Noma, H., & Mori, R. (2015).
Maternal and child health in Mongolia at 3 years
after childbirth: A population-based cross-sectionaldescriptive study. Maternal and Child Health
Journal (in press).
10. Kitamura, T., Ohashi, Y., Minatani, M., Haruna, M.,
Murakami, M., & Goto, Y. (2015). Disagreement
between parents on assessment of child temperament traits. Pediatrics international, 57(6), 1090-6.
11. Hirade, M., Miyazaki, F., Matsuzaki, M. (2015).
Investigation into birthing facility selection to
explain the decreasing number of births at birthing
centers: Applying a marketing concept perspective.
Journal of Japan Academy of Midwifery, 29(1),87-97.
12. Suto, M., Sasagawa, E., Yoshiasa, K., Matsuzaki, Y.,
Matsumoto, A., & Misago, C. (2015). The effect ofdiaperless parenting on the age at which toddlers
stop needing diapers. Japanese Journal of Healthand Human Ecology (in press).

293

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294

mental health nursing; and reducing the use of
seclusion and restraint. We are conducting studies incollaboration with researchers in other institutions anduniversities.

Publications
1. Hayasaka Y, Furukawa TA, Sozu T, Imai H,
Kawakami N, Horikoshi M. Enthusiasm forhomework and improvement in subthresholddepression during behavior therapy: Secondary
analysis of data from a randomized controlled
trial. BMC Psychiatry. 2015; 15: 302.
2. Umeda M, McMunn A, Cable N, Hashimoto H,
Kawakami N, Marmot M. Does an advantageous
occupational position make women happier incontemporary Japan? Findings from the JapaneseStudy of Health, Occupation, and Psychosocial
Factors Related Equity (J-HOPE). SSM Population Health. 2015; 1: 8-15.
3. Miyaki K, Song Y, Suzuki T, Eguchi H,
Kawakami N, Takahashi M, Shimazu A, Inoue A,
Kurioka S, Kan C, Tsutsumi A. DNA Methylation
Status of the Methylenetetrahydrofolate Reductase Gene is associated with Depressive Symptoms in Japanese Workers: A Cross-Sectional
Study. Journal of Neurology and Neurological
Disorders. 2015.
4. 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. 2015 Dec
1. [Epub ahead of print].
5. Ishikawa H, Yasunaga H, Matsui H, Fushimi K,
Kawakami N. Differences in cancer stage, treatment and in-hospital mortality between patientswith and without schizophrenia: retrospective
matched-pair cohort study. Br J Psychiatry. 2015
Nov 19. pii: bjp.bp.114.156265. [Epub ahead ofprint].
6. Suzuki T, Miyaki K, Song Y, Tsutsumi A,
Kawakami N, Shimazu A, Takahashi M, Inoue A,
Kurioka S. Relationship between sicknesspresenteeism (WHO-HPQ) with depression andsickness absence due to mental disease in a cohortof Japanese workers. J Affect Disord. 2015; 180:

14-20.
7. Inoue A, Kawakami N, Eguchi H, Miyaki K,
Tsutsumi A. Organizational Justice and Physiological Coronary Heart Disease Risk Factors inJapanese Employees: a Cross-Sectional Study. Int
J Behav Med. 2015; 22(6): 775-85.
8. Ryff CD, Miyamoto Y, Boylan JM, Coe CL,
Karasawa M, Kawakami N, Kan C, Love GD,
Levine C, Markus HR, Park J, Kitayama S.
Culture, inequality, and health: evidence from the
MIDUS and MIDJA comparison. Cult Brain.
2015; 3(1): 1-20.
9. Kawasaki S, Nishimura Y, Takizawa R, Koike S,
Kinoshita A, Satomura Y, Sakakibara E, Sakurada
H, Yamagishi M, Nishimura F, Yoshikawa A, Inai
A, Nishioka M, Eriguchi Y, Kakiuchi C, Araki T,
Kan C, Umeda M, Shimazu A, Hashimoto H,
Kawakami N, Kasai K. Using social epidemiology
and neuroscience to explore the relationshipbetween job stress and frontotemporal cortex
activity among workers. Soc Neurosci. 2015;10(3): 230-42.
10. Kitayama S, Park J, Boylan JM, Miyamoto Y,
Levine CS, Markus HR, Karasawa M, Coe CL,
Kawakami N, Love GD, Ryff CD. Expression ofanger and ill health in two cultures: an
examination of inflammation and cardiovascularrisk. Psychol Sci. 2015; 26(2): 211-20.
11. GBD 2013 Risk Factors Collaborators. Global,
regional, and national comparative risk
assessment of 79 behavioural, environmental andoccupational, and metabolic risks or clusters ofrisks in 188 countries, 1990-2013: a systematic
analysis for the Global Burden of Disease Study
2013. Lancet. 2015 Sep 10. pii: S0140-6736(15)00128-2. doi: 10.1016/S0140-6736(15)00128-2.
[Epub ahead of print].
12. GBD 2013 DALYs and HALE Collaborators.
Global, regional, and national disability-adjusted
life years (DALYs) for 306 diseases and injuries
and healthy life expectancy (HALE) for 188
countries, 1990-2013: quantifying the epidemiological transition. Lancet. 2015 Aug 27. pii:
S0140-6736(15)61340-X. doi: 10. 1016/S01406736(15)61340-X. [Epub ahead of print].
13. Ishikawa H, Kawakami N, Kessler RC; World
Mental Health Japan Survey Collaborators.

295Lifetime and 12-month prevalence, severity andunmet need for treatment of common mental
disorders in Japan: results from the final dataset ofWorld Mental Health Japan Survey. Epidemiol
Psychiatr Sci. 2015 Jul 7:1-13. [Epub ahead ofprint].
14. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence,prevalence, and years lived with disability for 301
acute and chronic diseases and injuries in 188
countries, 1990-2013: a systematic analysis for
the Global Burden of Disease Study 2013. Lancet.
2015 Jun 7. pii: S0140-6736(15)60692-4. doi: 10.
1016/S0140-6736(15)60692-4. [Epub ahead ofprint].
15. GBD 2013 Mortality and Causes of Death
Collaborators. Global, regional, and national agesex specific all-cause and cause-specific mortality
for 240 causes of death, 1990-2013: a systematic
analysis for the Global Burden of Disease Study
2013. Lancet. 2015 Jan 10; 385(9963):117-71.
Epub 2014 Dec 18.
16. Miki T, Kochi T, Kuwahara K, Eguchi M,
Kurotani K, Tsuruoka H, et al. Dietary patterns
derived by reduced rank regression (RRR) anddepressive symptoms in Japanese employees: the
Furukawa Nutrition and Health Study. Psychiatry
Research. 2015; 229(1-2): 214-9.
17. Takano A, Miyamoto Y, Kawakami N, Matsumoto
T. A study of therapeutic attitudes towards working with drug abusers: Reliability and validity of
the Japanese version of the Drug and Drug
Problems Perception Questionnaire. Archives of
Psychiatric Nursing. 2015; 29(5): 302–308.
18. Nakagawa Y, Inoue A, Kawakami N, Tsuno K,
Tomioka K, Nakanishi M, et al. Change inorganizational justice and job performance inJapanese employees: a prospective cohort study. J
Occup Health. 2015; 57(4):388-93.
19. Tsuno K, Kawakami N. Multifactor leadershipstyles and new exposure to workplace bullying: a
six-month prospective study. Industrial health.
2015; 53(2):139-51.
20. Imamura K, Kawakami N, Furukawa TA,
Matsuyama Y, Shimazu A, Kasai K. Effects of aninternet-based cognitive behavioural therapy
intervention on preventing major depressive

episodes among workers: a protocol for arandomised controlled trial. BMJ Open. 2015; 5:e007590.
21. Nakanishi M, Miyamoto Y, Long C, Arcand M.
The Japanese comfort care booklet about
palliative care for dementia in nursing homes.
International Journal of Palliative Nursing. 2015;21(8):385-91.
22. Imamura K, Kawakami N, Furukawa TA,
Matsuyama Y, Shimazu A, Umanodan R, et al.
Does Internet-based cognitive behavioral therapy(iCBT) prevent major depressive episode forworkers? A 12-month follow-up of a randomized
controlled trial. Psychological medicine. 2015;45(9): 1907-17.
23. Miyamoto Y, Hashimoto-Koichi R, Akiyama M,
Takamura S. Mental health and social service
needs for mental health service users in Japan: A
cross-sectional survey of client- and staffperceived needs. International Journal of Mental
Health Systems. 2015; 9:19.
24. Imamura K, Kawakami N, Furukawa T,
Matsuyama Y, Shimazu A, Umanodan R, et al.
Effects of an Internet-Based Cognitive Behavioral
Therapy Intervention on Improving WorkEngagement and Other Work-Related Outcomes:
An Analysis of Secondary Outcomes of a
Randomized Controlled Trial. J Occup Environ
Med. 2015; 57(5): 578-84.
25. Tsuno K, Kawakami N, Tsutsumi A, Shimazu A,
Inoue A, Odagiri Y, et al. Socioeconomic
determinants of bullying in the workplace: anational representative sample in Japan. PloS one.
2015; 10(3): e0119435.
26. Kan C, Kawakami N, Umeda M, Miller E; World
Mental Health Japan Survey Group 2002?2006.
Childhood adversities and adult use of potentiallyinjurious physical discipline in Japan. J Fam
Violence. 2015; 30(4): 515-527.
27. Imamura K, Kawakami N, Naganuma Y, Igarashi
Y. Development of Screening Inventories for
Bipolar Disorder at Workplace: a diagnostic
accuracy study. J Affect Disord. 2015;178:32–8.
28. Nakanishi M, Miyamoto Y. Documentation ofnursing home resident's preferences regarding
end-of-life care in Japan: Does the documentation
serve as an advanced directive in care planning?

296

European Journal for Person Centered Healthcare.
2015; 3:3.
29. Nakanishi M, Nakashima T, Shindo Y, Miyamoto
Y, Gove D, Radbruch L, van der Steen JT. An
evaluation of palliative care contents in national
dementia strategies in reference to the European
Association for Palliative Care white paper.
International Psychogeriatr. 2015; 27(9):1551611.
30. Shimazu A, Schaufeli W, Kamiyama K,
Kawakami N. Workaholism vs. Work Engagement: the Two Different Predictors of Future
Well-being and Performance. IntJ Behav Med.
2015; 22(1): 18-23.
31. Kanehara A, Umeda M, Kawakami N; World
Mental Health Japan Survey Group. Barriers tomental health care in Japan: Results from theWorld Mental Health Japan Survey. Psychiatry
Clin Neurosci. 2015; 69(9): 523-33.
32. Stickley A, Koyanagi A, Kawakami N; WHO
World Mental Health Japan Survey Group.
Childhood adversities and adult-onset chronic
pain: Results from the World Mental Health
Survey, Japan. Eur J Pain. 2015; 19(10): 1418-27.
33. Umeda M, Kawakami N, Kessler RC, Miller E;
World Mental Health Japan Survey Group 2002–
2006. Childhood adversities and adult use of
potentially injurious physical discipline in Japan.
J Fam Violence. 2015; 30(4): 515-527.
34. Miki T, Kochi T, Eguchi M, Kuwahara K,
Tsuruoka H, Kurotani K, Ito R, Akter S, Kashino I,
Pham NM, Kabe I, Kawakami N, Mizoue T, Nanri
A. Dietary intake of minerals in relation todepressive symptoms in Japanese employees: the
Furukawa Nutrition and Health Study. Nutrition.
2015; 31(5): 686-90

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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.,

Shinji Iizaka, R.N., P.H.N., Ph.D.

Project Research Associate
Shin’ichi Ikeda, Ph.D.,

WebsiteKoichi Yabunaka, Ph.D.

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 establishment of the Department of Wound Care Managementin April 2006. These two departments are currently
headed by 1 professor and assisted by 1 lecturer, 1
project lecturer, 2 research associates, 2 project
research associates, 2 part-time lecturers for undergraduate course, and 7 part-time lecturers for graduate
course. The student consists of 10 doctoral course
students, 8 master course students and 2 undergraduates. The goal of our department is to achieve“Evidence-based practice and development of gerontological nursing and wound care management”.

Teaching activities
1. Undergraduate course
1) Gerontological Nursing (3-4th yr/ 4 credits)
The aim of the 3rd year course is for students tounderstand the physical, psychological, and social
characteristics of the elderly population, and to learn
fundamental theories of gerontological nursing. The
main themes in the 2015 contents were as follows;a) Practical simulation for gerontological nursingb) Physical, psychological, and social characteristicsof the 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
understanding of the ailments and conditions required
to provide proper care to the elderly. The main themesin the 2015 contents were as follows;

298

a)
b)
c)
d)
e)

Age-related changes in the physiologic system
Aging and dementia
Aging and osteoporosis
Aging and respiratory disorders.
Aging and cardiovascular disorders, aging andrenal 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 theelderly
The above lectures were provided under the cooperation from the Department of Geriatric Medicine
and other departments at The University of Tokyo
Hospital.
2) Clinical Practice in Gerontological Nursing(4th yr/ 2 credits)
The aim of this practicum is to learn present situationof gerontological nursing through practicing in thelong-term care facility. The program in 2015 was
supported by the long-term care facility owned by
Medical Corporation Tatsuoka.
3) Bachelor’s thesis (4th yr/ 6 credits)
The followings were research themes in 2015;“Validity of malnutrition screening by Basic healthcheck list: Comparison with MNA-SF (in Japanese)”and “Virtual ultrasonic probe system to support
peripheral IV catheter site selection.” The latterbachelor’s thesis was awarded the prize for the most
exceptional article at the School of Integrated Health
Sciences, Faculty of Medicine. Additionally, thisthesis received the University of Tokyo President's
Awards.
2. Graduate course
1) Gerontological Nursing I(S1/ 2 credits)
The main theme of Gerontological Nursing I in 2015
was to understand the latest research related to thecare of elderly persons and to discuss future perspective of gerontological nursing from three viewpoints:
basic biology, engineering, and clinical nursing
research. Recent research papers were selected fromthese three fields and critically evaluated.

2) Gerontological Nursing II(A1/ 2 credits)
Gerontological Nursing II provided lectures regarding
the recent topics around gerontological medicine andnursing from the broad viewpoints including
biological, individual, and social aspects by the parttime lecturers, specialists of each research field. The
aim of this course was to understand and learn
scientific ways of thinking for gerontologicalconsiderations of the future Japanese community. The
main themes in 2015 were as follows;a) Evaluation method of ultrasonographic images
that help nursesb) The task of nursing in integrated community caresystemc) Role of mechanical engineering in nursingd) Nutritional management for elderly patientse) Good food and good healthf) Creation and dissemination of health value
innovationg) Nursing care for premature dementia patients andtheir family
3) Wound Care Management I(S2/ 2 credits)
The main topic of Wound Care Management I in 2015
was learning of basic knowledge (basic biology,
clinical research, and engineering) which is necessary
to understand the wound management studies.
The topics were as follows.
a) Basis of skin and wound healingb) Basic knowledge of pressure ulcers and nursing
approachc) Basis of clinical nursing researchd) Basis of engineering researche) Basis of molecular and cellular biologicalresearch
4) Wound Care Management II(A2/ 2 credits)
The main theme of Wound Care Management II in2015 was to obtain deeper insight in our own researchknowledge through the lectures and discussion by the
specialists with various basic and advanced research
fields.
The theme was as follows.
a) Wound Care Clinic performed by wound, ostomy,

299

b)
c)
d)
e)
f)
g)

and continence nurses
Healing process of pressure ulcers and risk factors
and care for refractory pressure ulcers
Pressure redistribution for pressure ulcer prevention
Treatment for diabetic foot ulcer or critical limb
ischemia
Pressure ulcer in home care settings
Why do dermatologist prescribe the ointment?
Toward advanced skin care5) Master’s thesis
The followings were research themes in 2015;“Development of the assessment method of extravasation in chemotherapy patients using thermographic patterns”“A novel direct skin assessment method for predicting
pressure ulcer development by using molecularbiomarkers for detecting local tissue response: An
experimental study in mice?”“Status of incidence and morphological characteristics
of pressure ulcers among inpatients with mental
illness”
5) Doctor’s thesis
The followings were research themes in 2015;“Investigation of external force on plantar associatedwith callus in diabetic neuropathy patients and its
relationship with their leg motions for foot ulcer
prevention”“Development of biomarkers for delayed woundhealing caused by pressure”“Preventing development and recurrence of skin tearin elderly patients at a long-term medical facility inJapan -Focusing on skin properties and morphological characteristics of injuries-““Intervention study for the prevention of aspiration
pneumonia by recommendation of swallowing carebased on the results of ultrasound examination”

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 at pressure ulcer multidisciplinary team rounds. We also attend the Foot Care
Outpatient Clinic held by the Department ofMetabolic Diseases and the Stoma Outpatient Clinic
held by the Departments of Urology and Colorectal
Surgery. In addition, we support the Department ofAdvanced Nursing Technology which was establishedin December 2012 as a social cooperation program topromote team nursing intervention and research
involving the clinical division, the nursing department,
and the nursing departments of Graduate school of
Medicine. Through this program, nurses canscientifically study the subject of nursing, including
research in epidemiologic surveys and molecular- andgene-level topics in cooperation. Furthermore, thetechnology and medical equipment developed bycompanies can be evaluated in the hospital, offering
new nursing technology suitable for needs in clinicalsites.
In 2015, we further promoted a new research
diagram “Bioengineering Nursing” which consists ofnursing biology that investigates the detailed
mechanism of the target phenomenon, nursing
engineering that develops technologies for the
clarified target, and nursing translational research that
evaluates the technologies in the clinical filed andfurthermore explores the new clinical problems. For
promoting this research framework to Japanese
researchers, we published a book “Bioengineering
Nursing” from University of Tokyo Press. We
organized introductory seminar for bioengineering
nursing research. We had many nursing researchersand clinical nurses from intra- and extramural ways.
We furthermore organized advanced hands-on seminarof bioengineering nursing research methodologies for
those who attended the introductory seminar and areinterested in this research framework.
Regarding international activities, our department
has been promoting collaborative research withresearchers in universities around the world. Our
counterparts include University of California, Los
Angeles (CA), Florida University (FL), Curtin

300

University (Australia), and The University of
Nottingham (UK). Professor Sanada has been working
as Secretary for World Union of Wound Healing
Societies and an International Board of Directors forInternational Lymphoedema Framework.
In 2015, we have launched a new air-mattresscalled “robotic mattress” which consists of continuousinterface pressure monitoring sensor in order toautomatically adjust inner air-cell pressure. This
product was co-developed under academic-industrial
alliance. We will evaluate clinical effectiveness of thisproduct.
2. Research fields and themes in 2015
1) Basic experimental studies
・ Development of a novel method for controllingwound infection focusing on gene expression ofbacteria and hosts
・ Evaluation of wound condition using exudates
・ Skin blotting for analyzing physiological status of
the skin・ Cutaneous wound healing and diabetes mellitus
・ Mechanisms of skin maceration
・ Research on scalp care science2) Nursing engineering
・ Development of a new air-mattress equipped withinterface pressure sensing system and automaticpressure control
・ Non-invasive detection of tissue injury and preinjury status using ultrasonography and thermography
・ Early detection of complications of peripheral
intravascular catheter by ultrasonography andthermography
・ Development of insole-type simultaneous measurement system of plantar pressure and shear
force during gait3) 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 inbreast cancer patients and its risk factors
・ Survey and international comparison oflymphoedema (collaboration with International
Lymphoedema Framework)
・ Methods for predicting skin tear development
・ Establishment of a novel diagnosis method oflatent dysphagia
・ 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.
・University of Tokyo President's Awards 2015
Noyori S. Virtual ultrasonic probe system tosupport peripheral IV catheter site selection
・Otsuka award from Japanese Society of Pressure
Ulcers.
Iizaka S, Koyanagi H, Sasaki S, Sekine R, Konya
C, Sugama J, Sanada H. Nutrition-related status andgranulation tissue colour of pressure ulcers
evaluated by digital image analysis in older patients.
J Wound Care. 2014;23(4):198-206.
・Presentation award from 45th Annual Congress ofJapanese Society for Wound Healing
Ikeda S, Minematsu T, Nakagami G, Sanada H.
Low concentration AHL can induce fibroblast
differentiation to myofibroblast through activationof mTOR pathway.
・Best poster award from 3rd Annual Congress of
Nursing Science and Engineering
Oya M, Murayama Y, Oe M, Tanabe H, Matsui Y,
Takahashi T, Otomo H, Komiyama C, Sanada H.
Continuous monitoring of temperature distribution
at the puncture site of peripheral intravascularcatheterization of chemotherapy using thermography.
・2015 Global Prospect and New Innovations for Best
Wound Care and Scar Management The Best Paper
Award
Nakagami G, Schultz G, Gibson DJ, Phillips P,
Kitamura A, Minematsu T, Miyagaki T, Hayashi A,
Sasaki S, Sugama J, Sanada H. Biofilm-guided
wound debridement: a preliminary analysis ofwound blotting membrane from pressure ulcers.
・ President award from 24th Annual Congress ofJapanese Society of Wound, Ostomy, and Continence Management

301

Koyano Y, Nakagami G, Matsumoto M, Sakai T,
Iuchi T, Yusuf S, Sugama J, Sanada H. Investigationof skin tear prevalence and its characteristics at thesite of patient ID wrist band at a long-term care
hospital.
・ President award from 24th Annual Congress ofJapanese Society of Wound, Ostomy, and Continence Management
Iizaka S, Sanada H. GIS analysis of wound,ostomy, and continence nurses in Tokyo metropolitan.

References
1. Nakagami G, Kimura N, Takehara K, Nakamura T,
Kawashima M, Tsunemi Y, Sanada H. Relationshipbetween activity of daily living and asteatosis in thelower legs among elderly residents in long-term careinstitutions: a cross-sectional study. Int Wound J.
2015;12(5):586-9.
2. Nakagami G, Sanada H, Sugama J. Development
and evaluation of a self-regulating alternatingpressure air cushion. Disabil Rehabil Assist Technol.
2015;10(2):165-9.
3. Kishi C, Minematsu T, Huang L, Mugita Y,
Kitamura A, Nakagami G, Yamane T, Yoshida M,
Noguchi H, Funakubo M, Mori T, Sanada H.
Hypoosmotic shock-induced subclinical inflammation of skin in a rat model of disrupted skin barrier
function. Biol Res Nurs. 2015;17(2):135-41.
4. Yamane T, Nakagami G, Yoshino S, Shimura M,
Kitamura A, Kobayashi-Hattori K, Oishi Y,
Nishijima Y, Minematsu T, Sanada H. Hydrocellularfoam dressings promote wound healing associatedwith decrease in inflammation in rat periwound skinand granulation tissue, compared with hydrocolloid
dressings. Biosci Biotechnol Biochem. 2015;79(2):185-9.
5. Iizaka S, Kaitani T, Nakagami G, Sugama J, Sanada
H. Clinical validity of the estimated energy requirement and the average protein requirement for
nutritional status change and wound healing in older
patients with pressure ulcers: A multicenterprospective cohort study. Geriatr Gerontol Int. 2015;15(11):1201-9.
6. Yabunaka K, Matsuo J, Hara A, Takii M, Nakagami
G, Gotanda T, Nishimura G, Sanada H. Sonographic

visualization of fecal loading in adults: comparison
with computed tomography. J Diagn Med Sonogr.
2015;31(2):86-92.
7. Oe M, Takehara K, Ohashi Y, Mugita Y, Murayama
R, Komiyama C, Ueki K, Kadowaki T, Sanada H.
Incidence of foot ulcers in patients with diabetes at auniversity hospital in Tokyo over a 5-year period.
Diabetol Int. 2015;6(1):55-9.
8. Sari Y, Sanada H, Minematsu T, Nakagami G,
Nagase T, Huang L, Noguchi H, Mori T, Yoshimura
K, Sugama J. Vibration inhibits deterioration in rat
deep-tissue injury through HIF1-MMP axis. Wound
Repair Regen. 2015;23(3):386-93.
9. Sari Y, Minematsu T, Huang L, Noguchi H, Mori T,
Nakagami G, Nagase T, Oe M, Sugama J,
Yoshimura K, Sanada H. Establishment of a novel
rat model for deep tissue injury deterioration. Int
Wound J. 2015;12(2):202-9.
10. Kaneko M, Minematsu T, Yoshida M, Nishijima Y,
Noguchi H, Ohta Y, Nakagami G, Mori T, Sanada H.
Compression-induced HIF-1 enhances thrombosis
and PAI-1 expression in mouse skin. Wound Repair
Regen. 2015;23(5):657-63.
11. Kitamura YA, Minematsu T, Nakagami G, Iizaka S,
Fujita H, Naito A, Takahashi K, Mori T, Sanada H.
Prediction of healing progress of pressure ulcers by
distribution analysis of protein markers on necrotic
tissue: A retrospective cohort study. Wound Repair
Regen. 2015;23(5):772-7.
12. Arias S, Cardiel E, Garay L, Sanada H, Mori T,
Noguchi H, Nakagami G, Rogeli P. Effects on
interface pressure and tissue oxygenation underischial tuberosities during the application of analternating cushion. J Tissue Viability. 2015;24(3):91-101.
13. Tsunemi Y, Takehara K, Miura Y, Nakagami G,
Sanada H, Kawashima M. Diagnosis of tinea pedis
by dermatophyte test strip. Br J Dermatol. 2015;
173(5):1323-4.
14. Nakagami G, Minematsu T, Morohoshi T, Yamane T,
Kanazawa T, Huang L, Asada M, Nagase T, Ikeda S,
Ikeda T, Sanada H. Pseudomonas aeruginosa
quorum-sensing
signaling
molecule
N-3oxododecanoyl homoserine lactone induces matrix
metalloproteinase 9 expression via the AP1 pathway
in rat fibroblasts. Biosci Biotechnol Biochem. 2015;
79(10):1719-24.

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15. Yoshimura M, Nakagami G, Iizaka S, Yoshida M,
Uehata Y, Kohno M, Kasuya Y, Mae T, Yamasaki T,
Sanada H. Microclimate is an independent risk
factor for the development of intraoperatively
acquired pressure ulcers in the park-bench position:
A prospective observational study. Wound Repair
Regen. 2015;23(6):939-47.
16. Tasaki N, Minematsu T, Mugita Y, Ikeda S,
Nakagami G, Sanada H. Telogen elongation in thehair cycle of ob/ob mice. Biosci Biotechnol
Biochem. 2015;80(1):74-9.
17. 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. Int
Wound J. 2015. doi: 10.1111/iwj.12454.
18. Tamai N, Akase T, Minematsu T, Higashi K, Toida T,
Igarashi K, Sanada H. Association between components of exudates and periwound moistureassociated dermatitis in breast cancer patients withmalignant fungating wounds. Biol Res Nurs. 2016;18(2):199-206.
19. Kaitani T, Nakagami G, Iizaka S, Fukuda T, Oe M,
Igarashi A, Mori T, Takemura Y, Mizokami Y,
Sugama J, Sanada H. Cost-utility analysis of anadvanced pressure ulcer management protocol
followed by trained wound, ostomy, and continence
nurses. Wound Repair Regen. 2015;23(6):915-21.
20. Yoshino S, Nakagami G, Ohira T, Kawasaki R,
Shimura M, Iwatsuki K, Sanada H, KobayashiHattori K, Oishi Y, Yamane T. Hydrocellular foam
dressing increases the leptin level in wound fluid.
Wound Repair Regen. 2015;23(5):703-10.
21. Mugita Y, Minematsu T, Huang L, Nakagami KG,
Ichikawa Y, Nagase T, Oe M, Noguchi H, Mori T,
Abe M, Sugama J, Sanada H. Histopathology ofincontinence-associated skin lesions: inner tissue
damage due to invasion of proteolytic enzymes andbacteria in macerated rat skin. PLoS One. 2015;
10(9):e0138117.
22. Amemiya A, Noguchi H, Oe M, Ohashi Y, Takehara
K, Ueki K, Kadowaki T, Sanada H, Mori T.
Comparison of gait features between feet with callus
or corns and normal feet using motion sensors in
people with diabetes and people without diabetes. J
Diabetes Sci Technol. 2015;10(2):614-5.

23. Sanada H, Mori T (eds). Bioengineering Nursing.
University of Tokyo Press, 2015.

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
Hiroshi Nishiura, MD, PhD

Assistant Professor
Stuart Gilmour, MPH, MStat, PhD
Shinji Nakaoka, MEng, PhD

Project assistant professor
Eiko Saito, MSc, PhD
Mayuka Yamazaki, MS
Anne Smith, MPH
Sarah Abe, MScPH, 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 (Hiroshi
Nishiura); two assistant professors (Stuart Gilmour
and Shinji Nakaoka); four project assistant professors(Eiko Saito, Mayuka Yamazaki ,Anne Smith, SarahAbe); three post-doctoral fellows; 10 adjunctlecturers; eight doctoral students; and twelve master’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).

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Finally, the fundamental role of the department is to
produce the next generations of leaders in global
health.

Education
All lectures in the department are conducted in
English, in order to ensure that student writing 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 governanceSocial 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.
Development and evaluation of food safety policy inJapan. Ministry of Health, Labour, and Welfare Healthand Labour Science Research Grants. PI: Kenji
ShibuyaAn evidence-based assessment of the Japanese healthsystem. Ministry of Health, Labour, and Welfare
Health and Labour Science Research Grants. PI: Kenji
Shibuya
Assessment of sustainable and effective universal
health coverage (UHC) systems and Japan’scontribution to UHC. Ministry of Health, Labour, and306

Welfare Health and Labour Science Research Grants.
PI: Kenji Shibuya
Global Health Entrepreneurship Program. PI: Kenji
Shibuya
AXA Chair on Health and Human Security, AXA
Research Fund
Comprehensive Research on Life-Style Related Diseases Including Cardiovascular Diseases and Diabetes
Mellitus: Projection of disease burden and economic
burden allowing for change in population structure,socioeconomic status, and lifestyles in Japan. Ministryof Health, Labour, and Welfare Health and Labour
Science Research Grants. PI: Manami Inoue.
Development and Evaluation of Cancer Prevention
Strategies in Japan. National Cancer Center, National
Cancer Center Research and Development Fund. CI:
Manami Inoue
The burden of cancer attributable to diabetes mellitus
in Japan. Ministry of Education, Culture, Sports,
Science and Technology, Grants-in-Aid for Scientific
Research (C). PI: 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
Detecting premonitory signs, real time forecasting anddesigning interventions against a pandemic using large
scale biological datasets. Japan Science and Technology Agency CREST project on the application of
bigdata analysis to real world. PI: Hiroshi Nishiura
Realizing policymaking against infectious diseases
using a mathematical model: Interventions against
infectious disease. Japan Science and Technology
Agency RISTEX program for Science for Policy
Making using Innovative Science and Technology
Advancement. PI: Hiroshi Nishiura
Development and improvement of research infrastructure for the use of mathematical modeling of
infectious diseases for health policy making. Japan

Agency for Medical and Research Development(AMED) Research Program. Commissioned Research
program against emerging and re-emerging infectious
diseases. PI: Hiroshi Nishiura
Quantifying the transmission dynamics using theillness onset information. Young Investigator Research
Program category A. Grants-in-Aid for Scientific
Research, Japan Society for the Promotion of Science.
PI: Hiroshi Nishiura
Optimization study of immunization program using amathematical model. Challenging Exploratory Research. Grants-in-Aid for Scientific Research, Japan
Society for the Promotion of Science. PI: Hiroshi
Nishiura
Donation for Scientific Research, Tokyo Society of
Medical Sciences. PI: Hiroshi Nishiura
Donation for Scientific Research, Public HealthResearch Center. PI: Hiroshi Nishiura
Developing estimation method to estimate HIV
infected individuals and understand the epidemiological dynamics. Ministry of Health, Labour andWelfare (MHLW), Japan.
Grant-in-aid program for controlling HIV/AIDS. PI:
Hiroshi Nishiura
Multi-scale modeling of dynamical immune responses: toward understandings of skin inflammatory
diseases. Ministry of Education, Culture, Sports,
Science and Technology, Grants-in-aid for young
scientists. PI: Shinji Nakaoka.
Construction of yeast artificial evolution systems.
Ministry of Education, Culture, Sports, Science andTechnology, Grants-in-aid for Scientific Research (C).
PI: Shinji Nakaoka.
Theory of multi-scale modeling for effective antivirus therapies development. Ministry of Education,
Culture, Sports, Science and Technology, Grants-inaid for Scientific Research (C). CI: Shinji Nakaoka.

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Publications
1. Svensson T, Inoue M, Sawada N, Iwasaki M,
Sasazuki S, Shimazu T, Yamaji T, Ikeda A,
Kawamura N, Mimura M, Tsugane S. The
association between complete and partial nonresponse to psychosocial questions and suicide:
the JPHC Study. The European Journal of Public
Health. 2014; 25(3):424-30.
2. Tsubokura M, Kato S, Nomura S, Morita T,
Sugimoto A, Gilmour S Kami M, Oikawa T,
Kanazawa Y. Absence of Internal Radiation
Contamination by Radioactive Cesium among
Children Affected by the Fukushima Daiichi
Nuclear Power Plant Disaster. Health Physics.
2015;108(1): 39-43.
3. Nakayama R, Koyanagi A, Stickley A, Kondo T,
Gilmour S, Arenliu A, Shibuya K. Social
networks and mental health in post-conflict
Mitrovica, Kosova. BMC Public Health. 2014;14:1169
4. Kim J, Shin S, Han K, Lee K, Kim J, Choi Y, Kim
D, Nam G, Yeo H, Lee H, Ko B. Relationshipbetween socioeconomic status and anemia
prevalence in adolescent girls based on the fourthand fifth Korean National Health and Nutrition
Examination Surveys. European Journal of
Clinical Nutrition. 2014; 68(2): 253-258.
5. Chowell G, Nishiura H. Transmission dynamics
and control of Ebola virus disease (EVD): a
review. BMC Medicine. 2014; 12:196
6. Tanaka K, Tsuji I, Tamakoshi A, Matsuo K,
Wakai K, Nagata C, Mizoue T, Inoue M, Tsugane
S, Sasazuki S; Research Group for the Development and Evaluation of Cancer Prevention
Strategies in Japan. Diabetes mellitus and livercancer risk: an evaluation based on a systematic
review of epidemiologic evidence among theJapanese population. Japanese Journal of ClinicalOncology. 2014;44(10):986-99.
7. Nishiura H, Chowell G. Early transmission
dynamics of Ebola virus disease (EVD), West
Africa, March to August 2014. Eurosurveillance.
2014;19(36): pii=20894.
8. Miki Y, Inoue M, Ikeda A, Sawada N, Nakaya T,
Shimazu T, Iwasaki M, Yamaji T, Sasazuki S,
Shibuya K, Tsugane S; JPHC Study Group.

Neighborhood deprivation and risk of cancer
incidence, mortality and survival: results from a
population-based cohort study in Japan. PLoS
One. 2014;9(9):e106729.
9. Weiderpass E, Sandin S, Lof M, Oh JK, Inoue M,
Shimazu T, Tsugane S, Adami HO. Endometrial
cancer in relation to coffee, tea, and caffeine
consumption: a prospective cohort study among
middle-aged women in Sweden. Nutrition andCancer. 2014;66(7):1132-43
10. Honjo K, Iso H, Inoue M, Sawada N, Tsugane S;
JPHC Study Group. Socioeconomic status
inconsistency and risk of stroke among Japanese
middle-aged women. Stroke. 2014;45(9):2592-8.
11. Mizumoto K, Ejima K, Yamamoto T, Nishiura H.
On the risk of severe dengue during secondary
infection: a systematic review coupled withmathematical modeling. Journal of vector borne
diseases. 2014;51(3):153-164.
12. Cowling B, Ip DK, Fang VJ, Suntarattiwong P,
Olsen S, Levy J, Uyeki T, Leung G, Peiris J,
Chotpitayasunondh T, Nishiura H, Simmerman J.
Modes of transmission of influenza B virus inhouseholds. PLOS ONE. 2014;9(9):e108850.
13. Tanimoto T, Kami M, Shibuya K. Misconduct:
Japan to learn from biomedical cases. Nature.
2014; 512: 371.
14. Saito E, Gilmour S, Rahman MM, Gautam GS,
Shreshta PK, Shibuya K. Incidence of andillnesses associated with catastrophic household
expenditure on health in Nepal: a cross-sectional
survey. Bulletin of the World Health Organization.
2014; 92:760-767.
15. Moreno R, Nababan H, Ota E,Wariki W, Ezoe S,
Gilmour S, Shibuya K. Structural andcommunity-level interventions for increasing
condom use to prevent transmission of HIV andother sexually transmitted infections. Cochrane
Database of Systematic Reviews. 2014; 7:CD
003363.
16. Murray C, Ortblad K, Guinovart C, Lim S,
Woltock T, et al. Global, regional and national
incidence and mortality for HIV, tuberculosis andmalaria during 1990-2013: a systematic analysis
for the Global Burden of Disease Study 2013. The
Lancet. 2014; 384(9947):1005-70.

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17. Shin S, Park E, Sun D, You T, Hwang S, Paik H,
Joung H. Development and Evaluation of a Webbased Computer-Assisted Personal Interview
System (CAPIS) for Open-ended Dietary
Assessments among Koreans. Clinical Nutrition
Research. 2014; 3: 115-125
18. Research Group for the Development and
Evaluation of Cancer Prevention Strategies inJapan. Meat consumption and colorectal cancer
risk: an evaluation based on a systematic review
of epidemiologic evidence among the Japanese
population. Japanese Journal of Clinical Oncology. 2014;44(7):641-50.
19. Shimazu T, Wakai K, Tamakoshi A, Tsuji I,
Tanaka K, Matsuo K, et al. Association ofvegetable and fruit intake with gastric cancer risk
among Japanese: A pooled analysis of four cohort
studies. Annals of Oncology. 2014; 25(6): 122833.
20. Tsubokura M, Kato S, Nomura S, Gilmour S,
Nihei M, Sakuma Y, Oikawa T, Kanazawa Y,
Kami M, Hayano R. Reduction of high levels ofinternal radio-contamination by dietary intervention in residents of areas affected by the
Fukushima Daiichi nuclear plant disaster: a caseseries. PLOS ONE. 2014; 9(6):e100302.
21. Nakaya T, Honjo K, Hanibuchi T, Ikeda A, Iso H,
Inoue M, Sawada N, Tsugane S; Japan Public
Health Center-based Prospective Study Group.
Associations of all-cause mortality with censusbased neighbourhood deprivation and population
density in Japan: a multilevel survival analysis.
PLoS One. 2014;9(6):e97802.
22. Shibuya K, Gilmour S, Oshima A. Time toreconsider thyroid cancer screening in Fukushima.
The Lancet. 2014; 383(9932): 1883-1884.
23. Gilmour S, Liao Y, Bilano V, Shibuya K. Burdenof disease in Japan: Using national and subnational data to inform local health policy.
Journal of Preventive Medicine and Public Health.
2014; 47(3): 136-143
24. Ng M, Fleming T, Robinson M, Thomson B,
Graetz N, et al. Global, regional, and national
prevalence of overweight and obesity in children
and adults during 1980—2013: a systematic
analysis for the Global Burden of Disease Study
2013. The Lancet. 2014; 384 (9945):766 - 781.

25. Nishiura H, Ejima K, Mizumoto K, Nakaoka S,
Inaba H, Imoto S, Yamaguchi R, Saito MM.
Cost-effective length and timing of school closure
during an influenza pandemic depend on theseverity. Theoretical Biology and Medical
Modelling. 2014;11:5.
26. Wang H, Liddell CA, Coates MM, Mooney MD,
Levitz CE, Schumacher AE, et al. Global,
regional, and national levels of neonatal, infant,and under-5 mortality during 1990–2013: asystematic analysis for the Global Burden of
Disease Study 2013. The Lancet. 2014; 384(9945):766-781.
27. Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS,
Shackelford KA, Steiner C, Heuton KR, et al.
Global, regional, and national levels and causes ofmaternal mortality during 1990–2013: asystematic analysis for the Global Burden of
Disease Study 2013. The Lancet. 2014; 384(9947):980-1004.
28. Sakurai-Komada N, Iso H, Koike KA, Ikeda A,
Umesawa M, Ikehara S, et al. Association
between chlamydophila pneumoniae infection
and risk of coronary heart disease for Japanese:
The JPHC study. Atherosclerosis. 2014;233(2):338-342
29. Eshak ES, Iso H, Yamagishi K, Kokubo Y, Saito I,
Yatsuya H, et al. Rice consumption is not
associated with risk of cardiovascular diseasemorbidity or mortality in Japanese men andwomen: a large population-based, prospective
cohort study. American Journal of ClinicalNutrition. 2014; 100(1): 199-207.
30. Yamauchi T, Inagaki M, Yonemoto N, Iwasaki M,
Inoue M, Akechi T, Iso H, Tsugane S, on behalf of
the JPHC Study Group. Death by suicide andother externally caused injuries following acancer diagnosis: the Japan Public Health Centerbased Prospective Study. Psychooncology. 2014;23(9):1034-1041.
31. Sawada N, Inoue M, Iwasaki M, Sasazuki S,
Yamaji T, Shimazu T, Tsugane S. Alcohol andsmoking and subsequent risk of prostate cancer inJapanese men: The Japan Public Health Centerbased prospective study. International Journal ofCancer. 2014;134(4):971-8.

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32. Zheng W, McLerran DF, Rolland BA, Fu Z,
Boffetta P, He J, et al. Burden of total andcause-specific mortality related to tobaccosmoking among adults aged >=45 years in Asia: apooled analysis of 21 cohorts. PLoS Medicine.
2014;11(4):e1001631.
33. Ejima K, Aihara K, Nishiura H. Probabilistic
differential diagnosis of Middle East respiratory
syndrome (MERS) using the time from immigration to illness onset among imported cases.
Journal of Theoretical Biology. 2014;346:47-53.
34. Ueno R, Nishiura H. Letter to the editor:
Diagnosis of a single imported dengue case who
had travelled to Japan – how serious is it for
travellers? Eurosurveillance. 2014. 19(8):pii=
20715.
35. Rahman MM. Health in Bangladesh: lessons andchallenges. Lancet.2014. 383(9922):1037. doi: 10.
1016/S0140-6736(14)60513-4.
36. Akter S, Rahman MM, Abe SK, Sultana S.
Prevalence of diabetes and prediabetes and theirrisk factors among Bangladeshi adults: anationwide survey. Bulletin of the World HealthOrganization. 2014; 92:204-213A.
37. Shakeshaft A, Doran C, Petrie D, Breen C,
Havard A, Abudeen A, Harwood E, Clifford A,
D'Este C, Gilmour S, Sanson-Fisher R. The
Effectiveness of Community Action in Reducing
Risky Alcohol Consumption and Harm: A Cluster
Randomised Controlled Trial. PLOS Medicine.
2014.11(3):e1001617.
38. Nakaoka S, Inaba H. Demographic modeling oftransient amplifying cell population growth.
Mathematical Biosciences and Engineering.
2014; 11(2): 363 - 384.
39. Nagata C, Mizoue T, Tanaka K, Tsuji I,
Tamakoshi A, Matsuo K, et al. Soy intake andbreast cancer risk: An evaluation based on asystematic review of epidemiologic evidence
among the Japanese population. Japanese Journalof Clinical Oncology. 2014;44(3):282-295.
40. Svensson T, Inoue M, Charvat H, Sawada N,
Iwasaki M, Sasazuki S, et al. Coping behaviors
and suicide in the middle-aged and older Japanesegeneral population: the Japan Public HealthCenter-based Prospective Study. Annals of
Epidemiology. 2014;24(1):199-205.

41. Bilano V, Ota E, Togoobaatar G, Mori R, Souza
JP. Risk Factors of Pre-Eclampsia/Eclampsia and
Its Adverse Outcomes in Low- and MiddleIncome Countries: A WHO Secondary Analysis.
PLOS ONE. 2014.
42. Sugimoto A, Gilmour S, Tsubokura M, Nomura S,
Kami M, Oikawa T, Kanazawa Y, Shibuya K.
Assessment of the Risk of Medium-Term Internal
Contamination in Minamisoma City, Fukushima,
Japan, after the Fukushima Dai-ichi Nuclear
Accident. Environmental Health Perspectives.
2014;122(6): 587-593.
43. Nabae K, Satoh H, Nishiura H, Tanaka-Taya K,
Okabe N, Oishi K, Matsumoto K, Hasegawa T.
Estimating the risk of parvovirus B19 infection inblood donors and pregnant women in Japan.
PLOS ONE. 2014;9(3):e92519.
44. Yoneoka D, Hisashige A, Ota E, Miyamoto K,
Nomura S, Segawa M, Gilmour S, Shibuya K. Are
Japanese Randomized Controlled Trials Up to the
Task? A Systematic Review. PLOS ONE. 2014;
9(3): e90127.
45. Tsubokura M, Hara K, Matsumura T, Sugimoto A,
Nomura S, Hinata M, Shibuya K, Kami M. The
Immediate Physical and Mental Health Crisis in
Residents Proximal to the Evacuation Zone After
Japan's Nuclear Disaster: An Observational Pilot
Study. Disaster Medicine and Public HealthPreparedness. 2014;8(1):30-36.
46. Wada K, Nagata C, Tamakoshi A, Matsuo K, Oze
I, Wakai K, et al. Body mass index and breast
cancer risk in Japan: a pooled analysis of eight
population-based cohort studies. Annals of
Oncology. 2014;25(2):519-524.

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Department of Community andGlobal HealthProfessor, Academic Leader
Masamine Jimba, MD, PhD, MPH
Assistant Professors
Junko Yasuoka, DSc, MPH
Keiko Nanishi, MD, PhD
Akira Shibanuma, MID
Specially-Appointed Assistant Professor
Kimiyo Kikuchi, PhD, MHSc
Project Researcher
Sumiyo Okawa, PhD, MHSc
Homepage: 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 (19992005), 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 activate
community-based activities and how to link abottom-up approach to national and international
policy. The department currently consists of: 1
department chair and professor, 3 assistant professors,
1 specially-appointed assistant professor, 1 project
researcher, 11 visiting lecturers, 15 doctoral course
students, 16 master’s course students, 4 research
students, and 25 visiting researchers. About 51% of
the students are international 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 JICA. The ‘healthand human security’ guideline is almost ready and will
be published in 2016.
In addition, we contributed to a WHO conferenceon school health and play a key role to strengthenschool health at global level.
Furthermore, we carried out a research project onmaternal and child health in Ghana in collaboration

311

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 strengthening human resources, we invitedhealth officers from Ghana, Myanmar, and Nepal to
Japan and held a workshop of maternal, neonatal andchild health.

Teaching Activities
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 graduate school curriculum is composed
mainly of community and global health advanced
courses, exercises and practical work. All curricula
focus on community health. Our main educational
activities other than curriculum include technicalassistance in writing Master’s and doctoral theses. We
always encourage students to publish their theses ininternational journals. In addition, we urge students togain experiences in the field and learn about real
global health from their experiences.
Because we have many international students, alllectures, practices, and discussions are carried out inEnglish. For those who don’t have health/medical
background, we provide a wide variety of curriculafrom basics to advanced level.
We also provide trainings to young leaders fromoverseas run by the JICA and lectures in different
universities.

Research Activities
The major objectives of our research activities are
the following two:1) To promote research which has a significant
impact on global and local societies;2) To promote research which contributes toendogenous development.
We aim at demonstrating research findings basedon community-based data directly collected from thefield. Therefore, we place high importance onfieldwork. At the same time, our department aims tocontribute to policy making and promoting actions forbetter health by making the best use of communitybased research. We carry out research by working intandem with different research institutes, internationalorganizations, JICA, NGOs, and universities indeveloping countries. We conduct research mainly indeveloping countries, but we also are 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.

References
1. Mlunde LB, Sunguya BF, Mbwambo JK,
Ubuguyu OS, Shibanuma A, Yasuoka J, Jimba M.
Correlates of health care seeking behaviour
among people who inject drugs in Dar es Salaam,
Tanzania. Int J Drug Policy. 2016 Apr;30:66-73.
2. Yeji F, Shibanuma A, Oduro A, Debpuur C,
Kikuchi K, Owusu-Agei S, Gyapong M, Okawa
S, Ansah E, Asare GQ, Nanishi K, Williams J,
Addei S, Tawiah C, Yasuoka J, Enuameh Y,
Sakeah E, Wontuo P, Jimba M, Hodgson A;
Ghana EMBRACE Implementation Research
Project Team. Continuum of Care in a Maternal,
Newborn and Child Health Program in Ghana:
Low Completion Rate and Multiple Obstacle
Factors. PLoS One. 2015 Dec 9;10(12):e0142849.
3. Wai KM, Shibanuma A, Oo NN, Fillman TJ, Saw
YM, Jimba M. Are Husbands Involving in Their
Spouses' Utilization of Maternal Care Services?:
A Cross-Sectional Study in Yangon, Myanmar.
PLoS One. 2015 Dec 7;10(12):e0144135.
4. Poudel KC, Poudel-Tandukar K, Palmer PH,
Mizoue T, Jimba M, Kobayashi J, Acharya B,
Pandey BD, Oka S. Coinfection of Sexually

312

Transmitted Infections among HIV-Positive
Individuals: Cross-Sectional Results of a
Community-Based Positive Living with HIV(POLH) Study in Nepal. J Int Assoc Provid AIDS
Care. 2015 Nov 2.
5. Okawa S, Chirwa M, Ishikawa N, Kapyata H,
Msiska CY, Syakantu G, Miyano S, Komada K,
Jimba M, Yasuoka J. Longitudinal adherence toantiretroviral drugs for preventing mother-tochild transmission of HIV in Zambia. BMC
Pregnancy Childbirth. 2015 Oct 12;15:258.
6. Saito J, Tabuchi T, Shibanuma A, Yasuoka J,
Nakamura M, Jimba M. 'Only Fathers Smoking'Contributes the Most to Socioeconomic
Inequalities:
ChangesinSocioeconomic
Inequalities in Infants' Exposure to Second Hand
Smoke over Time in Japan. PLoS One. 2015 Oct
2;10(10):e0139512.
7. Kikuchi K, Ansah EK, Okawa S, Enuameh Y,
Yasuoka J, Nanishi K, Shibanuma A, Gyapong M,
Owusu-Agyei S, Oduro AR, Asare GQ, Hodgson
A, Jimba M; Ghana EMBRACE Implementation
Research Project Team. Effective Linkages ofContinuum of Care for Improving Neonatal,
Perinatal, and Maternal Mortality: A Systematic
Review and Meta-Analysis. PLoS One. 2015 Sep
30;10(9):e0139288.
8. Jayatilleke AC, Jayatilleke AU, Yasuoka J, Jimba
M. Prevention of violence against women andgirls at the community level. Lancet. 2015 Aug 1;
386(9992):427-8.
9. Ong KI, Yi S, Tuot S, Chhoun P, Shibanuma A,
Yasuoka J, Jimba M. What are the factors
associated with depressive symptoms amongorphans and vulnerable children in Cambodia?
BMC Psychiatry. 2015 Jul 29;15:178.
10. Takahashi K, Sase E, Kato A, Igari T, Kikuchi K,
Jimba M. Psychological resilience and active
social participation among older adults withincontinence: a qualitative study. Aging Ment
Health. 2015 Jul 15:1-7.
11. Myint KZ, Nonaka D, Jimba M, Nanishi K,
Poudel KC, Yasuoka J, Miyagi M, Shinjo M,
Kobayashi J. Unnecessary Dieting Intention and
Behavior among Female Students in Naha City,
Japan. Trop Med Health. 2015 Jun;43(2):131-40.

12. Nanishi K, Green J, Taguri M, Jimba M.
Determining a Cut-Off Point for Scores of theBreastfeeding Self-Efficacy Scale-Short Form:
Secondary Data Analysis of an Intervention Studyin Japan. PLoS One. 2015 Jun 24; 10(6):e0129698.
13. Okawa S, Ansah EK, Nanishi K, Enuameh Y,
Shibanuma A, Kikuchi K, Yasuoka J, Gyapong M,
Owusu-Agyei S, Oduro AR, Asare GQ, Hodgson
A, Jimba M; Ghana EMBRACE Implementation
Research Project Team. High Incidence of
Neonatal Danger Signs and Its Implications for
Postnatal Care in Ghana: A Cross-Sectional Study.
PLoS One. 2015 Jun 19;10(6):e0130712.
14. Matsumoto-Takahashi EL, Tongol-Rivera P,
Villacorte EA, Angluben RU, Jimba M, Kano S.
Patient Knowledge on Malaria Symptoms Is a
Key to Promoting Universal Access of Patients toEffective Malaria Treatment in Palawan, thePhilippines. PLoS One. 2015 Jun 16; 10(6):e0127858.
15. Jayatilleke AU, Poudel KC, Dharmaratne SD,
Jayatilleke AC, Jimba M. Factors associated with
RTCs among for-hire three-wheeler drivers in Sri
Lanka: a case-control study. Inj Prev. 2015 Dec;
21(6):374-80.
16. Parajuli VJ, Macdonald S, Jimba M. SocialContextual Factors Associated with Alcohol Useamong Adolescents of Traditional Alcohol User
and Nonuser Ethnic Groups of Nepal. J Ethn
Subst Abuse. 2015;14(2):151-65.
17. Fujita M, Poudel KC, Green K, Wi T,
Abeyewickreme I, Ghidinelli M, Kato M, Vun
MC, Sopheap S, San KO, Bollen P, Rai KK,
Dahal A, Bhandari D, Boas P, Yaipupu J,
Sirinirund P, Saonuam P, Duong BD, Nhan do T,
Thu NT, Jimba M. HIV service delivery models
towards 'Zero AIDS-related Deaths': a collaborative case study of 6 Asia and Pacific countries.
BMC Health Serv Res. 2015 Apr 24;15:176.
18. Kikuchi K, Ansah E, Okawa S, Shibanuma A,
Gyapong M, Owusu-Agyei S, Oduro A,
Quansah-Asare G, Hodgson A, Jimba M;Ghana
EMBRACE Implementation Research Project.
Ghana's Ensure Mothers and Babies Regular
Access to Care (EMBRACE) program: study

313

protocol for a cluster randomized controlled trial.
Trials. 2015 Jan 27;16:22.
19. Jayatilleke AC, Yoshikawa K, Yasuoka J, Poudel
KC, Fernando N, Jayatilleke AU, Jimba M.
Training Sri Lankan public health midwives on
intimate partner violence: a pre- and postintervention study. BMC Public Health. 2015 Apr
7;15:331.
20. Kanamori S, Sow S, Castro MC, Matsuno R,
Tsuru A, Jimba M. Implementation of 5S
management method for lean healthcare at ahealth center in Senegal: a qualitative study ofstaff perception. Glob Health Action. 2015 Apr 7;
8:27256.
21. Sakisaka K, Chadeka EA, Nagi S, Mwandembo
DS, Jimba M. Introduction of a community watersupply in rural western Kenya: impact oncommunity wellbeing and child health. Int Health.
2015 May;7(3):204-11.
22. Thandar MM, Kyaw MP, Jimba M, Yasuoka J.
Caregivers' treatment-seeking behaviour forchildren under age five in malaria-endemic areasof rural Myanmar: a cross-sectional study. Malar
J. 2015 Jan 5;14:1.
23. Hongo H, Nanishi K, Shibanuma A, Jimba M. Is
baby-friendly breastfeeding support in maternity
hospitals associated with breastfeeding satisfaction among Japanese mothers? Matern Child
Health J. 2015 Jun;19(6):1252-62.
24. Jayatilleke A, Jayatilleke A, Jimba M, Yasuoka J.
Informal social control and intimate partner
violence. Inj Prev. 2015 Feb;21(1):70.
25. Takahashi K, Kato A, Igari T, Sase E, Shibanuma
A, Kikuchi K, Nanishi K, Jimba M, Yasuoka J.
Sense of coherence as a key to improve homebound status among older adults with urinary
incontinence. Geriatr Gerontol Int. 2015 Jul;
15(7):910-7.
26. Saito J, Keosada N, Tomokawa S, Akiyama T,
Kaewviset S, Nonaka D, Waikugul J, Kobayashi J,
Souvanvixay M, Jimba M. Factors influencing the
National School Health Policy implementation in
Lao PDR: a multi-level case study. Health Promot
Int. 2015 Dec;30(4):843-54.

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,
3 research associates, 8 graduate students, and 7
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.

316

References
1. Miyagawa T, Toyoda H, Hirataka A, Kanbayashi
T, Imanishi A, Sagawa Y, Kotorii N, Kotorii T,
Hashizume Y, Ogi K, Hiejima H, Kamei Y, Hida
A, Miyamoto M, Imai M, Fujimura Y, Tamura Y,
Ikegami A, Wada Y, Moriya S, Furuya H, Kato M,
Omata N, Kojima H, Kashiwase K, Saji H, Khor
SS, Yamasaki M, Wada Y, Ishigooka J, Kuroda K,
Kume K, Chiba S, Yamada N, Okawa M, Hirata K,
Uchimura N, Shimizu T, Inoue Y, Honda Y,
Mishima K, Honda M, and Tokunaga K. New
susceptibility variants to narcolepsy identified in
HLA class II region. Hum. Mol. Genet. 24(3):891-898, 2015.
2. Ikeda M, Yoshimura R, Hashimoto R, Kondo K,
Saito T, Shimasaki A, Ohi K, Tochigi M,
Kawamura Y, Nishida N, Miyagawa T, Sasaki T,
Tokunaga K, Kasai K, Takeda M, Nakamura J,
Ozaki N, and Iwata N. Genetic overlap between
antipsychotic response and susceptibility toschizophrenia. J. Clin. Psychopharmacol. 35(1):85-88, 2015.
3. Miyadera H, Ohashi J, Lernmark Å, Kitamura T,
and Tokunaga K: Cell surface MHC density
profiling reveals instability of autoimmunityassociated HLA. J. Clin. Invest. 125(1): 275-291,
2015.
4. Iio E, Matsuura K, Nishida N, Maekawa S,
Enomoto N, Nakagawa M, Sakamoto N,
Yatsuhashi H, Kurosaki M, Izumi N, Hiasa Y,
Masaki N, Ide T, Hino K, Tamori A, Honda M,
Kaneko S, Mochida S, Nomura H, Nishiguchi S,
Okuse C, Itoh Y, Yoshiji H, Sakaida I, Yamamoto
K, Watanabe H, Hige S, Matsumoto A, Tanaka E,
Tokunaga K, and Tanaka Y. Genome-wide
association study identifies a PSMD3 variant
associated with neutropenia in interferon-based
therapy for chronic hepatitis C. Hum. Genet.
134(3): 279-289, 2015.
5. Shimada-Sugimoto M, Otowa T, Miyagawa T,
Khor SS, Kashiwase K, Sugaya N, KawamuraY,
Umekage T, Kojima H, Saji H, Miyashita A,
Kuwano R, Kaiya H, Kasai K, Tanii H, Tokunaga
K, and Sasaki T. Immune-related pathways
including HLA-DRB1*13:02 are associated withpanic disorder. Brain Behav. Immun. 46: 96-103,

2015.
6. Ueta M, Sawai H, Sotozono C, Hitomi Y, Kaniwa
N, Kim MK, Seo KY, Yoon KC, Joo CK,
Kannabiran C, Wakamatsu TH, Sangwan V, Rathi
V, Basu S, Ozeki T, Mushiroda T, Sugiyama E,
Maekawa K, Nakamura R, Aihara M, Matsunaga
K, Sekine A, Gomes JÁP, Hamuro J, Saito Y,
Kubo M, Kinoshita S, and Tokunaga K. IKZF1, a
new susceptibility gene for cold medicine–related
Stevens-Johnson
syndrome/toxic
epidermal
necrolysis with severe mucosal involvements. J.
Allergy Clin. Immunol. 135(6): 1538-1545, 2015.
7. Khor SS, Yang W, Kawashima M, Kamitsuji S,
Zheng X, Nishida N, Sawai H, Toyoda H,
Miyagawa T, Honda M, Kamatani N, andTokunaga K. High-accuracy imputation for HLA
class I and II genes based on high-resolution SNP
data of population-specific references. Pharmacogenomics J. 15(6): 530-537, 2015. (Feb 2015,
Epub ahead of print)
8. Okamoto K, Honda K, Doi K, Ishizu T, Katagiri D,
Wada T, Tomita K, Ohtake T, Kaneko T,
Kobayashi S, Nangaku M, Tokunaga K, and Noiri
E: Glypican-5 increases susceptibility to nephrotic
damage in diabetic kidney. Am. J. Pathol. 185(7):1889-98, 2015.
9. Hitomi Y, Kawashima M, Aiba Y, Nishida N,
Matsuhashi M, Okazaki H, Nakamura M, andTokunaga K. Human primary biliary cirrhosis
susceptible allele of rs4979462 enhances
TNFSF15 expression by binding NF-1. Hum.
Genet. 134(7): 737-747, 2015.
10. Tamura M, Isojima T, Kawashima M, Yoshida H,
Yamamoto K, Kitaoka T, Namba N, Oka A,
Ozono K, Tokunaga K, and Kitanaka S. Detectionof hereditary 1,25-hydroxyvitamin D-resistantrickets caused by uniparental disomy of chromosome 12 using genome-wide single nucleotide
polymorphism array. PLoS ONE 10(7): e0131157,
2015.
11. Toyoda H, Miyagawa T, Koike A, Kanbayashi T,
Imanishi A, Sagawa Y, Kotorii N, Kotorii T,
Hashizume Y, Ogi K, Hiejima H, Kamei Y, Hida
A, Miyamoto M, Imai M, Fujimura Y, Tamura Y,
Ikwgami A, Wada Y, Moriya S, Furuya H,
Takeuchi M, Kirino Y, Meguro A, Remmers EF,
Kawamura Y, Otowa T, Miyashita A, Kashiwase

317

K, Khor SS, Yamasaki M, Kuwano R, Sasaki T,
Ishigooka J, Kuroda K, Kume K, Chiba S,
Yamada N, Okawa M, Hirata K, Mizuki N,
Uchimura N, Shimizu T, Inoue Y, Honda Y,
Mishima K, Honda M, and Tokunaga K. A
polymorphism in CCR1/CCR3 is associated with
narcolepsy. Brain Behav. Immun. 49: 148-155,
2015.
12. Aiba Y, Yamazaki K, Nishida N, Kawashima M,
Hitomi Y, Komori A, Kubo M, Tokunaga K, andNakamura M. Shared disease-susceptibility genes
between primary biliary cirrhosis and Crohn’sdisease in the Japanese population. J. Hum. Genet
60(9): 523-531, 2015.
13. Ueta M, Tokunaga K, Sotozono C, Sawai H, Yoon
KC, Kim MK, Seo KY, Joo CK, Tashiro K, andKinoshita S. HLA-A*02:06 and PTGER3polymorphism exerts additive effects in cold
medicine-related Stevens Johnson syndrome withsevere ocular complications. Hum. Genome Var.
2: 15023 Epub, 2015.
14. Jinam TA, Kanzawa-Kiriyama H, Inoue I,
Tokunaga K, Omoto K, and Saitou N. Uniquecharacteristics of the Ainu population in Northern
Japan J. Hum. Genet. 60(10): 565-571, 2015.
15. Liu X, Kawashima M, Miyagawa T, Otowa T, Latt
KZ, Thiri M, Nishida H, T Sugiyama T, Tsurusaki
Y, Matsumoto N, Mabuchi A, Tokunaga K, andSasaki T. Novel rare variations of oxytocin receptor (OXTR) gene in autism spectrum disorderindividuals. Hum. Genome Var. 2: 15024 Epub,
2015.
16. Liu X, Shimada T, Otowa T, Wu Y-Y, 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, and Gau SS-F.
Genome-wide association study of autism
spectrum disorder in the East Asian populations.
Autism Res. 9(3): 340-349, 2016. (August 2015,
Epub ahead of print)
17. Howe AS, Buttenschøn HN, Bani-Fatemi A,
Maron E, Otowa T, Erhardt A, Binder EB,
Gregersen NO, Mors O, Woldbye DP, Domschke
K, Reif A, Shlik J, Kõks S, Kawamura Y,
Miyashita A, Kuwano R, Tokunaga K, Tanii H,

Jordan W, Smoller JW, Sasaki T, Koszycki D, andLuca VD. Candidate genes in panic disorder:
Meta-analyses of 23 common variants in majoranxiogenic pathways. Mol. Psychiatry. 21(5)665-79, 2016. (Sep 2015, Epub ahead of print)
18. Miyagawa T, Toyoda H, Kanbayashi T, Imanishi
A, Sagawa Y, Kotorii N, Kotorii T, Hashizume Y,
Ogi K, Hiejima H, Kamei Y, Hida A, Miyamoto
M, Ikegami A, Wada Y, Takami M, Fujimura Y,
Tamura Y, Omata N, Yasuhiro M, Kondo H,
Moriya S, Furuya H, Kato M, Kojima H,
Kashiwase K, Saji H, Khor S-S, Yamasaki M,
Ishigooka J, Wada Y, Chiba S, Yamada N, Okawa
M, Kuroda K, Kume K, Hirata K, Uchimura N,
Shimizu T, Inoue Y, Honda Y, Mishima K, Honda
M, and Tokunaga K. An association analysis of
HLA-DQB1 with narcolepsy without cataplexy
and idiopathic hypersomnia with/without long
sleep time in a Japanese population. Hum.
Genome Var. 2: 15031 Epub, 2015.
19. Hu Y, Yoshida K, Cologne JB, Maki M, Morishita
Y, Sasaki K, Hayashi I, Ohishi W, Hida A,
kyoizumi S, Kusunoki Y, Tokunaga K, Nakachi K,
and Hayashi T. CD14 and IL18 gene polymorphisms associated with colorectal cancer
subsite risks among atomic bomb survivors. Hum.
Genome Var. 2: 15035 Epub, 2015.
20. Nishida N, Jun Ohashi J, Sugiyama M, Tsuchiura
T, Yamamoto K, Hino K, Honda M, Kaneko S,
Yatsuhashi H, Koike K, Yokosuka O, Tanaka E,
Taketomi A, Kurosaki M, Izumi N, Sakamoto N,
Eguchi Y, Sasazuki T, Tokunaga K, and Mizokami
M. Effects of HLA-DPB1 genotypes on chronic
hepatitis B infection in apanese. Tissue Antigens
86(6): 406-412, 2015.
21. Miyadera H, Bungener LB, Kusano S, Yokoyama
S, Tokunaga K, and Hepkema BG. Questionable
expression of unstable DQ heterodimer containing
HLA-DQA1*01:07. Tissue Antigens 86(6): 413418, 2015.

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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.

Homepage

Sayaka Takanashi, M.D., Ph.D.

http://www.sih.m.u-tokyo.ac.jp/devt.html

Introduction and Organization
Founded in 1966 as the Department of Maternal andChild Health, our department was the first one
established in Japan. With the subsequent expansionof research activities and the foundation of the
Graduate School of Medicine, it was renamed in 1998
as the Department of Developmental Medical
Sciences. Up to now, it has been engaged in experimental and epidemiologic studies to provide thescientific bases for all the activities to promote thephysical and mental health of mothers and children.
The experimental studies include those on the nervousand endocrine systems, infection, immunity andmetabolism, whereas the epidemiologic studies deal
with development, mother-to-child relationship 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 associates, one assistantclerk, one technical assistant, fifteen visiting lecturers,
thirteen visiting researchers, and nine 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) Medical microbiology and zoology
3) Maternal and child diseases
4) Immunology
5) Maternal and child health6) School health and nursing7) International health8) Introduction to General Health Science
2. Graduate course, the Graduate School of Medicine,
School of International Health Sciences

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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. Fukasawa T, Kubota T, Negoro T, Saitoh M,
Mizuguchi M, Ihara Y, Ishii A, Hirose S. A case ofrecurrent encephalopathy with SCN2A missense
mutation. Brain and Development 2015; 37(6):631-634.

2. Khamrin P, Thongprachum A, Takanashi S, Okitsu
S, Maneekarn N, Hayakawa S, Ushijima H.
Evaluation of immuno- chromatography tests for
detection of novel GII.17 norovirus in stool
samples. Eurosurveillance 2015; 20(28).
3. Mimaki M, Shiihara T, Watanabe M, Hirakata K,
Sakazume S, Ishiguro A, Shimojima K,
Yamamoto T, Oka A, Mizuguchi M. Holoprosencephaly with cerebellar vermis hypoplasia
in 13q deletion syndrome: Critical region for
cerebellar dysgenesis within 13q32.2q34. Brainand Development 2015; 37(7): 714-718.
4. Nakano Y, Monden Y, Mizuguchi M, Nagashima
M, Koike Y, Gunji Y, Takahashi N, Sugie H,
Momoi, M.Y. Acute encephalopathy with callosal,
subcortical and thalamic lesions. Neurology Asia
2015; 20(1): 85- 89.
5. Nara A, Nagai H, Yamaguchi R, Yoshida KI,
Iwase H, Mizuguchi M. An unusual autopsy caseof cytokine storm-derived influenza- associatedencephalopathy without typical histopathologicalfindings: autopsy case report. American Journalof Forensic Medicine and Pathology 2015; 36(1);
3-5.
6. Ogawa R, Ma Y, Yamaguchi M, Ito T, Watanabe Y,
Ohtani T, Murakami S, Uchida S, De Gaspari P,
Uezumi A, Nakamura M, Miyagoe-Suzuki Y,
Tsujikawa K, Hashimoto N, Braun T, Tanaka T,
Takeda S, Yamamoto H, Fukada S. Doublecortinmarks a new population of transiently amplifying
muscle progenitor cells and is required for
myofiber maturation during skeletal muscle
regeneration. Development. 2015; 142(1): 51-61.
7. Saitoh M, Ishii A, Ihara Y, Hoshino A, Terashima
H, Kubota M, Kikuchi K, Yamanaka G, Amemiya
K, Hirose S, Mizuguchi M. Missense mutations in
sodium channel SCN1A and SCN2A predisposechildren to encephalopathy with severe febrile
seizures. Epilepsy Research 2015; 117: 1-6.
8. Saitoh M, Shinohara M, Ishii A, Ihara Y, Hirose S,
Shiomi M, Kawawaki H, Kubota M, Yamagata T,
Miyamoto A, Yamanaka G, Amemiya K, Kikuchi
K, Kamei A, Akasaka M, Anzai Y, Mizuguchi M.
Clinical and genetic features of acute encephalopathy in children taking theophylline. Brain andDevelopment 2015; 37(3): 463-470.
9. Shimada S, Shimojima K, Sangu N, Hoshino A,

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Hachiya Y, Ohto T, Hashi Y, Nishida K, Mitani M,
Kinjo S, Tsurusaki Y, Matsumoto N, Morimoto M,
Yamamoto T. Mutations in the genes encoding
eukaryotic translation initiation factor 2B inJapanese patients with vanishing white matter
disease. Brain and Development. 2015; 37(10):960-966.
10. Tada H, Takanashi JI, Okuno H, Kubota M,
Yamagata T, Kawano G, Shiihara T, Hamano SI,
Hirose SI, Hayashi T, Osaka H, Mizuguchi M.
Predictive score for early diagnosis of acuteencephalopathy with biphasic seizures and late
reduced diffusion (AESD). Journal of Neurological Sciences 2015; 358(1-2): 62-65.
11. Takamatsu Y, Hagino Y, Sato A, Takahashi T,
Nagasawa SY, Kubo Y, Mizuguchi M, Uhl GR,
Sora I, Ikeda K. Improvement of learning andincrease in dopamine level in the frontal cortex bymethylphenidate in mice lacking dopamine transporter. Current Molecular Medicine 2015; 15(3):245-242.
12. Takanashi JI, Mizuguchi M, Terai M, Barkovich
AJ. Disrupted glutamate- glutamine cycle in acuteencephalopathy with biphasic seizures and late
reduced diffusion. Neuroradiology 2015; 57(11):1163-1168.
13. Takanashi JI, Shiihara T, Hasegawa T, Takayanagi
M, Hara M, Okumura A, Mizuguchi M. Clinicallymild encephalitis with a reversible splenial lesion(MERS) after mumps vaccination. Journal of the
Neurological Sciences 2015; 349(1-2): 226-228.
14. Thongprachum A, Takanashi S, Kalesaran AF,
Okitsu S, Mizuguchi M, Hayakawa S, Ushijima H.
Four-year study of viruses that cause diarrhea inJapanese pediatric outpatients. Journal of Medical
Virology 2015; 87(7): 1141-1148.
15. Tran DN, Pham TM, Ha MT, Hayakawa S,
Mizuguchi M, Ushijima H. Molecular epidemiology of influenza A virus infection amonghospitalized children in vietnam during postpandemic period. Journal of Medical Virology
2015; 87(6): 904-912.
16. Ushijima H, Thongprachum A, Tran DN,
Fujimoto T, Hanaoka N, Okitsu S, Takanashi S,
Mizuguchi M, Hayakawa S. Rapid diagnostic
tests apply for pediatric infections at outpatient
clinic setting. Clinical Laboratory 2015; 61(1-2):

195-199.
17. Yamamoto H, Okumura A, Natsume J, Kojima S,
Mizuguchi M. A severity score for acutenecrotizing encephalopathy. Brain and Development 2015; 37(3): 322-327.

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Department of Human Ecology
Professor
Chiho WATANABE, D. Hlth Sc.

Associate Professor
Masahiro UMEZAKI, Ph.D.

Research Associate
Hana SHIMIZU, Ph.D.
Shoko KONISHI, Ph.D.

Project Research Associate
Shinya YASUMOTO, Ph.D. (GRENE project)
Yosuke INOUE, Ph.D. (UEHAS program)

Homepage

http://www.humeco.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
We had six research/teaching faculties in FY2015,
two of them were woking for “GRENE” or “UEHAS”
program, respectively. Apart from the faculty staffs,
two supporting staffs, three doctoral candidates (oneforeign student), five master course students(including three foreign students), and one postdoctrol
fellow are working in the department. There are ten
extra-university lecturers delivering lectures in either
graduate or undergraduate course. Prof. Watanabeholds additional roles in the Integrated Research
System for Sustainability Science (IR3S) as well as in
the Earth Observation Data Integration & Fusion
Research Initiative (EDITORIA).

Teaching activities
The department is one of the six departments of the
School of International Health. Human Ecology
Special Lecture I focused on the basic components of
Human Ecology such as demography, nutrition, andenvironment and introducing the notion of humanecosystem. In “Human Ecology Special Lecture II”,emphases were on recent topics and ongoing
researches in the field of Human Ecology and relatedareas. With these classes for the Graduate Students,
we tried to describe Human Ecology as a basic
component of International Health, and gave examplesof the recent issues that have been dealt with andapproaches used in this field. The lectures for the
Graduate Course were given in English.
In the undergraduate course, the department is incharge of a part of the School of Integrated Health
Sciences, providing the lectures on “Human Ecology”,“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 U Tokyo in operating the program, “Urban
Engineering and Health in Asia” (UEHAS), which

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been adopted as one of the MEXT-funding “Reinventing Japan” project (PI= Prof. Takizawa, Dept. of
Urban Engineering). UEHAS is an educational
program at the graduate level entailing credit
exchange between U Tokyo and six universities in
ASEAN countries. Our department has been in chargeof 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 ourresearches tackle 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. We
also took part in a MEXT-funding program Green
Network of Excellence, in which so called “earthobservation data” will be used to solve health-related
issues. Almost all the studies require “transdisciplinary” approach, hence, we are collaboratingwith various domestic and overseas research institutes.
What follows is a list of major activities conducted in
the past year.
1. Environmental contamination by metals andmetalloids in South Asia and susceptibility factors
In the As-contaminated area in Bangladesh, .thearsenic exposure affected the IgG concentrations ofmothers and newborns differentially. In lowland Nepal,
the effects of prenatal exposure to several metals on
the neurodevelopment of newborns were examined
and followed up to six months.
2. Subsistence transition and adaptation:
In many Asian and Oceania countries, various typesof developmental projects have been undertaken
aiming at economic development, procurement of

natural resources, or accelerating tourism. Attempts todescribe such changes from the viewpoint of political
ecology were made in China as well as Papua New
Guinea.
3. Role of selenium in a population highly exposed
to methylmercury through fish consumption:
Relatively high concentration of methylmercury(MeHg) can be found in some predator fish species
through food chain, and health risks associated withexcessive consumption of such seafood items havebeen debated long time. On the other hand, fish isvery important source of some nutrients including
protein, polyunsaturated fatty acids, and minerals, andsome of these nutrients might interfere with MeHg
toxicity. Thus, net risk/benefit of eating fish are notimmediately clear. We examined the nutritional statusof selenium, a micronutrient for which fish serves as asignificant source. In collaboration with National
Institute of Minamata Diseases, it was reported that a
fish-eating population in Japan did not show the signof neurological symptoms despite the high Hg burden,
and a potential role of Se was suggested.
4. Adaptability to low protein diet
In Papua New Guinea Highlands, the people are fed
on low protein diets like sweet potatoes, whereas they
do not appear to be protein deficient. Hypothesizingthat this observation would be associated with a
specific composition of gut microbiome in these
populations, field studies and experimental studies
have been conducted.
For the estimation of protein intake of individuals,
food frequency questionnaire was developed andvalidated. The analysis of gut microbiome revealed
several bacteria that might support “efficient” protein
utilization of host.
5. Use of “earth-observation” data in the field ofhealth science through the Data Integration andAnalysis System (DIAS):
This project has been conducted as one of the
program under “Green Network of Excellence –environmental information” (GRENE-ei) project, inwhich various kinds of earth-observation data, stored
or modified in/through DIAS, would be utilized invarious scientific fields (so called Social Benefit Area).

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We have been running an “Eco-health” program, inwhich we tried to connect environmental and healthrelated information in the framework of “human”
ecology and tried to identify newly emerging healthrisks due to climate change and socio-demographicalchange. In this project, we have been collaboratingwith other Schools in U Tokyo, a couple of Japanese
universities and institutions, as well as many overseas
universities, governmental agencies, etc. Namely, weare trying to address the issue of heat and air pollution,
urban water issues, and tropical infectious diseases
associated with human land use. Combining thephysicochemical (secondary) data and (primary)health event data, (1) short-term effects of heat/coldon asthmatic attack, and (2) the effects of air pollution
on respiratory function among schoolchildren in
Dhaka were examined for up to one year. Also,
combining the data of human mobility, satelliteobserved thermal information, an estimate of heat
exposure of the residents in Dhaka was obtained,
which revealed different spatial distribution of thepeople from that of conventional estimate. In Lao
PDR, combining satellite-imagery of landuse andground surveillance of reservoir snails, a model wasdeveloped to predict high-risk areas of Liver fluke
infection. In Vietnam, a model to predict diarrhea
incidence after flood events was developed, in which
not only the primary infection but also the secondary
infection was taken into account. Each of thesemodels will be further refined and validated in thesubsequent trials.

References
1. Koyanagi A., Stickley A., Haro JM. (2015)
Psychotic-like experiences and nonsuidical selfinjury in England: results from a national survey.
PLoS One, 10:e0145533.
2. Kravchenko Z., Stickley A., Koyanagi A. (2015)
Close relationships matter: family well-being and its
effects on health in Russia. Europe-Asia Studies, 67:
1635-1655.
3. Elmelid A., Stickley A., Lindblad F., Schwab-Stone
M., Henrich CC., Ruchkin V. (2015) Depressive
symptoms, anxiety and academic motivation inyouth: Do schools and families make a difference?
Journal of Adolescence, 45:174-182.
4. Naito YI., Morita A., Natsuhara K., Tadokoro K.,
Baba J., Odani S., Tomitsuka E., Igai K., Tsutaya T.,
Yoneda M., Greenhill AR., Horwood PF., Soli KW.,
Phuanukoonnon S., Siba PM., Umezaki M. (2015)
Association of protein intakes and variation of
diet-scalp hair nitrogen isotopic discrimination
factor in Papua New Guinea highlanders. American
Journal of Physical Anthropology, 158:359-370.
5. Kamio Y., Haraguchi H., Stickley A., Ogino K.,
Ishitobi M., Takahashi H. (2015) Best discriminatorsfor identifying children with autism spectrum
disorder at an 18-month health check-up in Japan.
Journal of Autism and Developmental Disorders, 45:4147-4153.
6. Koyanagi A., Stickley A. (2015) The association
between sleep problems and psychotic symptoms in
the general population: a global perspective. Sleep,
38:1875–1885.
7. Yazawa A., Inoue Y., Stickley A., Li D., Du J.,
Watanabe C. (2015) The effects of season of birth on
the inflammatory response to psychological stress in
Hainan Island, China. PLoS One, 10:e0139602.
8. Sekiyama M., Jiang HW., Gunawan B., Dewanti L.,
Honda R., Shimizu-Furusawa H., Abdoellah O.,
Watanabe C. (2015) Double burden of malnutrition
in rural West Java: household-level analysis forfather-child and mother-child pairs and the association with dietary intake. Nutrients, 10:8376-8391.
9. Stickley A., Koyanagi A., Roberts B., Goryakin Y.,
McKee M. (2015) Crime and subjective well-being
in the countries of the former Soviet Union. BMC
Public Health, 15:1010.
10. Koyanagi A., Stickley A., Haro JM. (2015)
Subclinical psychosis and suicidal behavior in
England: Findings from the 2007 Adult PsychiatricMorbidity Survey. Schizophrenia Research, 168:
62-27.
11. Koyanagi A., Stickley A. (2015) The association
between psychosis and severe pain in communitydwelling adults: Findings from 44 low- and middleincome countries. Journal of Psychiatric Research,
69:19-26.
12. Sekiyama M., Shimmura T., Nakazaki M., Akbar IB,
Gunawan B, Abdoellah O, Masria S., Dewanti L.,
Ohtsuka R., Watanabe C. (2015) Organophosphorus

324

pesticide exposure of school children in agriculturalvillages in Indonesia. Journal of Pregnancy andChild Health, 2:153.
13. Chen SM., Du JW., Jin YM., Qiu L., Du ZH., Li
DD., Chen HY., Watanabe C., Umezaki M. (2015)
Risk factors for severe hand-foot-mouth disease inchildren in Hainan, China, 2011-2012. Asia-Pacific
Journal of Public Health, 27:715-722.
14. Greenhill AR., Tsuji H., Ogata K., Natsuhara K.,
Morita A., Soli K., Larkins JA., Tadokoro K., Odani
S., Baba J., Naito Y., Tomitsuka E., Nomoto K., SibaPM., Horwood PF., Umezaki M. (2015) Characterization of the gut microbiota of Papua New
Guineans using reverse transcription quantitative
PCR. PLoS One, 10:e0117427.
15. Morita A., Natsuhara K., Tomitsuka E., Odani S.,
Baba J., Tadokoro K., Igai K., Greenhill AR,
Horwood PF., Soli KW., Phuanukoonnon S., SibaPM., Umezaki M. (2015) Development, validation,and use of a semi-quantitative food frequency
questionnaire for assessing protein intake in Papua
New Guinean Highlanders. American Journal of
Human Biology, 27:349-357.
16. Hamamatsu Y., Watanabe C., Umezaki M. (2015)
Secondary sex ratio and marriage after disaster: a
reply to O’Donnell and Behie. Journal of Biosocial
Science, 47:417-420.
17. Leinsalu M., Stickley A., Kunst AE. (2015) Reduced
affordability of cigarettes and socio-economic
inequalities in smoking continuation in Stakhanov,Ukraine, 2009. European Journal of Public Health,
25:216-218.
18. Parajuli RP., Umezaki M., Fujiwara T., Watanabe C.
(2015) Association of cord blood levels of lead,arsenic, and zinc and home environment with neurodevelopmental indicators of 36 months children
living in Chitwan valley, Nepal. PLoS One, 10:e0120992.
19. Ser PH., Banu B., Jebunnesa F., Fatema K., Rosy N.,
Yasmin R., Furusawa H., Ali L., Ahmad SA.,
Watanabe C. (2015) Arsenic exposure increases
maternal but not cord serum IgG in Bangladesh.
Pediatrics International, 57:119-125.
20. Yoshida N., Inaoka T., Sultana N., Ahmad Sk. A.,
Mabuchi A., Shimizu H., Watanabe C. (2015)
Non-monotonic relationships between arsenic andselenium excretion and its implication on arsenic

methylation pattern in a Bangladeshi population.
Environmental Research, 140:300-307.
21. Jukkala T., Mäkinen IH., Stickley A. (2015) The
historical development of suicide mortality in Russia,
1870-2007. Archives of Suicide Research, 19:117130.
22. Shinsugi C., Stickley A., Konishi S., Ng CFS.,
Watanabe C. (2015) Seasonality of child andadolescent injury mortality in Japan, 2000-2010.
Environmental Health and Preventive Medicine, 20:
36-43.
23. Stickley A., Koyanagi A., Leinsalu M., Ferlander S.,
Sabawoon W., McKee M. (2015) Loneliness andhealth in Eastern Europe: Findings from Moscow,
Russia. Public Health, 129:403-410.
24. Stickley A., Koyanagi A., Roberts B., McKee M.
(2015) Urban-rural differences in psychologicaldistress in nine countries of the former Soviet Union.
Journal of Affective Disorders, 178:142-148.
25. Koyanagi A, Stickley A, Garin N, Miret M,
Ayuso-Mateos JL, Leonardi M, Koskinen S, Galas A,
Haro JM. (2015) The association between obesityand back pain in nine countries: a cross-sectional
study. BMC Public Health, 15:123.
26. Stickley A, Koyanagi A, Roberts B, Murphy A,
Kizilova K, McKee M. (2015) Male solitarydrinking and hazardous alcohol use in nine countriesof the former Soviet Union. Drug and Alcohol
Dependence, 150:105-111.
27. Nishihama Y., Yoshinaga J., Iida A., Konishi S., Imai
H. (2015) Menstrual cycle length and source of its
variation in female university students majoring in
nursing sciences. Nihon Eiseigaku Zasshi, 70:139148. [in Japanese]
28. Stickley A., Koyanagi A., Koposov R., Blatný M.,
Hrdlička M., Schwab-Stone M., Ruchkin V. (2015)
Correlates of weapon carrying in school among
adolescents in three countries. American Journal of
Health Behavior, 39:99-108.
29. Stickley A., Koyanagi A., Kawakami N., WHO
World Mental Health Japan Survey Group. (2015)
Childhood adversities and adult-onset chronic pain:
results from the World Mental Health Survey, Japan.
European Journal of Pain, 19:1418-1427.
30. Stickley A., Koyanagi A., Koposov R., McKee M.,
Murphy A., Ruchkin V. (2015) Binge drinking and325eating problems in Russian adolescents. Alcoholism:
Clinical and Experimental Research, 39:540-547.
31. Stickley A., Koyanagi A., Roberts B., Leinsalu M.,
Goryakin Y., McKee M. (2015) Smoking status,
nicotine dependence and happiness in nine countriesof the former Soviet Union. Tobacco Control, 24:
190-197.
32. Parajuli RP., Fujiwara T., Umezaki M., Watanabe C.
(2015) Home environment and cord blood levels of
lead, arsenic, and zinc on neurodevelopment of 24months children living in Chitwan valley, Nepal.
Journal of Trace Elements in Medicine and Biology,
41:89-95.
33. Tasmin S., Furusawa H., Ahmad SA., Faruquee MH.,
Watanabe C. (2015) Delta-aminolevulinic aciddehydratase (ALAD) polymorphism in lead exposed
Bangladeshi children and its effect on urinaryaminolevulinic acid (ALA). Environmental Research, 136:318-323.

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Department of
Biomedical Chemistry
Professor
Kiyoshi Kita, Ph.D.

Associate Professor
Yoh-ichi Watanabe, Ph.D.

Research Associate
Motomichi Matsuzaki, Ph.D.,

Homepage

Daniel Inaoka Ken, Ph.D.

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. Prof. Kita has moved from The Institute ofMedical Science, The University of Tokyo on March
1st, 1998.

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.

Research activities
Energy metabolism is essential for the survival,continued growth and reproduction of living organisms. From the standpoint of biological adaptation,
we have been studying on the molecular mechanismof energy transducing systems such as mitochondrialand bacterial respiratory chain. In addition, we areinterested in the basic biological reactions such asprotein synthesis. Our research have been focusing on
I. Human mitochondria
1) succinate-ubiquinone reductase
2) mitochondrial myopathy
II. Ascaris suum and Caenorhabditis elegans
1) molecular mechanism of adaptation to low
oxygen tension (regulation of gene expressionof mitochondrial proteins)2) mitochondrial fumarate reductase (structure
function relationship, enzyme evolution)3) C. elegans as a model system of parasitic
nematode (expression of foreign genes or
cDNAs, gene knockout)

327

III. Parasitic protozoa (Plasmodium falciparum,
Trypanosoma
brucei,
Trypanosoma
cruzi,
Cryptosporidium)1) characterization of mitochondria as a target forthe chemotherapy2) molecular biology of mitochondrial DNA3) structure-based drug design (SBDD)
IV. Protein synthesis and RNA maturation
1) Mitochondrial protein synthesis
2) tRNA splicing

References
1. Lactate retards the development of erythrocytic
stages of the human malaria parasite Plasmodium
falciparum. Hikosaka, K., Hirai, M., Komatsuya,K., Ono, Y. & Kita, K. (2015) Parasitol. Int. 64,
301-303
2. Direct evidence for the atovaquone action on the
Plasmodium cytochrome bc1 complex. Siregar,
J.E., Kurisu, G., Kobayashi, T., Matsuzaki, M.,
Sakamoto, K., Mi-ichi, F., Watanabe, Y., Hirai,
M., Matsuoka, H., Syafruddin, D., Marzuki, S. &Kita, K. (2015) Parasitol. Int. 64, 295-300
3. Inhibition of malaria parasite growth byquinomycin A and its derivatives through DNAintercalating activity. Hayase, H., Watanabe, H.,
Liang, L.C., Nogawa, T., Komatsuya, K., Kita, K.
& Osada, H. (2015) Biosci. Biotech. Biochem. 79,
633-635
4. Risk factors for Chagas disease among pregnant
women in El Salvador. Sasagawa, E., Aiga, H.,
Corado, E.Y., Cuyuch, B.L., Hernández, M.A.,
Guevara, A.V., Romero, J.E., Ramos, H.M.,
Cedillos, R.A., Misago, C. & Kita, K. (2015) Trop.
Med. Int. Health 20, 268-276
5. Design, synthesis, and biological evaluation of
air-stable nafuredin-γ analogs as complex I
inhibitors. Ohtawa, M., Matsunaga, M., Fukunaga,
K., Shimizu, R., Shimizu, E., Arima, S., Ohmori,J., Kita, K., Shiomi, K., Ōmura, S. & Nagamitsu,
T. (2015) Bioorg. Med. Chem. 23, 932-943
6. Pharmacophore Modeling for Anti-Chagas Drug
Design Using the Fragment Molecular Orbital
Method. Yoshino, R., Yasuo, N., Inaoka, D.K.,

Hagiwara, Y., Ohno, K., Orita, M., Inoue, M.,
Shiba, T., Harada, S., Honma, T., Balogun, E.O.,
da Rocha, J.R., Montanari, C.A., Kita, K. &Sekijima, M. (2015) PLoS One 10, e0125829
7. Mother-to-child transmission of Chagas disease in
El Salvador. Sasagawa, E., Aiga, H., Corado
Soriano, E.Y., Cuyuch Marroquín, B.L.,
Hernández Ramírez, M.A., Guevara de Aguilar,
A.V., Romero Chévez, J.E., Ramos Hernández,
H.M., Cedillos, R.A., Misago, C. & Kita, K.
(2015) Am. J. Trop. Med. Hyg. 93, 326-333
8. In vivo curative and protective potential of orally
administrated 5-aminolevulinic acid plus ferrous
ion against malaria. Suzuki, S., Hikosaka, K.,
Balogun, E.O., Komatsuya, K., Niikura, M.,
Kobayashi, K., Takahashi, K., Tanaka, T.,
Nakajima, M. & Kita, K. (2015) Antimicrob.
Agents Chemother. 59, 6960-6967
9. Knockdown of the coenzyme Q synthesis gene
Smed-dlp1 affects planarian regeneration andtissue homeostasis. Shiobara, Y., Harada, C.,
Shiota, T., Sakamoto, K., Kita, K., Tanaka, S.,
Tabata, K., Sekie, K., Yamamoto, Y. & Sugiyama,
T. (2015) Redox Biol. 6, 599-606

School of Public Health
1. Epidemiology and Health Sciences

329

Department of Social andPreventive Epidemiology
Professor
Satoshi Sasaki, M.D., Ph.D.

Associate
Keiko Asakura, M.D.,M.P.H.,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

330with 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. Shiraishi M, Haruna M, Martsuzaki M, Murayama
R, Sasaki S. The biomarker-based validity of abrief-type diet history questionnaire for estimating
eicosapentaenoic acid and docosahexaenoic acidintakes in pregnant Japanese women. Asia Pac J
Clin Nutr 2015; 24: 316-22.
2. Tani Y, Asakura K, Sasaki S, Hirota N, Notsu A,
Todoriki H, Miura A, Fukui M, Date C. The
influence of season and air temperature on water
intake by food groups in a sample of free-living
Japanese adults. Eur J Clin Nutr 2015; 69: 907-13.
3. Okubo H, Miyake Y, Tanaka K, Sasaki S, Hirota Y.
Maternal total caffeine intake, mainly from Japaneseand Chinese tea, during pregnancy was associatedwith risk of preterm birth: the Osaka Maternal andChild Health Study. Nutr J 2015; 35: 309-16.
4. Asakura K, Haga M, Sasaki S. Relative validity andreproducibility of a brief-type self-administered diethistory questionnaire for Japanese children aged 3-6
years: application of a questionnaire established for
adults in preschool children. J Epidemiol 2015; 25:
341-50.
5. Kobayashi S, Asakura K, Suga H, Sasaki S.
Cohabitational effect of grandparents on dietaryintake among young Japanese women and theirmothers living together: a multicenter crosssectional study. Appetite 2015; 91: 287-97.
6. Tani Y, Asakura K, Sasaki S, Hirota N, Notsu A,
Todoriki H, Miura A, Fukui M, Date C. Higher
proportion of total and fat energy intake during themorning may reduce absolute intake of energy
within the day. An observational study in free-living
Japanese adults. Appetite 2015; 92: 66-73.
7. Katagiri R, Asakura K, Sasaki S, Hirota N, Notsu A,
Miura A, Todoriki H, Fukui M, Date C. Estimationof habitual iodine intake in Japanese adults using 16
d diet records over four seasons with a newly

developed food composition database for iodine. Br
J Nutr 2015; 114: 624-34.
8. Okubo H, Sasaki S, Murakami K,Yokoyama T,
Hirota N, Notsu A, Fukui M, Date C. Designing
optimal food intake patterns to achieve nutritional
goals for Japanese adults through the use of linear
programming optimization models. Nutr J 2015;
14(1): 57.
9. Nishimura T, Murakami K, Livingstone MBE,
Sasaki S, Uenishi K, the Japan Dietetic Students'
Study for Nutrition and Biomarkers Group.
Adherence to the food-based Japanese dietaryguidelines in relation to metabolic risk factors inyoung Japanese woman. Br J Nutr 2015; 114(4):645-53.
10. Shinozaki K, Ouda M, Sasaki S, Kunitsugu I,
Shigeta M. Dietary fiber consumption decreases therisks of overweight and hypercholesterolemia inJapanese children. Ann Nutr Metab 2015; 67: 58-64.
11. 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 2015; 19(4): 650-7.
12. Miyake Y, Tanaka K, Okubo H, Sasaki S, Arakawa
M. Dietary vitamin D intake and prevalence ofdepressive symptoms during pregnancy in Japan.
Nutrition 2015; 31(1): 160-5.
13. Miyake Y, Tanaka K, Okubo H, Sasaki S, Arakawa
M. Intake of dairy products and calcium andprevalence of depressive symptoms during pregnancy in Japan: a cross-sectional study. BJOG 2015;
122(3): 336-43.
14. Shinozaki K, Okuda M, Sasaki S, Kunitsugu I,
Shigeta M. Dietary fiber consumption decreases therisks of overweight and hypercholesterolemia inJapanese children. Ann Nutr Metab 2015; 67(1):58-64.
15. Tanaka K, Hitsumoto S, Miyake Y, Okubo H, Sasaki
S, Miyatake N, Arakawa M. Higher vitamin D
intake during pregnancy is associated with reduced
risk of dental caries in young Japanese children. Ann
Epidemiol. 2015; 25(8): 620-5.
16. Katagiri R, Asakura K, Uechi K, Masayasu S,
Sasaki S. Adequacy of iodine intake in threedifferent Japanese adult dietary patterns: anationwide study. Nutr J 2015; 14: 129.

331

17. Murakami K, Livingstone MB, Sasaki S, Uenishi K,
Japan Dietetic Students' Study for Nutrition andBiomarkers Group. Ability of self-reported estimatesof dietary sodium, potassium and protein to detect
an association with general and abdominal obesity:
comparison with the estimates derived from 24 h
urinary excretion. Br J Nutr 2015; 113: 1308-1318.

332

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 2015.

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.

333

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. Hamada T, Yasunaga H, Nakai Y, et al. Severe
Bleeding after Percutaneous Transhepatic Drainage of the Biliary System: Effect of Antithrombotic Agents-Analysis of 34 606 Cases froma Japanese Nationwide Administrative Database.
Radiology 2015;274(2):605-13
2. Hamada T, Yasunaga H, Nakai Y, et al. Bleeding
After Endoscopic Sphincterotomy and Papillary
Balloon Dilation Among Users of Antithrombotic
Agents. Endoscopy 2015;47(11):997-1004
3. Hasegawa W, Yamauchi Y, Yasunaga H, et al.
Clinical Features of 280 Hospitalized Patientswith Lymphangioleiomyomatosis in Japan. Respirology 2015;20(1):160-5
4. Hasegawa W, Yamauchi Y, Yasunaga H, et al.
Factors that predict in-hospital mortality ineosinophilic granulomatosis with polyangiitis.
Allergy 2015;70(5):585-90.
5. Ishitsuka K, Matsui H, Michihata N, Fushimi K,
Nakamura T, Yasunaga H. Medical Proceduresand Outcomes of Japanese Patients with Trisomy
18 or Trisomy 13: Analysis of a Nationwide
Administrative Database of Hospitalized Patients.
American Journal of Medical Genetics Part A.
2015;167(8):1816-21.
6. Isogai T, Yasunaga H, Matsui H, et al.
Effectiveness of inferior vena cava filters on inhospital mortality as an adjuvant to antithrombotic
therapy for pulmonary embolism: propensity
score and instrumental variable analyses. Am J
Med 2015;128(3):312.e23-31.
7. Isogai T, Yasunaga H, Matsui H, et al. Hospital
Volume and Cardiac Complications of Endomyocardial Biopsy: A Retrospective Cohort Studyof 9508 Adult Patients Using a Nationwide

Inpatient Database in Japan. Clinical Cardiology
2015;38(3):164-70
8. Isogai T, Yasunaga H, Matsui H, et al. Serious
Cardiac Complications in Coronary Spasm
Provocation Tests Using Acetylcholine or
Ergonovine: Analysis of 21,512 Patients from the
Diagnosis Procedure Combination Database inJapan. Clinical Cardiology 2015;38(3):171-7.
9. Isogai T, Yasunaga H, Matsui H, et al. Effect ofIntravenous Immunoglobulin on In-Hospital
Mortality for Fulminant Myocarditis: Propensity
Score Analyses. Journal of Cardiac Failure 2015;21(5):391-7
10. Isogai T, Yasunaga H, Matsui H, et al. Effect ofweekend admission for acute myocardial
infarction on in-hospital mortality: a retrospective
cohort study. International Journal of Cardiology
2015;179:315–320.
11. Isogai T, Yasunaga H, Matsui H, et al. Clinical
Practice Patterns in Constrictive Pericarditis
Patients with Heart Failure: A Retrospective
Cohort Study Using a National Inpatient Databasein Japan. Clinical Cardiology 2015;38(12):740-6
12. Iwagami M, Yasunaga H, Noiri E, et al. Choice ofrenal replacement therapy modality in intensive
care units: data from a Japanese Nationwide
Administrative Claim Database. Journal of
Critical Care 2015;30(2):381-5
13. Iwagami M, Yasunaga H. Current state ofcontinuous renal replacement therapy for acutekidney injury in Japanese intensive care units in2011: analysis of a national administrative
database. Nephrology Dialysis Transplantation
2015;30(6):988-95.
14. Iwamoto T, Hashimoto H, Horiguchi H, Yasunaga
H. Effectiveness of hospital functions for acuteischemic stroke treatment in in-hospital mortality:
results from a nationwide survey in Japan.
Journal of Epidemiology 2015;25(8):522-8.
15. Kanehara A, Yamana H, Yasunaga H, et al.
Psychiatric Intervention and Repeated Admission
to Emergency Centres Due to Drug Overdose. BJP
Open 2015;1 (2):158-163
16. Kikuchi H, Hashimoto H, Yasunaga H. PrivacyPreserving Epidemiological Analysis for a Distributed Database of Hospitals. AsiaJCIS 2015:85- 90.

334

17. Matsui H, Fushimi K, Yasunaga H. Variation in
Risk-Standardized Mortality of Stroke among
Hospitals in Japan. PlosOne 2015; 10(10):e0139216.
18. Matsumoto M, Koike S, Matsubara S, Kashima S,
Ide H, Yasunaga H. Selection and concentration ofobstetric facilities in Japan: a longitudinal study
based on the national census data. Journal of
Obstetrics and Gynaecology Research 2015;41(6):919-25
19. Michihata N, Matsui H, Fushimi K, Yasunaga H.
Guideline-Concordant Treatment of Kawasaki
Disease with Immunoglobulin and Aspirin and theIncidence of Coronary Artery Aneurysm. Clinical
Pediatrics 2015;54(11):1076-80.
20. Michihata N, Matsui H, Fushimi K, Yasunaga H.
Clinical features of adult patients admitted topediatric wards in Japan. Journal of Adolescent
Health 2015;57(4):421-4.
21. Miyakawa K, Goto Y, Sunohara M, Yasunaga H,
Nagase T. Serratia marcescens lung abscess withreview of a Japanese national inpatient database.
Case Reports in Internal Medicine 2015;2(2):40-43.
22. Momosaki R, Yasunaga H, Matsui H, Abo M.
Effect of dysphagia rehabilitation on oral intake inelderly patients with aspiration pneumonia.
Geriatrics & Gerontology International 2015;15(6):694-9
23. Momosaki R, Yasunaga H, Matsui H, et al. Effectof Early Rehabilitation by Physical Therapists on
In-hospital Mortality after Aspiration Pneumonia
in the Elderly. Archives of Physical Medicine andRehabilitation 2015;96(2):205-9.
24. Morita K, Sasabuchi Y, Matsui H, Fushimi K,
Yasunaga H. Outcomes After Early or Late
Timing of Surgery for Infective Endocarditis with
Ischemic Stroke: A Retrospective Cohort Study.
Interactive CardioVascular and Thoracic Surgery
2015; doi:10.1093/icvts/ivv235.
25. Naganuma M, Matsui H, Koizumi J, Fushimi K,
Yasunaga H. Short-term Outcomes Following
Elective Transcatheter Arterial Embolization forSplenic Artery Aneurysms: Data from a Nationwide Administrative Database. Acta Radiologica
Open 2015;4(9):1–5
26. Niikura R, Yasunaga H, Yamaji Y, et al. Factors

affecting in-hospital mortality in patients withlower gastrointestinal tract bleeding: a retrospective study using a national database in Japan.
J Gasrtoenterol 2015;50(5):533-40.
27. Odagiri H, Yasunaga H, Matsui H, Fushimi K,
Iizuka T, Kaise M. Hospital volume and theoccurrence of bleeding and perforation following
colorectal endoscopic submucosal dissection:
analysis of a national administrative database inJapan. Diseases of the Colon & Rectum 2015;
58(6):597-603
28. Odagiri H, Matsui H, Fushimi K, Kaise M,
Yasunaga H. Factors predicting perforation related
to diagnostic balloon-assisted enteroscopy: analysis of the Diagnosis Procedure Combination database in Japan. Endoscopy 2015;47(2):143-6
29. Odagiri H, Iizuka T, Yasunaga H. Unusual case of
a submucosal tumor in the sigmoid colon. Saudi J
Gastroenterology 2015;21(2):119-20.
30. Odagiri H, Yasunaga H, Matsui H, Fushimi K,
Iizuka T, Kaise M. Difference in Outcomes ofRectal Foreign Bodies between Males andFemales: a Retrospective Analysis of a National
Inpatient Database in Japan. Digestion 2015;
92(3):165-70
31. Ogura K, Fujiwara T, Yasunaga H, et al.
Development and External Validation of Nomograms Predicting Distant Metastases and Overall
Survival after Neoadjuvant Chemotherapy andSurgery for Patients with Non-metastatic Osteosarcoma: A Multi-institutional Study. Cancer
2015;121:3844–385
32. Ohya J, Chikuda H, Kato H, Horiguchi H,
Takeshita K, Tanaka S, Yasunaga H. Risks of
in-hospital death and complications after fusion
surgery in patients with atlantoaxial subluxation:
analysis of 1,090 patients using the JapaneseDiagnosis Procedure Combination Database.
World Neurosurgery 2015;83(4):603-607
33. Ohya J, Chikuda H, Oichi T, Horiguchi H,
Takeshita K, Tanaka S, Yasunaga H. Perioperative
Stroke in Patients Undergoing Elective Spinal
Surgery: A Retrospective Analysis Using theJapanese Diagnosis Procedure Combination Database. BMC Musculoskeletal Disorders 2015;16:276
34. Ono S, Ishomaru M, Matsui H, Fushimi K,

335

Yasunaga H. Effect of Hospital Volume on
Outcomes of Surgery for Cleft Lip and Palate.
Journal of Oral and Maxillofacial Surgery. 2015;
73(11):2219-24.
35. Sako A, Yasunaga H, Matsui M, et al. Hospitalization for hypoglycemia in Japanese diabetic
patients: a retrospective study using a national
inpatient database, 2008–2012. Medicine 2015;
94(25):e1029
36. Sasabuchi Y, Yasunaga H, Sanui M, Alan LT. The
Dose-Response Relationship Between Body Mass
Index and Mortality in Subjects Admitted to the
ICU With and Without Mechanical Ventilation.
Respiratory Care 2015;60(7):983-91.
37. Sasabuchi Y, Yasunaga H, Matsui H, et al. The
volume-outcome relationship in critically illpatients in relation to the ICU-to-hospital bed
ratio. Crit Care Med 2015;43(6):1239-45
38. Sasabuchi Y, Yasunaga H, Matsui H, et al.
Carperitide increases the need for renal replacement therapy after cardiovascular surgery. Journalof Cardiothoracic and Vascular Anesthesia 2015;29(6):1426-31
39. Sato M, Tateishi R, Yasunaga H, et al. Variceal
hemorrhage – Analysis of 9987 cases from a Japanese nationwide database. Hepatology Research
2015;45(3):288-93
40. Shoda N, Yasunaga H, Horiguchi H, et al.
Prophylactic effect of fondaparinux andenoxaparin for preventing pulmonary embolism
after total hip or knee arthroplasty: a retrospective
observational study using the Japanese Diagnosis
Procedure Combination Database. Modern Rheumatology 2015;11:1-5.
41. Sugihara T, Yasunaga H, Yu C, et al. Perioperative
Outcome Comparisons Between Open and
Laparoscopic Nephroureterectomy Among a
Population-Based Cohort from 2010 to 2012.
Journal of Endourology 2015;29(7):770-6
42. Suzuki S, Yasunaga H, Matsui H, , et al. Factors
Associated with Severe Epiglottitis in Adults:
Analysis of Japanese Inpatient Database.
Laryngoscope 2015;125(9):2072-8.
43. Suzuki S, Yasunaga H, Matsui H, , et al.
Complication Rates After Functional Endoscopic
Sinus Surgery: Analysis of 50,734 JapanesePatients. Laryngoscope 2015;125(8):1785-91.

44. Tagami T, Matsui H, Horiguchi H, Fushimi K,
Yasunaga H. Thoracic aortic injury in Japan: anationwide retrospective cohort study. Circ J
2015; 79: 55–60
45. Tagami T, Matsui H, Horiguchi H, Fushimi K,
Yasunaga H. Recombinant human soluble
thrombomodulin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational
nationwide study. J Thrombosis Haemost 2015;
13(1):31-40.
46. Tagami T, Matsui H, Fushimi K, Yasunaga H. Useof recombinant human soluble thrombomodulin inpatients with sepsis-induced disseminated intravascular coagulation after intestinal perforation.
Frontiers in Medicine, section Intensive Care
Medicine and Anesthesiology 2015;2:7.
47. Tagami T, Matsui H, Fushimi K, Yasunaga H.
Validation of the prognostic burn index: anationwide retrospective study. Burns 2015;41(6):1169-75
48. Tagami T, Matsui H, Fushimi K, Yasunaga H.
Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after
abdominal sepsis. Thrombosis and Haemostasis
2015;114(3):537-45.
49. Tagami T, Matsui H, Fushimi K, Yasunaga H.
Intravenous Immunoglobulin and Mortality inPneumonia Patients with Septic Shock: An Observational Nationwide Study. Clinical Infectious
Diseases 2015;61(3):385-92
50. Tagami T, Matsui H, Fushimi K, Yasunaga H.
Intravenous immunoglobulin use in septic shock
patients after emergency laparotomy. Journal of
Infection 2015;71(2):158-66
51. Tagami T, Matsui H, Fushimi K, Yasunaga H.
Low-dose corticosteroid treatment and mortality
in refractory abdominal septic shock after
emergency laparotomy. Annals of Intensive Care
2015;5(1):32
52. Tagami T, Matsui H, Horiguchi H, Fushimi K,
Yasunaga H. Low-dose corticosteroid use andmortality in severe community-acquired pneumonia patients Eur Respir J. 2015;45(2):463-72
53. Takeuchi M, Tomomasa T, Yasunaga H, Horiguchi
H, Fushimi K. Descriptive Epidemiology ofChildren Hospitalized for Inflammatory Bowel

336

Disease in Japan. Pediatrics International 2015;57(3):443-8.
54. Tamiya H, Yasunaga H, Matusi H, , et al.
Hypnotics and the occurrence of bone fractures in
hospitalized dementia patients: a matchedcase-control study using a national inpatient
database. Plos One 2015 Jun 10;10(6):e0129366.
55. Tamiya H, Yasunaga H, Matusi H, , et al.
Comparison of short-term mortality and morbidity
between parenteral and enteral nutrition for adults
without cancer: a propensity-matched analysis
using a national inpatient database. American
Journal of Clinical Nutrition 2015;102(5):1222-8.
56. Tsuda Y, Yasunaga H, Horiguchi H, et al.
Association between dementia and postoperativecomplications after hip fracture surgery in theelderly: Analysis of 87654 patients using anational administrative database. Archives oforthopaedic and trauma surgery 2015;135(11):1511-7
57. Wada T, Yasunaga H, Inokuchi R, , et al.
Relationship between hospital volume and earlyoutcomes in acute ischemic stroke patients treatedwith recombinant tissue plasminogen activator.
International Journal of Stroke 2015;10(1):73-8.
58. Wada T, Yasunaga H, Inokuchi R, , et al. Effectiveness of surgical rib fixation on prolonged
mechanical ventilation in patients with traumatic
rib fractures: a propensity-score matched analysis.
Journal of Critical Care 2015;30(6):1227-31
59. Yamamoto H, Hashimoto H, Nakamura Horiguchi
H, Yasunaga H. Relationship between hospital
volume and hemorrhagic complication after
percutaneous renal biopsy: results from the Japanese Diagnosis Procedure Combination Database.
Clinical and Experimental Nephrology 2015;19(2):271-7.
60. Yamana H, Matsui H, Fushimi K, Yasunaga H.
Treatment options and outcomes of hospitalised
tuberculosis patients: a nationwide study. The
International Journal of Tuberculosis and Lung
Disease 2015;19(1):120-6
61. Yamana H, Matsui H, Sasabuchi Y, Fushimi K,
Yasunaga H. Categorized diagnoses and procedure records in an administrative database improved mortality prediction. J Clin Epidemiol
2015;68(9):1028-35.

62. Yamana H, Matsui H, Sasabuchi Y, Fushimi K,
Yasunaga H. Procedure-based severity index for
inpatients: development and validation using
administrative database. BMC Health Services
Research 2015;15:261.
63. Yamauchi Y, Yasunaga H, Matsui H, , et al.
Comparison of in-hospital mortality in patientswith obstructive airway disease. Respirology.
2015;20(6):940-6.
64. Yamauchi Y, Yasunaga H, Matsui H, et al.
Comparison of clinical characteristics andoutcomes between aspiration pneumonia andcommunity-acquired pneumonia in patients withchronic obstructive pulmonary disease. BMC
Pulmonary Medicine 2015;15(1):69.
65. Yasunaga H. Effect of Japanese Herbal Kampo
Medicine Goreisan on Reoperation Rates afterBurr-hole Surgery for Chronic Subdural Hematoma: Analysis of a National Inpatient Database.
Evidence-Based Complementary and Alternative
Medicine 2015; Article ID 817616

337

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. Health counseling
3. Patient-provider communication (1): Patient perspective
4. Patient-provider communication (2): Education ofhealth care professionals
5. Interpersonal communication skills for behavioral
changes
6. Public health communication skills for behavioral
changes
7. Evaluation and research in health communication
8. Public relations and communication fromhealthcare company
9. Media and communication (1): Television
10. Media and communication (2): News paper
11. Media and communication (3): Internet
12. Media doctor Japan
13. Entertainment education
14. Communicating for policy and advocacy[Health Communication Practice]
1. Coaching
2. Manners in interpersonal relationship3. MBTI (Myers-Briggs Type Indicator)
4. Mass communication: Press conference
5. Internet communication
We also provide lectures and practical instruction in
medical informatics / economics as part of the PhD
program of the Faculty of Medicine. In the under-

338

graduate program, Professor Kiuchi presents a lecture
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.

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References
1. Sasaki M., Ishikawa H., Kiuchi T., Sakamoto T.,
Marukawa S. Factors affecting layperson
confidence in performing resuscitation of out-ofhospital cardiac arrest patients in Japan. Acute
Medicine & Surgery. 2015; 2(3): 183-189.
2. Okuhara T., Ishikawa H., Okada H., Kiuchi T.
Readability, suitability, and health content assessment of cancer screening announcements inmunicipal newsletters in Japan. Asian Pacific
Journal of Cancer Prevention. 2015; 16 (15):6719-27.
3. Nakayama K., Osaka W., Togari T., Ishikawa H.,
Yonekura Y., Sekido A., Matsumoto M.
Comprehensive health literacy in Japan is lower
than in Europe: a validated Japanese-language
assessment of health literacy. BMC Public Health.
2015; 15(1): 505.
4. Suka M., Odajima T., Okamoto M., Sumitani M.,
Igarashi A., Ishikawa H., Kusama M., Yamamoto
M., Nakayama T., Sugimori H. Relationshipbetween health literacy, health information access,health behavior, and health status in Japanesepeople. Patient Education & Counseling. 2015;
98(5): 660-8.
5. Maruo T, Seo Y, Yamada S, Arita T, Ishizu T,
Shiga T, Dohi K, Toide H, Furugen A, Inoue K,
Daimon M, Kawai H, Tsuruta H, Nishigami K,
Yuda S, Ozawa T, Izumi C, Fumikura Y, Wada Y,
Doi M, Okada M, Takenaka K, Aonuma K. The
Speckle Tracking Imaging for the Assessment of
Cardiac Resynchronization Therapy (START)
study. Circ J 2015;79(3):613-622.

School of Public Health
2. Behavioral Health Sciences

341

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 four courses in the master
degree program for public health, and five 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342

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.
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 inter-

vention in work place.

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 environments 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.
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.

343

Publications
1. Kawakami N, Hashimoto H, Kondo N (Eds)(2015) Society and Health: Integrated approach
toward smaller health disparities The Univ. Tokyo
Publishing (In Japanese)
2. Kondo N. Social capital and social inequality indisaster settings. In. Chou J. (Ed). Healthcare inmega disasters. (2015) Nakayama shoten. (InJapanese) Peer-reviewed papers
3. Zhang CY, Hashimoto H. How do patients andproviders react to different incentives in the
Chinese multiple health security systems? Chin
Med J (Engl). 2015 Mar 5;128(5):632-7. doi:
10.4103/0366-6999.151661.
4. 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. 2015 Mar 24.
5. Kawasaki S, Nishimura Y, Takizawa R, Koike S,
Kinoshita A, Satomura Y, Sakakibara E, Sakurada
H, Yamagishi M, Nishimura F, Yoshikawa A, Inai
A, Nishioka M, Eriguchi Y, Kakiuchi C, Araki T,
Kan C, Umeda M, Shimazu A, Hashimoto H,
Kawakami N, Kasai K. Using social epidemiology
and neuroscience to explore the relationshipbetween job stress and frontotemporal cortex
activity among workers. Soc Neurosci. 2015 Jun;
10(3):230-42. doi:10.1080/17470919.2014.997370.
6. Yamamoto H, Hashimoto H, Nakamura M,
Horiguchi H, Yasunaga H. Relationship between
hospital volume and hemorrhagic complication
after percutaneous renal biopsy: results from theJapanese diagnosis procedure combination database. Clin Exp Nephrol. 2015 Apr;19(2):271-7.
doi: 10.1007/s10157-014-0986-x.
7. Iwamoto T, Hashimoto H, Horiguchi H, Yasunaga
H. Effectiveness of Hospital Functions for Acute
Ischemic Stroke Treatment on In-Hospital
Mortality: Results From a Nationwide Survey inJapan. J Epidemiol. 2015 Aug 5;25(8):522-8. doi:
10.2188/jea.JE20140181.
8. Umeda M, McMunn A, Cable N, Hashimoto H,
Kawakami N, Marmot M. Does an advantageous

occupation make women happier in contemporary
Japan? Findings from Japanese Study of Health,Occupation, and Psychological Factors Related
Equity (J-HOPE). Soc Sci Med Pop doi:10.1016/j.
ssmph.2015.09.002.
9. Sasaki M, Sakamoto T, Hiraide A, Kobayashi D,
Sato H, Hashimoto H. Cost benefit analysis of
public access defibrillation in Japan. 96(supp1):78-, 2015.
10. 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 patientswith type 2 diabetes: a cross-sectional study. BMJ
Open Diab Res Care 2016;4:e000156 doi:10.
1136/bmjdrc-2015-000156.
11. Murakami K, Kondo N, Ohkubo T, Hashimoto H.
The effect of fathers’ and mothers’ educational
level on adult oral health in Japan. Community
Dent Oral Epidemiol. 2016 Feb 12. doi: 10.1111/
cdoe.12216.
12. Tani Y, Kondo K, Kondo N. Eating alone and dietand BMI among Older Japanese: JAGES.
Koseinoshihyou 2015;62(13):9-15. (In Japanese)
13. Tsukahara T*, Ogura S, Sugahara T, Sekihara M,
Furusawa T, Kondo N, et al. The choice of
healthcare providers for febrile children after
introducing non-professional health workers in amalaria endemic area in Papua New Guinea.
Frontiers in Public Health. 2015 2015-December24;3.
14. Saito T, Konso K, Murata C, Jiang M, Suzuki K,
Kondo N. Gender- and geographical differences insocial behaviors and leisure time activities inJapan: JAGES. Nippoinkoshueiseizasshi.. 2015;
62(10):596-608. (In Japanese)
15. Yamakita M*, Kanamori S, Kondo N, Kondo K.
Correlates of Regular Participation in Sports
Groups among Japanese Older Adults: JAGES
Cross-Sectional Study. PLoS One. 2015;10(10):e0141638.
16. Hayashi K, Kawachi I, Ohira T, Kondo K, Shirai
K, Kondo N*. Laughter and Subjective HealthAmong Community-Dwelling Older People inJapan: Cross-Sectional Analysis of the Japan
Gerontological Evaluation Study Cohort Data. J
Nerv Ment Dis. 2015 Dec;203(12):934-42.

344

17. Tani Y*, Sasaki Y, Haseda M, Kondo K, Kondo N.
Eating alone and depression in older men andwomen by cohabitation status: The JAGES
longitudinal survey. Age Ageing. 2015 Nov;44(6):1019-26.
18. Chao D*, Hashimoto H, Kondo N. Dynamic
impact of social stratification and social influenceon smoking prevalence by gender: An agent-basedmodel. Soc Sci Med. 2015 Dec;147:280-7.
19. Tani, Y., Kondo, N*., Takagi, D., Saito, M.,
Hikichi, H., Ojima, T., & Kondo, K. (2015).
Combined effects of eating alone and living alone
on unhealthy dietary behaviors, obesity andunderweight in older Japanese adults: Results of
the JAGES. Appetite, 95, 1-8. doi: http://dx.doi.
org/10.1016/j.appet.2015.06.005
20. Nakade M, Takagi D, Suzuki K, Aida J, Ojima T,
Kondo K, Kondo N*. Influence of socioeconomic
status on the association between body mass index
and cause-specific mortality among older Japanese adults: The AGES Cohort Study. Prev Med.
2015;77:112-8.
21. Ueda P, Kondo N*, Fujiwara T. The global
economic crisis, household income and preadolescent overweight and underweight: a nationwide birth cohort study in Japan. Int J Obes
(Lond). 2015 Sep;39(9):1414-20.
22. Hikichi H*, Kondo N, Kondo K, Aida J, Takeda T,
Kawachi I. Effect of a community intervention
programme promoting social interactions onfunctional disability prevention for older adults:
propensity score matching and instrumental
variable analyses, JAGES Taketoyo study. J
Epidemiol Community Health. 2015 April 17,
2015.
23. Koyama S, Aida J, Kawachi I, Kondo N,
Subramanian SV, Ito K, et al. Social support
improves mental health among the victims
relocated to temporary housing following theGreat East Japan Earthquake and Tsunami.
Tohoku J Exp Med. 2014;234(3):241-7.
24. Kondo N, Saito M, Hikichi H, Aida J, Ojima T,
Kondo K, et al. Relative deprivation in income
and mortality by leading causes among older
Japanese men and women: AGES cohort study. J
Epidemiol Community Health. 2015 Jul; 69(7):680-5.

25. Takahashi S, Ishiki M, Kondo N, Ishiki A,
Toriyama T, Takahashi S, et al. Health effects of a
farming program to foster community social
capital of a temporary housing complex of the2011 great East Japan earthquake. Disaster Med
Public Health Prep. 2015 Apr;9(2):103-10.
26. Odonkor CA, Hurst PV, Kondo N, Makary MA,
Pronovost PJ. Beyond the Hospital Gates:
Elucidating the Interactive Association of Social
Support, Depressive Symptoms, and Physical
Function with 30-Day Readmissions. Am J Phys
Med Rehabil. 2015 Jul;94(7):555-67.
27. Hikichi H, Kondo K, Aida J, Kondo N. social
relationships in disaster medical care settings:
interview surveys for public health nurses after
the Great east japan Earthquake. shudansaigaiigakuzasshi. 2015;20(1):51-6. (In Japanese) Nonpeer reviewed papers
28. Hashimoto H. [Ethics and conflict of interest in
clinical research: sociological view]. Nihon Jinzo
Gakkai Shi. 2015;57(8):1311-5.
29. Tani Y, Kondo K, Kondo N. the associations
between eating alone and diet and BMI:JAGES.
koseinoshihyou. 2015;62(13). (In Japanese)
30. Kono N. Five tips for community intereventions
aiming to reduce health disparities. Hokenshi
Journal. 2015. 71.11：950−956. (In Japanese)
31. Kondo N (2015) Public health activities targeting
those who are not conscious about health.
Hokenshi journal. 2015 (In Japanese) Vol.71.
No.9(2015-9)：740-745

School of Public Health
3. Health Services Sciences

346

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Research Associate
Toki Saito, Ph.D.

Homepage:

http://park.itc.u-tokyo.ac.jp/CIEMedUTokyo/wp/

Introduction and Organization
Information engineering in Japan places a great dealof weight on computer hardware, software, and dataprocessing. It is a discipline that seeks objective dataand emphasizes the conception of new methods ofdata transfer, storage, processing, and input/output. It
also targets research on developing computer devices
and systems.
Reviewing the history of the application ofcomputers in medicine, calculating machines forsupporting scientists and technologists first appearedin the 1950s. In the 1960s, computers were used foraccounting and various statistics. The personal
computer appeared in the 1980s and was adopted for
personal use in many professions. The systematizationof large hospitals, such as university hospitals, pushedahead rapidly.
In the 1990s, the computer began to be used as atool to help human thinking, such as in presentations,design, and discovery. When computers became
connected to each other through the internet, thedistribution of information became very easy andrapid, not only within organizations, but 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 health information infrastructures, electrical clinicalguidelines, and knowledge navigation systems.
In response to the needs of the time, the Departmentof Clinical Information Engineering (CIE) wasestablished at the School of Public Health in April
2007. Its predecessor was the clinical informationengineering division of clinical bioinformatics, using
Special Coordination Funds for Promoting Scienceand Technology from the Ministry of Education,
Culture, Sports, Science, and Technology, of Japan.

Teaching activities
The purpose of the Department of Clinical Information Engineering is to nurture talented people whohave 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
weekly conferences at which the students present the347

progress on their own research projects and discuss
their future directions.

Research activities
Our research covers the biomedical computer
applications that focus on biomedical data (collection,
analysis, and representation). It constitutes a
combination of information science, computer science,and clinical science designed to assist in the
management and processing of data, information, andknowledge to support the practice and delivery ofclinical care. Our laboratory is engaged in thefollowing research activities:(1) Medical Decision-making: We focus on how to
improve health outcomes by advancing
systematic approaches to clinical decisionmaking and policy formation in health care using
information engineering methodology (IEM),
especially electrical clinical guidelines andencoded knowledge.
(2) Data Mining & Knowledge Discovery from
Databases: It is necessary to collate heterogeneous information, such as the clinical indications
for a drug, drug side effects, pharmacokinetics,
metabolic pathways, and drug response genes for
single nucleotide polymorphisms (SNPs). These
data are distributed and managed in various
clinical databases. We are studying ways tointegrate distributed biomedical data andknowledge mining with virtualized databasetechnologies, such as auto-indexing and technicalterm 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 tomo-

graphy (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. Yoshino M, Kin T, Ito A, Saito T, Nakagawa D,
Ino K, Kamada K, Mori H, Kunimatsu A,
Nakatomi H, Oyama H, Saito N. Combined useof diffusion tensor tractography and multifusedcontrast-enhanced FIESTA for predicting facialand cochlear nerve positions in relation tovestibular schwannoma. Journal of neurosurgery
123(6) 1480-1488 2015.
2. Yoshino M, Kin T, Ito A, Saito T, Nakagawa D,
Ino K, Kamada K, Mori H, Kunimatsu A,
Nakatomi H, Oyama H, Saito N. Feasibility ofdiffusion tensor tractography for preoperative
prediction of the location of the facial andvestibulocochlear nerves in relation to vestibular
schwannoma. Acta neurochirurgica 157(6) 93946; discussion 946 2015.
3. Yoshino M, Kin T, Ito A, Saito T, Nakagawa D,
Kamada K, Mori H, Kunimatsu A, Nakatomi H,
Oyama H, Saito N. Diffusion tensor tractographyof normal facial and vestibulocochlear nerves.
International journal of computer assisted
radiology and surgery 10(4) 383-392 2015.
4. Yoshino M, Saito T, Kin T, Nakagawa D,
Nakatomi H, Oyama H, Saito N. A Microscopic
Optically Tracking Navigation System That Uses
High-resolution 3D Computer Graphics. Neurologia medico-chirurgica 55(8) 674-679 2015.

Endowed Department

349

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

350

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 2015, we received 45 requests and made2447 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 30 in 2015, 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
is provided 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 May 19 in 2015,
and to sophomore students on February 2 in 2016.
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 27 in 2015. In
addition to that, the same lecture provided by Dr.

Koide took place as the series of medical common
lectures XXXIII on January 26 in 2015.
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 September 15-16 in2015, 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 “Epidemiologicalresearch with database” on May 27 and as“Pharmacovigilance with database” on June 3 in 2015.
And Dr. Koide provided a lecture as “-ClinicalPharmacology-, Evaluation of Drug Efficacy and
Safety" (3) Pharmacoepidemiology”, which was given
to the sixth-grade students at Tokyo University ofpharmacy and Sciences on July 2 in 2015. 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 September 10,
2015. Moreover, Dr. Koide has lectured on ICT
literacy as 15 series at faculty of International Liberal
Arts, Juntendo University, from October 7 in 2015 toJanuary 27 in 2016.
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. Therefore, we expand our scope of humanresource development for not only clinical epidemiology, but also clinical research and trial.

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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. And Dr. Koide
was chosen as a member of a working group for thethird party use of the national claim database (NDB)
managed by the health insurance bureau in theministry of health, labor and welfare in Japan.
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.

Specifically, our recent findings suggest theunprecedented 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.

References
1. Kubota K, Kamijima Y, Sato T, Ooba N, Koide D,
Iizuka H, Nakagawa H. Epidemiology of psoriasis
and palmoplantar pustulosis: a nationwide study
using the Japanese national claims database. BMJ
Open. 2015. 5(1):e006450.

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2. 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. J Cardiol. 2016 Jan 8. pii: S09145087(15)00390-1. doi: 10.1016/j.jjcc.2015.11.014.
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?
J Cardiol. 2016 Mar 1. pii: S0914-5087(16)00032-0.
doi: 10.1016/j.jjcc.2016.02.003

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Department of Ubiquitous
Preventive Medicine
Associate Professor
Yuichi Ikeda, M.D., Ph.D. (2015.11〜)
Yasushi Imai, M.D., Ph.D. (2014.12〜2015.7)

Assistant Professor
Yuichi Ikeda, M.D., Ph.D. (2014.7〜2015.10)

Introduction and Organization

Research Activities

As an official department in the Graduate School of
Medicine of the University of Tokyo, the Departmentof Ubiquitous Preventive Medicine was established inAugust 1st, 2007, with a donation from threepharmaceutical companies, Toa-Eiyo Ltd., Shionogi &Co., Ltd. and NEC Corporation to the University(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.

Our goal is to create diagnostic and therapeutic basis
for prevention and early detection of cardiovasculardisease by utilizing advanced techniques of biochemistry and molecular pharmacology.
Weespecially focus on the discovery of bioactive
molecules and diagnostic biomarkers in order topromote translational research, which connects basic
scientific findings to tangible clinical application.
One of our achievements is the establishment of anovel technique for detecting post-translational
modification and degradation of B-type natriuretic
peptide, one of the most important biomarkers in
cardiovascular pathologies such as ischemic heartdisease and heart failure. This unique technique wasdeveloped in collaboration with Shimadzu Corporation. We have already confirmed and published its
utility in clinical practice (Clin Chem, in press),further, issued press-release from the University ofTokyo Hospital.
In addition to the development of diagnostic
techniques, we have also established several screening
systems towards the discovery of bioactive substancesthat are involved in the pathogenesis of cardiovasculardisease. 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354

preventive medicine for health promotion.

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. Ikeda Y*, Kumagai H, Motozawa Y, Suzuki J,
Komuro I: Next generation ARBs: going beyond
modulation of the renin-angiotensin system. Int
Heart J. 56:585-586, 2015. (*corresponding
author)
2. Nakayama A, Morita H, Nakao T, Yamaguchi T,
Sumida T, Ikeda Y, Kumagai H, Motozawa Y,
Takahashi T, Imaizumi A, Hashimoto T, Nagai R,
Komuro I: A food-derived flavonoid luteolin
protects against angiotensin II-induced cardiac
remodeling. PLoS One 10(9): e0137106, 2015.
3. Ikeda Y*, Kumagai H, Motozawa Y, Suzuki J,
Komuro I: Biased agonism of the angiotensin II
type I receptor: a potential strategy for thetreatment of acute heart failure. Int Heart J. 56:
485-488, 2015. (*corresponding author)
4. Motozawa Y, Uozumi H, Maemura S, Nakata R,
Yamamoto K, Takizawa M, Kumagai H, Ikeda Y,
Komuro I, Ikenouchi H: Acute myocardial
infarction that resulted from poor adherence tomedical treatment for giant coronary aneurysm:
the importance of patient education in the chronic
phase of Kawasaki disease. Int Heart J. 56:551554, 2015.
5. Ikeda Y, Takimoto E, Komuro I: SH2B1: a new
player in the regulation of cardiac hypertrophic
response in failing hearts. Cardiovasc Res. 107:
197-199, 2015.

6. 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, Yanagisawa M:
Monitoring ß-arrestin recruitment via ß-lactamase
enzyme fragment complementation: purificationof peptide E as a low-affinity ligand for
mammalian bombesin receptors. PLoS One 10(6):e0127445, 2015. (*corresponding author)
7. 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 One
10(5): e0129394, 2015 (*co-first author)
8. Ono S, Fujishiro M, Ikeda Y, Komuro I, Koike K:
Recent clinical management of anti-thrombotic
agents for gastrointestinal endoscopy afterrevision of guideline in Japan. Dig Endosc. 27:
649-656, 2015.
9. Mochizuki S, Ikeda Y, Arai T, Matsuo K: Towardfurther prevention of bleeding after gastricendoscopic submucosal dissection. Dig Endosc.
27:295-297, 2015.
10. Lee IT, Chang AS, Manandhar M, Shan Y, Fan J,
Izumo M, Ikeda Y, Motoike T, Dixon S, Seinfeld
JE, Takahashi JS, Yanagisawa M: Neuromedin
S-producing neurons act as essential pacemakers
in the suprachiasmatic nucleus to couple clockneurons and dictate circadian rhythms. Neuron
85:1086-1102, 2015.

355

Division of Chronic Kidney Disease(CKD) Pathophysiology
Division Chief (Associate Professor)
Reiko Inagi, Ph.D.

Assistant Professor
Kumi Shoji, M.D., Ph.D.
Tzu-Ming Jao, Ph.D.
Yoshihisa Nakatani, M.D., Ph.D. (Division of Nephrology and Endocrinology)

PhD Students
Yu Ishimoto, M.D. (Division of Nephrology and Endocrinology)
Akira Okada, M.D. (Division of Nephrology and Endocrinology)

Visiting Researcher
Kittisak Sinpitukkul, Msc.
(Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand)
Manoch Rattanasompattikul, MD.
(Renal Unit, Medical Department, Golden Jubillee Medical Center, Mahidol University,
Bangkok, Thailand)

Lab Technician
Ikumi Okuaki, B.S.

Homepage

http://www.todai-ckd.com

Introduction and Organization

which progresses over time carries a number of risks.

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.
Additional causes include the aging of society andother social factors. The kidney is called a silent organ,
and CKD progresses without subjective symptoms. It
is now evident, however, that asymptomatic CKD

One risk is the possible progression of CKD to
end-stage kidney failure, which requires renal
replacement therapy. A second risk is the development
and progression of lifestyle-related diseases, such asheart attack and arteriosclerosis. The kidneys work
closely with the heart and other organs, and a decrease
in renal function causes dysfunction of the heart andblood vessels. This adverse impact of the progressionof CKD on other organs underlines the importance of
the kidneys in maintaining general health. Further,many researchers have also focused on the vicious

356

spiral of aging and CKD: aging worsens the
progression of CKD, while CKD accelerates aging.
With our modern lifestyles and the super-aging society,
CKD cannot be separated from lifestyle-relateddiseases, and senility cannot be separated from CKD.
Creating a healthy, long-lived society full of energy
and vigor requires that the quality of life (QOL) of theelderly be improved. In turn, total medical
expenditures will also be decreased. These are important issues requiring urgent solutions. Against thisbackground, the Division of CKD Pathophysiology
was newly established in November 2013 withsupport from Kyowa Hakko Kirin Co., Ltd. The aimof the Division is to aid and support the control CKD
and the creation of a healthy, long-lived society. The
Division takes an innovative approach to identifying
the pathophysiology of CKD, and works to develop
more effective CKD preventive and therapeuticstrategies. Through these research activities, our goal
is to contribute to the creation of a healthy, long-lived
society in which the elderly can live a happy andindependent 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 CDK in
patients with diabetes, and developing diagnostic

and therapeutic drugs targeting such factors.

Research Funds
・ Japan Society for the Promotion of Science,
Grants-in-Aid for Scientific Research25461207 (to Reiko Inagi, Analysis of pathophysiological significance of microRNA that
regulates hypoxic and ER stress responses),
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),
25893045 (to Kumi Shoji, Identification of thefunction of Sperm- associated antigen 4, a novel
hypoxia-inducible factor 1 target, in the kidney)・ Yakult Bio-Science Foundation (to Reiko Inagi,
pathophysiological contribution of gut microbiota
in CKD progression)AwardsDr. Yu Ishimoto received the Best Abstract Award ofKidney Summit 2015 (2015 Dec. in Tokyo).
Dr. Yu Ishimoto received the Investigators Award in
the 5th Chronic Kidney Disease Frontier Meeting(2016 Feb. in Nagoya).

References
1. Inagi R. The gut-kidney connection in advanced
chronic kidney disease. Kidney Res Clin Pract.
2015 Dec;34(4):191-3.
2. Ishimoto Y, Inagi R. Mitochondria: a therapeutictarget in acute kidney injury. Nephrol Dial
Transplant. 2016 Jul;31(7):1062-9.
3. Persson P, Friederich-Persson M, Fasching A,
Hansell P, Inagi R, Palm F. Adenosine A2 a
receptor stimulation prevents proteinuria in
diabetic rats by promoting an anti-inflammatory
phenotype without affecting oxidative stress. Acta
Physiol (Oxf). 2015 Jul;214(3):311-8.
4. Nangaku M, Inagi R, Mimura I, Tanaka T.
Epigenetic Changes Induced by Hypoxia--

357

Inducible Factor: a Long Way Still To Go as aTarget for Therapy？ J Am Soc Nephrol. 2015
Jul;26(7):1478-80.
5. Motonishi S, Nangaku M, Wada T, Ishimoto
Y,Ohse T, Matsusaka T, Kubota N, Shimizu A,
Kadowaki T, Tobe K, Inagi R. Sirtuin1 maintains
actin cytoskeleton by deacetylation of cortactin in
injured podocytes. J Am Soc Nephrol. 2015 Aug;26(8):1939-59.

358

Department of Molecular Structure
and Dynamics
Project Professor
Nobutaka Hirokawa, M. D.

Project Associate
Tadayuki Ogawa, Ph. D.

Homepage

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. Morikawa, M., H. Yajima, R. Nitta, S. Inoue, T.
Ogura, C. Saito, and N. Hirokawa. X-ray andCryo-EM structures reveal mutual conformationalchanges of Kinesin and GTP-state microtubules
upon binding. EMBO J. 34: 1270-1286, 2015.
2. Farkhondeh, A., S. Niwa, Y. Takei, and N.
Hirokawa. Characterizing KIF16B in neurons
reveals a novel intramolecular "stalk inhibition"mechanism that regulates its capacity to potentiate
the selective somatodendritic localization of earlyendosomes. J. Neurosci. 35 : 5067–5086, 2015.
3. Hirokawa. N. Introduction to the ECR Special
Issue on Molecular Motors. Exp Cell Res 334: 1,
2015.
4. Hirokawa, N. and Y. Tanaka. Kinesin superfamily
proteins (KIFs): Various functions and theirrelevance for important phenomena in life anddiseases. (Review Article) Exp Cell Res 334:

359

5.

6.

7.

8.

16-25, 2015.
Ichinose, S., T. Ogawa, and N. Hirokawa.
Mechanism of Activity-dependent Cargo Loading
via the Phosphorylation of KIF3A by PKA and
CaMKIIa. Neuron 87: 1022–1035, 2015.
Ogawa, T. and N. Hirokawa. Microtubule destabilizer KIF2A undergoes distinct site-specificphosphorylation cascades that differentially affectneuronal morphogenesis. Cell Reports 12: 1–15,
2015.
Takei, Y., Y. S. Kikkawa, N. Atapour, T.
K.Hensch, and N. Hirokawa.
Defects insynaptic plasticity, reduced NMDA-receptor
transport, and instability of PSD proteins in micelacking microtubule-associated protein 1A(MAP1A). J Neurosci 35(47): 15539 –15554,
2015.
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

360

Department of Continence
Medicine
Professor
Yasuhiko Igawa, M.D.,Ph.D.

Research Associate
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

361

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, Ogawa S, Sugiyama R, Homma Y,
Igawa Y. Influence of urethane- anesthesia on theeffect of resiniferatoxin treatment on bladderfunction in rats with spinal cord injury. Neurourol
Urodyn. 2015 Mar; 34(3)274-9
2. Kakutani S, Fukuhara H, Taguchi S, Nagata M,
Niimi A, Hattori M, Miyazaki H, Fujimura T,
Nakagawa T, Kume H, Igawa Y, Homma Y.
Combination of docetaxel, ifosfamide andcisplatin (DIP) as a potential salvage chemotherapy for metastatic urothelial carcinoma. Jpn J
Clin Oncol. 2015 Mar; 45(3):281-5.
3. Aizawa N, Homma Y, Igawa Y. Effects of
L-arginine, mirabegron, and oxybutynin on the
primary bladder afferent nerve activities synchronized with reflexic, rhythmic bladder contractionsin the rat. Neurourol Urodyn. 2015 Apr; 34(4):368-74.
4. Aizawa N, Ito H, Sugiyama R, Fujimura T, Suzuki
M, Fukuhara H, Homma Y, Igawa Y. Selective
inhibitory effect of imidafenacin and 5-hydroxymethyl tolterodine on capsaicin-sensitive C-fibersof the primary bladder mechanosensitive afferent
nerves in the rat. J Urol. 2015 Apr; 193(4):142332.
5. Kanatani A, Nakagawa T, Kawai T, Naito A, Sato
Y, Yoshida K, Nozaki K, Nagata M, Yamada Y,
Azuma T, Suzuki M, Fujimura T, Fukuhara H,
Nishimatsu H, Kume H, Igawa Y, Homma Y.
Adjuvant chemotherapy is possibly beneficial for
locally advanced or node-positive bladder cancer.
Clin Genitourin Cancer. 2015 Apr;13(2):e107-12.
6. Yamaguchi O, Marui E, Igawa Y, Takeda M,
Nishizawa O, Ikeda Y, Ohkawa S. Efficacy and
Safety of the Selective β3 -Adrenoceptor Agonist
Mirabegron in Japanese Patients with Overactive
Bladder: A Randomized, Double-Blind, PlaceboControlled, Dose-Finding Study. Low Urin Tract
Symptoms. 2015 May; 7(2):84-92.

7. Fujimura T, Yamada Y, Sugihara T, Azuma T,
Suzuki M, Fukuhara H, Nakagawa T, Kume H,
Igawa Y, Homma Y. Nocturia in men is a chaotic
condition dominated by nocturnal polyuria. Int J
Urol. 2015 May; 22(5):496-501.
8. Ito H, Aizawa N, Fujita Y, Suzuki M, Fukuhara H,
Homma Y, Kubota Y, Ito M, Andersson KE, Igawa
Y. Long-term caloric restriction in rats may
prevent age-related impairment of in vitro bladderfunction. J Urol. 2015 Jun; 193(6):2123-30.
9. Akiyama Y, Nomiya A, Niimi A, Yamada Y,
Fujimura T, Nakagawa T, Fukuhara H, Kume H,
Igawa Y, Homma Y. Botulinum toxin type A
injection for refractory interstitial cystitis: A
randomized comparative study and predictors oftreatment response. Int J Urol. 2015 Sep; 22(9):835-41.
10. Yokoyama O, Igawa Y, Takeda M, Yamaguchi T,
Murakami M, Viktrup L. Tadalafil for lower
urinary tract symptoms secondary to benign
prostatic hyperplasia: a review of clinical data in
Asian men and an update on the mechanism ofaction. Ther Adv Urol. 2015 Oct;7(5):249-64.
11. Yamada Y, Nomiya A, Niimi A, Igawa Y, Ito T,
Tomoe H, Takei M, Ueda T, Homma Y. A survey
on clinical practice of interstitial cystitis in Japan.
Transl Androl Urol. 2015 Oct; 4(5):486-90.
12. Kamei J, Furuta A, Akiyama Y, Niimi A, Ichihara
K, Fujimura T, Fukuhara H, Kume H, Homma Y,
Igawa Y. Video-urodynamic effects of mirabegron,a β3-adrenoceptor agonist, in patients with lowcompliance bladder. Int J Urol. 2015 Oct; 22(10):956-61.
13. Yamaguchi O, Kakizaki H, Homma Y, Igawa Y,
Takeda M, Nishizawa O, Gotoh M, Yoshida M,
Yokoyama O, Seki N, Okitsu A, Hamada T,
Kobayashi A, Kuroishi K. Safety and efficacy of
mirabegron as add-on therapy in patients withoveractive bladder treated with solifenacin: apostmarketing, open-label study in Japan (MILAI
study). BJU Int 2015 Oct; 116(4)612-22
14. Maeda D, Akiyama Y, Morikawa T, Kunita A, Ota
Y, Katoh H, Niimi A, Nomiya A, Ishikawa S,
Goto A, Igawa Y, Fukayama M, Homma Y.
Hunner-Type (Classic) Interstitial Cystitis: A
Distinct Inflammatory Disorder Characterized
by Pancystitis, with Frequent Expansion of Clonal

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B-Cells and Epithelial Denudation. PLoS One.
2015 Nov 20;10(11):e0143316.

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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

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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. Yamato A, Soda M, Ueno T, Kojima S, Sonehara
K, Kawazu M, Sai E, Yamashita Y, Nagase T,
Mano H. “Oncogenic activity of BIRC2 andBIRC3 mutants independent of nuclear factorkappaB-activating potential” Cancer Sci 106:1137-1142, 2015.
2. Yamaguchi H, Kawazu M, Yasuda T, Soda M,
Ueno T, Kojima S, Yashiro M, Yoshino I,
Ishikawa Y, Sai E, Mano H. “Transforming
somatic mutations of mammalian target of
rapamycin kinase in human cancer” Cancer Sci
106:1687-1692, 2015.
3. Suzuki HI, Katsura A, Yasuda T, Ueno T, Mano
H, Sugimoto K, Miyazono K. “Small-RNA asymmetry is directly driven by mammalian Argonautes” Nat Struct Mol Biol 22:512-521, 2015.
4. Mano H. “Second-generation ALK inhibitors”
Clin Adv Hematol Oncol 13:416-417, 2015.
5. Mano H. “The EML4-ALK oncogene: targetingan essential growth driver in human cancer” Proc
Jpn Acad Ser B Phys Biol Sci 91:193-201, 2015.
6. Ikeda K, Horie-Inoue K, Ueno T, Suzuki T, Sato
W, Shigekawa T, Osaki A, Saeki T, Berezikov E,
Mano H, Inoue S. “miR-378a-3p modulates
tamoxifen sensitivity in breast cancer MCF-7 cells
through targeting GOLT1A” Sci Rep 5:13170,
2015.
7. Hashizume O, Ohnishi S, Mito T, Shimizu A,
Iashikawa K, Nakada K, Soda M, Mano H,
Togayachi S, Miyoshi H, Okita K, Hayashi J.
“Epigenetic regulation of the nuclear-coded
GCAT and SHMT2 genes confers human ageassociated mitochondrial respiration defects” Sci
Rep 5:10434, 2015.

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Department of MolecularPsychiatry
Associate Professor
Kazuya Iwamoto,Ph.D.

Assistant Professor
Miki Bundo, Ph.D.

Homepage

http://www.molpsy.com

Introduction and Organization
Major mental disorders such as schizophrenia,
affective disorders, and developmental disorders aresevere disorders showing high prevalence rate inevery population. They not only bring long-lasting
suffering to patients and their families, but also cause
tremendous loss from an economical view. Surprisingly, cause of illness and pathophyshiology of mental
disorders remain largely unclear. The Department of
Molecular Psychiatry has been established at theGraduate School of Medicine, University of Tokyo
from February 2010 to January 2013, by the donationfrom Astellas Pharma, Dainippon Sumitomo Pharma,and Yoshitomi Yakuhin, and from February 2013, by
the donation from Dainippon Sumitomo Pharma, andYoshitomi Yakuhin. The aim of this department is tocontribute the understanding of cause of illness andpathophysiology of major mental disorders at themolecular level, through the close collaboration with
Department of Neuropsychiatry at the University ofTokyo.

Research activities
Specimen derived from mental disorders as well asanimal models are examined by comprehensive
approaches from genetic, molecular biological,
cellular and behavioral point of views. Especially, we
will focus on the study of blood samples provided
from Department of Neuropsychiatry at the Universityof Tokyo and postmortem brains provided from brainbanks.

Publication
1. Sugawara H, Bundo M, Asai T, Sunaga F, Ueda
J, Ishigooka J, Kasai K, Kato T, Iwamoto K.
Effects of quetiapine on DNA methylation inneuroblastoma cells. Progress in NeuroPsychopharmacology and Biological Psychiatry
2015,56:117-121.

366

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.

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 projector, a project
lecturer and a project assistant professor. In addition, aproject researcher is belonging to our department 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.

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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. Masakatsu Fujie,
Waseda University and other speakers related toengineering 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 third seminar for
nursing science and engineering. The staffs in our
department had engineering-related lectures and introduction of research using ultrasonography.

Research activities
Our research themes are to investigate causes of
diseases and/or wounds due to daily life activity, andto develop instrument for effective monitoring andpreventing diseases and/or wounds. We study scienceand technology of natural human monitoring, nursing
engineering, and human behavior sensing thoroughly.
We are seeking a new interdisciplinary researchdomain between engineering and nursing, and willing
to realize comfortable daily life through theseresearches.
We are developing the methodology to support healthy
and comfortable daily life by 1) monitoring daily life
naturally, 2) understanding the typical behaviors, and
3) predicting diseases, injuries, and accidents using
various sensing technology.

Main themes of our department are the following:a) Development of monitoring systems for patient on
a bed and vital sign measurement system using
mattressb) Construction of behavior measurement in dailyliving environment using simple sensors and algorithm for typical behavior pattern extraction andtransition estimation of human behavior patternc) Three dimensional leg movement measurement
and spatiotemporal 3D leg state measurement for
prevention of foot ulcerd) Clinical research for current status and management of incontinencee) 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.
As for the research related to prevention of diabetic
foot ulcer, we supported the doctor course student,
who was belonging to Department of GerontologicalNursing/Wound Care Management. She developed a
new measurement system and conducted observational
study. The system consists of small force sensors
directly attached on the plantar, which can capture
both vertical and horizontal forces, and small motions
sensors, which can measure movement of the legs andthe foots. The clinical study identified cut-off value ofplantar force parameters for callus formation, andrevealed what gait parameters were related toelevation of plantar force parameters. She wrote
dissertation “Investigation of external force on plantar
associated with callus in diabetic neuropathy patientsand its relationship with their leg motions for footulcer prevention” and graduated.
In this year, we started new research theme andsupport an undergraduate student. He developed a new
system for support of nurses to insert needles into
peripheral vein. The system consists of head mountdisplay which provides the pre-scanned ultrasoundimage including vein information, and camera which

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can detect the nurse’s fingertip position and rotation.
The nurses can select the suitable vein for catheter
needle insertion using the system. The student wrote
the graduation thesis “Virtual ultrasonic probe system
to support peripheral IV catheter site selection”. Hereceived the prize of school of integrated healthscience. He also received “the University of Tokyo
President’s Award for Students” based on hisacademic achievement and graduation thesis.

References
1. Taketoshi Mori, Kazuyuki Komichi, Hiroshi
Noguchi, Yumi Umeda-Kameyama, Hiromi
Sanada, Masahiro Akishita and Kazuhiko Ohe.
Anomaly detection in home monitoring system
for the elderly using financial theories. Journal of
Nursing Science and Engineering (JSNE), Vol. 3,
No. 1, pp. 21-30, 2016.
2. Maki Kaneko, Takeo Minematsu, Mikako Yoshida,
Yoshimi Nishijima, Hiroshi Noguchi, Yasunori
Ohta, Gojiro Nakagami, Taketoshi Mori, Hiromi
Sanada. Compression-induced HIF-1 enhances
thrombosis and PAI-1 expression in mouse skin.
Wound Repair and Regeneration. 2015;23(5):657663. DOI: 10.1111/wrr.12312
3. Aya Kitamura, Mikako Yoshida, Takeo
Minematsu, Gojiron Nakagami, Shinji Iizaka,
Hideki Fujita, Ayumi Naito, Kazuo Takahashi,
Taketoshi Mori, Hiromi Sanada. Prediction ofhealing progress of pressure ulcers by distribution
analysis of protein markers on necrotic tissue: A
retrospective cohort study. Wound repair and regeneration. 2015 Sep; 23(5):772-7. DOI: 10.1111/
wrr.12316
4. Sandra Arias,Pablo Rogeli, Sandra Arias, Eladio
Cardiel, Laura Garay, Hiromi Sanada,TaketoshiMori, Hiroshi Noguchi, Gojiro Nakagami.Effects
on interface pressure and tissue oxygenation
under ischial tuberosities during the application ofan alternating cushion. Journal of Tissue Viability.
10.1016/j.jtv.2015.05.002. [Epub ahead of print
2015-06-19]. Vol.24, Issue 3, pp.91-101, 2015.
5. Toshiko Kaitani, Gojiro Nakagami, Shinji Iizaka,
Takashi Fukuda, Makoto Oe, Ataru Igarashi,
Taketoshi Mori, Yukie Takemura, Yuko Mizokami,
Junko Sugama and Hiromi Sanada. Cost-utility

analysis of an advanced pressure ulcer management protocol followed by trained wound, ostomy,
and continence nurses. Accepted manuscript
online: 18 AUG 2015 06:21PM EST | DOI: 10.
1111/wrr.12350
6. Mikako Yoshida, Ryoko Murayama, Kumi Hotta,
Yoshihide Higuchi, Hiromi Sanada. Differences inmotor learning of pelvic floor muscle contraction
between women with and without stress urinary
incontinence: Evaluation by transabdominal ultrasonography. Neurourol Urodyn. 2015 Sep 9. doi:
10.1002/nau.22867. [Epub ahead of print]
7. Yuko Mugita, Takeo Minematsu, Lijuan Huang,
Gojiro Nakagami, Chihiro Kishi, Yoshie Ichikawa,Takashi Nagase, Makoto Oe, Hiroshi Noguchi,
Taketoshi Mori, Masatoshi Abe, Junko Sugama,
Hiromi Sanada. (2015) Histopathology ofincontinence-associated skin lesions: inner tissue
damage due to invasion of proteolytic enzymes
and bacteria in macerated rat skin. PLoS ONE 10(9): e0138117. doi:10.1371/journal.pone.0138117
8. Hiroshi Noguchi, Makoto Oe, Kimie Takehara,
Taketoshi Mori, Hiromi Sanada. Reliability andvalidity of an on-site measurement and visualization system to measure plantar pressure andshear force in footwear for the education ofdiabetic patients. Journal of Japanese Society
Wound, Ostomy, and Continence Management,
Vol. 19, No. 3, pp. 327-335, 2015.
9. Morishi Fukuda, Keiko Tabata, Tomoe Nishizawa,
Misako Dai, Gojiro Nakagami, Hiroshi Noguchi,
Toshio Nakatani, Mayumi Okuwa, Hiroi 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 ofWound, Ostomy, and Continence Management,
Vol. 19, No. 4, pp. 365-77, 2015.
10. Ayumi Amemiya, Hiroshi Noguchi, Makoto Oe,
Yumiko Ohashi, Kimie Takehara, Kohjiro Ueki,
Takashi Kadowaki, Hiromi Sanada, and TaketoshiMori. Comparison of gait features between feetwith callus or corns and normal feet using motion
sensors in people with diabetes and people
without diabetes. J Diabetes Sci Technol, Vol. 10,
No. 2, pp. 614-615, 2016. , first published on
November 17, 2015 as doi:10.1177/19322968156

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16135
11. Mine Yoshimura, Gojiro Nakagami, Shinji Iizaka,
Mikako Yoshida, Yoko Uehata, Michihiro Kohno,
Yusuke Kasuya, Tomoko Mae, Tokashi Yamasaki,
Hiromi Sanada. Microclimate is an independentrisk factor for development of intraoperatively
acquired pressure ulcers in the park-bench
position: a prospective observational study.
Wound Repair Regen. vol. 23, No. 6, pp.939-47,
2015. doi: 10.1111/wrr.12340.

370

Department of Youth Mental
HealthAssociate Professor
Tsuyoshi Araki, M.D., Ph.D.

Lecturer
Akiko Kanehara , MPH, PSW.

Associate
Aya Kikutsugi, O.T.

Homepage

http:// plaza.umin.ac.jp/~youth-mh/

Introduction and Organization

Clinical activities

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.

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.

371

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.

References
1. Kawasaki S, Nishimura Y, Takizawa R, Koike S,
Kinoshita A, Satomura Y, Sakakibara E, Sakurada
H, Yamagishi M, Nishimura F, Yoshikawa A, Inai
A, Nishioka M, Eriguchi Y, KakiuchiC, Araki T,
Kan C, Umeda M, Shimazu A, Hashimoto H,
Kawakami N, and Kasai K: Using social
epidemiology and neuroscience to explore therelationship between job stress and frontotemporal cortex activity among workers. Soc
Neurosci 10(3): 230-42, 2015
2. Tada M, Nagai T, Kirihara K, Koike S, Suga M,
Araki T, Kobayashi T and Kasai K: Differential
Alterations of Auditory Gamma Oscillatory
Responses Between Pre-onset High-risk Individuals and First-episode Schizophrenia. Cereb Cortex
26(3):1027-35, 2016
3. Kuwabara H, Araki T, Yamasaki S, Ando S, Kano
Y and Kasai K: Regional differences in posttraumatic stress symptoms among children after
the 2011 tsunami in Higashi-Matsushima, Japan.
Brain Dev. 37:130-6, 2015

372

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 which target cytokines orcell surface molecules have been developed and play
an important role in the treatment of autoimmune
diseases. In Japan, biologic agents are available forthe treatment of rheumatoid arthritis, psoriasis, Behcet
disease and inflammatory bowel diseases. Thesediseases are treated in the Department of Allergy &Rheumatology, Dermatology, Orthopedics Gastroenterology, Surgical oncology & vascular surgery, andOphthalmology. The Department of Immunotherapy
Management was established in April 2013, andrenewed through donations from new seven pharmaceutical companies (Mitsubishi-Tanabe, Chugai,
Ayumi, Taishotoyama, Nipponkayaku, UCB Japan,
Abbvie) in June 2016. The Department of Allergy &Rheumatology, Dermatology and Orthopedics work incollaboration.
Biologics agents include infliximab, infliximab BS,
adalimumab, golimumab, certolizumab pegol,etanercept, tocilizumab, abatacept, ustekinumab andsecukinumab. The Jak kinase inhibitor tofacitinib isonly one small molecule. Not only biologic agents but
also small molecules have been developed insuccession. However, it is difficult to predict theefficacy and toxicity of these agents by the background characteristics of patients with rheumatoid
arthritis. The aims of this department are to propose an
optimal treatment strategy for each patient and toestablish a platform to investigate novel biologics

through analyses of immunological changes by
biologics treatments and the relationship between
biologics response and biomarkers or genetic
information.

Clinical activities
We established a new booth for outpatients withrheumatoid arthritis who are receiving biologic agents
which is available every morning from Monday to
Friday. We focus on total rheumatoid arthritis carewith biologic agents. Moreover, we examine outpatients with psoriasis or Behcet’s disease before
biologics treatment and judge whether biologics
treatments can be used safely. In every Friday
afternoons, we evaluate for outpatient with psoriatic
arthritis including accurate diagnosis and monitoringdisease activity by clinical and imaging examinations.

Teaching activities
As for education, we take part in providing
information of biologic agents for patients who are thecandidates to receive biologics, including necessity,
benefits, safety, complications, procedures and costs.
Every time when a new biologic agent becomes
available for prescription, we provide information of
the agent for medical staffs. Moreover, we are giving
lectures about biologics treatment for medical students
at bed-side learning programs or at systematic lecture
courses.

373

Research activities
As for research, we are investigating novel biologics
through analyses of immunological changes by
biologics treatments and the relationship between
biologics response and biomarkers or genetic
information.

References
1. Kanda H: disease modified anti-rheumatic drugs
and these side effects. Medical Practice 32(5)872-5, 2015
2. Kanda H: connective tissue diseases associatedwith chronic heart failure. Diagnosis and Treatment 103(Suppl.) 371-8,2015
3. Kawaguchi N, Kanda H, Nagatomo R, Shimosaka
H, Okubo T, Ikeda H, Yatomi Y: Evaluation of
BioPlex2200 ANA Screen for the Detection of
Autoantibodies in Patients with Suspected Connective Tissue Diseases. Igakukensa 64(3)337-42,
2015
4. Kanda H: Evaluation of the nonsteroidal antiinflammatory drugs-sparing effect of etanercept inankylosing spondyloarthritis Riumatika 54(3)318-22, 2015

374

Department of medical researchand the management ofmusculoskeletal pain
Associate Professor
Koh Matsudaira, M.D,Ph.D.

Assistant 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:

3753) 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. Yoshimura N, Akune T, Fujiwara S, Shimizu Y,
Yoshida H, Nishiwaki Y, Sudo A,Omori G,
Yoshida M, Shimokata H, Suzuki T, Muraki S,
Oka H, Nakamura K. Incidence of disability andits associated factors in Japanese men and women:
the Longitudinal Cohorts of Motor System Organ(LOCOMO) study. J Bone Miner Metab, in press.
2. Muraki S, Akune T, Nagata K, Ishimoto Y,
Yoshida M, Tokimura F, Tanaka S, Kawaguchi H,
Nakamura K, Oka H, Yoshimura N. Does
osteophytosis at the knee predict health-related
quality of life decline? A 3-year follow-up of the
ROAD study. Clin Rheumatol , in press.
3. Yoshimura N, Muraki S, Oka H, Nakamura K,
Kawaguchi H, Tanaka S, Akune T. Serum levelsof 25-hydroxyvitamin D and the occurrence ofmusculoskeletal diseases: a 3-year follow-up to
the road study. Osteoporos Int, in press.
4. Kagotani R, Yoshida M, Muraki S, Oka H,
Hashizume H, Yamada H, Enyo Y, Nagata K,
Ishimoto Y, Teraguchi M, Tanaka S, Nakamura K,
Kawaguchi H, Akune T, Yoshimura N. Prevalenceof diffuse idiopathic skeletal hyperostosis (DISH)
of the whole spine and its association with lumbar
spondylosis and knee osteoarthritis: the ROAD
study. J Bone Miner Metab, in press
5. Ohashi S, Ohnishi I, Oka H, Matsumoto T, Bessho
M, Nakamura K, Tanaka S. Theeffect of cartilage
degeneration on ultrasound speed in humanarticular cartilage. Mod Rheumatol, in press.
6. Yoshimura N, Muraki S, Oka H, Tanaka S, Ogata
T, Kawaguchi H, Akune T, Nakamura K. Erratum

376

to: Association between new indices in thelocomotive syndrome risk test and decline inmobility: third survey of the ROAD study. J
Orthop Sci, in press.
7. Yoshimura N, Muraki S, Oka H, Tanaka S,
Kawaguchi H, Nakamura K, Akune T. Factors
affecting changes in the serum levels of
25-hydroxyvitamin D: a 3-yearfollow-up of the
ROAD study. Osteoporos Int, in press.
8. 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 hip pain in Japanese men and women: theROAD study. Osteoarthritis Cartilage, in press.
9. 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, in press
10. 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, in press
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, in press
12. Nomura T, Asada F, Takano K, Matsudaira K.
The current state along with outstanding issues
related to email-based guidance by physicaltherapists aiming to prevent low back pain among
workers. JJOMT, in press.
13. 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, 201614. 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, 2016
Jan 30. [Epub ahead of print]
15. 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, 2016 Jan 30.
[Epub ahead of print]
16. Coggon D, Ntani G, 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, Masood Kadir M,
Warnakulasuriya SS, Matsudaira K, Nyantumbu
B, Sim MR, Harcombe H, Cox K, Marziale MH,
Sarquis LM, Harari F, Freire R, Harari N, Monroy
MV, Quintana LA, Rojas M, Salazar Vega EJ,
Harris EC, Serra C, Martinez JM, Delclos G,
Benavides FG, Carugno M, Ferrario MM, Pesatori
AC, Chatzi L, Bitsios P, Kogevinas M, Oha K,
Sirk 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: 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. 2016 Jan
5. [Epub ahead of print]
17. Matsudaira K, Hiroe M, Kikkawa M, Suzuki M,
Isomura T, Oka H, Hiroe K, Hiroe K. Can
standing back extension exercise improve or
prevent low back pain in Japanese care workers? J
Man Manip Ther 23: 205-209, 2015
18. Katsuhira J, Matsudaira K, Yasui T, Iijima S, Ito
A: Efficacy of a trunk orthosis with joints
providing resistive force on low back load inelderly persons during static standing. Clin Interv
Aging 10: 1413-1420, 2015
19. Kikuchi N, Matsudaira K, Sawada T, Oka H:
Psychometric properties of the Japanese versionof the Tampa Scale for Kinesiophobia (TSK) inpatients with whiplash neck injury pain and/or
low back pain. J Orthop Sci 20: 985-992, 2015
20. Oka H, Matsudaira K, Fujii T, Okazaki H, Shinkai
Y, Tsuji Y, Tanaka S, Kato R: Risk factors forprolonged treatment of whiplash-associateddisorders. Plos One 10: e0132191,2015
21. Takahashi M, Matsudaira K, Shimazu A:
Disabling low back pain associated with night
shift duration: sleep problems as a potentiator.
Am J Ind Med 58: 1300-1310, 2015.
22. Matsudaira K, Kawaguchi M, Isomura T, Inuzuka

377K, Koga T, Miyoshi K, Konishi H: Assessment of
psychosocial risk factors for the development of
non-specific chronic disabling low back pain in
Japanese workers- Findings from the Japan epidemiological research of Occupation-related Backpain (JOB) study. Ind Health 53: 368-377, 2015
23. Ogihara S, Yamazaki T, Maruyama T, Oka H,
Miyoshi K, Azuma S, Yamada T, Murakami M,
Kawamura N, Hara N, Terayama S, Morii J, Kato
S, Tanaka S. Prospective multicenter surveillance
and risk factor analysis of deep surgical site infection after posterior thoracic and/or lumbar spinal
surgery in adults. J Orthop Sci 20:71-77, 201524. Ohya J, Oshima Y, Takeshita K, Oka H, Chikuda
H, Taniguchi Y, Matsubayashi Y, Tanaka S.
Patient satisfaction with double-door laminoplasty
for cervical compression myelopathy . J Orthop
Sci 20: 64-70, 2015
25. Muraki S, Akune T, En-Yo Y, Yoshida M, Suzuki
T, Yoshida H, Ishibashi H,Tokimura F, Yamamoto
S, Tanaka S, Nakamura K, Kawaguchi H,
26. Oka H, Yoshimura N. Joint space narrowing, bodymass index, and knee pain: the ROAD study.
Osteoarthritis Cartilage 23: 874-881, 2015.
27. Yamada H, Terada M, Iwasaki H, Endo T, Okada
M, Nakao S, Hashizume H, Minamide A,
Nakagawa Y, Nishi H, Tsutsui S, Oka H, Yoshida
M. Improved accuracy of diagnosis of lumbar
intra and/or extra-foraminal stenosis by use of
three-dimensional MR imaging: comparison withconventional MR imaging. J Orthop Sci 20:287294, 201528. Yamada H, Oka H, Iwasaki H, Endo T, Kioka M,
Ishimoto Y, Nagata K, TakiguchiN, Hashizume H,
Minamide A, Nakagawa Y, Kawai M, Tsutsui S,
Yoshida M. Development of a support tool for theclinical diagnosis of symptomatic lumbar intraand/or extra-foraminal stenosis. J Orthop Sci 20:
811-817, 2015.
29. Yoshimura N, Muraki S, Oka H, Tanaka S, Ogata
T, Kawaguchi H, Akune T, Nakamura K. Association between new indices in the locomotive
syndrome risk test and decline in mobility: thirdsurvey of the ROAD study. J Orthop Sci 20:
896-905, 2015.
30. Kato S, Oshima Y, Oka H, Chikuda H, Takeshita Y,
Miyoshi K, Kawamura N, Masuda K, Kunogi J,

Okazaki R, Azuma S, Hara N, Tanaka S, Takeshita
K. Comparison of the Japanese Orthopaedic
Association (JOA) score and modified JOA(mJOA) score for the assessment of cervicalmyelopathy: a multicenter observational study.
PLoS One 10:e0123022, 2015.
31. Ohya J, Chikuda H, Kato S, Hayakawa K, Oka H,
Takeshita K, Tanaka S, Ogata T. Elevated levelsof phosphorylated neuro filament heavy subunit in
the cerebrospinal fluid of patients with lumbar
spinal stenosis: preliminary findings. Spine J 15:
1587-1592, 2015.
32. Nakamura M, Hashizume H, Oka H, Okada M,
Takakura R, Hisari A, Yoshida M, Utsunomiya H.
Physical Performance Measures Associated With
Locomotive Syndrome in Middle-Aged and Older
Japanese Women. J Geriatr Phys Ther 38: 202207, 2015.

378

Department of Molecular Sciences
on DiabetesProfessor
Kohjiro Ueki, M.D.,Ph.D.

Assistant Professor
Masatoshi Kobayashi, M.D.,Ph.D.

Homepage

http://dm.umin.jp/dmsd/

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 between the tissues.

Teaching activities
As for under-graduate education, our department
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
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 b 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 b 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379

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.
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.

References
1. 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; J-DOIT3 Study Group. Design ofand rationale for the Japan Diabetes Optimal
Integrated Treatment study for 3 major risk
factors of cardiovascular diseases (J-DOIT3): a
multicenter, open-label, randomized, parallelgroup trial. BMJ Open Diabetes Res Care. 2016
Jan 25;4(1):e000123.
2. 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 patientswith type 2 diabetes: a cross-sectional study. BMJ
Open Diabetes Res Care. 2016 Jan 5;4(1):e000156
3. 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. 2016 Mar;157(3):1029-42

4. Amemiya A, Noguchi H, Oe M, Ohashi Y,
Takehara K, Ueki K, Kadowaki T, Sanada H, Mori
T. Comparison of Gait Features Between Feet
With Callus or Corns and Normal Feet Using
Motion Sensors in People With Diabetes andPeople Without Diabetes. J Diabetes Sci Technol.
2015 Nov 17;10(2):614-5.
5. Okada-Iwabu M, Iwabu M, Ueki K, Yamauchi T,
Kadowaki T. Perspective of Small-Molecule
AdipoR Agonist for Type 2 Diabetes and Short
Life in Obesity. Diabetes Metab J. 2015 Oct;39(5):363-72.
6. Fujishiro M, Izumida Y, Takemiya S, Kuwano Y,
Takamoto I, Suzuki R, Yamauchi T, Ueki K,
Kadowaki T. A case of insulin allergy successfully
managed using multihexamer-forming insulin
degludec combined with liraglutide. Diabet Med.
2015 Oct 20.
7. Shiomi Y, Yamauchi T, Iwabu M, Okada-Iwabu M,
Nakayama R, Orikawa Y, Yoshioka Y, Tanaka K,
Ueki K, Kadowaki T. A Novel Peroxisome
Proliferator-activated Receptor (PPAR)α Agonist
and PPARγ Antagonist, Z-551, Ameliorates Highfat Diet-induced Obesity and Metabolic Disordersin Mice. J Biol Chem. 2015 Jun 5;290(23):1456781.

Endowed Department(22nd Century Medical and Research Center)381

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 reallydifficult to guarantee consistent quality. However, we
do everything possible to provide the cultured cellswith the 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.

382

Clinical activities
We provide outpatient services for cancer patients.
The following clinical trials are underway in our
department:
Dendritic cell therapy
1. UMIN registration number ： UMIN000002837
active, recruiting. IRB number ： 2759. Safety,
efficacy and immunogenicity of autologous tumor
lysate-pulsed dendritic cell therapy after resectionof stage2A (T2N0,T3N0) esophageal cancer
2. UMIN registration number ： UMIN000006646
active, recruiting. IRB number：P2011025-11Z
Safety, efficacy and immunogenicity of concomitant interferon alpha and autologous tumor lysatepulsed dendritic cell therapy in patients withadvanced renal cell carcinomaγδ T cell therapy for advanced cancer
3. UMIN registration number ： UMIN000006128
active, recruiting. IRB number： P2011018-11Z.
Adoptive immunotherapy using zoledronateexpanded autologous γδ T cells for patients with
non-small cell lung cancer refractory to standard
treatment.
4. UMIN registration number ： UMIN000001419
active, recruiting. IRB number ： 2120-(1). The
efficacy and safety of autologous γδ T cell transfer
therapy for esophageal cancer
5. UMIN registration number ： UMIN000004130
active, recruiting. IRB number ： P201019-11Z.
Intraperitoneal autologous γδ T cell therapy forrefractory gastric cancer with ascites
6. UMIN registration number ： UMIN000008097
active, recruiting. IRB number ： P201019-11Z.
Combination of chemotherapy with docetaxel /cisplatin / fluorouracil (DCF) and autologous γδ Tcell transfer therapy for esophageal cancer.
7. UMIN registration number ： UMIN000011184
active, recruiting. IRB number： P2012053-11Z.
Hepatic arterial infusion of autologous gamma/delta T cell for advanced hepatocellular carcinoma
Immunomodulator (anti-CCR4 mAb) :Investigator-initiated clinical trials
8. UMIN registration number：UMIN000010050

Open public recruiting. IRB number：201304011DX<Phase Ia>
To assess the safety and pharmacokinetics ofweekly repeated doses of Mogamulizumab.
<Phase Ib>
To assess the safety and effect of Treg depletionof weekly repeated doses of Mogamulizumab.
Teaching activities

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 of 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

383

application of new knowledge to clinical practice.

List of Publications
1. Hirano K, Hosoi A, Matsushita H, Iino T, Ueha S,
Matsushima K, Seto Y, Kakimi K. The nitricoxide radical scavenger carboxy-PTIO reduces theimmunosuppressive activity of myeloid-derived
suppressor cells and potentiates the antitumor
activity of adoptive cytotoxic T lymphocyte
immunotherapy. Oncoimmunology. 2015Apr 1;
4(8):e1019195.
2. 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.
3. Kurose K, Ohue Y, Wada H, Iida S, Ishida T,
Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T,
Kakimi K, Nishikawa H, Udono H, Oka M, Ueda
R, Nakayama E. Phase Ia Study of FoxP3+ CD4
Treg Depletion by Infusion of a Humanized AntiCCR4 Antibody, KW-0761, in Cancer Patients.
Clin Cancer Res. 2015 Oct 1;21(19):4327-36.
4. Futami J, Nonomura H, Kido M, Niidoi N,
Fujieda N, Hosoi A, Fujita K, Mandai K, Atago Y,
Kinoshita R, Honjo T, Matsushita H, Uenaka A,
Nakayama E, Kakimi K. Sensitive Multiplexed
Quantitative Analysis of Autoantibodies to Cancer
Antigens with Chemically S-Cationized FullLength and Water-Soluble Denatured Proteins.
Bioconjug Chem. 2015 Oct 21;26(10):2076-84.
5. Guidance Development Review Committee;
Working Group for Clinical Studies of Cancer
Immunotherapy; Working Group for Effector Cell
Therapy; Working Group for CMC/Non-clinicalStudies; Working Group for Cancer Vaccines andAdjuvants; Working Group for Anti-immune
Checkpoint Therapy and Comprehensive Cancer
Immunotherapy; Biostatistics Subcommittee.
2015 Guidance on cancer immunotherapy development in early-phase clinical studies. Cancer Sci.
2015 Dec;106(12):1761-71.

6. Karasaki T, Nagayama K, Kawashima M, Hiyama
N, Murayama T, Kuwano H, Nitadori JI, Anraku
M, Sato M, Miyai M, Hosoi A, Matsushita H,
Kikugawa S, Matoba R, Ohara O, Kakimi K,
Nakajima J. Identification of Individual CancerSpecific Somatic Mutations for Neoantigen-Based
Immunotherapy of Lung Cancer. J Thorac Oncol.
2015 Dec 29;11(3):324-333.

Presentation
conference

atInternational

1. 2015/7/10, ICCIM2015 (International Conferenceof Cancer Immunotherapy and Macrophages2015), Tokyo, Japan, (Symposium ・ Invited)
Kazuhiro Kakimi, CTL-therapy induced Tumor
immunosuppressive Environment

384

Division of Total Renal Care
Medicine
Project Associate Professor
Norio Hanafusa, M.D., Ph.D.

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

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/jinsikkan.html※ The following information is the same as that of the previous year for certain reasons.

Introduction and Organization

Clinical activities

More than 310 thousands of patients receive dialysis
treatment due to end-stage renal disease in Japan.
These dialysis therapies comprise hemodialysis andperitoneal dialysis. However, the majority ofend-stage renal disease (ESRD) population receives
hemodialysis as their renal replacement therapies,
while only limited population currently receives
peritoneal dialysis.
Peritoneal
dialysishasadvantages
overhemodialysis in terms of higher quality of life and of
higher probability of working, because this therapy isdone at home and requires less frequent visits tomedical facilities. Hemodynamic stability is one of themost beneficial aspects of peritoneal dialysis fromperspective of medical care. These points makeperitoneal dialysis suitable for the patients with severe
derangement of cardiac function; such patients
become common among dialysis population because
demographics have quite largely changed recent years.
Moreover, existence of ample residual renal function,
which reportedly relates to the better survival or
relates to less morbidity among end-stage renal
disease patients, can be maintained during longer
periods by peritoneal dialysis than by hemodialysis.
This division is established in 2004 sponsored by
Terumo Co. Ltd. in collaboration with Department ofNephrology and Endocrinology, in order to make theknowledge and the technics of peritoneal dialysis
more popular among dialysis community.

We have been focusing on total renal care medicine,including pre-dialysis care, therapeutic option forrenal replacement therapies, and above all, peritoneal
dialysis. Vascular access placement had been within
the scope of our division.

Teaching activities
As for education, we take part in providing
information of peritoneal dialysis for those who
consider to commence the therapy. We are making
lectures at CKD school designed for the patients withCKD twice a year. Brief lectures are made for medical
staffs at the clinical wards in collaboration with
Terumo, Co., Ltd. Moreover, we also are making
lectures about peritoneal dialysis for medical students
at bed-side learning programs or at systematic lecture
courses.

Research activities
As for research, we are studying advantages of“hybrid therapy” in which patients are treated byperitoneal dialysis combined with hemodialysis.
Encapsulating peritoneal sclerosis is also the target ofour research. This is a potentially fatal complication of
peritoneal dialysis. We are studying the strategies
against or preventing this complication both in vivo
and in vitro.
We are developing the system by which we can385

convey proper information about choice of renal
replacement therapies both inside and outside of ouruniversity hospital. Moreover, we are focusing on thedevelopment of better peritoneal dialysis technics.

References
1. Yamashita T, Doi K, Hamasaki Y, Matsubara T,
Ishii T, Yahagi N, Nangaku M, Noiri E.
Evaluation of urinary tissue inhibitor of
metalloproteinase-2 in acute kidney injury: aprospective observational study. Crit Care. 2014
Dec 19;18(6):716.
2. Nakai S, Hanafusa N, …, Tsubakihara Y. An
overview of regular dialysis treatment in Japan (asof 31 December 2012). Ther Apher Dial. 2014
Dec;18(6):535-602.
3. Tagawa M, Hamano T, Nishi H, Tsuchida K,
Hanafusa N, Fukatsu A, Iseki K, Tsubakihara Y.
Mineral Metabolism Markers Are Associated with
Myocardial Infarction and Hemorrhagic Stroke
but Not Ischemic Stroke in Hemodialysis Patients:
A Longitudinal Study. PLoS One. 2014 Dec 10;9(12):e114678.
4. Hamasaki Y, Doi K, Tanaka M, Kume H,
Ishibashi Y, Enomoto Y, Fujita T, Homma Y,
Nangaku M, Noiri E. Increased peritoneal
permeability at peritoneal dialysis initiation is apotential cardiovascular risk in patients using
biocompatible peritoneal dialysis solution. BMC
Nephrol. 2014 Nov 1;15:173.
5. Hirahashi J, Kawahata K, Arita M, Iwamoto R,
Hishikawa K, Honda M, Hamasaki Y, Tanaka M,
Okubo K, Kurosawa M, Takase O, Nakakuki M,
Saiga K, Suzuki K, Kawachi S, Tojo A, Seki G,
Marumo T, Hayashi M, Fujita T. Immunomodulation with eicosapentaenoic acid supports
the treatment of autoimmune small-vessel
vasculitis. Sci Rep. 2014 Sep 18;4:6406.
6. Hanafusa N, Nomura T, Hasegawa T, Nangaku M.
Age and anemia management: relationship ofhemoglobin levels with mortality might differ
between elderly and nonelderly hemodialysis
patients. Nephrol Dial Transplant. 2014 Dec;
29(12):2316-26.
7. Sumida M, Doi K, Kinoshita O, Kimura M, Ono
M, Hamasaki Y, Matsubara T, Ishii T, Yahagi N,

Nangaku M, Noiri E. Perioperative plasma
neutrophil gelatinase-associated lipocalin measurement in patients who undergo left ventricularassist device implantation surgery. Circ J. 2014;
78(8):1891-9.
8. Hanafusa N, Noiri E, Nangaku M. Vascular accesspuncture under ultrasound guidance. Ther Apher
Dial. 2014 Apr;18(2):213-4.
9. Doi K, Ishizu T, Tsukamoto-Sumida M, Hiruma T,
Yamashita T, Ogasawara E, Hamasaki Y, Yahagi
N, Nangaku M, Noiri E. The high-mobility groupprotein B1-Toll-like receptor 4 pathway
contributes to the acute lung injury induced bybilateral nephrectomy. Kidney Int. 2014 Aug;86(2):316-26.

386

Department of Integrated
Molecular Sciences on Metabolic
Diseases
Project Associate Professor
Masato Iwabu, M.D., Ph.D. (November 2015~)
Project Research Associate
Miki Okada-Iwabu, Ph.D. (November 2015~)

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 on environmental and genetic factors including gene expression
from patients being treated at University of Tokyo
Hospital, and which allows safe and effective use ofdrugs being developed in patients with lifestylerelated 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, identification ofmolecular 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

387such as the metabolic syndrome, diabetes and cardiovascular disease associated with obesity and to put
relevant molecular targets identified in the process toeffective 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 Research Laboratory has also been credited with discovering that
adiponectin is highly active in its high molecularweight form as a ligand to the adiponectin receptors
and that its quantitative measurement is useful in the
diagnosis of insulin resistance and the metabolic
syndrome. Not only that, the DIMSMD ResearchLaboratory has found that, via the adiponectin
receptors, the plant-derived peptide osmotin activates
the AMPK pathway which has a critical role inprotecting against lifestyle-related diseases. Currently,
the DIMSMD Research Laboratory is proactively
engaged in the development of definitive treatments
for lifestyle-related diseases that draw on ligands
specific for the adiponectin receptors.

References• Iwabu M, Okada-Iwabu M, Yamauchi T,
Kadowaki T. Adiponectin/adiponectin receptor indisease and aging. npj Aging and Mechanisms of
Disease. 1, 15013, 2015

388

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.

389

References
1. Suzuki J, Imai Y, Aoki M, Fujita D, Aoyama N,
Tada Y, Akazawa H, Izumi Y, Isobe M, Komuro I,
Nagai R, Hirata Y. High incidence and severity of
periodontitis in Marfan syndrome patients inJapan. Heart Vessels 30(5): 692-695, 2015.
2. Suzuki J, Aoyama N, Aoki M, Tada Y, Wakayama
K, Akazawa H, Shigematsu K, Hoshina K, Izumi
Y, Komuro I, Miyata T, Hirata Y, Isobe M.
Incidence of periodontitis in Japanese patientswith cardiovascular diseases -A comparison between abdominal aortic aneurysm and arrhythmia.
Heart Vessels 30(4), 498-502, 2015.
3. Takamura C, Suzuki J (corresponding author),
Ogawa M, Watanabe R, Tada Y, Maejima Y,
Akazawa H, Komuro I, Isobe M. Suppression ofmurine autoimmune myocarditis achieved withdirect renin inhibition. J Cardiol. pii: S09145087(15)00295-6, 2015.
4. Hirakawa H, Zempo H, Ogawa M, Watanabe R,
Suzuki J (corresponding author), Akazawa H,
Komuro I, Isobe M. A DPP-4 inhibitor suppresses
fibrosis and inflammation on experimental
autoimmune myocarditis in mice. PlosOne. Mar
13;10(3):e0119360. 2015.
5. Zempo H, Sugita Y, Ogawa M, Watanabe R,
Suzuki J (corresponding author), Isobe M. A
P2X7 receptor antagonist attenuates experimental
autoimmune myocarditis via suppressed myocardial CD4+ T and macrophage infiltration and
NADPH oxidase 2/4 expression in mice. Heart
Vessels. 30(4), 527-533, 2015.
6. Amano J, Akashima T, Terasaki T, Wada Y,
Ito-Amano M, Suzuki J, Isobe M. Characteristics
of cardiac allograft vasculopathy induced byimmunomodulation in the miniature swine. Ann
Thorac Cardiovasc Surg. 21(1):45-52, 2015.
7. Tezuka D, Terashima M, Kato Y, Toriihara A,
Hirasawa K, Sasaoka T, Yoshikawa S, Maejima Y,
Ashikaga T, Suzuki J, Hirao K, Isobe M. Clinicalcharacteristics of definite or suspected isolated
cardiac sarcoidosis: application of cardiac MRI
and FDG-PET/CT. J Card Fail. 21(4):313-22.
2015.
8. Ikeda Y, Kumagai H, Okazaki H, Fujishiro M,
Nomura S, Takeda N, Toko H, Takimoto E,

Akazawa H, Morita H, Suzuki J, Yamazaki T,
Komuro I, Yanagisawa M. Monitoring β-arrestin
recruitment via β-lactamase enzyme fragmentcomplementation: purification of peptide E as a
low-affinity ligand for mammalian bombesin
receptors. PlosOne. 10: e0127445, 2015.
9. Kumagai H, Ikeda Y, Motozawa Y, Fujishiro M,
Okazaki H, Nomura S, Takeda N, Harada M,
Toko H, Takimoto E, Akazawa H, Morita H,
Suzuki J, Yamazaki T, Komuro I, Yanagisawa M.
Quantitative measurement of GPCR endocytosis
via pulse-chase covalent labeling. PlosOne.
10(5):e0129394, 2015.
10. Yabumoto C, Akazawa H, Yamamoto R, Yano M,
Kudo-Sakamoto Y, Sumida T, Kamo T, Yagi H,
Shimizu Y, Saga-Kamo A, Naito A, Oka T, Lee
JK, Suzuki J, Sakata Y, Uejima E, Komuro I.
Angiotensin II receptor blockade promotes repairof skeletal muscle through down-regulation of
aging-promoting C1q expression. Sci Rep. 5:14453, 2015.
11. Yano M, Akazawa H, Oka T, Yabumoto C,
Kudo-Sakamoto Y, Kamo T, Shimizu Y, Yagi H,
Naito A, Lee JK, Suzuki J, Sakata Y, Komuro I.
Monocyte-derived extracellular Nampt-dependent
biosynthesis of NAD+ protects the heart againstpressure overload. Sci Rep. 5:15857, 2015.
12. 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, 2015.
13. Ueshima D, Ashikaga T, Shimura T, Hatano Y,
Sasaoka T, Kurihara K, Yoshikawa S, Maejima Y,
Isobe M. Popliteal Retrograde Approach is
Effective and Safe for Superficial Femoral Artery
Chronic Total Occlusion. Ann Vasc Dis. 8(3):220-6, 2015.
14. Terao C, Matsumura T, Yoshifuji H, Kirino Y,
Maejima Y, Nakaoka Y, Takahashi M, Amiya E,
Tamura N, Nakajima T, Origuchi T, Horita T,
Matsukura M, Kochi Y, Ogimoto A, Yamamoto
M, Takahashi H, Nakayamada S, Saito K, Wada
Y, Narita I, Kawaguchi Y, Yamanaka H, Ohmura
K, Atsumi T, Tanemoto K, Miyata T, Kuwana M,
Komuro I, Tabara Y, Ueda A, Isobe M, Mimori T,

390

Matsuda F. Takayasu arteritis and ulcerative
colitis: high rate of co-occurrence and genetic
overlap. Arthritis Rheumatol. 67(8):2226-32,
2015.
15. 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.
2015 Mar 18. [Epub ahead of print]
16. Zempo H, Suzuki J, Ogawa M, Watanabe R, Isobe
M. A different role of angiotensin II type 1areceptor in the development and hypertrophy ofplantaris muscle in mice. J Applied Genet. 2015
May 30. [Epub ahead of print]
17. 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.
2015 Dec 10. [Epub ahead of print]
18. 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 by myocardial
infarction in the presence of renal failure.
Hypertens Res. 2015 Dec 10. [Epub ahead ofprint]English Review
1. Suzuki J, Aoyama N, Izumi Y, Isobe M, Komuro
I, Hirata Y. Effect of periodontitis on cardiovascular manifestations in Marfan syndrome -A
cricital common role of TGF-β-. Int Heart J. 56:
121-124, 2015.
2. Ikeda Y, Kumagai H, Motozawa Y, Suzuki J,
Komuro I. Biased Agonism of the Angiotensin II
Type I Receptor. Int Heart J. 56(5):485-8, 2015.
3. Isobe M, Tezuka D. Isolated cardiac sarcoidosis:
clinical characteristics, diagnosis and treatment.
Int J Cardiol. 182:132-40, 2015.
4. Maejima Y, Chen Y, Isobe M, Gustafsson ÅB,
Kitsis RN, Sadoshima J. Recent progress inresearch on molecular mechanisms of autophagyin the heart. Am J Physiol Heart Circ Physiol.
308(4):H259-68, 2015.
5. Maejima Y, Isobe M, Sadoshima J. Regulation of
autophagy by beclin 1 in the heart. J Mol Cell
Cardiol. 2015 Nov 3. [Epub ahead of print]

6. Ikeda Y, Kumagai H, Motozawa Y, Suzuki J,
Komuro I. Next Generation ARBs. Int Heart J.
2015 Nov 9. [Epub ahead of print]
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. 2015 Dec 3. [Epub aheadof print]
8. Tada Y, Suzuki J. Oxidative stress and myocarditis.
Curr Pharm Des. 2015 Dec 22. [Epub ahead ofprint]

391

Department of Translational
Research for Healthcare andClinical Science
Project Associate Professor
Hiroyuki Morita, M.D.,Ph.D.

Project Research Associate
Kazutaka Ueda, M.D.,Ph.D.

Introduction and Organization
Our department was open in January 2005,
contributed by Hitachi, Ltd. and Hitachi Medical
Corporation. Since then, the construction of clinicalinformation database has been performed incollaboration with the Department of Cardiovascular
Medicine of this University (Professor and Chairman;
Dr. Ryozo Nagai). From 2008 to 2010, our research
activities were supported by Theravalues Corporationand Hitachi, Ltd. In January 2011, new mission started
under the contribution of DVx Inc., WIN INTERNATIONAL CO.,LTD. and Mitsubishi Tanabe Pharma.
The aim of our department is to improve the clinicalinformation database to the better one and put that into
practical use in developing the clinical research.
Our department belongs to the 22nd century medical
center in the University of Tokyo Hospital, which was
founded as the front line of university-industry
partnerships. As our research foothold is located in thehospital, we could keep the close connection with thebedside. Our department is thought to be suited for
obtaining the maximum output in clinical research.

Research activities
The onset and progression of the disease are thought
to be caused by the environmental and/or genetic
factors. What is the best way to identify thepathogenesis and the factors predicting the prognosis?
The answer should be the filing of the clinicalinformation.
We are constructing the effective framework to makethe relevant clinical data available for research andperforming the investigation to resolve the clinicalquestions, followed by the translation of its fruits tothe bedside.
Another mission is to confer the explicit scientificre-evaluation on the health issues (e.g. eating habits,
exercise, lifestyle) which have been believed to be
empirically effective. This mission has to be followedby the prompt publicity of the “accurate” data led byour re-evaluation.
The realization of these missions above could becompleted in a close collaboration with the academic
groups and private enterprises. In this regard, we areready to discuss and think together with anybody
anytime.
In summary, our research field covers the issues asfollows;
1. Development of information analysis system andsystematization of clinical information
2. Clinical and/or genomic research utilizing theclinical information analysis system
3. Scientific verification of eating habits, exercise
and lifestyle
4. Analysis on the current state of the medical
system
5. Spread of accurate medical information to society
utilizing the information technology

392

Research Grants
A Grant from the Ministry of Health, Labour andWelfare (2013-2017) (to Morita H)
A Grant from the Ministry of Education, Culture,
Sports, Science and Technology (2012-2016) (toMorita H)
A Grant from the Ministry of Education, Culture,
Sports, Science and Technology (2015) (to Morita H)

References
1. Sumida T, Naito AT, Nomura S, Nakagawa A,
Higo T, Hashimoto A, Okada K, Sakai T, Ito M,
Yamaguchi T, Oka T, Akazawa H, Lee JK,
Minamino T, Offermanns S, Noda T, Botto M,
Kobayashi Y, Morita H, Manabe I, Nagai T,
Shiojima I, Komuro I.
Complement C1q-induced activation of β-cateninsignalling causes hypertensive arterial remodelling.
Nature Communications 6: 6241, 2015
2. Hirokawa M, Morita H, Tajima T, Takahashi A,
Ashikawa K, Miya F, Shigemizu D, Ozaki K,
Sakata Y, Nakatani D, Suna S, Imai Y, Tanaka T,
Tsunoda T, Matsuda K, Kadowaki T, Nakamura Y,
Nagai R, Komuro I, Kubo M.
A genome-wide association study identifies
PLCL2 and AP3D1-DOT1L-SF3A2 as new
susceptibility loci for myocardial infarction in
Japanese.
European Journal of Human Genetics 23: 374380, 2015
3. Kimura K, Daimon M, Morita H, Kawata T,
Nakao T, Okano T, Lee SL, Takenaka K, Nagai R,
Yatomi Y, Komuro I.
Evaluation of right ventricle by speckle tracking
and conventional echocardiography in rats withright ventricular heart failure.
International Heart Journal 56: 349-353, 2015
4. Nakayama A, Morita H, Hamamatsu A, Miyata T,
Hoshina K, Nagayama M, Takanashi S,
Sumiyoshi T, Komuro I.
Coronary atherosclerotic lesions in patients with aruptured abdominal aortic aneurysm.
Heart and Vessels 30: 304-308, 2015
5. Yagi H, Hatano M, Takeda N, Harada S, Suzuki Y,
Taniguchi Y, Shintani Y, Morita H, Kanamori N,

Aoyama T, Watanabe M, Manabe I, Akazawa H,
Kinugawa K, Komuro I.
Congenital contractural arachnodactyly without
FBN1 or FBN2 gene mutations complicated bydilated cardiomyopathy.
Internal Medicine 54: 1237-1241, 2015
6. Morita H, Komuro I.
Mendelian randomisation study for statin
treatment.
Lancet 385: 1945-1946, 2015
7. Kimura K, Morita H, Daimon M, Kawata T,
Nakao T, Lee SL, Hirokawa M, Ebihara A,
Nakajima T, Ozawa T, Yonemochi Y, Aida I,
Motoyoshi Y, Mikata T, Uchida I, Komori T,
Kitao R, Nagata T, Takeda S, Komaki H, Segawa
K, Takenaka K, Komuro I.
Prognostic impact of venous thromboembolism inpatients with Duchenne muscular dystrophy:
Prospective multicenter 5-year cohort study.
International Journal of Cardiology 191: 178180, 2015
8. 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 ONE 10: e0129394, 2015
9. Ikeda Y, Kumagai H, Okazaki H, Fujishiro M,
Motozawa Y, Nomura S, Takeda N, Toko H,
Takimoto E, Akazawa H, Morita H, Suzuki JI,
Yamazaki T, Komuro I, Yanagisawa M.
Monitoring β-arrestin recruitment via β-lactamase
enzyme fragment complementation: purificationof peptide E as a low-affinity ligand for mammalian bombesin receptors.
PLoS ONE 10: e0127445, 2015
10. Imai Y, Morita H, Takeda N, Miya F, Hyodo H,
Fujita D, Tajima T, Tsunoda T, Nagai R, Kubo M,
Komuro I.
A deletion mutation in myosin heavy chain 11
causing familial thoracic aortic dissection in two
Japanese pedigrees.
International Journal of Cardiology 195: 290292, 2015
11. Takeda N, Morita H, Fujita D, Inuzuka R,

393

Taniguchi Y, Nawata K, Komuro I.
A deleterious MYH11 mutation causing familial
thoracic aortic dissection.
Human Genome Variation 2: 15028, 2015
12. Fujita D, Takeda N, Morita H, Kato M,
Nishimura H, Inuzuka R, Taniguchi Y, Nawata K,
Hyodo H, Imai Y, Hirata Y, Komuro I.
A novel mutation of TGFBR2 causing LoeysDietz syndrome complicated with pregnancyrelated fatal cervical arterial dissections.
International Journal of Cardiology 201: 288290, 2015
13. Nakayama A, Morita H, Nakao T, Yamaguchi T,
Sumida T, Ikeda Y, Kumagai H, Motozawa Y,
Takahashi T, Imaizumi A, Hashimoto T, Nagai R,
Komuro I.
A food-derived flavonoid luteolin protects against
angiotensin II-induced cardiac remodeling.
PLoS ONE 10: e0137106, 2015
14. Takeda N, Morita H, Fujita D, Inuzuka R,
Taniguchi Y, Imai Y, Hirata Y, Komuro I.
Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: casereport and review of literature.
American Journal of Medical Genetics Part A
167A: 2382-2387, 2015

394

Department of Joint Disease
Research
Project Associate Professor
Noriko Yosihmura, M.D., Ph.D.
Shigeyuki Muraki, M.D., Ph.D.

Homepage

http:// www.h.u-tokyo.ac.jp/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, and prevention 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, of whichaims 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 and 3rd follow-ups were performed in 20082010, and 2012-13, respectively. A 4th comprehensive
clinic visit is planned from 2015.

References
1. Yoshimura N, Muraki S, Oka H, Nakamura K,
Kawaguchi H, Tanaka S, Akune T: Serum levelsof 25-hydroxyvitamin D and occurrence ofmusculoskeletal diseases, such as osteoporosis,
knee osteoarthritis and lumbar spondylosis: A
three-year follow-up of the road study.
Osteoporos Int 26:151–161, 2015
2. Yoshimura N, Akune T, Fujiwara S, Shimizu Y,
Yoshida H, Nishiwaki Y, Sudo A, Omori G,
Yoshida M, Shimokata H, Suzuki T, Muraki S,
Oka H, Nakamura K: Incidence of disability andits associated factors in Japanese men andwomen: The Longitudinal Cohorts of Motor
System Organ (LOCOMO) study. J Bone Miner
Metab 33: 186-191, 2015
3. Kagotani R, Yoshida M, Muraki S, Oka H,
Hashizume H, Yamada H, Enyo Y, Nagata K,
Ishimoto Y, Teraguchi M, Tanaka S, Nakamura K,
Kawaguchi H, Akune T, Yoshimura N:
Prevalence of diffuse idiopathic skeletal hyperostosis (DISH) of whole spine and its association
with lumbar spondylosis and knee osteoarthritis:
The ROAD Study. J Bone Miner Metab 33: 221-

395

229, 2015
4. Teraguchi M, Yoshimura N, Muraki S, Yamada H,
Oka H, Minamide A, Nakagawa Y, Ishimoto Y,
Nagata K, Kagotani R, Tanaka S, Kawaguchi H,
Nakamura K, Akune T, Yoshida M: The association of combination of disc degeneration,
endplate signal change, and Schmorl's node withlow back pain in a large population study: the
Wakayama Spine Study. Spine J 15:622-628,
2015
5. Yoshimura N, Muraki S, Oka H, Tanaka S,
Kawaguchi H, Nakamura K, Akune T: Mutual
associations among musculoskeletal diseases andmetabolic syndrome components: A 3-year
follow-up of the ROAD study. Mod Rheumatol
25:38-48, 2015
6. Muraki S, Akune T, Ishimoto Y, Nagata K,
Yoshida M, Tokimura F, Tanaka S, Oka H,
Kawaguchi H, Nakamura K, Yoshimura N: Does
osteophytosis at the knee predict health-related
quality of life decline? A 3-year follow-up of the
ROAD study. Clin Rheumatol 34: 1589-1597,
2015
7. Muraki S, Akune T, En-yo Y, Yoshida M, Suzuki
T, Yoshida H, Ishibashi H, Tokimura F,
Yamamoto S, Tanaka S, Nakamura K,
Kawaguchi H, Oka H, Yoshimura N: Joint space
narrowing, body mass index and knee pain: The
ROAD study. Osteoarthritis Cartilage 23: 874881, 2015
8. Mure K, Yoshimura N, Hashimoto M, Muraki S,
Oka H, Tanaka S, Kawaguchi H, Nakamura K,
Akune T, Takeshita T: Urinary 8-isoprostaglandin F2a as a marker of metabolic risks
in the general Japanese Population: The ROAD
Study. Obesity 23,1517-1524, 2015
9. Ogata T, Muranaga S, Ishibashi H, Ohe T,
Izumida R, Yoshimura N, Iwaya T, Nakamura K:
Development of a screening program to assess
motor function in the adult population: A crosssectional observational study. J Orthop Sci 20:
888-895, 2015
10. Yoshimura N, Muraki S, Oka H, Tanaka S, Ogata
T, Kawaguchi H, Akune T, Nakamura K:
Association between new indices in the locomotive syndrome risk test and decline inmobility: third survey of the ROAD study. J

Orthop Sci 20:896-905, 2015
11. Yoshimura N, Muraki S, Oka H, Nakamura K,
Kawaguchi H, Tanaka S, Akune T: Factors
affecting changes in the serum levels of
25-hydroxyvitamin D: A 3-year follow-up of the
ROAD study. Osteoporos Int 26:151-161, 201512. Muraki S, Akune T, Teraguchi M, Kagotani R,
Asai Y, Yoshida M, Tokimura F, Tanaka S, Oka H,
Kawaguchi H, Nakamura K, Yoshimura N:
Quadriceps muscle strength, radiographic knee
osteoarthritis and knee pain: the ROAD study.
BMC Musculoskelet Disord 2015 Oct 16; 16:305
13. Enyo Y, Yoshimura N, Yamada H, Hashizume H,
Yoshida M: Radiographic natural course oflumbar degenerative spondylolisthesis and its
risk factors related to the progression and onset
in a 15-year community-based cohort study: theMiyama study. J Orthop Sci 20: 978-984, 2015
14. 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
15. 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, in press
16. 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,

396

Gray A, Salazar Vega EJ.: Clssification ofneck/shoulder pain in epidemiologic research: A
comparison of personal and occupational
characteristics, disability and prognosis among
12,195 workers from 18 countries. Pain, in press
17. 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, in press

397

Department of Health Management
and Policy
Project Professor
Soichi Koike, M.D., Ph.D., M.P.H., M.B.A.

Project Associate Professor
Ryuichi Yamamoto, M.D., Ph.D.

Project Assistant Professor
Tatsuo Hiramatsu, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/hmp/

Introduction and Organization
The Department of Health Management and Policy
is an endowed department affiliated with the “22ndCentury Medical and Research Center,” which is a
center of industry-academia collaboration establishedby the University of Tokyo Hospital. Since its
establishment in 2005, the department has established
a complex research infrastructure of clinical epidemiology and clinical economics, medical policy studies,and medical management studies; academicallyutilized medical information network covering
multicenter; and provided interdisciplinary researches
and policy recommendations to achieve improvementof the quality and efficiency of health care in higher
dimension.
With donations from Nissay Information Technology Co., Ltd., the Department launched its firstcourses on April 1, 2005. As of March of 2015,
donations have been made to the Department from thefollowing six companies: Nissay Information
Technology Co., Ltd., Chugai Pharmaceutical Co.,
Ltd., Shionogi & Co., Ltd., Asahi Kasei Pharma
Corporation, CRECON Research & Consulting Inc.,and Otsuka Pharmaceutical Co., Ltd. The cooperative
departments are the Department of Medical Informatics and Economics, Division of Social Medicine,
Graduate School of Medicine, the Department ofClinical Epidemiology and Health Economics, Schoolof Public Health, and the Department of Biostatistics,
School of Public Health.
The department has completed its roles and closed
at the end of the fourth term of the department history,
March 31, 2016.

Research activities
We are working on the following activities, widely
contributing to the health of the people by utilizing
medical care information.
1) Health policy researches utilizing official statistics
data.
Since health policy researches utilizing official
statistical survey data can be performed rapidly andcost effectively as compared to conducting a new
survey, remarkable contribution can be expected to thepromotion of the evidence based health policy.
In this department, in particular, by performing ananalysis of the official statistics data of the Ministry of
Health, Labour and Welfare such as medical doctors,
dentists and pharmacists investigation, medical
facilities survey, and the patient survey, we perform
health policy researches regarding evaluation of initialclinical training system, regional and departmentspecific distribution of medical doctors, career path of
medical doctors and the medical specialist system.

3982) Researches on the use of medical information andthe protection of personal information.
The progression sheet of the "new information andcommunications technology strategy" which thegovernment was determined in June 2010 mentions
the study on the development of guidelines and how toprovide not only for the provision of the receipt
information database to third parties but also third
party provision of DPC data.
In this department, along with the research on theuse of medical information and the protection of
personal information, Dr. Yamamoto is involved
actively in the development process of the healthpolicy as the Chair of "Experts meeting for theprovision of receipt information" of the Ministry of
Health, Labour and Welfare and as a member of
personal data review meeting of the Cabinet
Secretariat.
3) Pharmacoepidemiological studies of drug side
effects using a medical information database.
Researches that aggregate and analyze medical datasuch as hospital information system records andinsurance claims to help safety assessment of
medicines have been started in many countries recent
years. In this department, taking advantage of agovernmental project "Medical information databaseinfrastructure development (MID-NET)" and the
University of Tokyo Hospital medical record data, weare advancing researches on automatical perceiving ofadverse events and automatic detection of side effects
signal of pharmaceutical products.
4) We have also put the following research into
practice.
- Regional and departmental disparities in the supplyof doctors.
- Relationship between the volume and outcomes ofsurgical operations.
- Economic evaluation of healthcare services.
- Policy evaluation study of occupational health, suchas prevention of death from overwork.
- Research on systems that contribute to medical
safety.
- Research for the sustainable development of regional
healthcare systems.
- Research on nationwide public-access defibrillatorsand improvement of outcomes after out-of-hospital
cardiac arrests.

References
1. Department of Health Management and Policy,
Graduate School of Medicine, the University ofTokyo. Utilization of medical information andprotection the personal information. Tokyo:
EDITEX; 2015. (Japanese)
2. Yamamoto R. Chapter 5, "The mechanism tosupport personal information protection", Whole
picture of the new social infrastructure My
number，Tokyo: Nikkei BP; 2015. (Japanese)
3. Kawaguchi H, Koike S. Association between theDensity of Physicians and Suicide Rates in Japan:
Nationwide Ecological Study Using a Spatial
Bayesian Model. PLoS One. 2016;11(2):e0148288
4. Koike S, Matsumoto M, Ide H, Kashima S,
Atarashi H, Yasunaga H. The effect of concentrating obstetrics services in fewer hospitals on
patient access: a simulation. Int J Health Geogr.
2016;15(1):4.
5. Koike S, Shimizu A, Matsumoto M, Ide H,
Atarashi H, Yasunaga H. Career pathways ofboard-certified surgeons in Japan. Surg Today.
2015 [Epub ahead of print].
6. Yamamoto R. Current status and issues of theutilization of medical big data in Japan，Japanesejournal of public health 2015;79(9):614-8.

399

Department of Computational
Diagnostic Radiology andPreventive Medicine
Project Professor
Naoto Hayashi, MD, PhD

Project Associate Professor
Kansei Uno, MD, PhD, Takeharu Yoshikawa, MD, PhD

Project Research Associate
Mika Nagasaki, MD, PhD, Kensuke Asaba, MD, PhD, Eriko Maeda, MD, PhD, Aya
Watanabe, MD, PhD, Soichiro Miki, MD, PhD, Fumiko Mori, MD, PhD

Project researcher
Yukihiro Nomura, PhD, Mitsutaka Nemoto, PhD

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/computer.html
Introduction and Organization
The Department of Computational Diagnostic
Radiology and Preventive Medicine (CDRPM) wasestablished in May 2005. It is under the supervision of
the Department of Radiology.
The aim of our research project is as follows: (1) tocreate a large database of health screening clinicaldata including medical images, (2) to develop methods
to analyze large volumes of medical images and to
search for algorithms to detect subtle abnormal
findings in these images, and (3) to evaluate theclinical usefulness of such image processing methods
and to apply the system in clinical settings.
The department comprises three project associate
professors, five project research associates and two
project researchers, along with a medical staff ofapproximately 50 employees in the health-screening
center.

Clinical Activities
CDRPM is responsible for the clinical activities in the

CDRPM Health Screening Center. The following
diagnostic imaging modalities are installed tofacilitate high level of diagnostic accuracy: positronemission computed tomography/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.

Research Activities
1) Health screening database
We have developed a unique health screening
information system in order to facilitate daily

400

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) Takata M, Amiya E, Watanabe M, Yamada N,
Watanabe A, Kawarasaki S, Ozeki A, Nakao T,
Hosoya Y, Ando J, Komuro I.: The association
between orthostatic increase in pulse pressure andischemic heart disease. Clin.Exp.Hypertens. 1-7,
2015.
(2) Takata M, Amiya E, Watanabe M, Ozeki A,
Watanabe A, Kawarasaki S, Nakao T, Hosoya Y,
Uno K, Saito A, Murasawa T, Ono M, Nagai R,
Komuro I.: Brachial artery diameter has a
predictive value in the improvement of flowmediated dilation after aortic valve replacement
for aortic stenosis. Heart Vessels 30:218-226,
2015.
(3) Takao H, Hayashi N, Ohtomo K.: Brain
morphology is individual-specific information.
Magn.Reson.Imaging 33:816-821,2015.

(4) Yoshida Y, Sakamoto M, Maeda E, Ohtsu H, Ota
S, Asamura H, Nakajima J.: Can image analysis
on high-resolution computed tomography predict
non-invasive growth in adenocarcinoma of thelung? Ann. Thorac. Cardiovasc. Surg. 21:8-13,
2015.
(5) Nakashima R, Watanabe C, Maeda E, Yoshikawa
T, Matsuda I, Miki S, Yokosawa K.: The effect ofexpert knowledge on medical search: medical
experts have specialized abilities for detecting
serious lesions. Psychol.Res. 79:729-738,2015.
(6) Takahashi M, Myojo M, Watanabe A, Kiyosue A,
Kimura K, Ando J, Hirata Y, Komuro I.: Effect of
purified eicosapentaenoic acid on red cell
distribution width in patients with ischemic heartdisease. Heart Vessels 30:587-594,2015.
(7) Veillon L, Go S, Matsuyama W, Suzuki A,
Nagasaki M, Yatomi Y, Inokuchi J.:
Identification of Ganglioside GM3 MolecularSpecies in Human Serum Associated with Risk
Factors of Metabolic Syndrome. PLoS One 10:
e0129645, 2015.
(8) Nishimura S, Nagasaki M, Kunishima S,
Sawaguchi A, Sakata A, Sakaguchi H, Ohmori T,
Manabe I, Italiano JE,Jr, Ryu T, Takayama N,
Komuro I, Kadowaki T, Eto K, Nagai R.:
IL-1alpha induces thrombopoiesis throughmegakaryocyte rupture in response to acuteplatelet needs. J.Cell Biol. 209:453-466,2015.
(9) Goto M, Abe O, Aoki S, Hayashi N, Ohtsu H,
Takao H, Miyati T, Matsuda H, Yamashita F,
Iwatsubo T, Mori H, Kunimatsu A, Ino K, Yano
K, Ohtomo K.: Longitudinal gray-matter volume
change in the default-mode network: utility ofvolume standardized with global gray-mattervolume for Alzheimer's disease: a preliminary
study. Radiol.Phys.Technol. 8:64-72,2015.
(10) Maeda E, Tomizawa N, Yamamoto K, Kanno S,
Akahane M, Ino K, Uehara M, Sakamoto A,
Semboku T, Torigoe R, Ohtomo K.: Optimized
heart rate for 320-row cardiac CT can be feasibly
predicted from prescan parameters. Springerplus
4:697-015-1478-5. eCollection,2015.
(11) Yamagata K, Uno K, Mori K, Seto Y.: Unusual U
wave induced by reconstructed retrosternal
esophagus. Clin.Case Rep. 3:949-951,2015.

401

Department of Clinical Motor
System Medicine
Project Associate Professor
Shigeyuki Muraki, M.D., Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/rinsyo_undouki.html
Introduction and Organization

References

The department of Clinical Motor System Medicine
was established in 22nd Century Medical andResearch Center in 2005, which is an endowment
department supported by Eisai Co., Ltd. and in close
collaboration with department of Orthopaedic Surgery
and department of Human Genetics. Our department
has been established for the study of locomotor system
medicine.

1. Yoshimura N, Akune T, Fujiwara S, Shimizu Y,
Yoshida H, Nishiwaki Y, Sudo A, Omori G, Yoshida
M, Shimokata H, Suzuki T, Muraki S, Oka H,
Nakamura K. Incidence of disability and its
associated factors in Japanese men and women: The
Longitudinal Cohorts of Motor System Organ(LOCOMO) study J Bone Miner Metab. 2015;33:
186-91..
2. Kagotani R, Yoshida M, Muraki S, Oka H,
Hashizume H, Yamada H, Enyo Y, Nagata K,
Ishimoto Y, Teraguchi M, Tanaka S, Nakamura K,
Kawaguchi H, Akune T, Yoshimura N. Prevalenceof diffuse idiopathic skeletal hyperostosis of thewhole spine and its association with knee
osteoarthritis: the ROAD study. J Bone Miner Metab.
2015;33:221-9.
3. Nagata K, Yoshimura N, Hashizume H, Muraki S,
Ishimoto Y, Yamada H, Takiguchi N, Nakagawa Y,
Minamide A, Oka H, Kawaguchi H, Nakamura K,
Akune T, Yoshida M. The prevalence of cervicalmyelopathy among subjects with narrow cervicalspinal canal in a population-based MRI study: The
Wakayama Spine Study. Spine J 2014;14:2811-7.
4. Muraki S, Akune T, Nagata K, Ishimoto Y, Yoshida
M, Tokimura F, Tanaka S, Kawaguchi H, Nakamura
K, Oka H, Yoshimura N. Does Osteophytosis at theKnee Predict Health-related Quality of Life
Decline? A 3-Year Follow-up of the ROAD Study
Clin Rheumatol. 2015;34:1589-97.
5. Yoshimura N, Muraki S, Oka H, Nakamura K,
Kawaguchi H, Tanaka S, Akune T. Serum levels of
25-hydroxyvitamin D and the occurrence of

Research activities
Our research field covers observational epidemiology
and main target diseases are osteoarthritis, spondylosis
and osteoporosis. Osteoarthritis and osteoporosis aremajor public health issues in the elderly that cause
impairment of ADL/QOL. The number of patientswith these diseases is rapidly increasing in Japan,
however, few epidemiologic indices have been
established and there is an urgent need for a comprehensive and evidence-based prevention strategy.
We set up a large-scale nationwide osteoarthritis/
osteoporosis cohort study called ROAD (Research on
Osteoarthritis/osteoporosis Against Disability) in 2005
for the pursue of etiological evidence. We have to datecreated a baseline database with detailed clinical andgenomic information on three population-based
cohorts with total 3,040 participants in urban,
mountainous and seacoast communities of Japan.
Recruitment and baseline visits began in October 2005
and were completed over a 1.5-year period, with thelast visit in March 2007. A third comprehensive clinic
visit have been already completed in 2013.

402

musculoskeletal diseases: A three-year follow-up to
the ROAD study Osteoporos Int 2015;26:151-61.
6. Yoshimura N, Muraki S, Oka H, Tanaka S,
Kawaguchi H, Nakamura K, Akune T. Mutual
associations among musculoskeletal diseases andmetabolic syndrome components: A 3-year followup of the ROAD study Modern Rheum 2015;25:
438-48. .
7. Teraguchi M, Yoshimura N, Hashizume H, Muraki S,
Yamada H, Oka H, Minamide A, Nakagawa H,
Ishimoto Y, Nagata K, Kagotani R, Tanaka S,
Kawaguchi H, Nakamura K, Akune T, Yoshida M.
The association of combination of disc degeneration,
endplate signal change, and Schmorl's node withlow back pain in a large population study: the
Wakayama Spine Study Spine J 2015;15:622-8.
8. Muraki S, Akune T, En-yo Y, Yoshida M, Suzuki T,
Yoshida H, Ishibashi H, Tokimura F, Yamamoto S,
Tanaka S, Nakamura K, Kawaguchi H, Oka H,
Yoshimura N. Joint space narrowing, body massindex, and knee pain: The ROAD study
Osteoarthritis Cartilage 2015;23:874-81.
9. Mure K, Yoshimura N, Hashimoto M, Muraki S,
Oka H, Tanaka S, Kawaguchi H, Nakamura K,
Akune T, Takeshita T. Urinary 8-isoprostane as a
Biomarker of Metabolic Syndrome Risk in the
General Japanese Population: The ROAD Study.
Obesity 2015;23:1517-24..
10. Yoshimura N, Muraki S, Oka H, Nakamura K,
Kawaguchi H, Tanaka S, Akune T.
Factors
affecting changes in the serum levels of 25hydroxyvitamin D: A 3-year follow-up of the ROAD
study. Osteoporos Int 2015;26:2597-605.
11. Yoshimura N, Muraki S, Oka H, Tanaka S, Ogata T,
Kawaguchi H, Akune T, Nakamura K. Association
between new indices in the locomotive syndrome
risk test and decline in mobility: third survey of the
ROAD study J Orthop Sci 2015;20:896-905.
12. 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 andwomen: The ROAD study. Osteoarthritis Cartilage
2016;24:117-23.
13. Muraki S, Akune T, Teraguchi M, Kagotani R, AsaiY, Yoshida M, Tokimura F, Tanaka S, Oka H,
Kawaguchi H, Nakamura K, Yoshimura N.

Quadriceps muscle strength, radiographic knee
osteoarthritis and knee pain: The ROAD study.
BMC musculoskeletal disorders 2015;16:305.
14. Kodama R, Muraki S, Oka H, Iidaka T, Teraguhi 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 Modern
Rheum (in press).
15. Teraguchi M, Yoshimura N, Hashizume H, Muraki S,
Yamada H, Oka H, Minamide A, Nakagawa H,
Ishimoto Y, Nagata K, Kagotani R, Tanaka S,
Kawaguchi H, Nakamura K, Akune T, Yoshida M.
Metabolic syndrome components are associatedwith the intervertebral disc degeneration: The
Wakayama Spine Study Plos One 2016;11:e0147565
16. Iwahashi H, Yoshimura N, Hashizume H, Yamada H,
Oka H, Shinto K, Ishimoto Y, Nagata K, Teraguchi
M, Kagotani R, Muraki S, Akune T, Tanaka S,
Kawaguchi H, Minamide A, Nakagawa Y, Yoshida
M. The association between the cross-sectional areaof the dural sac and low back pain in a large
population: The Wakayama Spine Study Plos One,in press.
17. Teraguchi M, Samartzis D, Hashizume H, YamadaH, Muraki S, Oka H, Cheung J, Kagotani R,
Iwahashi H, Tanaka S, Kawaguchi H, Nakamura K,
Akune T, Cheung K, Yoshimura N, Yoshida M.
Classification of high intensity zones of the lumbar
spine and their association with other spinal MRI
phenotypes: the Wakayama Spine Study. Plos One,in press.

403

Department of Health Care Safety
Management (Tokio Marine &Nichido)Project Adjunct Professor
Yasushi Kodama, M.D., LL.M., Ph.D. (until 30th Nov, 2015)

Project Adjunct Assoc. Professor
Masaki Anraku, M.D., Ph.D. (from 1th Jan, 2016)

Project Assistant Professor
Shoko Ogawa, M.D. (until 30th Nov, 2015)

Maiko Mizuki, M.P.H. (from 1th Des, 2015)

Project Researcher
Maiko Mizuki, M.P.H. (until 30th Nov, 2015)
Reiko Segawa, R.N., M.S.

Project Academic Support Specialist
Kahori Hayashi , JD. (since 16th June until 15th June, 2015)
Shogo Higashi , JD. (since 16th June until 15th June, 2015)
Yuriko Kobashi

Visiting Researcher
Tomoko Matsuura, M.S., Shinji Nagakawa, M.D., Ph.D., Kahoko Nakazawa, M.D., Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/iryou_anzen.html
http://square.umin.ac.jp/MSMCM/
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404

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
cases received per year) to 2004 (1110 new cases peryear), with the pace that has doubled every ten years.
Though the number of civil health care lawsuits showsa trend for decrease after 2004, many medical
treatment disputes resulted in lawsuits in 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
Papers (In Japanese)
1. Yasushi Kodama. The current state of conflict ofinterest and regulation in clinical research” Japan
Pharmaceutical Industry Legal Affairs Association.” Legal mind” No. 363, 44 – 79, Sep, 2015.
2. Yasushi Kodama. “Towards strengthening
governance, what should do the management?”
Japan National Council of Social Welfare and theManagement Association, social welfare corporations, “Management Association” Vol. 385, 14 -23,
Oct, 2015.
3. Yasushi Kodama. “A Study on Improving the
Operation of Centers to Improve the Safety of
Medical Care” Grant-in-aid for scientific researchfrom the Ministry of Health, Labour and Welfare,(Study Chair Yasushi Kodama), 2015–16.
4. Yasushi Kodama. “A Study of the Safety of
Medical Care and the System to Retrain
Physicians in the US” 23rd Grant for a Joint
International Study (2014) from the Pfizer HealthResearch Foundation,Study Chair, December
2014–November 2015
Conference Presentations
Domestic Meetings (in Japanese)
1. Yasushi Kodama. “The expectation of Medical
Alternative Dispute Resolution” Japan Arbitrstion
Center, April 22, 2015
2. Yasushi Kodama. “Understandings for the roles
and effects of the Patient Safety Support Centers.”

405

Joint Meeting of the Patient Safety Support
Centers. May 12, 2015.
3. Yasushi Kodama. The current state of conflict ofinterest and regulation in clinical research” Japan
Pharmaceutical Industry Legal Affairs Association.
Mar 19, 2015.
4. Yasushi Kodama. “Basic legal knowledge
concerning medical practice disputes - medicalcare safety” Japan Hospital Association Medical
safety supervisor training workshop, Jun 21, 2015
5. Yasushi Kodama. “The legal problems ofEndoscopy exam and treatment” Japan Gastroenterological Endoscopy Society, Jun 21, 2015
6. Yasushi Kodama. “Reason and humanity inmedical practice disputes” Japan Society for
Negotiation Studies, Jun 27, 2015.
7. Yasushi Kodama. “The present state of medicalcare litigation and the problem of medical
records” National Hospital Organization Researchconcerning treatment information management,
Aug 21, 2015.
8. Yasushi Kodama. “Risk communication seen froma lawyer” Pharmaceutical and Medical Device
Regulatory Science Society of Japan Pharmaceutical Development, Sep 14, 2015
9. Yasushi Kodama. “Risk communication seen froma lawyer” Pharmaceutical and Medical Device
Regulatory Science Society of Japan Pharmaceutical Development, Oct 13, 2015
10. Yasushi Kodama. “Doctors - dentists and the legal
system” Health, Labor and Welfare Ministry
Physician re-education group training, October 18,
2014
11. Yasushi Kodama. “The current state of conflict ofinterest and regulation in clinical research”
Society for Regulatory Science of Medical
Products Academic meeting lecture, Nov 23, 201512. Shogo Higashi, Kahori Hayashi, Shoko Ogawa,
Ryoko Hatanaka, Koidhiro Nandate, Yasushi
Kodama. “The Structure of the investigation
disposal caused disgraceful affair of doctor”
Japanese Society for Quality and Safety in
Healthcare 9th annual scientific meeting. Nov.,
2015.
13. Kahori Hayashi, Shogo Higashi, Shoko Ogawa,
Ryoko Hatanaka, Koidhiro Nandate, Yasushi
Kodama. “A Study of the Safety of Medical Careand the System to Retrain Physicians in the US”
Japanese Society for Quality and Safety in
Healthcare 9th annual scientific meeting. Nov.,
2015.
14. Shoko Ogawa, Segawa Reiko, Nagakawa Shinji,
Kahoko Nakazawa, Kahori Hayashi, Shogo
Higashi, Maiko Mizuki, Yasushi Kodama.
“Understandings for the roles and effects of thePatient Safety Support Centers” Japanese Society
for Quality and Safety in Healthcare 9th annual
scientific meeting. Nov., 2015.
15. Nagakawa Shinji, Maiko Mizuki, Shoko Ogawa,Segawa Reiko, Yasushi Kodama. “The present
state of medical care litigation and the problem of
medical records” Japanese Society for Quality and
Safety in Healthcare 9th annual scientific meeting.
Nov., 2015.
16. Maiko Mizuki,Shoko Ogawa, Segawa Reiko,Nagakawa Shinji, Kahoko Nakazawa, Kahori
Hayashi, Shogo Higashi, Yasushi Kodama.
“Making of training material on consultation.”
Japanese Society for Quality and Safety in
Healthcare 9th annual scientific meeting. Nov.,
2015.
17. Maiko Mizuki, “Improving medical coordination
function” Japanese Society for Homecare
Medicine. Sep., 2016.
International Meetings
1. Shoko Ogawa, Reiko Segawa, Tomoko Matsuura,
Maiko Mizuki, Yasushi Kodama,Mitigating How
can local governments improve patients safety.
The International Forum on Quality and Safety in
Healthcare 2015.London.
2. Reiko Segawa, Shoko Ogawa, Tomoko Matsuura,
Maiko Mizuki, Yasushi Kodama, Introduction ofa New Training Method to improve the Communication Skills of the Advocate Desk Staff.
The International Forum on Quality and Safety in
Healthcare 2015.London.

406

Department of Healthcare Quality
Assessment
Professor
Hiroaki Miyata, Ph.D.

Associate Professor
Shun Kosaka, M.D., Ph.D.

Assistant Professor
Hiraku Kumamaru, M.D., Sc.D.

Researcher
Hiroki Nogawa, M.D., Ph.D., Norimichi Hirahara, Ph.D., Junichi Okubo, Arata Takanashi,

Clerical Staff
Chieko Fujimura, Naohiro Kato, Eriko Fukuchi,

Clerical Staff (Secretary)
Nanayo Kyogoku, Takayo Nakamura,
Keita Otsugu, Hitomi Okamoto (NCD Liaison)

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. HQA has collaborated
with the Department of Health Economics andEpidemiology Research since 2009 and with the
Department of Pediatric Surgery since 2010. In 2012,
the Department of Health and Social Behavior joinedin the collaboration circle, replacing with the
Department of Health Economics and Epidemiology
Research.
The objective of providing healthcare is not just the
reduction of medical cost but to provide high quality
healthcare services to all patients.
Institute ofMedicine states that healthcare reform should focus on

improving patients’ physical health as well as
healthcare value for patients. In the 21st century, thisviewpoint, together with insight from healtheconomics, has been the first priority in the field of
medicine and healthcare.
“Quality improvement
initiative,” therefore, needs to adjust the healthcare
systems to accommodate the fee-for-service perspectives while improving the clinical environment for
both patients and providers.
HQA has been collaborating with various healthcare
professional committees as they play key roles in thequality improvement initiatives in the field. HQA
supports them with systematic data collection, data
management, practical analysis and useful feedback.
Our benchmarking projects are based on clinicaldatabase and they drive quality improvement in eachrelated field. With such positive-sum competition,
patients will receive better healthcare service,407

physicians will be rewarded for their excellence, andhealthcare costs will be contained. Three principles
should guide this transformation: (a) the goal is tomeet patients’ values, (b) medical practice should beorganized around medical conditions and care cycles,and (c) the results — risk-adjusted outcomes andmedical costs spent — must be scientifically measured
and evaluated.

academic roles in the project since its birth. The
actual data entry started from January 1st, 2011, andsince then NCD has been collecting approximately
95% of all surgical operations across Japan in thecollaboration with the clinical societies. NCD is also
connected with the participating societies’ board ofcertification systems, which makes it unique among
other large-scale clinical registries in the world.

Research activities

Today more than 4,500 hospitals and clinics are
participating in NCD with the accumulated data of 4.8
million cases (approximately 1.2 million each year).
Just like JCVSD’s JapanSCORE and RiskCalculator,
feedback tools based on the NCD data have been
provided to different subspecialty areas.
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.

HQA, in the joint research activity with Japan
Cardiovascular Surgery Database (JCVSD), hasdeveloped risk models for different groups of surgicalprocedures that help us implement several practical
tools aimed for medical professionals. One of those
tools is JapanSCORE, which allows a user to calculatea patient’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.
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.
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 “big data” toimprove the quality of surgery as well as surgicalsciences in Japan. HQA has been playing important

References
1. Ikegami Y, Kohsaka S, Miyata H, Ueda I, Fuse J,
Sakamoto M, Shiraishi Y, Numasawa Y, Negishi
K, Nakamura I, Maekawa Y, Momiyama Y,
Fukuda K. Outcomes of Percutaneous Coronary
Intervention Performed With or Without Preprocedural Dual Antiplatelet Therapy. Circ J,
79(12):2598-607 2015
2. Miyata H, Tomotaki A, Motomura N, Takamoto S.
Operative mortality and complication risk model
for all major cardiovascular operations in JapanAnn Thorac Surg ,99(1):130-9 2015 Jan
3. Aizawa Y, Kunitomi A, Nakajima K, Kashimura S,
Katsumata Y, Nishiyama T, Kimura T, Nishiyama
N, Tanimoto Y, Kohsaka S, Takatsuki S, Fukuda
K. Risk factors for early replacement of cardiovascular implantable electronic devices, Int J
Cardiol, 178:99-101 2015 Jan 15
4. Numasawa Y, Kohsaka S, Miyata H, Noma S,
Suzuki M, Ishikawa S, Nakamura I, Nishi Y, Ohki
T, Negishi K, Takahashi T, Fukuda K. Genderdifferences in in-hospital clinical outcomes after408

percutaneous coronary interventions: an insightfrom a Japanese multicenter registry; PLoS One,
10(1) 2015 Jan 30
5. Arakawa M, Miyata H, Uchida N, Motomura N,
Katayama A, Tamura K, Sueda T, Takamoto S.
Postoperative atrial fibrillation after thoracic
aortic surgery. Ann Thorac Surg,99(1):103-8 2015
Jan
6. Okita Y, Miyata H, Motomura N, Takamoto S;
Japan Cardiovascular Surgery Database Organization. A study of brain protection during total arch
replacement comparing antegrade cerebral
perfusion versus hypothermic circulatory arrest,with or without retrograde cerebral perfusion:
analysis based on the Japan Adult Cardiovascular
Surgery Database. J Thorac Cardiovasc Surg, 149(2 Suppl):S65-73 2015 Feb
7. Anazawa T, Miyata H, Gotoh M. Cancer registries
in Japan: National Clinical Database and sitespecific cancer registries Int J Clin Oncol, 20(1):5-10. 2015 Feb
8. Dohi M, Miyata H, Doi K, Okawa K, Motomura
N, Takamoto S, Yaku H; Japan Cardiovascular
Surgery Database. The off-pump technique in
redo coronary artery bypass grafting reduces
mortality and major morbidities: propensity scoreanalysis of data from the Japan Cardiovascular
Surgery Database; Eur J Cardiothoracic Surg,
47(2):299-307 2015 Feb
9. Numasawa Y, Kohsaka S, Miyata H, Kawamura A,
Noma S, Suzuki M, Nakagawa S, Momiyama Y,
Naito K, Fukuda K. Impact of body mass index on
in-hospital complications in patients undergoing
percutaneous coronary intervention in a Japanesereal-world multicenter registry PLoS One, 10(4)2015 Apr 14
10. Inohara T, Kohsaka S, Abe T, Miyata H,
Numasawa Y, Ueda I, Nishi Y, Naito K, Shibata M,
Hayashida K, Maekawa Y, Kawamura A, Sato Y,
Fukuda K. Development and validation of a prepercutaneous coronary intervention risk model ofcontrast-induced acute kidney injury with an
integer scoring system. Am J Cardiol, 115(12):1636-42 2015 Jun 15
11. Endo A, Kawamura A, Miyata H, Noma S, Suzuki
M, Koyama T, Ishikawa S, Nakagawa S, Takagi S,
Numasawa Y, Fukuda K, Kohsaka S; JCD-KICS

Investigators. Angiographic Lesion Complexity
Score and In-Hospital Outcomes after Percutaneous Coronary Intervention. PLoS One,
10(6) 2015 Jun 29
12. Saze Z, Miyata H, Konno H, Gotoh M, Anazawa
T, Tomotaki A, Wakabayashi G, Mori M. Risk
Models of Operative Morbidities in 16,930 Critically Ill Surgical Patients Based on a Japanese
Nationwide Database Medicine (Baltimore), 94(30) 2015 Jul
13. Hoashi T, Miyata H, Murakami A, Hirata Y,
Hirose K, Matsumura G, Ichikawa H, Sawa Y,
Takamoto S. The current trends of mortality
following congenital heart surgery: the Japan
Congenital Cardiovascular Surgery Database
Interact Cardiovasc Thorac Surg, 21(2):151-6
2015 Aug
14. Kurita N, Miyata H, Gotoh M, Shimada M, Imura
S, Kimura W, Tomita N, Baba H, Kitagawa Y,
Sugihara K, Mori M. Risk Model for Distal
Gastrectomy When Treating Gastric Cancer on theBasis of Data From 33,917 Japanese PatientsCollected Using a Nationwide Web-based Data
Entry System Ann Surg, 262(2):295-303 2015
Aug
15. Nishi H, Miyata H, Motomura N, Toda K,
Miyagawa S, Sawa Y, Takamoto S. Propensitymatched analysis of minimally invasive mitralvalve repair using a nationwide surgical database
Surg Today, 45(9):1144-52 2015 Sep.
16. Inohara T, Kohsaka S, Miyata H, Ueda I,
Hayashida K, Maekawa Y, Kawamura A,
Numasawa Y, Suzuki M, Noma S, Nishi Y,
Fukuda K. Real-World Use and Appropriatenessof Coronary Interventions for Chronic Total
Occlusion (from a Japanese Multicenter Registry)
Am J Cardiol, 116(6):858-64 2015 Sep 15
17. Ri M, Miyata H, Aikou S, Seto Y, Akazawa K,
Takeuchi M, Matsui Y, Konno H, Gotoh M, Mori
M, Motomura N, Takamoto S, Sawa Y, Kuwano H,
Kokudo N. Effects of body mass index (BMI) on
surgical outcomes: a nationwide survey using a
Japanese web-based database Surg Today, 45(10):1271-9 2015 Oct
18. Takahara T, Wakabayashi G, Beppu T, Aihara A,
Hasegawa K, Gotohda N, Hatano E, Tanahashi Y,
Mizuguchi T, Kamiyama T, Ikeda T, Tanaka S,

409

Taniai N, Baba H, Tanabe M, Kokudo N, Konishi
M, Uemoto S, Sugioka A, Hirata K, Taketomi A,
Maehara Y, Kubo S, Uchida E, Miyata H,
Nakamura M, Kaneko H, Yamaue H, Miyazaki M,
Takada T. Long-term and perioperative outcomesof laparoscopic versus open liver resection forhepatocellular carcinoma with propensity scorematching: a multi-institutional Japanese study J
Hepatobiliary Pancreat Sci, 22(10):721-7 2015
Oct
19. Nakamura M, Wakabayashi G, Miyasaka Y,
Tanaka M, Morikawa T, Unno M, Tajima H,
Kumamoto Y, Satoi S, Kwon M, Toyama H, Ku Y,
Yoshitomi H, Nara S, Shimada K, Yokoyama T,
Miyagawa S, Toyama Y, Yanaga K, Fujii T,
Kodera Y; Study Group of JHBPS; JSEPS,
Tomiyama Y, Miyata H, Takahara T, Beppu T,
Yamaue H, Miyazaki M, Takada T. Multicentercomparative study of laparoscopic and open distal
pancreatectomy using propensity score-matching
J Hepatobiliary Pancreat Sci, 22(10):731-6 2015
Oct
20. Beppu T, Wakabayashi G, Hasegawa K, Gotohda
N, Mizuguchi T, Takahashi Y, Hirokawa F, Taniai
N, Watanabe M, Katou M, Nagano H, Honda G,
Baba H, Kokudo N, Konishi M, Hirata K,
Yamamoto M, Uchiyama K, Uchida E, Kusachi S,
Kubota K, Mori M, Takahashi K, Kikuchi K,
Miyata H, Takahara T, Nakamura M, Kaneko H,
Yamaue H, Miyazaki M, Takada T. Long-term andperioperative outcomes of laparoscopic versus
open liver resection for colorectal liver metastaseswith propensity score matching: a multiinstitutional Japanese study J Hepatobiliary
Pancreat Sci, 22(10):711-20 2015 Oct
21. Nakagoe T, Miyata H, Gotoh M, Anazawa T, Baba
H, Kimura W, Tomita N, Shimada M, Kitagawa Y,
Sugihara K, Mori M. Surgical risk model for acutediffuse peritonitis based on a Japanese nationwide
database: an initial report on the surgical and 30day mortality Surg Today, 45(10):1233-43 2015
Oct
22. Inohara T, Miyata H, Ueda I, Maekawa Y, Fukuda
K, Kohsaka S. Use of Intra-aortic Balloon Pumpin a Japanese Multicenter Percutaneous Coronary
Intervention Registry JAMA Intern Med, 175(12):1980-2 2015 Dec

23. Inohara T, Miyata H, Ueda I, Maekawa Y, Fukuda
K, Kohsaka S. Use of Intra-aortic Balloon Pumpin a Japanese Multicenter Percutaneous Coronary
Intervention Registry JAMA Intern Med, 175(12):1980-2 2015 Dec
24. Anazawa T, Paruch JL, Miyata H, Gotoh M, Ko
CY, Cohen ME, Hirahara N, Zhou L, Konno H,
Wakabayashi G, Sugihara K, Mori M. Comparisonof National Operative Mortality in Gastroenterological Surgery Using Web-based Prospective
Data Entry Systems Medicine (Baltimore), 94(49)2015 Dec

410

Department of Anti-Aging
Medicine
Professor
Satoshi Inoue, M.D., Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/koukarei.html
Introduction and Organization
The Department of Anti-Aging Medicine wasestablished at the 22nd Century Medical and ResearchCenter of University of Tokyo Hospital in 2006. This
department has a close relationship with the Department of Geriatric Medicine at the Graduate School of
Medicine, University of Tokyo. The goal of thisresearch program is to understand the genetic andenvironmental factors that contribute to aging, and thepathogenesis of age-related disorders, including
obesity, diabetes, metabolic disorders, osteoporosis,
osteoarthritis, sarcopenia, atherosclerosis, dementia,
age-related macular degeneration, prostate cancer,
mammary carcinoma, and immunocompromised conditions. In particular, the program aims to clarify theroles of sex hormones estrogen and androgen in
normal, aging and disease processes. Through basic
biomedical research, our department will reveal agedependent changes at cellular, tissue, and whole-bodylevels, and will contribute to the development ofmolecule-targeted treatment and alternative preventionof age-related processes and diseases.

Research activities
Aging causes degeneration and dysfunction of cells invarious organs, leading to the development of multiple
disorders in elderly people, as exemplified by obesity,
glucose intolerance, dyslipidemia. Osteoporosis,
osteoarthritis, and sarcopenia are also common bone,
joint, and muscle disorders, respectively, among
elderly people. In addition, aging is an important risk
factor for the prognosis of hormone-dependent tumors,

prostate cancer and mammary carcinoma. Since aging
and age-related disorders affect the quality of dailyliving and lifespan of elderly people, we will identify
the genetic and environmental factors that control
aging processes using recent technology of human
genetics, genomics and molecular and cellularbiology.
Our recent findings contribute to the progress in threefollowing research fields.
1. We originally identified estrogen-responsive finger
protein (Efp/TRIM25) as an estrogen target genethrough genome binding-site cloning technique. Efp
has a structure of the TRIM/RBCC protein, with
RING finger, B-box, and coiled-coil domains, and it
has been shown as a critical molecule that promotes
the progression of mammary carcinoma. In addition
we recently discovered that Efp has anotherimportant role in antiviral defenses. Extending our
findings on TRIM25, we also study the functions ofother TRIM proteins in normal states and in cancer
and immune response, including TRIM5α, TRIM17(Terf), TRIM39, TRIM44, TRIM47 and TRIM63.
2. Using chromatin immunoprecipitation (ChIP)
microarray analysis, ChIP-sequencing, RNAsequencing, CAGE-sequencing and systems biological approach, we discovered novel androgen
responsive genes including UGT1A1, CDH2, APP,
FOXP1, ArfGAP3, 14-3-3ζ, miR148a and noncoding RNAs such as miR-29, miR-148a, SOCS2AS1 and CTBP1-AS. We also focused on collabo-

411

rating factors such as FOXP1, RUNX1, Oct1 and
CtBP1/2. The tumor-promoting effects of thesegenes including APP and CTBP1-AS have beenshown in in vivo models of prostate cancer.
3. As a genetic approach, we performed large-scale
single nucleotide polymorphisms (SNP) analyses to
identify disease-related factors for osteoporosis,
osteoarthritis, sarcopenia, and age-related maculardegeneration. Through genome-wide associatedstudy (GWAS) and candidate gene approach, we
identified several interesting disease-related genes
and focused on the functional studies for thesegenes combining mouse genetics to solve thefunctions of disease-related genes in physiologicaland pathophysiological states, we discovered
PRDM16 involved in sarcopenia and SLC25A24
involved in obesity.
Our intensive studies will provide novel molecularevidences for aging processes, which will be usefulfor the establishment of anti-aging medicine and thedevelopment of novel therapeutic modalities forage-related disorders.

References
1. Ujihira T, Ikeda K, Suzuki T, Yamaga R, Sato W,
Horie-Inoue K, Shigekawa T, Osaki A, Saeki T,
Okamoto K, Takeda S, Inoue S: MicroRNA574-3p, identified by microRNA library-based
functional screening, modulates tamoxifen response in breast cancer. Sci Rep 5, 7641, 2015.
2. Takayama K, Suzuki T, Tsutsumi S, Fujimura T,
Urano T, Takahashi S, Homma Y, Aburatani H,
Inoue S: RUNX1, an androgen- and EZH2regulated gene, has differential roles in ARdependent and -independent prostate cancer.
Oncotarget 6, 2263-2276, 2015.
3. Azuma K, Casey SC, Urano T, Horie-Inoue K,
Ouchi Y, Blumberg B, Inoue S: Pregnane X
receptor knockout mice display aging-dependent
wearing of articular cartilage. PLoS ONE 10,e0119177, 2015.
4. Urano T, Shiraki M, Sasaki N, Ouchi Y, Inoue S:
SLC25A24 as a novel susceptibility gene for low
fat mass in humans and mice. J Clin Endocrinol

Metab 100, E655-E663, 2015.
5. Izumi G, Koga K, Nagai M, Urata Y, Takamura
M, Harada M, Hirata T, Hirota Y, Ogawa K,
Inoue S, Fujii T, Osuga Y: Cyclic stretch
augments production of neutrophil chemokines,
matrix metalloproteinases, and Activin A in
human endometrial stromal cells. Am J Reprod
Immunol 73, 501-506, 2015.
6. Azuma K, Shiba S, Hasegawa T, Ikeda K, Urano
T, Horie-Inoue K, Ouchi Y, Amizuka N, Inoue S:
Osteoblast-specific γ-glutamyl carboxylase- deficient mice display enhanced bone formation withaberrant mineralization. J Bone Miner Res 30,
1245-1254, 2015.
7. Ikeda K, Horie-Inoue K, Ueno T, Suzuki T, Sato
W, Shigekawa T, Osaki A, Saeki T, Berezikov E,
Mano H, Inoue S: miR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells
through targeting GOLT1A. Sci Rep 5, 13170,
2015.
8. Takayama K, Misawa A, Suzuki T, Takagi K,
Hayashizaki Y, Fujimura T, Homma Y, Takahashi
S, Urano T, Inoue S: TET2 repression by androgen hormone regulates global hydroxymethylation
status and prostate cancer progression. Nat
Commun 6, 8219, 2015.
9. Saito-Kanatani M, Urano T, Hiroi H, Momoeda
M, Ito M, Fujii T, Inoue S: Identification of
TRIM22 as a progesterone-responsive gene in
Ishikawa endometrial cancer cells. J Steroid
Biochem Mol Biol 154, 217-225, 2015.
10. Miyazaki T, Ikeda K, Sato W, Horie-Inoue K,
Okamoto K, Inoue S: MicroRNA library-based
functional
screening
identified
androgensensitive miR-216a as a player in bicalutamide
resistance in prostate cancer. J Clin Med 4, 18531865, 2015.
11. Fujimura T, Takahashi S, Kume H, Urano T,
Takayama K, Yamada Y, Suzuki M, Fukuhara H,
Nakagawa T, Inoue S, Homma Y: Toremifene, aselective estrogen receptor modulator, significantly improved biochemical recurrence in bone metastatic prostate cancer: a randomized controlled
phase II a trial. BMC Cancer 15, 836, 2015.
12. Zhang P, Elabd S, Hammer S, Solozobova V, Yan
H, Barte F, Inoue S, Heinrich T, Wittbrodt J,
Loosli F, Davidson G, Blattner C: TRIM25 has a412

dual function in the p53/Mdm2 circuit. Oncogene
34, 5729-5738, 2015.
13. Nakajima Y, Osakabe A, Waku T, Suzuki T,
Akaogi K, Fujimura T, Homma Y, Inoue S,
Yanagisawa J: Estrogen exhibits a biphasic effecton prostate tumor growth through the ERβ-KLF5
pathway. Mol Cell Biol 36, 144-156, 2016.
14. Matsushita S, Suzuki K, Ogino Y, Hino S, Sato T,
Suyama M, Matsumoto T, Omori A, Inoue S,
Yamada G: Androgen regulates Mafb expression
through its 3’UTR during mouse urethral masculinization. Endocrinology 157, 844-857, 2016.
15. 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.
16. Huang L, Zhang H, Cheng CY, Wen F, Tam POS,
Zhao P, Chen H, Li Z, Chen L, Tai Z, Yamashiro
K, Deng S, Zhu X, Chen W, Li C, Lu F, Li Y,
Cheung CMG, Shi Y, Miyake M, Lin Y, Gong B,
Liu X, Sim KS, Yang J, Mori K, Zhang X,
Cackett PD, Tsujikawa M, Nishida K, Hao F, Ma
S, Lin H, Chen J, Fei P, Lai TYY, Tang S, Laude
A, Inoue S, Yeo IY, Sakurada Y, Zhou Y, Iijima
H, Honda S, Lei C, Zhang L, Zheng H, Jiang D,
Zhu X, Wong TY, Khor CC, Pang CP, Yoshimura
N, Yang Z: A missense variant in FGD6 confers
increased risk of polypoidal choroidal vasculopathy. Nat Genet 48, 640-647, 2016.
17. Urano T, Shiraki M, Kuroda T, Tanaka S, Uenishi
K, Inoue S: Preventive effects of raloxifene treatment on agerelated weight loss in postmenopausal
women. J Bone Miner Metab (in press).
18. 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 (in press)
19. 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 and castration-

resistant prostate cancer growth. Oncogene (inpress)
20. Misawa A, Takayama K, Urano T, Inoue S:
Androgen-induced lncRNA SOCS2-AS1 promotes
cell growth and inhibits apoptosis in prostatecancer cells. J Biol Chem (in press)
21. Onodera Y, Takagi K, Miki Y, Takayama K,
Shibahara Y, Watanabe M, Ishida T, Inoue S,
Sasano H, Suzuki T: TACC2 (transforming acidic
coiled-coil protein 2) in breast carcinoma as apotent prognostic predictor associated with cellproliferation. Cancer Med (in press).
22. Misawa A, Inoue S: Estrogen-related receptors inbreast cancer and prostate cancer. Front
Endocrinol (Lausanne) 6, 83, 2015.
23. Urano T, Inoue S: Recent genetic discoveries inosteoporosis, sarcopenia and obesity. Endocr J 62,
475-484, 2015.
24. Takayama K, Inoue S: The emerging role ofnon-coding RNA in prostate 1 cancer progression
and its implication on diagnosis and treatment.
Brief Funct Genomics 15, 257-265, 2016.
25. Takayama K, Inoue S: The role of androgenregulated long noncoding RNAs in prostate cancer.
(2015) Long noncoding RNAs, Chapter 11(edited Kurokawa R) Springer Japan, Tokyo, (pp.
191-210)

413

Department of Clinical Trial DataManagement
Project Assistant Professor
Tempei Miyaji, M.S.

Project Researcher
Takuhiro Yamaguchi, Ph.D.

Homepage

http://ctdm.umin.jp/

Introduction and Organization

the world.

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

Teaching activities
1. Development of systematic educational programsof CDM and holding of seminars, which include; Design of clinical trials
 CDM
 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
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 collabora-

414tion 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 replication-competent, recombinant herpes simplex
virus type 1 (G47delta) in patients with progressive
glioblastoma” and “A clinical study of an oncolytic
herpes simplex type 1 (HSV-1) G47delta for patientswith castration resistant prostate cancer” which areconducted at Translational Research Center (TRAC)
and Department of Urology in the University of Tokyo
Hospital respectively. Moreover, we also havecollaborative works outside of University of Tokyo
Hospital for several clinical research. For example,
our department support “Exploratory Clinical Trial on
Methods and Effects of Tojisha-Kenkyu for Autism
Spectrum Disorder” which conducted at ResearchCenter for Advanced Science and Technology, The
University of Tokyo and “Psychometric Property ofJapanese version of Patient Reported Outcome Common Terminology Criteria for Adverse Event”
which conducted at Department of Pharmacy, Tokyo
Medical University Hospital. Finally, as thecollaborative department of the Clinical Research
Support Center (CresCent), we also involved in theirprojects as biostatisticians and clinical data mangers.

4.

5.

6.

7.

8.

References
1. Kinoshita H, Maeda I, Morita T, Miyashita M,
Yamagishi A, Shirahige Y, Takebayashi T,
Yamaguchi T, Igarashi A, Eguchi K. Place ofdeath and the differences in patient quality ofdeath and dying and caregiver burden. Journal of
Clinical Oncology 2015; 33(4): 357-63.
2. Shiraya T, Kato S, Araki F, Yamaguchi T, Kaiya T.
Comparison of burn sizes resulting fromphotocoagulation using a transpupillary laser andan endolaser. Acta Ophthalmologica 2015 Jan 7.
doi: 10.1111/aos.12656. No abstract available.
PMID: 25565294
3. Miyano K, Minami K, Yokoyama T, Ohbuchi K,
Yamaguchi T, Murakami S, Shiraishi S,
Yamamoto M, Matoba M, Uezono Y. Tramadol
and its metabolite m1 selectively suppress
transient receptor potential ankyrin 1 activity, but

9.

not transient receptor potential vanilloid 1 activity.
Anesthesia & Analgesia 2015; 120(4): 790-8.
Kunimatsu-Sanuki S, Iwase A, Araie M, Aoki Y,
Hara T, Nakazawa T, Yamaguchi T, Ono H,
Sanuki T, Itoh M. An assessment of driving fitness
in patients with visual impairment to understandthe elevated risk of motor vehicle accidents. BMJ
Open 2015; 5(2): e006379.
Aoki A, Tan X, Yamagishi R, Shinkai S, Obata R,
Miyaji T, Yamaguchi T, Numaga J, Ito H, Yanagi
Y. Risk Factors for Age-Related Macular Degeneration in an Elderly Japanese Population: The
Hatoyama Study.Investigative Ophthalmology &Visual Science 2015; 56(4): 2580-5.
Kizawa Y, Morita T, Miyashita M, Shinjo T,
Yamagishi A, Suzuki S, Kinoshita H, Shirahige Y,
Yamaguchi T, Eguchi K. Improvements inPhysicians' Knowledge, Difficulties, and SelfReported Practice After a Regional Palliative Care
Program. Journal of Pain and Symptom Management 2015; 50(2): 232-40.
Omodaka K, Takada N, Yamaguchi T, Takahashi
H, Araie M, Nakazawa T. Characteristic
correlations of the structure-function relationshipin different glaucomatous disc types. Japanese
Journal of Ophthalmology 2015; 59(4): 223-9.
Iwase S, Kawaguchi T, Yotsumoto D, Doi T,
Miyara K, Odagiri H, Kitamura K, Ariyoshi K,
Miyaji T, Ishiki H, Inoue K, Tsutsumi C, Sagara Y,
Yamaguchi T. Efficacy and safety of an aminoacid jelly containing coenzyme Q10 andL-carnitine in controlling fatigue in breast cancer
patients receiving chemotherapy: a multiinstitutional, randomized, exploratory trial(JORTC-CAM01). Support Care in Cancer 2015
Jun 24. PMID: 26105516
Takenaka K, Nishida T, Asano-Mori Y, Oshima K,
Ohashi K, Mori T, Kanamori H, Miyamura K,
Kato C, Kobayashi N, Uchida N, Nakamae H,
Ichinohe T, Morishima Y, Suzuki R, Yamaguchi T,
Fukuda T.Cytomegalovirus reactivation after
allogeneic hematopoietic stem cell transplantation
is associated with a reduced risk of relapse inpatients with acute myeloid leukemia whosurvived to day 100 aftertransplantation: the Japan
Society for Hematopoietic Cell Transplantation
Transplantation-related Complication Working

415Group. Biology of Blood and Marrow Transplantation 2015 Jul 23. pii: S1083-8791(15)00496-6.
doi:
10.1016/j.bbmt.2015.07.019.
PMID: 26211985
10. Iwase S, Kawaguchi T, Tokoro A, Yamada K,
Kanai Y, Matsuda Y, Kashiwaya Y, Okuma K,
Inada S, Ariyoshi K, Miyaji T, Azuma K, Ishiki H,
Unezaki S, Yamaguchi T. Assessment of CancerRelated Fatigue, Pain, and Quality of Life inCancer Patients at Palliative Care Team Referral:
A Multicenter Observational Study (JORTC
PAL-09). PLoS One 2015; 10(8): e0134022.
11. Kawaguchi T, Sekine Y, Azuma K, Yamaguchi T,
Soeda H, Takeuchi H, Amano K, Fukutake K,
Akashi T, Unezaki S. Quantitative assessment of
the effect of pharmacist counseling on decisional
conflict - Analysis in the patients infected withhuman immunodeficiency virus -.Japanese
Journal of Pharmaceutical Health Care andSciences 2015; 39(12).
12. Miyaji T, Nagasawa M, Yamaguchi T, Tsutani K.
Tackling the Pharmaceutical Frontier: Regulationof cannabinoid-based medicines in postwar Japan.
Cannabis and Cannabinoid Research. January
2016, 1(1): 31-37.
13. Yamamoto D, Iwase S, Tsubota Y, Ariyoshi K,
Kawaguchi T, Miyaji T, Sueoka N, Yamamoto C,
Teramoto S, Odagiri H, Kitamura K, Nagumo Y,
Yamaguchi T. Randomized study of orally administered fluorinated pyrimidines (capecitabine
versus S-1) in women with metastatic or recurrent
breast cancer: Japan Breast Cancer Research
Network 05 Trial. Cancer Chemother Pharmacol.
2015 Jun; 75(6): 1183-9.
14. Ariyoshi K, Miyaji T, Maeda I, Iwase S,
Yamaguchi T. Development of a Research
Network and an Infrastructure for the Nationwide
Registry Study in Palliative Care in Japan.
Pharmacoepidemiol Drug Saf, 2015 Sep; 24(s1):455
15. Iwase S, Kawaguchi T, Miyaji T, Ishiki H,
Ariyoshi K, Yamaguchi T. Assessment of CancerRelated Fatigue, Pain, and Quality of Life inCancer Patients after Palliative Care Team
Referral: A Multicenter Observational Study(JORTC PAL-09). J Clin Oncol 2015; 33 (suppl;
abstr e20550).

416

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

417

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.

References (English only)
1. 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 and stimulate osteoblast differentiation
through mTORC1 signaling. Bioessays. 38(8):717-25. 2016.
2. Kariya Y, Honma M, Suzuki H. Mechanism
analyses and mechanism-based prediction foradverse drug reactions using systems pharmacology. Nihon Yakurigaku Zasshi. 147(2):89-94.
2016
3. Notomi T, Kuno M, Hiyama A, Ezura Y, Honma
M, Ishizuka T, Ohura K, Yawo H, Noda M.
Membrane depolarization regulates intracellular
RANKL transport in non-excitable osteoblasts.
Bone. 81:306-14. 2015
4. Amemiya T, Honma M, Kariya Y, Ghosh S,
Kitano H, Kurachi Y, Fujita K, Sasaki Y, Homma
Y, Abernethy DR, Kume H, Suzuki H. Elucidationof the molecular mechanisms underlying adverse
reactions associated with a kinase inhibitor using
systems toxicology. npj Syst Biol Appl. 1:15005.
2015.

418

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 Hospitalin 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 hearttransplant, pediatric heart transplant, ventricular assist
device, and regenerative therapy. The Department has
been also supported by fourteen 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 patients with severe PH are referred toour hospital because the University of Tokyo Hospitalhas been approved as a lung 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 hospitalare followed up once a month in the out-patient clinic,
and undergo myocardial biopsy once a month in thefirst year and once a year afterwards. When some
symptom or findings which suggest rejection aredetected, patients will undergo in-hospital treatment.
2. Ventricular Assist Device (VAD) Therapy
We recently implant not only extracorporeal
pulsatile but also implantable ventricular assist device(VAD). All candidates fell into end-stage heart failure
before VAD implantation, and a significant number ofthem were rescued with heart transplantation or bridge
to recovery. We implant centrifugal VAD(EVAHEART and DuraHeart) or axial VAD(HeartMate II and Jarvik 2000) considering patients
physics and clinical status). We also assisted VAD
implantation in affiliate or cooperative hospital in2012 to establish VAD network in Shinsyu University
Hospital, Saku General Hospital, Akita University

419

Hospital, Gunma Prefectural Cardiovascular Center,and Nagoya Tokusyukai Hospital.

Board Examination by 10th postgraduate year.

Research Activities
3. Treatment of PH
Although pulmonary arterial hypertension (PAH)
was a disease of poor prognosis, the treatment outcome of 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
therapy of these drugs is increasingly prevalent for the
management of PAH. We join the nationwide PH
registry to establish 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 clinicalpractice on diagnosis of cardiovascular disease in theautumn term at the 2nd grade. We expose the students
to daily clinical works as well as research works
during the course of “Free Quarter” and “Research
Lab Visit”, which are scheduled in the summer andspring vacations at 1st and 2nd grade. Joint lectureswith 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 and postoperative care, based onparticipatory practice. There are also twelve small
key-lectures on cardiovascular surgery. Hands-on
practice is provided during the “Clinical clerkship”
one-month course in the last months of 3rd grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/ subspecialty training
programs to allow the residents to pass Cardiovascular

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 andsurgical heart failure treatment, played an internationally leading 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 externalcounterpulsation, 3) basic and clinical research on
regenerative therapy, 4) establishment of social
support system for patients with implantable LVAD.
We have organized 4series of clinical trial of
implantable rotary blood pump LVAD, EVAHEART,
DuraHeart, Jarvik 2000, and HeartMate II since 2007.

References
1. Imamura T, Kinugawa K, Fujino T, Inaba T, Maki
H, Hatano M, Kinoshita O, Nawata K, Kyo S,
Ono M. Aortic insufficiency in patients withsustained left ventricular systolic dysfunction
after axial flow assist device implantation. Circ J.
2015; 79: 104-11.
2. Fukada I, Araki K, Minatsuki S, Fujino T, Hatano
M, Numakura S, Abe H, Ushiku T, Iwase T, Ito Y.
Imatinib alleviated pulmonary hypertension
caused by pulmonary tumor thrombotic microangiopathy in a patient with metastatic breast
cancer. Clin Breast Cancer. 2015 Apr;15(2):e167-70.
3. Imamura T, Kinugawa K, Nitta D, Fujino T, Inaba
T, Maki H, Hatano M, Kinoshita O, Nawata K,
Yao A, Kyo S, Ono M. Is the internal jugular veinor femoral vein a better approach site forendomyocardial biopsy in heart transplant
recipients? Int Heart J. 2015;56(1):67-72.
4. Imamura T, Kinugawa K, Nitta D, Inaba T, Maki

420

H, Hatano M, Kinoshita O, Nawata K, Kyo S,
Ono M. Readmission due to driveline infection
can be predicted by new score by using serum
albumin and body mass index during long-term
left ventricular assist device support. J Artif
Organs. 2015 Jun;18(2):120-7.
5. Imamura T, Kinugawa K, Nitta D, Inaba T, Maki
H, Hatano M, Komuro I. Novel scoring systemusing cardiopulmonary exercise testing predicts
prognosis in heart failure patients receiving
guideline-directed medical therapy. Circ J. 2015;
79(5):1068-75.
6. Minatsuki S, Miura I, Yao A, Abe H, Muraoka H,
Tanaka M, Imamura T, Inaba T, Maki H, Hatano
M, Kinugawa K, Yao T, Fukayama M, Nagai R,
Komuro I. Platelet-derived growth factor
receptor-tyrosine kinase inhibitor, imatinib, iseffective for treating pulmonary hypertension
induced by pulmonary tumor thrombotic microangiopathy. Int Heart J. 2015;56(2):245-8.
7. Imamura T, Kinugawa K, Nitta D, Fujino T, Inaba
T, Maki H, Hatano M, Kinoshita O, Nawata K,
Yao A, Kyo S, Ono M. Late rejection occurred inrecipients who experienced acute cellular rejection within the first year after heart transplantation.
Int Heart J. 2015;56(2):174-9.
8. Imamura T, Kinugawa K, Okada I, Kato N, Fujino
T, Inaba T, Maki H, Hatano M, Kinoshita O,
Nawata K, Kyo S, Ono M. Parasympathetic
reinnervation accompanied by improved postexercise heart rate recovery and quality of life inheart transplant recipients. Int Heart J. 2015;
56(2):180-5.
9. Imamura T, Kinugawa K, Doi K, Hatano M,
Fujino T, Kinoshita O, Nawata K, Noiri E, Kyo S,
Ono M. Plasma neutrophil gelatinase-associatedlipocalin and worsening renal function during
everolimus therapy after heart transplantation. Int
Heart J. 2015;56(1):73-9.
10. Fujino T, Yao A, Hatano M, Inaba T, Muraoka H,
Minatsuki S, Imamura T, Maki H, Kinugawa K,
Ono M, Nagai R, Komuro I. Targeted therapy isrequired for management of pulmonary arterial
hypertension after defect closure in adult patientswith atrial septal defect and associated pulmonary
arterial hypertension. Int Heart J. 2015;56(1):86-93.

11. Imamura T, Kinugawa K, Nitta D, Fujino T, Inaba
T, Maki H, Hatano M, Kinoshita O, Nawata K,
Kyo S, Ono M. Novel scoring system using
postoperative cardiopulmonary exercise testing
predicts future explantation of left ventricularassist device. Circ J. 2015;79(3):560-6.
12. Imamura T, Kinugawa K, Nitta D, Hatano M,
Kinoshita O, Nawata K, Ono M. Biventricular
failure with low pulmonary vascular resistance
was managed by left ventricular assist device
alone without right-sided mechanical support. J
Artif Organs. 2015 Mar 13. [Epub ahead of print]
13. Imamura T, Kinugawa K, Nitta D, Inaba T, Maki
H, Hatano M, Kinoshita O, Nawata K, Kyo S,
Ono M. Opening of native aortic valve accomplished after left ventricular assist device implantation in patients with insufficient preoperative
Beta-blocker treatment. Int Heart J. 2015 May 13;56(3):303-8.
14. Imamura T, Kinugawa K, Nitta D, Hatano M,
Komuro I. Should cardiac resynchronization
therapy be a rescue therapy for inotropedependent patients with advanced heart failure? J
Card Fail. 2015 Jun;21(6):535-8.
15. Imamura T, Kinugawa K, Nitta D, Hatano M, Ono
M. Opening of Aortic Valve during Exercise is
Key to Preventing Development of Aortic
Insufficiency during Ventricular Assist Device
Treatment. ASAIO J. 2015 ; 61(5): 514-9.
16. Imamura T, Kinugawa K, Nitta D, Hatano M,
Kinoshita O, Nawata K, Kyo S, Ono M.
Prophylactic Intra-Aortic Balloon Pump Before
Ventricular Assist Device Implantation Reduces
Perioperative Medical Expenses and Improves
Postoperative Clinical Course in INTERMACS
Profile 2 Patients. Circ J. 2015 May 13. [Epubahead of print]
17. Yagi H, Hatano M, Takeda N, Harada S, Suzuki
Y, Taniguchi Y, Shintani Y, Morita H, Kanamori
N, Aoyama T, Watanabe M, Manabe I, Akazawa
H, Kinugawa K, Komuro I. Congenital Contractural Arachnodactyly without FBN1 or FBN2
Gene Mutations Complicated by Dilated Cardiomyopathy. Intern Med. 2015;54(10):1237-41.
18. Imamura T, Kinugawa K, Nitta D, Hatano M,
Kinoshita O, Nawata K, Ono M. Perioperative
Hypoalbuminemia Affects Improvement in421

Exercise Tolerance After Left Ventricular Assist
Device Implantation. Circ J. 2015 May 28. [Epubahead of print]
19. Ko T, Hatano M, Nitta D, Muraoka H, Minatsuki
S, Imamura T, Inaba T, Maki H, Yao A,
Kinugawa K, Komuro I. A case of interferon-αinduced pulmonary arterial hypertension after
living donor liver transplantation. Heart Vessels.
2015 Jun 17. [Epub ahead of print]
20. Muraoka H, Imamura T, Hatano M, Maki H, Yao
A, Kinugawa K, Komuro I. Secure Combination
Therapy With Low-Dose Bosentan andAmbrisentan to Treat Portopulmonary Hypertension Minimizing Each Adverse Effect. Int
Heart J. 2015 Jul 13;56(4):471-3.
21. Imamura T, Kinugawa K, Nitta D, Hatano M,
Kinoshita O, Nawata K, Ono M. Advantage ofPulsatility in Left Ventricular Reverse Remodeling and Aortic Insufficiency Prevention
During Left Ventricular Assist Device Treatment.
Circ J. 2015 Jun 25. [Epub ahead of print]
22. Kato NP, Okada I, Imamura T, Kagami Y, Endo
M, Nitta D, Fujino T, Muraoka H, Minatsuki S,
Maki H, Inaba T, Kinoshita O, Nawata K, Hatano
M, Yao A, Kyo S, Ono M, Jaarsma T, Kinugawa
K. Quality of Life and Influential Factors inPatients Implanted With a Left Ventricular Assist
Device. Circ J. 2015 Aug 10. [Epub ahead ofprint]
23. 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. 2015 Aug 10. pii: S09145087(15)00219-1.
24. Nitta D, Kinugawa K, Imamura T, Endo M,
Amiya E, Inaba T, Maki H, Hatano M, Komuro I.
An Experience of Landiolol Use for an Advanced
Heart Failure Patient With Severe Hypotension.
Int Heart J. 2015;56(5):564-7.
25. Hasumi E, Fujiu K, Imamura T, Iwata H, Sawaki
D, Hosoya Y, Ando J, Kojima T, Shimizu Y,
Oguri G, Matsubara T, Hatano M, Akazawa H,
Watanabe M, Ono M, Komuro I.Cardiac Arrest
Triggered by Subepicardial Aneurysm Without
Cardiac Rupture. Circ J. 2015 Oct 27. [Epubahead of print]

26. 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. 2015;56(6):676-8.
27. 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.
2015 ;203:733-739.
28. 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. 2015 Dec 4.
[Epub ahead of print]
29. Okada K, Naito AT, Higo T, Nakagawa A,
Shibamoto M, Sakai T, Hashimoto A, Kuramoto
Y, Sumida T, Nomura S, Ito M, Yamaguchi T,
Oka T, Akazawa H, Lee JK, Morimoto S, Sakata
Y, Shiojima I, Komuro I. Wnt/β-Catenin Signaling Contributes to Skeletal Myopathy in Heart
Failure via Direct Interaction With Forkhead Box
O. Circ Heart Fail. 2015 Jul;8(4):799-808
30. 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, Yanagisawa M. Monitoring β-arrestin recruitment via β-lactamase enzyme
fragment complementation: purification of
peptide E as a low-affinity ligand for mammalianbombesin receptors. PLoS One. 2015 Jun 1;10(6):e0127445.
31. 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 One.
2015 May 28;10(5):e0129394.
32. Sumida T, Naito AT, Nomura S, Nakagawa A,
Higo T, Hashimoto A, Okada K, Sakai T, Ito M,

422

Yamaguchi T, Oka T, Akazawa H, Lee JK,
Minamino T, Offermanns S, Noda T, Botto M,
Kobayashi Y, Morita H, Manabe I, Nagai T,
Shiojima I, Komuro I.
Complement C1qinduced activation of β-catenin signalling causes
hypertensive arterial remodelling. Nat Commun.
2015 Feb 26;6:6241.

Social Cooperation Program424

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 anotherassistant professor, a doctoral student (he earned Ph.D.
degree in Mar. 2015), two guest researchers and two
technical assistants.

Teaching activities
The department staffs gave several lectures forundergraduate and graduate students. For undergraduate students, Drs. Shimizu and Kita delivered
several lectures on biochemistry. Dr. Kita gave
lectures on “Proteome and metabolome” for master’s
students and “Principles and Applications of Mass
Spectrometry” for doctoral students.

Research activities
Our research interests cover following topics.

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425

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 responsible for malaria protein
delivery to the host erythrocyte membrane. Since
parasites develop inside human erythrocytes, clean
separation of parasite 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. 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)
2. 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)
3. 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)
4. 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)
5. Hayakawa EH, Tokumasu F, Usukura J, Matsuoka
H, Tsuboi T, Wellems TE. Imaging of thesubsurface structures of "unroofed" plasmodium
falciparum-infected erythrocytes. Exp. Parasitol.,
153, 174-179 (2015)
6. 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

426

following intraplantar formalin injury. MolecularPain, 11.11 (2015)
7. 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)
8. 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)
9. 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)
10. 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)
11. 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)
12. 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)
13. 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)

14. 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)15. 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)16. 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)17. 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)

427

Verbal Analysis of Pathophysiology
Project Associate Professor
Shinichi TOKUNO, M.D.,Ph.D.

Project Lecturer
Shunji MITSUYOSHI, Ph.D., Kento DOI, M.D.,Ph.D.

Homepage

http://www.univ.tokyo/

Introduction and Organization

accelerate our research our research.

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
Initial faculties were Shinichi TOKUNO, M.D.,
Ph.D., Project Associate Professor and Kento DOI,
M.D.,Ph.D., Project Lecturer when the department
established on September 2015. After that, Shunji
MITSUYOSHI, Ph.D., Project Lecturer joined us.
These three researcher started our program.
FY 2016, two project researchers and three guest
researchers will attend our department, and they will

Teaching activities
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 of engineering.
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

428

2)

3)

4)

5)



1)

2)

3)



Currently, by analyzing the voice for long term
about two weeks, it was possible to substantially
identify the voice of patients and healthy subjects.
In the future, to increase the accuracy, we will
increase the number of cases.
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 of pathophysiology technology to other than the stressdepression
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), neurological disorders (Parkinson's
disease), dementia (including; Alzheimer's
disease), cardiovascular disease (ischemic heartdisease) 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. Validity of a voice-based evaluation method for
effectiveness of behavioural therapy, S Shinohara,
S Mitsuyoshi, M Nakamura, Y Omiya, G
Tsumatori, S Tokuno, Pervasive Computing
Paradigms for Mental Health. Springer International Publishing, 2015. 43-51.
2. Stress Evaluation by Voice: From Prevention toTreatment in Mental Health Care, S Tokuno,
ESMSJ (Econophysics, Sociophysics & otherMultidisciplinary Sciences Journal) 5 (1) 2015;30-35
3. Development of Verbal Analysis Pathophysiology,
S Mitsuyoshi, ESMSJ (Econophysics, Sociophysics & other Multidisciplinary Sciences
Journal) 5 (1) 2015; 11-16
4. The novel technology of stress check for the nurse,
S Tokuno, Nurshing; 35(9): pp67-76 07/2015(Japanese)
5. Case study of medical evacuation before and after
the Fukushima Daiichi nuclear power plant
accident in the great east Japan earthquake.
Okumura T, Tokuno S. Disaster and Military
Medicine, 2015, 1.1: 1
6. Rumor-Related and Exclusive Behavior Coveragein Internet News Reports Following the 2009
H1N1 Influenza Outbreak in Japan. Shigemura J,
Harada N, Tanichi M, Nagamine M, Shimizu K,
Katsuda Y, Tokuno S, Tsumatori G, Yoshino A.
Disaster Med Public Health Prep. ;9(4): pp459-63.
08/2015 doi: 10.1017/dmp.2015.57.
7. Check again! ECG monitor mastering guide, S
Tokuno, Nurshing; 34(11): pp59-69 09/2014(Japanese)429

Functional Regulation of
Adipocytes
Project Associate Professor
Hironori Waki, M.D., Ph.D.

Project Lecturer
Takuya Sugiyama, M.D., Ph.D.

Homepage
Introduction and Organization
The prevalence of obesity and related diseases arerising to epidemic proportions worldwide. The
identification of secreting molecules including leptin
and adiponectin—termed “adipokines”—led to therecognition that adipose tissue functions as an
endocrine organ, in addition to a storage depot forexcess calories. Today, dysregulation of adipokines isrecognized as an important factor in the pathogenesisof insulin resistance. The discovery that thiazolidinediones — insulin-sensitizing anti- diabetics — areagonists for a nuclear hormone receptor peroxisome
proliferator-activated receptor γ (PPARγ) — themaster regulator of adipocyte differentiation — also
led to the recognition that the adipogenic genetranscription network play a critical role in systemic
glucose and lipid metabolism. There are two types ofadipocytes; brown and white. Compared to white
adipocytes, which are specialized in storing excessenergy, brown adipocytes are known to burn excessenergy and produce heat in response to various stimuli
including cold and considered an attractive cellulartarget for the treatment of obesity. Recent evidence
that brown adipocytes exist in adult humans and an
advance in our understanding of a transcription
regulatory network that defines brown adipocytephenotype has boosted intensive research of this area.
Finally, it was shown that obese adipose tissue
contains not only hypertrophic adipocytes but also
inflammatory cells including macrophages. Role ofinteraction of these cells and adipocytes is one of hot
topics in the field.
Our laboratory was established as a social
Cooperation Program in 2011 with a contribution ofNovartis Pharma K.K. The aim of our research is tounderstand functional regulation of adipocytes innormal and in disease state, which is critical forunderstanding the pathogenesis of obesity and relateddiseases. In order to accomplish this goal, we take avariety of experimental approaches including genomewide epigenomic analysis, genetic engineering
techniques, and biochemical methods, to investigate
normal functions and dysfunctions in diseases ofadipocytes and other organs closely related to obesity
and type 2 diabetes.

Teaching activities
We teach a class “obesity” in a lecture series ofsymptomatology for the 4th year medical students. We
also teach a class “obesity, diabetes and dyslipidemia”
in Medical Science Graduate Program, The Universityof Tokyo. We train, on a regular basis, graduate andpost-graduate students in Nutrition and Metabolism,
Internal Medicine, Graduate School of Medicine, The
University of Tokyo.

Research activities
Epigenetic analyses of adipocytes by using nextgeneration sequencer (NGS)430

NGS is one of breakthrough technologies in genome
science. NGS technologies have revolutionized how
we study the epigenome and transcriptional regulationof genes. ChIP, using specific antibodies followed by
NGS (ChIP-seq), allows genome-wide mapping ofbinding sites of transcription factors and genomic
regions of specific chromatin modifications. These
new approaches provide novel insights never before
gained and broaden our understanding of epigenetic
regulation of gene expression. We investigate epigenome and epigenetic regulation of genes in adipocytes
in normal and disease states, particularly focusing on
adipocyte-specific transcription regula¬tory mechanisms and identification of new regulators. We
mapped adipocyte-specific regulatory elements in the
genome by employing Formaldehyde- Assisted
Isolation of Regulatory Elements coupled with highthroughput sequencing (FAIRE-seq) and demonstrated
the critical role of multiple distal enhancers in
adipogenic gene expression. We also conductedcomputational motif analyses of DNA sequence inthose regions and identified the NFI transcription
factors as novel regulators of adipocyte differentiation(PLoS Genet 7(10), 2011 e1002311). We are currently
conducting epigenetic analyses of brown and white
adipocytes, adipocyte progenitors and adipocytes inhealth and disease state and aim to elucidate themolecular mechanisms underlying the transcriptional
regulatory network.
Diabetes research is challenged to reveal the functionof candidate genes implicated by recent genome-scalestudies. Pancreatic beta cell research has hampered byits lack of scalable yet reliable genetic screening
system, and a method for assessing dynamic cell
movements in real-time. We devised novel platformsto (1) prospectively purify native multi-potent
pancreatic progenitors and differentiated cell lineages,(2) recapitulate pancreatic organogenesis in 3D,
permitting efficient genetic manipulations andscreens; as well as (3) integrated genomics strategy toreveal novel regulators essential for islet development(Etv1, Prdm16, Runx1t1 and Bcl11a) (Cecil et al 2014
PLoS Genet), (4) methods for quantitative assessmentof live-cell phenotypes (Pouerstein et al 2015
Diabetes), and (5) genetic complementation analysis.
These powerful strategies will open up a newopportunity for comprehensive understanding of
mechanisms of dysfunctional beta cell in diabetes,
normal development of beta cell; and for engineeringand expanding beta cells in vitro.
Our ultimate goal is to propel our research focusing on
mechanisms of obesity, type 2 diabetes and the metabolic syndrome by using comprehensive epigenomic,
genomic, biochemical and genetic engineering
approaches.

References
1. Waki H, Yamauchi T, Kadowaki T: [Epigenetics
and Life-style diseases]. Clinical calcium. 2016.3;
26(3): 426-432
2. Sugiyama T, Tamaru S, Kagawa Y (Translation);
Goni L, Milagro FI, Cuervo M, Martínez JA:
Single-nucleotide polymorphisms and DNA methylation markers associated with central obesity
and regulation of body weight. Nutrition Reviews
2015.8, 23 (4) p277–300

431

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432

Department of Gerontological Nursing/Wound Caremanagement.
The followings were Master’s themes in 2014;“Development of the assessment method of extravasation in chemotherapy patients using thermographic
patterns”

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. A cross-sectional studyof pelvic floor disorders, the risk factors for development of diabetic foot disorders, and venipuncture 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 2015
• 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 3rd Conference of Nursing
Science and Engineering“Continuous thermographic observation of temperature distribution change at the insertion site
during chemotherapy with peripheral intravenous
catheter”

References
1. Tanabe H, Takahashi T, Murayama R, Yabunaka K,
Oe M, Matsui Y, Arai R, Uchida M, Komiyama C,
Sanada H. Using Ultrasonography for Vessel
Diameter Assessment to Prevent Infiltration. J
Infus Nurs. 2016;39(2):105-11.
2. Murayama R, Uchida M, Oe M, Takahashi T, Oya
M, Komiyama C, Sanada H. Patient risk factors fordeveloping sign- and symptom-related peripheral
intravenous catheter failure: A retrospective study.
Journal of Japanese Society of Wound, Ostomy andContinence Management. 2015;19(4):394-402.
3. Murayama R, Takahashi T, Tanabe H, Yabunaka K,
Oe M, Oya M, Uchida M, Komiyama C, Sanada H.
The relationship between the tip position of an
indwelling venous catheter and the subcutaneousedema. BioScience Trends. 2015; 9(6):414-419.
4. Amemiya A, Noguchi H, Oe M, Ohashi Y,
Takehara K, Ueki K, Kadowaki T, Sanada H, Mori
T. Comparison of Gait Features Between Feet With
Callus or Corns and Normal Feet Using Motion
Sensors in People With Diabetes and People
Without Diabetes. J Diabetes Sci Technol. 2015.
doi:10.1177/1932296815616135
5. Mugita Y, Minematsu T, Huang L, Nakagami G,
Kishi C, Ichikawa Y, Nagase T, Oe M, Noguchi H,
Mori T, Abe M, Sugama J, Sanada H.
Histopathology of Incontinence-Associated Skin

433

6.

7.

8.

9.

Lesions: Inner Tissue Damage Due to Invasion ofProteolytic Enzymes and Bacteria in Macerated
Rat Skin.PLoS One.2015; 10(9):e0138117.
Kaitani T, Nakagami G, Iizaka S, Fukuda T, Oe M,
Igarashi A, Mori T, Takemura Y, Mizokami Y,
Sugama J, Sanada H. Cost-utility analysis of anadvanced pressure ulcer management protocol
followed by trained wound, ostomy, and continence nurses. Wound Repair Regen. 2015. doi: 10.
1111/wrr.12350.
Noguchi H, Oe M, Takehara K, Mori T, Sanada H.
Reliability and validity of an on-site measurement
and visualization system to measure plantar pressure and shear force in footwear for the educationof diabetic patients, J. Jpn WOCM., 2015;19(3):327-335.
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 ofself-monitoring of blood glucose in elderly diabetic
patients. Journal of Nursing Science and Engineering. 2015;2(3):164-173.
Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. The biomarker-based validity of abrief-type diet history questionnaire for estimating
eicosapentaenoic acid and docosahexaenoic acidintakes in pregnant Japanese women. Asia Pac J
Clin Nutr. 2015;24(2):316-22.

Social Cooperation Program(22nd Century Medical and Research Center)435

Department of Ubiquitous Health
Informatics
Associate Professor
Waki Kayo, M.D., M.P.H., Ph.D.

Assistant Professor
Fujiu Katsuhito, 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 then evaluated the relation of patients’ intake
nourishment and urinary sodium to their potassium
ratio. The possibility was suggested that the sodium topotassium ratio might serve as a new index of foodfiber intake. We started development of an automaticfunction that can evaluate whether a patient’s meal is“good” or “not good”—according to guideline
nutritional needs/restrictions of such patients—based
solely on image processing of the meal photoroutinely sent by the patients. Because we also
recognized the advantage of a synthetic sound thatwould act as an advice feedback to call the patient’s
attention to that advice, we investigated use-intentionof such a sound with around 30 diabetics. Given thepositive result, we investigated implementation, andare going to incorporate this feature into the system.
In addition, we supported the research project of a
doctor’s degree candidate—“Intention of using an
ICT-based self-management tool among patients with436

diabetes: A cross sectional study”—from the department of Adult Health/Palliative Care Nursing. We
plan to conduct a further study to apply the use of thesystem in clinical environments.
 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,
and we plan to study the effects of GlucoNote for the
next five years.
 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. It will beavailable to the public, and a clinical trial will be
conducted.
 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.
Evaluation of SMART-D’s effectiveness continues tobe the subject of further study in the coming year.
 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. A
one-month clinical trial for physically unimpaired
people suggested the usefulness of using the support
application for health care. A clinical trial for
diabetics continues.
 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 will be with 100 diabetics.

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.

References(Original article)
1. Waki K, Aizawa K, Kato S, Fujita H, Lee H,
Kobayashi H, Ogawa M, Mouri K, Kadowaki T,
Ohe K. DialBetics With a Multimedia Food
Recording Tool, FoodLog: Smartphone-Based
Self-Management for Type 2 Diabetes. J Diabetes
Sci Technol. 2015 May; 9 (3): 534-40.
2. Kurasawa H, Hayashi K, Fujino A, Takasugi K,
Haga T, Waki K, Noguchi T, Ohe K. MachineLearning-Based Prediction of a Missed Scheduled
Clinical Appointment by Patients With Diabetes. J
Diabetes Sci Technol. 2015 Nov 10. pii: 1932296
815614866.
3. Tan X, Fujiu K, Manabe I, Nishida J, Yamagishi J,
Nagai E, Yanagi Y, Choroidal neovascularization
is inhibited via an intraocular decrease of
inflammatory cells in mice lacking complement
component C3, Sci Rep, 2015, 15702

437

4. Niwa R, Hasumi R, Fujiu K, Ueharra M, Nitta D,
Hatano M, Akazawa H, Watanabe M, Komuro I, A
case of multiple coronary artery-left ventricular
micro fistulas complicated with hepatic arteriovenous fistulae, Int Heart J, 57, 123-126,2016.
5. Makimoto H, Fujiu K, Shimizu K, Lin T, Amiya E,
Asada K, Kojima T, Daimon M, Meyer C,
Komuro I, Impaired heart rate variability inpatients with non-diabetic chronic kidney disease– prominent disruption of vagal control and daily
fluctuation, IJC Metabolic & Endocrine, in press.
6. Hasumi E, Fujiu K, Imamura T, Iwata H, Sawaki
D, Hosoya Y, Ando J, Kojima T, Shimizu Y, Oguri
G, Matsubara T, Hatano M, Akazawa H, Watanabe
M, Ono M, Komuro I, Cardiac Arrest Triggeredby Subepicardial Aneurysm Without Cardiac
Rupture, Circ J, 80, 538-540, 2016
7. Matsubara T, Fujiu K Asada K, Kojima T,
Makimoto H, Yamagata K, Shimizu Y, Hasumi E,
Hatano M, Akazawa H, Komuro I, Direct Left
Atrial Intracardiac Echocardiography Guided
Ablation for Atrial Fibrillation without Employing
Contrast medium, Int J Cardiol, 2016, 733-739
8. Ogata F, Fujiu K, Matsumoto S, Nakayama Y,
Shibata M, Oike , Koushima I, Watabe T, Nagai R,
Manabe I, Excess lymphangiogenesis cooperatively induced by macrophages and CD4+ T
cells drives the pathogenesis of lymphedema, The
Journal of Investigative Dermatology, 136, 706714, 2016
9. Nishio M, Nakahara M, Saeki K, Fujiu K, Iwata H,
Manabe I, You A, Saeki K. Pro- vs anti-stenotic
capacities of type-I vs type-II human induced
pluripotent-derived endothelial cells. World J
Transl Med 2015; in press
10. Yokota J, Fujiu K, Kojima T, Komuro I, PseudoReentry of Atrial Tachycardia after Surgical
Repair of Congenital Heart Disease, J Cardiovasc
Electrophysiol, doi: 10.1111/jce.12932
11. Kato S, Waki K, Nakamura S, Osada S,
Kobayashi H, Fujita H, Kadowaki T, Ohe K.
Validating the use of photos to measure dietaryintake—the method used by DialBetics, asmartphone-based self-management system fordiabetes patients. Diabetology International. DOI:
10.1007/s13340-015-0240-0(Others)
1. 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. 2015;17(3):e77. 3. (Letterto the Editor.)
2. Shibuta T, Waki K, Lee H, Tomizawa N,
Yamamoto-Mitani N, Igarashi A, Kato S, Fujita H,
Yamauchi T, Kadowaki T, Ohe K. Intention ofpatients to use ICT-based diabetes selfmanagement systems: A cross-sectional survey.
Diabetes. 2015; 64 (Suppl 1): A631.

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

440

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
Shigeo Okubo, Ph.D.

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
2014, 243,212 outpatient blood sampling were
performed in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2015, over 5,235,624

serum enzyme tests (such as AST and ALT), and569,280 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, gene analysis tests and urinalysis.
In 2015, 1,221,168 samples were examined for complete blood cell counts, cell surface marker analysis,
prothrombin time, fibrinogen, glucose, and HbA1C
tests, and 249,240 urine samples were examined.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2015, 45,930 ECG, 24,224
pulmonary function tests, 9,961 echocardiography
tests, 17,957 abdominal echography tests, and 13,634
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441

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 fifth and sixth year medical students,
in small groups of 6-7 students for one-week duration.
In this course, students learn clinical and practicalknowledge and techniques on various laboratory tests.
Students from professional schools also study
laboratory medicine under the guidance of members inClinical Laboratory 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. Amano, Y., Ishikawa, R., Sakatani, T., Ichinose, J.,
Sunohara, M., Watanabe, K., Kage, H., Nakajima,J., Nagase, T., Ohishi, N., and Takai, D. Oncogenic TPM3-ALK activation requires dimerization through the coiled-coil structure of TPM3.
Biochem. Biophys. Res. Commun. 457: 457-460,
2015.

2. 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.doi:
10.1016/j.jjcc.2015.10.007, 2015.
3. Chiang, SJ., Daimon, M., Wang, LH., Hung, MJ.,
Chang, NC., Lin, HC. Association between Mitral
Valve Prolapse and Open-Angle Glaucoma. Heart.
101: 609-615, 2015.
4. Daikoku, T., Yatomi, Y., and Yumoto, M.
Statistical learning of music- and language-likesequences and tolerance for spectral shifts.
Neurobiol. Learn. Mem. 118: 8–19, 2015.
5. Fukuda, S., Watanabe, H., Iwakura, K., Daimon,
M., Ito, H., Yoshikawa, J. Multi-center Investigations of the Prevalence of Abdominal Aortic
Aneurysm in Elderly Japanese Patients with
Hypertension: the AAA Japan Study. Circ. J. 79:
524-529, 2015.
6. Ichikawa, M., Nagamatsu, T., Schust, D.J.,
Kawai-Iwasawa, Y., Kawana, K., Yamashita, T.,
Osuga, Y., Aoki, J., Yatomi, Y., and Fujii, T.
Placental autotaxin expression is diminished inwomen with pre-eclampsia. J. Obstet. Gynaecol.
Res. 41: 1406-1411, 2015.
7. Kawata, T., Daimon, M., Miyazaki, S., Ichikawa,R., Maruyama, M., Chiang, SJ., Ito, C., Sato, F.,
Watada, H., Daida, H. Coronary microvascularfunction is independently associated with left
ventricular filling pressure in patients with type 2
diabetes mellitus. Cardiovasc. Diabetol. 14: 98,
2015.
8. Kimura, K., Daimon, M., Morita, H., Kawata, T.,
Nakao, T., Okano, T., Lee, S.L., Takenaka, K.,
Nagai, R., Yatomi, Y., and Komuro, I. Evaluationof right ventricle by speckle tracking andconventional echocardiography in rats with rightventricular heart failure. Int. Heart. J. 56: 349353, 2015.
9. Kimura, K., Morita, K., Daimon, M., Kawata, T.,
Nakao, T., Lee, SL., Hirokawa, M., Ebihara, A.,
Nakajima, T., Ozawa, T., Yonemochi, Y., Aida, I.,
Motoyoshi, Y., Mikata, T., Uchida, I., Komori, T.,
Kitao, R., Nagata, T., Takeda, S., Komaki, H.,
Segawa, K., Takenaka, K., Komuro, I. Prognostic
Impact of Venous Thromboembolism in Patients442with Duchenne Muscular Dystrophy: Prospective
Multicenter 5-Year Cohort Study. Int. J. Cardiol.
191: 178-180, 2015.
10. Kurano, M., Dohi, T., Nojiri, T., Kobayashi, T.,
Hirowatari, Y., Inoue, A., Kano, K., Matsumoto,H., Igarashi,K., Nishikawa, M., Miyauchi, K.,
Daida, H., Ikeda, H. Aoki, J. , and Yatomi, Y.
Blood levels of serotonin are specificallycorrelated with plasma lysophosphatidylserine
among the glycero-lysophospholipids.
BBA Clinical. 4: 92–98, 2015.
11. Kurano, M., Hara, M., Satoh, H., and Tsukamoto,K. Hepatic NPC1L1 Overexpression Ameliorates
Glucose Metabolism in Diabetic Mice Via
Suppression of Gluconeogenesis. Metabolism. 64:
588-596, 2015.
12. Kurano, M., Tsukamoto, K., Hara, M., Ohkawa,R., Ikeda, H., and Yatomi, Y. LDL Receptor and
ApoE are Involved in the Clearance of ApoMassociated Sphingosine 1-phosphate. J. Biol.
Chem. 290: 2477-2488, 2015.
13. Kurano, M., Suzuki, A., Inoue, A., Tokuhara, Y.,
Kano, K., Matsumoto, H., Igarashi, K., Ohkawa,R., Nakamura, K., Dohi, T., Miyauchi, K., Daida,
H., Tsukamoto, K., Ikeda, H., Aoki, J., and Yatomi,
Y. Possible Involvement of Minor Lysophospho
lipids in the Increase in Plasma Lysophosphatidic
Acid in Acute Coronary Syndrome. Arterioscler.
Thromb. Vasc. Biol. 35: 463-470, 2015.
14. Makimoto, H., Fujiu, K., Shimizu, K., Amiya, E.,
Asada, K., Kojima, T., Daimon, M., Meyer, C.,
Komuro, I. Impaired heart rate variability inpatients with non-diabetic chronic kidney disease- prominent disruption of vagal control and daily
fluctuation. IJC Metabolic & Endocrine. 9: 22-27,
2015.
15. Makimoto, H., Fujiu,K., Shimizu, K., Lin, T.,
Amiya, E., Asada, K., Kojima, T., Daimon, M.,
Meyer, C., and, Komuro, I. Impaired heart ratevariability in patients with non-diabetic chronic
kidney disease-prominent disruption of vagal
control and daily fluctuation，Int. J. Cardiol. 9:22-27, 2015.
16. Maruo, T., Seo, Y., Yamada, S., Arita, T., Ishizu,T., Shiga, T., Dohi, K., Toide, H., Furugen, A.,
Inoue, K., Daimon, M., Kawai, H., Tsuruta, H.,
Nishigami, K., Yuda, S., Ozawa, T., Izumi, C.,

Fumikura, Y., Wada, Y., Doi, M., Okada, M.,
Takenaka, K., Aonuma, K. The Speckle Tracking
Imaging for the Assessment of Cardiac Resynchronization Therapy (START) Study. Circ. J.
79: 613-622, 2015.
17. Masuda, A., Jona, M., Satoh, Y., Terashima, M.,
Shimosaka, H., Nannya, Y., Yokota, H., Kurokawa,M., and Yatomi, Y. The criteria to suspect chronic
myeloid leukemia using absolute basophil counts
in peripheral blood. Int. J. Hematol.101: 626-628,
2015.
18. Mikami, S., Tateishi, R., Hagiwara, S., Sato, M.,
Minami, T., Uchino, K., Enooku, K., Sato, T.,
Nakagawa, H., Masuzaki, R., Asaoka, Y., Kondo,
Y., Shiina, S., Ikeda, H., Omata, M., Yoshida, H.,
and Koike, K. Tumor markers are more useful inpatients undergoing surveillance for hepatocellular carcinoma with unreliable results byultrasonography. Hepatol. Res. 45: 415-422,
2015.
19. 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. doi: 10.1111/bjh.13804, 2015.
20. Miyazaki, K., Koike, Y., Kunishima, S., Ishii, R.,
Danbara, M., Horie, R., Yatomi, Y., andHigashihara, M. Immature platelet fraction
measurement is influenced by platelet size and isa useful parameter for discrimination of macrothrombocytopenia. Hematology 20: 587-592,
2015.
21. Murono, K., Kazama, S., Yamaguchi, H., Kawai,K., Ishihara, S., Sunami, E., Kitayama, J., Satoh,Y., Kurihara, M., Yatomi, Y., and Watanabe, T.
Detection of carcinoembryonic antigen mRNA in
peritoneal lavage by the transcription-reverse
transcription concerted method indicates poor
prognosis in patients with stage II and III coloncancer. Surgery 157: 322-330, 2015.
22. Nagai, H., Kuwahira, I., Schwenke, D.O.,
Tsuchimochi, H., Nara, A., Ogura, S., Sonobe, T.,
Inagaki, T., Fujii, Y., Yamaguchi, R., Wingenfeld,
L., Umetani, K., Shimosawa. T,, Yoshida, K.,
Uemura, K., Pearson, J.T., and Shirai, M. Pulmo-

443

nary Macrophages Attenuate Hypoxic Pulmonary
Vasoconstriction via β3AR/iNOS Pathway in Rats
Exposed to Chronic Intermittent Hypoxia. PLoS
One. 10: e0131923, 2015.
23. Nakatani, S., Akaishi, M., Asanuma, T.,
Hashimoto, S., Izumi, C., Iwanaga, S., Kawai, H.,
Daimon, M., Toide, H., Hayashida, H., Yamada, H.
Guidelines from the Japanese Society of
Echocardiography: Guidance for the management
and maintenance of echocardiography equipment.
J. Echocardiogr. 13: 1–5, 2015.
24. Nara, A., Nagai, H., Shintani-Ishida, K., Ogura, S.,
Shimosawa, T., Kuwahira, I., Shirai, M., andYoshida, KI. Pulmonary Arterial Hypertension in
Rats Due to Age-related Arginase Activation inIntermittent Hypoxia. Am. J. Respir. Cell Mol.
Biol. 53: 184-192, 2015.
25. Nishikawa, M., Kurano, M., Ikeda, H., Aoki, J.,
and Yatomi, Y. Lysophosphatidylserine has
Bilateral Effects on Macrophages in the
Pathogenesis of Atherosclerosis. J. Atheroscler.
Thromb. 22: 518-526, 2015.
26. Nomura Y, Kaneko M, Miyata K, Yatomi Y, andYanagi Y. Bevacizumab and Aflibercept Activate
Platelets via FcγRIIa. Invest. Ophthalmol. Vis.
Sci. 56: 8075-8082, 2015.
27. Ohkawa, R., Kurano, M., Mishima, Y., Nojiri, T.,
Tokuhara, Y., Kishimoto, T., Nakamura, K.,
Okubo, S., Hosogaya, S., Ozaki, Y., Yokota, H.,
Igarashi, K., Ikeda, H., Tozuka, M., and Yatomi, Y.
Possible involvement of sphingomyelin in theregulation of the plasma sphingosine 1-phosphatelevel in human subjects. Clin. Biochem. 48:
690-697, 2015.
28. Ohta, S., Nishiyama, T., Sakoda, M., Machioka,
K., Fuke, M., Ichimura, S., Inagaki, F., Shimizu,
A., Hasegawa, K., Kokudo, N., Kaneko, M.,
Yatomi, Y., and Ito, T. Development of carboxymethyl cellulose nonwoven sheet as a novel
hemostatic agent. J. Biosci. Bioeng. 119: 718-723,
2015.
29. Oyama, D., Adachi, Y., Yumoto, M., Hashimoto, I.,
and Uehara, G. Dry phantom for magnetoencephalography -Configuration, calibration, andcontribution. J. Neurosci Methods. 251: 24-36,
2015.

30. Sakamoto, K., Nakata, H., Yumoto, M., Sadato, N.,
and Kakigi, R. Mastication accelerates Go/No-go
decisional processing: An event-related potential
study. Clin Neurophysiol. 126: 2099-2107, 2015.
31. Sato, M., Hikita, H., Hagiwara, S., Sato, M.,
Soroida, Y., Suzuki, A., Gotoh, H., Iwai, T.,
Kojima, S., Matsuura, T., Yotsuyanagi, H., Koike,
K., Yatomi, Y., and Ikeda, H. Potential associations between perihepatic lymph node enlargement and liver fibrosis, hepatocellular injury, or
hepatocarcinogenesis in chronic hepatitis B virus
Infection. Hepatol. Res. 45: 397-404, 2015.
32. Tokuhara, Y., Kurano, M., Shimamoto, S.,
Igarashi, K., Nojiri, T., Kobayashi, T., Masuda, A.,
Ikeda, H., Nagamatsu, T., Fujii, T., Aoki, J., andYatomi, Y. PLoS One.10: e0130074, 2015.
33. Uetake, Y., Ikeda, H., Irie, R., Tejima, K., Matsui,
H., Ogura, S., Wang, H., Mu, S., Hirohama, D.,
Ando, K., Sawamura, T., Yatomi, Y., Fujita, T.,and
Shimosawa, T. High-salt in addition to high-fat
diet may enhance inflammation and fibrosis inliver steatosis induced by oxidative stress anddyslipidemia in mice. Lipids in Health andDisease 14: 6, 2015.
34. Veillon, L., Go, S., Matsuyama, W., Suzuki, A.,
Nagasaki, M., Yatomi, Y., and Inokuchi, J.
Identification of Ganglioside GM3 MolecularSpecies in Human Serum Associated with Risk
Factors of Metabolic Syndrome. PLoS One 10:
e0129645, 2015.
35. Wanaka, K., Asada, R., Miyashita, K., Kaneko, M.,
Endo, H., and Yatomi, Y. Novel HIT antibody
detection method using Sonoclot® coagulation
analyzer. Thromb. Res. 135: 127-129, 2015.
36. Watanabe, K., Amano, Y., Ishikawa, R., Sunohara,
M., Kage, H., Ichinose, J., Sano, A., Nakajima, J.,
Fukayama, M., Yatomi, Y., Nagase, T., Ohishi, N.,
and Takai, D. Histone methylation-mediatedsilencing of miR-139 enhances invasion of nonsmall-cell lung cancer. Cancer Med. 4: 1573-1582,
2015.
Review article:
1. J Daimon, M. Can We Predict or Prevent
Progression of Aortic Stenosis? Circ. J. 79:19081909, 2015.

444

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
Kazuhiro Fukatsu. M.D., Ph.D.
Yushi Uetera, 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
The centralized management of operating rooms(OR) first began at the University of Tokyo Hospitalin July 1955. The office, so called the surgical center,
was located 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.
A total of 8,485, 9,550, 9921, 9,944, 10,394,
10,170, 10,752, 11,235, 11,150 and 10,960 operations
were performed in 2006, 2007, 2008, 2009 2010, 2011,2012, 2013, 2014 and 2015 fiscal year, respectively.
The number of operations in 2015 fiscal year counts
for approximately 1.8 times comparing to that in 2001.
These days more and more patients undergo the445

operation, 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
is a basic training course for a scrub nurse or a

446

circulating 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（2015）
1. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Time-dependent influenceon assessment of contaminated environmental
surfaces in oprating rooms. Am J Infect Control
2015; 951-5.
2. Niwa H, Maeyama Y, Kikuchi S, Kawaguchi H,
Daimon T, Furuya Y, Ito H, Mizuno N, Otsu M,
Yasuhara H, Sasako M. Impacts of cancerassociated stromal cells on growth of humangastric cancer cell lines. Can Cell Microenviron
2015; 2(4): e921.
3. Moriya T, Fukatsu K, Iwaya K, Noguchi M,
Saitoh D, Miyazaki M, Hase K, Yamamoto J. The
influence of dietary restriction on hepatic mononuclear cell numbers and functions in mice. J Surg
Res. 2015 Sep; 198(1):120-6. doi: 10.1016/j.jss.
2015. 05. 061. Epub 2015 Jun 4.

447

Department of Clinical Radiology
Professor (department manager)
Kuni Ohtomo, M.D., Ph.D. (until March, 2016)

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 three of 1.5-Tesla and three 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,448

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.

449

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 8 undergraduate students
from the faculty of pharmaceutical sciences (as ofJanuary 1st, 2016). In addition, project associate
professor (Masashi Honma, Ph.D.) and project
research associate (Shogo Miura, Ph.D.) are involvedin our work.

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450

department. This section also takes statistics ofevery information of drug affairs. Drug management section takes care of supplying and safekeeping of all the in-hospital medicines (2,453
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 1st and 2nd ICU section.
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 2015)
Number of items on in-hospital formulary: 2,453
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
423,079 ps.
(outside :350,816 ps.)(inside :72,263 ps.)out-patient chemotherapy:
12,719 ps.
in-patients :233,325 ps.
injection drugs:
207,742 ps.
IVH:
3,592 ps.
chemotherapy:
10,022 pp.
TDM consultations (annual) :15,990 pp.
Numbers of hospital pharmaceutical cares (annual):
16,895 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 two series of lectures for the undergraduate
students: "Clinical Pharmacy I" (compulsory subject)and "Clinical Pharmacy II" (an optional course). 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 practical451

developments and future visions of the department ofpharmacy are presented in this lecture. In addition tothem, we accept undergraduate and graduate students
from the faculty of pharmaceutical sciences andfaculty of medicine. They are doing various research
activities.
Six year course education system has been launchedin the field of pharmaceutical sciences since 2006. In
this system, the clinical training by pharmacists at thehospital is one of the most important curriculums. In
2015, 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. On the other hand, we
have had an original one-year post-graduate training
course for pharmacists since long time before startingthe 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
2015, 15 pharmacists finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

1. Elucidation of the molecular mechanism which
controls in vivo disposition of lipids / bile acids /uric acid, and establishment of new therapy forlife-style related diseases based on those
integrated understanding.
2. Elucidation of the dynamic regulatory mechanismof bone resorption / bone formation, and establishment of new therapy for bone metabolic disease
based on those integrated understanding.
3. Establishment of the way to quantitative understanding and prediction of pharmacological-effectand side-effect of drugs directed against particularmolecular target. Finally, these outputs would be
feedbacked to early drug development stages.
4. Elucidation of the molecular mechanism related tothe adverse effect of drugs using large-scale“-omics” analysis. Finally, the quantitative information would be applied to develop strategies toprevent / treat the adverse effect.
5. Absolute quantification of factors determining thepharmacokinetic profiles of drugs and its application to clinical pharmacokinetics and pharmacology field.

Research

1. Takada T, Yamanashi Y, Konishi K, Yamamoto T,
Toyoda Y, Masuo Y, Yamamoto H, Suzuki H.
NPC1L1 is a key regulator of intestinal vitamin K
absorption and a modulator of warfarin therapy.
Sci Transl Med. 2015;7:275ra23.
2. Uchino T, Miyazaki Y, Ohkawa T, Yamazaki T,
Yanagihara Y, Yoshimori T, Komatsu M, Suzuki H,
Kagawa Y. Reconstitution of l-asparaginase insiliconized syringes with shaking and headspace
air induces protein aggregation. Chem Pharm
Bull (Tokyo). 2015;63:770-9.
3. Shirota K, Kaneko M, Sasaki M, Minato K,
Fujikata A, Ohta S, Hisaka A, Suzuki H. Analysisof the disposition of a novel p38 MAPK inhibitor,
AKP-001, and its metabolites in rats with a simple
physiologically based pharmacokinetic model.
Drug Metab Dispos. 2015;43:217-26.
4. Satake K, Toyoda Y, H. N. Drugs affecting
epigenetic modifications of abc transporters for
drug resistance. Resistance to Targeted ABC
Transporters in Cancer. 2015:273-97.

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:

Publications

452

5. Ito N, Ito K, Ikebuchi Y, Toyoda Y, Takada T,
Hisaka A, Oka A, Suzuki H. Prediction of drugtransfer into milk considering breast cancer
resistance protein (BCRP)-mediated transport.
Pharm Res. 2015;32:2527-37.
6. Honma M, Ikebuchi Y, Kariya Y, Suzuki H.
Establishment of optimized in vitro assay methods
for evaluating osteocyte functions. J Bone Miner
Metab. 2015;33:73-84.
7. Furukawa J, Inoue K, Maeda J, Yasujima T, Ohta
K, Kanai Y, Takada T, Matsuo H, Yuasa H.
Functional identification of SLC43A3 as anequilibrative nucleobase transporter involved inpurine salvage in mammals. Sci Rep. 2015;5:15057.
8. Chiba T, Matsuo H, Kawamura Y, Nagamori S,
Nishiyama T, Wei L, Nakayama A, Nakamura T,
Sakiyama M, Takada T, Taketani Y, Suma S, Naito
M, Oda T, Kumagai H, Moriyama Y, Ichida K,
Shimizu T, Kanai Y, Shinomiya N. NPT1/
SLC17A1 is a renal urate exporter in humans andits common gain-of-function variant decreases therisk of renal underexcretion gout. Arthritis
Rheumatol. 2015;67:281-7.
9. Ando H, Hisaka A, Suzuki H. A new
physiologically based pharmacokinetic model forthe prediction of gastrointestinal drug absorption:
Translocation model. Drug Metab Dispos. 2015;
43:590-602.
10. Amemiya T, Honma M, Kariya Y, Ghosh S,
Kitano H, Kurachi K, Fujita K, Sasaki Y, Homma
Y, Abernethy D, Kume H, Suzuki H. Elucidationof the molecular mechanisms underlying adverse
reactions associated with a kinase inhibitor using
systems toxicology. npj Systems Biology andApplications. 2015;1:15005.

453

Delivery Unit
Professor
Tomoyuki Fujii

LecturerTakeshi 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 lecturer
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 and out-patientcare for pregnant women including the activities in thedelivery units.

Activities
Total number of delivery cases was 965 in 2015.
Recently, cases of obstetrical emergencies like
abruptio placentae, eclampsia and uterine rupturestransported from neighboring hospitals have been
increasing. Two or three doctors and three midwives
are on duty every night. Our service is an importantpart of Tokyo Metropolitan Service System for
Maternal Welfare and Perinatal Medicine.

References[See Department of Perinatal Medicine.]

454

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Lecturer
Yusuke Shinoda, M.D.

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455

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.

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) Motion analysis of patients with joint disorders in
the lower extremities
2) Motion analysis of motor development in children
3) Early detection, diagnosis, and progression prevention of musculoskeletal disorders in the elderly
4) Rehabilitation approaches for patients with hemophilia
5) Rehabilitation approaches for patients with spina
bifida6) Treatment and rehabilitation for patients withcongenital limb deficiencies
7) Disabilities and handicaps in patients with skeletal
dysplasias
8) Analysis of musculo-skeletal involvement incongenital insensitivity to pain

References
1. Goto M, Takedani H, Nitta O, Kawama K: Joint
function and arthropathy severity in patients withhemophilia. J Jpn Phys Ther Assoc 18: 15-22,
2015
2. Inokuchi H, Tojima M, Mano H, Ishikawa Y,
Ogata N, Haga N: Neck range of motion measurements using a new three-dimensional motion
analysis system: validity and repeatability. Eur
Spine J 24(12): 2807-2815, 2015
3. Kaneoka A, Krisciunas GP, Walsh K, Raade AS,
Langmore SE: A comparison of 2 methods ofendoscopic laryngeal sensory testing: A preliminary study. Ann Otol Rhinol Laryngol 124(3):187-193, 2015
4. Kaneoka A, Pisegna JM, Miloro KV, Lo M, Saito
H, Riquelme LF, LaValley MP, Langmore SE:
Prevention of healthcare-associated pneumonia
with oral care in individuals without mechanicalventilation: A systematic review and metaanalysis of randomized controlled trials. InfectControl Hosp Epidemiol, 36(8): 899-906, 2015
5. Nagata E, Haga N, Fujisawa Y, Fukami M,
Nishimura G, Ogata T: Femoral-tibial-digital
malformations in a boy with the Japanese founder
triplication of BHLHA9. Am J Med Genet Part A
167A(12): 3226-3228, 2015
6. Haga N, Kubota M, Miwa Z: Hereditary sensory
and autonomic neuropathy types IV and V in
Japan. Pediatr Int 57: 30-36, 2015
7. Nakahara Y, Suzuki R, Katagiri T, Toguchida J,
Haga N: Phenotypic differences of patients withfibrodysplasia ossificans progressiva due top.Arg258Ser variants of ACVR1. Human Genome
Variation 2; 15055, 2015

456

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, twonurses, 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. 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.

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2. 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]
3. 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.
4. Fukatsu K. Impact of the feeding route on gut
mucosal immunity. Curr Opin Clin Nutr Metab
Care. 2014 Mar;17(2):164-70
5. 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.
6. 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]
7. 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
8. 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.
9. 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.

10. Fukatsu K. The long road to optimizing theparenteral provision of nutrients. JPEN J Parenter
Enteral Nutr. 2012 Mar;36(2):157-8.
11. 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.
12. 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.
13. Fukatsu K. Friend or foe? Linkage between
hormonal response and innate immunity. J Surg
Res. 2012 Jan;172(1):83-4.
14. 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.

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Division of Diagnostic Pathology
Professor (Director)
Masashi Fukayama, M.D., Ph.D.*

Associate Professor (Deputy Director)
Junji Shibahara, M.D., Ph.D.*
Takeshi Sasaki, M.D., Ph.D. (Chief, Telepathology & Remote Diagnosis Promotion Center)

Associate Professor
Tetsuo Ushiku, M.D., Ph.D.*

Lecturer
Teppei Morikawa, M.D., Ph.D.,
Masako Ikemura, M.D., Ph.D. * (Office for “Promotion of CPC Education and General
Integrative Medicine”)

Lecturer (Hospital)
Aya Shinozaki-Ushiku, M.D., Ph.D.

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.,

Ryu Miyagawa, Ph.D.* (Research, Investigation of Health Hazard by Radiation)
Shogo Tajima, M.D. *Mariko Tanaka, M.D., Ph.D. *Clinical Fellow
Sayaka Funata, 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 also started
Outpatient Clinic of Pathology, and Dr. Sasaki
explained the detail of cancer pathology to the patientswith breast cancer.
To promote the application of development ofgenomic medicine to clinical practice, we set up
Center for Genome Pathology Standardization(Tailor-made Medical Treatment Program, funded by
Ministry of Education, Culture, Sports, Science, andTechnology) (http://genome-project.jp/). The missionof the Center is to investigate basic technologies fortissue banking, and to hold seminars for doctors andtechnicians (Drs. Sasaski, Morikawa, Kunita).

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Clinical activities (diagnostic
pathology and autopsy)
The annual statistics of the pathologic practice in 2015
fiscal year consisted of 16,739 cases of histologicalexamination (23,378 specimens), 17,959 cases ofcytology (24,034 specimens), 892 of frozen histology,
468 of intra-operative cytology, 45 cases of autopsy(16.4% of the autopsy rate), and 1 autopsy case fromother hospitals.
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. Shibahara, 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 (Dr. Ushiku). Biopsy conferences are also heldin the cases of kidney (Drs. Shintani, Hayashi), andskin (Dr. 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. Six 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
six junior residents (total 16 months) in 2014 for theirsecond year program of the internship.

Research activities
Dr. Sasaki is in charge of the research to evaluate
feasibility of telepathology for daily practice ofdiagnostic pathology.
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.9, 10, 27 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 with projects developing PET and in vivo
imaging of cancers with Departments of Upper GI
tract Surgery 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.
21 in Department of Pathology and Diagnostic
Pathology).

References (Case Reports Only)
See the corresponding section of Department of
Pathology and Diagnostic Pathology(1) Anzai H, Kazama S, Kiyomatsu T, Nishikawa T,
Tanaka T, Tanaka J, Hata K, Kawai K, Yamaguchi
H, Nozawa H, Kanazawa T, Ushiku T, Ishihara S,
Sunami E, Fukayama M, Watanabe T. Alphafetoprotein-producing early rectal carcinoma: arare case report and review. World J Surg Oncol.
2015 May, 13: 180.
(2) Fukada I, Araki K, Minatsuki S, Fujino T, Hatano

460

M, Numakura S, Abe H, Ushiku T, Iwase T, Ito Y.
Imatinib alleviated pulmonary hypertension
caused by pulmonary tumor thrombotic microangiopathy in a patient with metastatic breast
cancer. Clin Breast Cancer. 2015, Apr, 15(2):e167-70(3) Higo T, Miyagaki T, Nakamura F, Shinohara A,
Asano H, Abe H, Senda N, Yoshizaki A,
Fukayama M, Kurokawa M. Paraneoplastic
pemphigus occurring after bendamustine andrituximab therapy for relapsed follicular lymphoma. Ann Hematol. 2015 Apr, 94(4): 683-5.
(4) Higo T, Kobayashi T, Yamazaki S, Ando S, Gonoi
W, Ishida M, Okuma H, Nakamura F, Ushiku T,
Ohtomo K, Fukayama M, Kurokawa M. Cerebral
embolism through hematogenous disseminationof pulmonary mucormycosis complicating
relapsed leukemia. Int J Clin Exp Pathol. 2015
Oct, 8(10): 13639-42.
(5) Ikemura M, Kunita A, Miwa Y, Jimbo K, Mori K,
Seto Y, Fukayama M. Gut wall replacing type ofgastrointestinal stromal tumor presenting as aperforation of the ileal diverticulum. Pathol. Res.
Prac. 2015 Nov, 211(11): 892-5.
(6) Ishii T, Goto Y, Matsuzaki H, Ohishi N,
Sakamoto Y, Saito R, Matsusaka K, Shibahara J,
Nagase T Pulmonary metastasis of combined
hepatocellular and cholangiocarcinoma: A uniqueradiographic presentation with air-space consolidation masquerading as pneumonia and primary
pulmonary adenocarcinoma Intern Med，2015,
54(11): 1389-1392.
(7) Makino K, Kume H, Morikawa T, Niimi A,
Fujimura T, Nakagawa T, Fukuhara H, Homma Y.
Adenocarcinoma at anastomotic site ofureterosigmoidostomy potentially of urothelial
origin spreading to the upper urinary tract. Case
Rep Urol. 2015 Nov, 2015, 564082(8) Makise N, Morikawa T, Kawai T, Nakagawa T,
Kume H, Homma Y, Fukayama M. Squamous
differentiation and prognosis in upper urinary
tract urothelial carcinoma. Int J Clin Exp
Pathol. 2015 June, 8(6): 7203-9.
(9) Makise N, Morikawa T, Takeshima Y, Fujimura T,
Homma Y, Fukayama M. Urinary bladderurothelial carcinoma with concurrent plasmacytoid and micropapillary differentiations: A

report of two cases with an emphasis on serum
carbohydrate antigen 19-9. Pathol Int. 2015 Sep,
65(9): 495-500.
(10) Matsumiya R, Hosono O, Yoshikawa N, Uehara
M, Kobayashi H, Oda A, Matsubara E, Tanada S,
Shintani Y, Nagayama K, Nakajima J, Tanaka H
Elevated serum IgG4 complicated by pericardial
involvement with a patchy 18F-FDG uptake in
PET/CT: Atypical presentation of IgG4-relateddisease Intern Med. 2015, 54(18), 2337-41.
(11) Miyama Y, Morikawa T, Nakagawa T, Homma Y,
Fukayama M. Lipid cell and micropapillary
variants of urothelial carcinoma of the ureter.
Case Rep Oncol. 2015 Nov, 8(3): 515-9.
(12) Nakayama T, Takahashi Y, Morita S, Dejima H,
Matsutani N, Kawamura M. A case of pulmonary
granuloma associated with mycobacterium avium
complex infection arising from the surgicalmargin after segmentectomy. Int Canc Conf J.
2015 Aug 05(13) Nozawa H, Ishihara S, Morikawa T, Tanaka J,
Yasuda K, Ohtani K, Nishikawa T, Tanaka T,
Kiyomatsu T, Kawai K, Hata K, Kazama S,
Yamaguchi H, Sunami E, KitayamaJ, Fukayama
M, Watanabe T. Metachronous tubulovillous andtubular adenomas of the anal canal. Diagn Pathol.
2015 Aug, 10: 139.
(14) Oichi T, Chikuda H, Morikawa T, Mori H,
Kitamura D, Higuchi J, Taniguchi Y,
Matsubayashi Y, Oshima Y, Tanaka S. Concurrent
spinal schwannoma and meningioma mimicking asingle cervical dumbbell-shaped tumor: casereporJ Neurosurg Spine. 2015 Dec, 23(6), 784-7.
(15) Saito H, Hamasaki Y, Tojo A, Shintani Y, Shimizu
A, Nangaku M. Phospholipase A2 receptor
positive membranous nephropathy long after
living donor kidney transplantation between
identical twins. Nephrology 2015 Jul, 20(Suppl
S2): 101-4.
(16) Shinya Y, Miyawaki S, Nakatomi H, Okano A,
Imai H, Shin M, Sato K, Tsuchida T, Hayashi T,
Terao Y, Numakura S, Morikawa T, Shibahara J,
Kikuta S, Kondo K, Tatsuno K, Mori H,
Kunimatsu A, Tsuji S, Saito N. Recurrent cerebral
aneurysm formation and rupture within a shortperiod due to invasive aspergillosis of the nasal
sinus; pathological analysis of the catastrophic

461

clinical course. Int J Clin Exp Pathol. 2015 Oct,8(10): 13510-22(17) Urabe M, Yamagata Y, Aikou S, Mori K,
Yamashita H, Nomura S, Shibahara J, Fukayama
M, Seto Y. Solitary fibrous tumor of the greater
omentum, mimicking gastrointestinal stromal
tumor of the small intestine: a case report. Int
Surg. 2015 May, 100(5): 836-40(18) Yagi H, Amiya E, Shintani Y, Nitta D, Numakura
S, Hosoya Y, Watanabe M, Fukayama M, Komuro
I. A representative case of hereditary transthyretin
amyloidosis complicated by intramyocardial
hemorrhage. Amyloid. 2015 Mar, 22(1):70-2.
(19) Yagi H, Hatano M, Takeda N, Harada S, Suzuki Y,
Taniguchi Y, Shintani Y, Morita H, Kanamori N,
Aoyama T, Watanabe M, Manabe I, Akazawa H,
Kinugawa K, Komuro I. Congenital contracturalarachnodactyly without FBN1 or FBN2 genemutations complicated by dilated cardiomyopathy.
Intern Med. 2015, 54(10): 1237-41.

462

Department of Corneal
Transplantation
Associate Professor
Satoru Yamagami, 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 Satoru Yamagami).

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 120 corneal
transplantations were performed in 2015. In addition
to the full-thickness corneal transplantation, 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.

463

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 expression andfunction of novel mucin, drug delivery system with
soft contact lenses, corneal graft rejection andstatistical analysis of long term results in corneal
transplantation.

References
1. Akiyama-Fukuda R, Usui T, Yamagami S:
Diagnosis of dry eye by tear meniscus measurements using anteriro segment swept source opticalcoherence tomography. Cornea 11:S115-20, 2015
2. Arita R, Mori N, Shirakawa R, Asai K, Imanaka T,
Fukano Y, Nakamura M, Amano S:Meibum Colorand Free Fatty Acid Composition in Patients With
MeibomianGland
Dysfunction.
InvestOphthalmol Vis Sci 56:4403-4412,2015
3. Arita R, Morishige N, Shirakawa R, Sato Y,
Amano S:Effects of Eyelid Warming Devices on
Tear Film Parameters in Normal Subjects andPatients withMeibomian Gland Dysfunction. Ocul
Surf. 13:321-330,2015
4. Arita R, Morishige N, Koh S, Shirakawa R,
Kawashima M, Sakimoto T, Suzuki T, Tsubota K:
Increased Tear Fluid Production as a Compensatory Response to Meibomian Gland Loss: A
Multicenter Cross-sectional Study.Ophthalmology
122:925-933,2015
5. Miyata K, Honbo M, Nejima R, Minami K,
Amano S: Long-term Effect of surface lightscattering in a foldable acrylic intraocular lens. J
Cataract Refract Surg 41: 1205-1209, 2015.
6. Toyono T, Usui T, Yokoo S, Taketani Y,
Nakagawa S, Kuroda M, Yamagami S, Amano S:
Angiopoietin-loke 7 is an anti-angiogenic protein
required to prevent vascularization of the cornea.

PLos One 10, e0116838, 2015
7. Yoshida J, Heflin T, Zambrano A, Pan Q, Meng H,
Wang J, Stark WJ, Daoud YJ: Gamma-IrradiatedSterile Cornea for Use in Corneal Transplants in a
Rabbit Model. Middle East Afr J Ophthalmol.
22:346-51. 2015
8. Yoshida J, Wicks RT, Zambrano AI, Tyler BM,
Javaherian K, Grossman R, Daoud YJ, Gehlbach
P, Brem H, Stark WJ: Inhibition of Corneal
Neovascularization by Subconjunctival Injectionof Fc-Endostatin, a Novel Inhibitor of Angiogenesis. J Ophthalmol. 137136, 2015

464

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)
Mizuki Ogura, 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 870 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 2015, 14 patients (including 2 children) received
autologous HSCT and 20 patients (including 8
children) allogeneic HSCT. We cooperate with themembers of Department of Hematology and Oncology,
Hematology/Oncology group in the Department ofPediatrics, and Department of Transfusion Medicine.

Allogeneic hematopoietic stem cell transplantation:
Bone marrow cells are operatively harvested andinfused without preservation. For peripheral blood
stem cell transplantation, leukapheresis is performed
with the use of an automated continuous flow blood
cell separator, and harvested cells are preserved at-196°C in cooperation with Department of Transfusion Medicine. Recently, transplantation after preconditioning of reduced intensity (RIST for reducedintensity HSCT or NST for non- myeloablative
HSCT) is commonly performed for the elderly andpatients with organ dysfunction. The development of
this strategy is expanding the eligibility of transplant
recipients. Allogeneic HSCT for the elderly is
performed under the admission of ethical committeeof the Faculty of Medicine.
High-dose chemotherapy with or without autologous stem cell support: High-dose chemotherapy isadministered according to the malignant disease. For
the autologous stem cell support, peripheral blood
stem cell is usually selected as a source of stem cells.
Similar procedures used in the allogeneic stem cell
harvest are performed for leukapheresis and preservation of autologous stem cell.

465

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. Yasudo H, Ando T, Hiwatari M, Oka A. Suplatast
tosilate for treating cutaneous mastocytosis.
Pediatr Dermatol. 2015; 32:e118-9.
2. Hoshino A, Nomura K, Hamashima T, Isobe T,
Seki M, Hiwatari M, Yoshida K, Shiraishi Y,
Chiba K, Tanaka H, Miyano S, Ogawa S, Takita J,
Kanegane H. Aggressive transformation ofanaplastic large cell lymphoma with increased
number of ALK-translocated chromosomes.Int J
Hematol. 2015; 101:198-202.

3. Arai Y, Aoki K, Takeda J, Kondo T, Eto T, Ota S,
Hashimoto H, Fukuda T, Ozawa Y, Kanda Y, KatoC, Kurokawa M, Iwato K, Onizuka M, Ichinohe T,
Atsuta Y, Takami A; AML and MDS Working
Group of Japan Society for Hematopoietic Cell
Transplantation. J Hematol Oncol. 2015; 8:102.
4. Nakane T, Fukuda T, Kanda J, Taniguchi S, Eto T,
Ohashi K, Nakamae H, Kurokawa M, Mori T,
Morishima Y, Nagamura-Inoue T, Sakamaki H,
Atsuta Y, Murata M. Age influences post-graftversus-host disease non-relapse mortality in adults
with acute graft-versus-host disease of varying
severity following allogeneic hematopoietic celltransplant. Leuk Lymphoma. 2015; 56:2392-7.
5. Uni M, Shinohara A, Nukina A, Nakamura F,
Nannya Y, Mizoguchi M, Okazaki M, Tatsuno K,
Moriya K, Kurokawa M. Successful managementof Rothia aeria pneumonia during the peritransplant period: first reported case in allogeneic
hematopoietic stem cell transplant. Leuk
Lymphoma. 2015; 56:248-50.

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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.

467

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

8131

8796

9822

10262

10556

10963

11376

11840

11740

11874

Colonoscopy

4327

4360

4679

4996

5152

5208

5688

6000

6043

6394

Bronchoscopy

201

201

165

226

255

197

196

169

218

310

438

484

402

518

551

630

698

763

766

882

Enteroscopy

-

-

133

181

311

282

282

375

396

228

Laryngoscopy

127

91

63

75

70

108

83

128

102

105

Colposcopy

58

117

256

307

361

378

365

404

327

295

Total

13282

14043

15520

16566

17256

17764

18688

19679

19592

20088

EGD

EUS

*

**

*Esophagogastroduodenoscopy, **Endoscopic ultrasonography

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

(4)

References(1) Ono S, Fujishiro M, Yoshida N, Doyama H,
Kamoshida T, Hirai S, Kishihara T, Yamamoto Y,
Sakae H, Imagawa A, Hirano M, Koike K.
Thienopyridine derivatives as risk factors forbleeding following high risk endoscopic
treatments: Safe Treatment on Antiplatelets(STRAP) study. Endoscopy. 2015 Jul;47(7):632-7.
(2) Okushin K, Takahashi Y, Yamamichi N,
Shimamoto T, Enooku K, Fujinaga H, Tsutsumi T,
Shintani Y, Sakaguchi Y, Ono S, Kodashima S,
Fujishiro M, Moriya K, Yotsuyanagi H,
Mitsushima T, Koike K. Helicobacter pylori
infection is not associated with fatty liver disease
including non-alcoholic fatty liver disease: alarge-scale cross-sectional study in Japan. BMC
Gastroenterol. 2015 Dec;15(1):247.
(3) Yamamichi N, Shimamoto T, Takahashi Y,
Sakaguchi Y, Kakimoto H, Matsuda R, Kataoka
Y, Saito I, Tsuji Y, Yakabi S, Takeuchi C,
Minatsuki C, Niimi K, Asada-Hirayama I,
Nakayama C, Ono S, Kodashima S, Yamaguchi
D, Fujishiro M, Yamaji Y, Wada R, Mitsushima
T, Koike K. Trend and risk factors ofdiverticulosis in Japan: age, gender, and lifestyle/metabolic-related factors may cooperatively

(5)

(6)

(7)

affect on the colorectal diverticula formation.
PLoS One. 2015 Apr 10;10(4):e0123688.
Ono S, Fujishiro M, Ikeda Y, Komuro I, Koike K.
Recent clinical management of anti-thrombotic
agents for gastrointestinal endoscopy afterrevision of guideline in Japan. Dig Endosc. 2015
Sep;27(6):649-56.
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 One.
2015 May 28;10(5):e0129394.
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, Yanagisawa M.
Monitoring β-arrestin recruitment via β-lactamase
enzyme fragment complementation: purificationof peptide E as a low-affinity ligand for
mammalian bombesin receptors. PLoS One. 2015
Jun 1;10(6):e0127445.
Fujishiro M, Higuchi K, Kato M, Kinoshita Y,
Iwakiri R, Watanabe T, Takeuchi T, Sugisaki N,
Okada Y, Ogawa H, Arakawa T, Fujimoto K;
PLANETARIUM Study Group. Long-term
efficacy and safety of rabeprazole in patientstaking low-dose aspirin with a history of peptic
ulcers: a phase 2/3, randomized, parallel-group,
multicenter, extension clinical trial. J Clin
Biochem Nutr. 2015 May;56(3):228-39.

468(8) 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 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.
2015 Jul 30. [Epub ahead of print](9) 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.
(10) 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.
(11) Mori G, Nakajima T, Asada K, Shimazu T,
Yamamichi N, Maekita T, Yokoi C, Fujishiro M,
Gotoda T, Ichinose M, Ushijima T, Oda I.
Incidence of and risk factors for metachronous
gastric cancer after endoscopic resection andsuccessful Helicobacter pylori eradication: resultsof a large-scale, multicenter cohort study in Japan.
Gastric Cancer. 2015 Sep 29. [Epub ahead ofprint](12) 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.
(13) 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.](14) 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(15) 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, 2008, Esophagus 2015;12:130–
157(16) 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.
(17) 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. 2015
Oct 20. [Epub ahead of print](18) 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.
(19) 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.
(20) Fujishiro M, Iguchi M, Kakushima N, Kato M,
Sakata Y, Hoteya S, Kataoka M, Shimaoka S,

469

Yahagi N, Fujimoto K. Guidelines for endoscopic
managements of non-variceal upper gastrointestinal bleeding. Dig Endosc. 2016 Feb 22.
doi: 10.1111/den.12639. [Epub ahead of print](21) 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 Mar 12. [Epubahead of print](22) Sakaguchi Y, Tsuji Y, Yamamichi N, Fujishiro M,
Koike K. Successful closure of a large perforation
during colorectal endoscopic submucosal dissection by application of polyglycolic acid sheets
and fibrin glue. Gastrointest Endosc. 2016 Mar 14.
pii: S0016-5107(16)01048-8. doi: 10.1016/j.gie.
2016.03.787.
(23) 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.
(24) Watanabe Y, Yamaji Y, Kobayashi Y, Yoshida S,
Sugimoto T, Yamada A, Watabe H, Hirata Y,
Koike K. Association between colorectal polyps
and hypertension treatment. J Dig Dis. 2015 Nov;
16(11):649-55. doi: 10.1111/1751-2980.12289(25) Yamada A, Niikura R, Yoshida S, Hirata Y,
Koike K. Endoscopic management of colonic
diverticular bleeding. Dig Endosc. 2015 Nov;
27(7):720-5. doi: 10.1111/den.12534. Epub 2015
Sep 8. Review(26) Yamada A, Niikura R, Kobayashi Y, Suzuki H,
Yoshida S, Watabe H, Yamaji Y, Hirata Y, Koike
K. Risk factors for small bowel angioectasia: The
impact of visceral fat accumulation. World J
Gastroenterol. 2015 Jun 21;21(23):7242-7. doi:
10.3748/wjg.v21.i23.7242(27) Sugimoto T, Yamaji Y, Sakitani K, Isomura Y,
Yoshida S, Yamada A, Hirata Y, Ogura K,
Okamoto M, Koike K. Neutrophil infiltration andthe distribution of intestinal metaplasia isassociated with metachronous gastric cancer
following endoscopic submucosal dissection. Can
J Gastroenterol Hepatol. 2015 Aug-Sep; 29(6):321-5. Epub 2015 Jun 12.

(28) Shichijo S, Hirata Y, Sakitani K, Yamamoto S,
Serizawa T, Niikura R, Watabe H, Yoshida S,
Yamada A, Yamaji Y, Ushiku T, Fukayama M,
Koike K. Distribution of intestinal metaplasia as apredictor of gastric cancer development. J
Gastroenterol Hepatol. 2015 Aug;30(8):1260-4.
doi: 10.1111/jgh.12946(29) Matsuzawa T, Ishida H, Yoshida S, Isayama H,
Kuwai T, Maetani I, Shimada M, Yamada T,
Saito S, Tomita M, Koizumi K, Hirata N, Sasaki
T, Enomoto T, Saida Y. A Japanese prospective
multicenter study of self-expandable metal stentplacement for malignant colorectal obstruction:short-term safety and efficacy within 7 days ofstent procedure in 513 cases. Gastrointest Endosc.
2015 Oct; 82(4):697-707.e1. doi: 10.1016/j.gie.
2015.03.1978. Epub 2015 May 12.
(30) 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. 2015 Dec 18.
[Epub ahead of print]

470

Department of Hemodialysis andApheresis
Professor
Masaomi Nangaku, M.D.,Ph.D.

Associate Professor
Eisei Noiri, M.D.,Ph.D.

Lecturer
Akihiko Matsumoto, M.D., Ph.D.

Introduction and Organization
Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for
Hemodialysis in 2000 at the University Hospital. The
Center for Hemodialysis was further renovated andstarted operations in Fall of 2006. This new Center for
Hemodialysis is equipped with one pressure control
unit in addition to 12 hemodialysis machines under astate-of-the-art hemodialysis control system. Ourconcept of a hemodialysis controlling system is a hub
to transfer all digital and analog data from patients andto monitor machines, including blood purification
machines, to the host computer in our hospital,
centralizing all data and administering medical coding
and billing robustly. Blood purification machines in
the ICU are also connectable to this system, which
was developed collaboratively with Nihon Kohden
Corp. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.

Clinical activities
1.
2.

Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
Regular hemodialysis therapy for hospitalized

3.
4.

5.
6.
7.
8.
9.

ESRD patients. Please note that our center does
not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasma exchange for neurodegenerative diseases,
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.

Teaching activities
1.

2.
3.
4.
5.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acutekidney injury and acute renal failure.
Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course to
second year residents on request.
Our state-of-the-art blood purification protocols

471

6.

are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. English and Chinese version of“Apheresis Pocket Manual” is available for
global experts of Apheresis therapy.
Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.

Research activities
1.
2.
3.
4.
5.
6.
7.
8.
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. 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. Available online 31 December(2015)
2. 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 factor-binding
protein-1. Nephrology (Carlton). Oct 19 (2015)
3. 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)
4. 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)
5. 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)
6. 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)
7. 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)
8. Imamura T, Kinugawa K, Doi K, Hatano M, Fujino
T, Kinoshita O, Nawata K, Noiri E, Kyo S, Ono M.
Plasma neutrophil gelatinase-associated lipocalin
and worsening renal function during everolimus
therapy after heart transplantation. Int Heart J.
56, 73-79 (2015)
9. 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)
10. 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)
11. Fujita D, Takahashi M, Doi K, Abe M, Tazaki J,
Kiyosue A, Myojo M, Ando J, Fujita H, Noiri E,
Sugaya T, Hirata Y, Komuro I. Response of urinary

472

liver-type fatty acid-binding protein to contrast
media administration has a potential to predict
one-year renal outcome in patients with ischemic
heart disease. Heart Vessels. 30, 296-303 (2015)

473

Clinical Research Support Center
Professor
Tsutomu Yamazaki, M.D., Ph.D.

Associate Professor
Chie Sakanaka, M.D., Ph.D.

Project Lecturer
Tetsuya Ueda, M.D., Ph.D.

Assistant Professor
Shuichi Kawarasaki, M.D., Ph.D.
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.
Keiko Ueda, 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 supports
not only industry-sponsored clinical trials, but also
investigator-initiated, clinical researches. Institutionalguidelines, forms and templates for investigatorinitiated clinical research were prepared in 2002
according to the principle of the ICH-GCP and madeavailable to the public on our website, aiming at thecontribution to the improvement of clinical research inJapan. The support was provided to the investigators
mainly in terms of protocol development andprotection of human research participants.
Given the increasing volume of clinical research
conducted in our hospital, demand mounted for the

structural framework to support investigator-initiated,
especially multicenter, researches has been mounting
rapidly.
It is an important mission of university hospitals todevelop novel therapeutics by clinical trials. Highethical and scientific standards as well as highreliability are now being required for the implementation of clinical research, including investigatorinitiated translational research or trials for the
off-label use of approved drugs.
In response to the above mentioned 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

474

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 newdivisions such as Operation Division, Biostatistics
Division, Data Management Division, Monitoring
Division and Safety Information Division. Activitiesof these Divisions include protocol formulation,
project management, study design/statistical analysis,
data management, monitoring and assistance withsafety information reporting, respectively.
The Center was selected in 2011 as an MHLWfunded Center of Excellence for early stage andexploratory clinical trials of drugs for psychiatric andneurological diseases, enabling the Center to reinforce
the staff and to be equipped with phase 1 facilities.
Thus, the third unit, i.e., Phase 1 unit (P1 unit) wasestablished in May 2012 with 13 beds exclusively
used for clinical trials. It is featured as an integrated
Phase 1 unit with expertise from both exploratory
researchers and clinical investigators in the relevant
fields.
Clinical Research Support Center can support bothclinical trials and clinical researches by providing
seamless support to research in any phase ofdevelopment can
In response to the research misconduct events inseveral university hospitals including our hospital andintegration of “Ethical Guidelines for Epidemiologic
Studies” and “Ethical Guidelines for Clinical Studies”
under “Ethical Guidelines for Medical and HealthResearch Involving Human Subjects” in 2015, thecenter examined the realignment of clinical researchfunctions aimed at strengthening governance functionsof the University of Tokyo Hospital, revised rules andprocedures in order to implement research ethics
system under new guidelines.

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 January 2015, we established Clinical Research
Governance division and later Office of Clinical

As of March 2016, the Center staff includes
professor, associate professor, project lecturer,

In April 2016, we transferred ethical review process of
specific clinical trials (involving invasion andintervention) to the Faculty of Medicine IRB to ensuretransparency of clinical research.
In addition, IRB for evaluating industry-sponsoredand investigator-initiated clinical trials was newly
established in the hospital. With respect to thesecretarial duties, center will continue to takeresponsibilities.
Moreover, a specific clinical research steeringcommittee was established under the hospital director
and external audit committee to seek external
evaluation.
Moreover, we integrated clinical research management system by strengthening conflicts of interest
management, created educational environment forclinical research personnel, formed collaboration withthe 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 Clinical Research Support Center undertook
responsibilities for secretarial and administrative
duties.
Furthermore, we established 3 new divisions outside
the unit, education and training division, clinical trial
implementation division and university hospital
network promotion division.

475

3 assistant professors, 3 project assistant professor, 11
pharmacists, 20 nurses (full-time equivalent, FTE), 11
laboratory technicians (FTE), 3 clinical psychologists,
project senior specialist, 10 medical technical staffs, 2
project academic support specialists, 3 project
academic support staffs and 7 clerical staff members.

Clinical Research Support
Activities
The duties of the Center range from serving as thesecretariat for the IRB to supporting theimplementation 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 wasshifted 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, with the expansion of the scope of IRB

review, 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 2015 included, as for industrysponsored trials for marketing approval, 32 newprotocol applications, 81 study extension applications,354 protocol amendment applications, 831 SAE/safety
information reports, 34 study closure or termination
reports. As for investigator-initiated clinical research,
the Center processed 43 new protocols (including 20
applications for compassionate use of unapproved
drugs) 213 applications for protocol amendment, 233
SAE/safety information reports, and 82 reports forstudy closure or termination.
Protocol presentations of industry-sponsored trials
prior to application to IRB totaled 16 applications.
Preliminary
consultation
andguidanceforinvestigator-initiated research application 40 and 43
applications, respectively.
Clinical Research Support Center managed
drug/device inventory for 90 clinical trials (drug 87,
devices 3) for regulatory approval, 4 post marketing
research, 29 investigator-initiated clinical research,and 11 cases of compassionate use, 2 tissueengineered medical products in fiscal 2015. The
number of prescriptions processed was 1040 for
research for approval and post marketing researchcombined, 946 for investigator-initiated clinicalresearch. We are currently managing trial drugs
centrally for 6 multicenter research. We masked
investigational drugs for 4 double-blind placebo
controlled research. We are also in charge of the
primary review of clinical research safety informationand of maintaining the database on clinical research ingeneral.
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 investigator-

476

initiated research have been employed as needed. The
number of research participants that CRCs interactedwith was 5573 in 2015. The number of monitoring
visits was 669 in 2015.
As part of patient awareness campaign, we
continued updating the Center homepage, preparedleaflets and distributed them at outpatient receptions.
The leaflets contain information about research
currently recruiting participants.
Our outpatient clinic for trial participants was
moved to the second central clinic building, which
was newly opened in November 2006. The new clinic
has reception desks for consultation and own waiting
space.
<Central Coordinating Unit>
Central Coordinating Unit, established in 2010,
has been 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 thecentral coordinating unit, starting from May 2015.
Moreover, since clinical departments were placed incharge of monitoring and data management of all
exploratory studies, and the center undertook
responsibility for supervision 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).
Which also include8 investigator-initiated trials,
6 Advanced Medical Care B Programs and6 clinical research on regenerative medicine.
With respect to post marketing research, that are
funded by companies, we signed contract with thesponsor prior to the beginning of the clinicalresearch to manage conflict of interest (COI),
thereby establishing academia-initiated clinicalresearch system based on scientifically valid design.
We started investigator-led clinical trials on
pharmaceutical products and medical device inFebruary 2012. The application for approval was
filed with regulatory institution in November 2014
and received approval for manufacturing andmarketing in June 18, 2015.

Two Phase-1 Investigator-initiated trials are nearcompletion. One Investigator-initiated trial forregenerative medicine and one clinical trial for
supporting outside facility.
<P1 Unit>
Since its establishment in May 2012, Phase-1 Unit
has undertaken various preparations to respond toearly phase clinical research, such as development
of SOP program, procedure manuals, establishmentof in-house collaboration system, on-the job
training for staff and the system for recruiting
health volunteers. P1 unit conducted its very firstclinical study in October 2012. In fiscal year 2016,
we completed; first-in-human phase 1 study inhealthy volunteers, post-marketing clinical trial,bioequivalence study for a generic drug, phase I
study in postmenopausal women, and investigatorinitiated clinical trial of disease-modifying drug (toassess effect of food) on Alzheimer’s disease as the
Early/Exploratory Clinical Trial Development
Project.
In addition, we have been conducting an
investigator initiated first-in-human phase I study inhealthy volunteers since September 2015.

< University Hospital Clinical Trial Alliance>
To cope with the so-called `drug lag problem`
relating to the drugs unapproved in Japan,
participation in global research was an urgent
necessity. For this purpose, University Hospital
Clinical Trial Alliance (UHCT Alliance) comprised of
6 national university hospitals (The University ofTokyo, Niigata University, Gunma University,
Tsukuba University, Tokyo Medical and Dental
University and Chiba University) located in thecentral part of Japan was established in 2006 and hassince been in collaboration toward improvement ofclinical trial environments. The Alliance Office wasbased in the University of Tokyo Hospital. In Alliance
an organizational structure has been established thatcan cooperatively attract research and smoothly
process them for IRB approval. A course to educate
the staff in preparation for global research has been
put in place. In 2007 Shinshu University and in 2013
Yamanashi University joined the Alliance as the 7th
and 8th member university, respectively. And in 2015
the University of Tokyo the Institute of Medical

477

Science joined the Alliance as the 8th member
university 9 hospitals.
From April 2009 on, a 5-year special research grantfrom the Ministry of Education, Culture, Sports,
Science and Technology for the promotion of UHCT
Alliance allowed to set up a full-time office andfurther expand the activities. Operational subsidies
that the University of Tokyo received were distributed
to each university based on a joint project agreement.
Each university and the Office were given its own task
to cooperatively promote the mission of the whole
Alliance. From April 2014 on, another special grant
was given to the collaborative activities among theuniversities in translational research and training
programs of investigators and staff in clinicalresearch.
Until the end of March 2015, 71 protocols wereintroduced to the Alliance including 41 multinational
trials. The Alliance helped to assess feasibility in 16
research and to select the participating sites in 48.
Cooperative protocol presentation (hearing) sessions
were held for 37 protocols. Based on the data of 20
research, industry sponsors applied for drug approval
from Ministry of Health, Labour and Welfare and 19
drugs have been so far approved.
As part of the Alliance activities we developed aclinical research support system, UHCT ACReSS, tosupport glass-root clinical researchers in the quality
and project management. UHCT ACReSS is a
Web-based participant-allocation and data collection
system, which is easily customized by researchers.
The system is being used practically by 131 projects
as of March 2016, and also commercially available
with the brand name ‘HOPE eACReSS’ of Fujitsu
Corporation.
Activities between the UHCT Alliance and the
University of Tokyo TR based regional network
started in 2014, as seeds development project ofAlliance member schools, as a result, 5 seeds havebeen accepted in seeds A in 2015.
<National University Hospital Clinical Research
Initiative>
In October 2012, National University Hospital
Clinical Research Initiative (NUH-CRI) was launchedwith our leading role and included all national
university hospitals in Japan (42 universities and 45
hospitals). The administrative affairs of the Initiative

have been taken over by the Alliance Office since thepreparatory meeting in July 2012.
To establish continuous learning curriculum forresearchers and other professionals, UHCT Alliancedeveloped continuous curriculum for systematicclinical research education in 2015. NUH-CRI is
considering to share them as one of the common
program of education at the National University
Hospital.
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 created for investigatorinitiated research and provided to each university
hospital by the National University Hospital Councilof Japan.

Education/Training
The Center has been accepting all medical students
in final yeasr for training course in ‘ClinicalClerkship’ since it become mandatory in 2013.
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, whotook 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, 2000 participants are registered
for the program.
In 2015, we introduced clinical instructor system

478

In which 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 2014, 5-day training
was held under the auspices of the hospital, in which
95 trainees from university hospitals across thecountry participated.
To develop lifelong learning curriculum forresearchers and other professionals, we hold Working
Group meetings on clinical research with relevant
departments once a month. In 2015, we developed
continuous curriculum for systematic clinical researcheducation (blended learning: combination of online
and face-to-face education)
We held a joint workshop with 8 alliance
universities in the Kanto Koshinetsu area, consistingof writing clinical research protocol, data management,
monitoring workshop and clinical research lecture
series. Workshops were attended by 42, 157, 114 and141 people respectively.
Data management workshop was held jointly with
National University Hospital Clinical Research
Promotion Initiative, in fiscal 2014, a total of 87
people participated.
Annual “Clinical Research Seminar” was organizedin March and had nearly 300 participants fromacademia and companies.

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 2015, the Center was involved in 23
presentations in scientific meetings, of which 17 wereas lead presenters, international conferences 3(A.Kishi). The Japan Society of Clinical Pharmacology and Therapeutics 1 (M.Nakamura), Conference
on CRC and Clinical Research (A. Katsuura, Y.

Wakabayashi), other presentations 11 (T. Yamazaki, Y.
Uemura, M. Takata, A. Kishi) 5 lectures (T. Yamazaki,
C. Sakanaka, M. Takata), 25 publications andacademic papers etc. (English papers 7, Japanese
papers 1, review papers 14 and 3 Japanese books)

Publications
1) 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 0127445,2015
2) 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 One
10(5): 0129394,2015
3) Takata M, Amiya E, Watanabe M, Ozeki A,
Watanabe A, Kawarasaki S, Nakao T, Hosoya Y,
Uno K, Saito A, Murasawa T, Ono M, Nagai R,
Komuro I. Brachial artery diameter has a
predictive value in the improvement of flowmediated dilation after aortic valve replacement
for aortic stenosis. Heart Vessels. 2015 Mar; after
aortic valve replacement for aortic stenosis. Heart
Vessels. 2015Mar; 30(2):218-26.
4) Iimuro S, Imai E, Watanabe T, Nitta K, Akizawa T,
Matsuo S, Makino H, Ohashi Y, Hishida A.
Hyperbaric area index calculated from ABPM
elucidates the condition of CKD patients: theCKD-JAC study. Clin Exp Nephrol. 2015 Feb;
19(1):114-24.
5) Takata M, Amiya E, Watanabe M, Ozeki A,
Watanabe A, Kawarasaki S, Nakao T, Hosoya Y,
Uno K, Saito A, Murasawa T, Ono M, Nagai R,
Komuro I. Brachial artery diameter has a
predictive value in the improvement of flowmediated dilation after aortic valve replacement
for aortic stenosis. Heart Vessels. 2015 Mar; 30(2):218-26.

479

6) Yamada T, Hara K, Svensson AK, Shojima N,
Hosoe J, Iwasaki M, Yamauchi T, Kadowaki T.
Successfully achieving target weight loss influences
subsequent maintenance of lower weight anddropout from treatment. Obesity. 2015 Jan;23(1):183-91.

480

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

481

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

482

•
•

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.

483

Organ Transplantation Service
Director and Professor
Norihiro KOKUDO

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/1512ishokugeka/index.html※ The following information is the same as that of the previous year for certain reasons.
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 400 casesof living donor liver transplantation has been
performed, and the 5-year survival rate is around 85%
which is much superior to the national average(~70%). The University of Tokyo Hospital has been
one of the authorized institutions for heart transplantation, lung transplantation, and deceased donorliver transplantation.

References (2014)
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 forhepatocellular carcinoma. Transpl Int. 2014;27:
391-8.

484

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.

485

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 Translational Research for Healthcare andClinical Science, 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

486

Medicine. In addition, examinations in the Department
are administered in collaboration with three Central
Clinical Facilities (Clinical Laboratory Center,
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 two weeks
after the examination. We also offer each examinee afree 20-minute consultation so that we can help
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) 2015from April 1, to March 31,
2016, the total number of examinees (who had basic
examinations and optional examinations) was 7,621,
including 2,796 in basic examinations, 518 incomplete cardiovascular examinations, 12 in home
blood pressure screening, 684 in complete cerebrovascular examinations, 98 in check up dementia,
355in colorectal cancer screening, 513 in uterine
cancer screening, 643 in breast cancer screening,
588in lung cancer screening, 1007 in tumor marker
diagnosis, 344 in estimation of gastric cancer risk,
911in upper gastrointestinal endoscopy (later), and 52 inoral/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 2015, we issued

487

850letters of referral to other departments in our
hospital and 38 to other hospitals.
We have expanded our public relations efforts andduring the FY 2015 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 (60 posters). Our homepage (the above
URL) has been constantly updated to provide thelatest information for examinees.

References
Academic Papers in English
1. 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., Yanagisawa M.:
Monitoring β-arrestin recruitment via β-lactamase
enzyme fragment complementation: purification of
peptide E as a low-affinity ligand for mammalianbombesin receptors. PLoS One 0127445,2015
2. 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 One 10(5):0129394,2015
3. Motozawa Y., Uozumi H., Maemura S., Nakata R.,
Yamamoto K., Takizawa M., Kumagai H., Ikeda Y.,
Komuro I, Ikenouchi H.: Acute myocardial
infarction that resulted from poor adherence tomedical treatment for giant coronary aneurysm: theimportance of patient education in the chronic phaseof Kawasaki disease. Int Heart J. 56:551-554,2015
4. Lee IT., Chang AS., Manandhar M., Shan Y., Fan J.,
Izumo M., Ikeda Y., Motoike T., Dixon S., Seinfeld
JE., Takahashi JS., Yanagisawa M.: Neuromedin
S-producing neurons act as essential pacemakers inthe suprachiasmatic nucleus to couple clock neurons
and dictate circadian rhythms. Neuron 85:1086-1102,
2015
5. Nakayama A., Morita H., Nakao T., Yamaguchi T.,
Sumida T., Ikeda Y., Kumagai H., Motozawa Y.,
Takahashi T., Imaizumi A., Hashimoto T., Nagai R.,
Komuro I.: A food-derived flavonoid luteolin

protects against angiotensin II-induced cardiac
remodeling. PLoS One 10(9): e0137106,2015
6. Ono S., Fujishiro M., Ikeda Y., Komuro I., Koike
K.: Recent clinical management of anti-thrombotic
agents for gastrointestinal endoscopy after revisionof guideline in Japan. Dig Endosc. 27:649-656,2015
7. Ikeda Y., Kumagai H., Motozawa Y., Suzuki J.,
Komuro I.: Biased agonism of the angiotensin II
type I receptor: a potential strategy for the treatmentof acute heart failure. Int Heart J. 56:485-488,2015
8. Mochizuki S., Ikeda Y., Arai T., Matsuo K.: Towardfurther prevention of bleeding after gastricendoscopic submucosal dissection. Dig Endosc. 27:
295-297,2015
9. Ikeda Y., Takimoto E., Komuro I.: SH2B1: a new
player in the regulation of cardiac hypertrophic
response in failing hearts. Cardiovasc Res. 107:197199,2015
10. Ikeda Y., Kumagai H., Motozawa Y., Suzuki J.,
Komuro I.: Next generation ARBs: going beyond
modulation of the renin-angiotensin system. Int
Heart J. 56:585-6,2015
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 the Month.
Am J Gastroenterol. 2015 Nov;110(11):1535.
12. 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 . 2015 May 5. [Epub ahead of print]
13. 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
and enlarged 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. 2015 Oct 20. [Epubahead of print]

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14. Yamamichi N, Shimamoto T, Takahashi Y,
Sakaguchi Y, Kakimoto H, Matsuda R, Kataoka Y,
Saito I, Tsuji Y, Yakabi S, Takeuchi C, Minatsuki C,
Niimi K, Asada-Hirayama I, Nakayama C, Ono S,
Kodashima S, Yamaguchi D, Fujishiro M, Yamaji Y,
Wada R, Mitsushima T, Koike K. : Trend and risk
factors of diverticulosis in Japan: age, gender, andlifestyle/metabolic-related factors may cooperatively
affect on the colorectal diverticula formation. PLoS
One. 2015 Apr 10;10(4):e0123688.
15. Tsuji Y, Fujishiro M, Kodashima S, Ono S, Niimi K,
Mochizuki S, Asada-Hirayama I, Matsuda R,
Minatsuki C, Nakayama C, Takahashi Y, Sakaguchi
Y, Yamamichi N, Koike K.: Polyglycolic acid sheets
and fibrin glue decrease the risk of bleeding afterendoscopic submucosal dissection of gastricneoplasms (with video). Gastrointest Endosc. 2015
Apr;81(4):906-12. doi: 10.1016/j.gie.2014.08.028.
Epub 2014 Oct 29.
16. Sakaguchi Y, Tsuji Y, Ono S, Saito I, Kataoka Y,
Takahashi Y, Nakayama C, Shichijo S, Matsuda R,
Minatsuki C, Asada-Hirayama I, Niimi K,
Kodashima S, Yamamichi N, Fujishiro M, Koike K.
Polyglycolic acid sheets with fibrin glue can prevent
esophageal stricture after endoscopic submucosal
dissection. :Endoscopy. 2015 Apr;47(4):336-40.
17. Komuro J, Kaneko M, Ueda K, Nitta S, Kasao M,
Shirai T. Adrenal insufficiency causes lifethreatening arrhythmia with prolongation of QTinterval. Heart and Vessels. In press, 2015
International Conferences
1. Efficacy and safety of non-exposed endoscopic
wall-inversion surgery (NEWS) as a novel fullthickness resection technique for gastric tumor.
Keiko Niimi, Susumu Aikou, Sinya Kodashima,
Nobutake Yamamichi, Hiroharu Yamashita,
Mitsuhiro Fujishiro, Yasuyuki Seto, Kazuhiko
Koike. DDW (Washington DC)
2. Efficacy and safety of non-exposed endoscopic
wall-inversion surgery (NEWS) as an advanced
method of full-thickness resection technique forgastric tumor. :Keiko Niimi, Susumu Aikou,
Daisuke Yamaguchi, Yoshiki Sakaguchi, Sinya
Kodashima, Nobutake Yamamichi, Hiroharu
Yamashita, Mitsuhiro Fujishiro, Yasuyuki Seto,
Kazuhiko Koike. UEGW (Barcelona)

3. The learning curve for endoscopic ultrasound guided
fine needle aspiration of gastrointestinal tract
lesions. :Keiko Niimi, Yousuke Nakai, Itsuko
Asada-Hirayama, Yoshiki Sakaguchi,
ChihiroMinatsuki, Itaru Saito, Yosuke Kataoka, Chihiro
Takeuchi, Seiichi Yakabi, Yosuke Tsuji, Satoshi
Ono, Shinya Kodashima, Nobutake Yamamichi,
Mitsuhiro Fujishiro, Kazuhiko Koike. APDW(Taipei)

489

Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D., Ph.D.

Vice Director
Kazuto Hoshi, M.D., Ph.D.

Project Associate Professors
Hiroyuki Koyama, M.D., Ph.D.,

Taku Saito, M.D., Ph.D.,

Atsuhiko Hikita, M.D., Ph.D.,

Keiichi Hishikawa, M.D., Ph.D.,

Takeshi Miyamoto, M.D., Ph.D.,

Satoru Yamagami, 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.,

Seiichi Yokoo, 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.

490

July, 2002 Department of Bone & Cartilage
Regenerative Medicine founded by a donation from
TAKEDA Chemical Industries., Ltd.
September, 2002 Department of Regeneration
Medicine for Hematopoiesis founded by a donationfrom KIRIN Brewery Co., Ltd.
November, 2002 Department of Clinical Renal
Regeneration founded by a donation from MOCHIDA
Pharmaceutical Co., Ltd.
November, 2002 Department of MENICON
Cartilage & Bone Regeneration founded by a donationfrom MENICON Co., Ltd.
March, 2003 The Cell Processing Center set up on
the 8th floor of the In-patient Ward B.
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.

Research activities
As for corneal regeneration, our goal is the practicalapplication of corneal regenerative medicine, such as
the corneal epithelium, endothelium. We tried todevelop a low-cost regenerative medicine that can be“the world’s first regenerative medicine single-use

system” for the goal. In addition, we are conducting
functional analysis on reconstruction of cornea with
cultured epithelium, endothelium, and artificial stroma,
research on adult stem cell biology and manipulation
technology in corneal tissues and amniotic membranefor ocular surface reconstruction, and establishment
and operation of venture companies.
As for vascular regeneration, we aim at establishment of effective and safe “therapeutic
angiogenesis” and its clinical application, developmentof non-invasive soft-tissue reconstruction techniqueassisted by induction of angiogenic reactions anddevelopment of the techniques to induce microcirculation to regenerated organs. To achieve thesegoals, we are conducting research on angiogenic genetherapy using non-viral vector, development of drugdelivery method for therapeutic angiogenesis andresearch on induction of angiogenic reactions in
soft-tissue.
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
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.

491

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.
As for regenerative medicine for hematopoiesis, we
aim to develop effective systems for in vitro
expansion of cord blood hematopoietic stem cells(CB-HSCs) and its clinical application to humanhematopoietic stem cell transplantation, and for
inducing various hematopoietic components from
HSCs and embryonic stem cells. To achieve thesegoals, we are conducting research on the regulatory
mechanisms of proliferation, self-renewal, anddifferentiation of human hematopoietic stem cells(HSCs), plasticity of HSCs and clinical application of
the in vitro expansion and differentiation system of
HSCs.
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 started aninvestigator-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 anengineered airway by cells originated from trachea
tissue. In addition, the fundamental study of theamniotic fluid cell is performed to create new therapy
for new born babies.

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 in thefour departments as a result of basic research. In
Project for Regenerative Medicine of Hematopoiesis,
clinical study on expansion of human cord blood
hematopoietic cells (Institutional Review Board
approval number #351) has been started. In Department of Vascular Regeneration, clinical studies on
claudication limbs and severe ischemic limbs causedby peripheral vascular diseases (IRB approval number#825 and #826) have been started and continued
without causing major side effects. In Department ofCorneal Tissue Regeneration, clinical studies ontransplantation of cultured autologous oral mucous
epithelial sheet on amniotic membrane for ocularsurface reconstruction, and corneal endothelial stem
cell transplantation for decrease in number of corneal
endotheliums (IRB approval number #363 and #898)
have been started. In Department of Bone & Cartilage
Regenerative Medicine, a clinical study on bone
implants into non-loading parts (IRB approval number#1310) was conducted on 10 patients successfully anda large-scale clinical trial was started across the nation.
In project for cartilage regeneration, an investigatorinitiated clinical trial “A clinical trial for thevalidation of safety and efficacy of the implant-type
tissue-engineered cartilage using autologous cells”
have been started. As stated above, we are proceedingtranslational research aiming at clinical application oftissue engineering and regenerative medicine.
Contribution to the Hospital

Contribution to the Hospital
Division of Tissue Engineering, as a cooperative
research facility in the Hospital, opens expensive
special machines that each laboratory cannot afford to492

equip 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. 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
UI, Tanaka S, Saito T. Comparison of mouse andhuman ankles and establishment of mouse ankle
osteoarthritis models by surgicallyinduced instability. Osteoarthritis Cartilage. 2016 Apr;24(4):688-97. doi: 10.1016/j.joca.2015.11.008.
2. Saito T, Yano F, Mori D, Kawata M, Hoshi K,
Takato T, Masaki H, Otsu M, Eto K, Nakauchi H,
Chung UI, Tanaka S. Hyaline cartilage formationand tumorigenesis of implanted tissues derived
from human induced pluripotent stem cells.
Biomed Res. 2015;36(3):179-86. doi: 10.2220/
biomedres.36.179.
3. Saito T, Ohba S, Yano F, Seto I, Yonehara Y,
Takato T, Ogasawara T. Runx1 and Runx3 Are
Downstream Effectors of Nanog in Promoting
Osteogenic Differentiation of the Mouse Mesenchymal Cell Line C3H10T1/2. Cell Reprogram.
2015 Jun;17(3):227-34. doi: 10.1089/cell.2014.
0059.
4. Okuma T, Hirata M, Yano F, Mori D, Kawaguchi
H, Chung UI, Tanaka S, Saito T. Regulation ofmouse chondrocyte differen- tiation by CCAAT/
enhancer-binding proteins. Biomed Res. 2015;
36(1):21-9. doi: 10.2220/ biomedres.36.21.
5. Miyamoto T, Katsuyama E, Kanagawa H, Fujie A,
Miyamoto H, Yoshida S, Mori T, Miyamoto K,
Sato Y, Kobayashi T, Nakamura M, Matsumoto
M, Nishiwaki Y, Hirose H, Kanda T, Saito I,
Toyama Y. Vitamin D Deficiency with HighIntact PTH Levels is More Common in Younger
than in Older Women: A Study of Women Aged
39-64 Years. Keio J Med. 2016;65(2):33-38. doi:
10.2302/kjm.2015-0010-OA.
6. Tando T, Sato Y, Miyamoto K, Morita M,
Kobayashi T, Funayama A, Kanaji A, Hao W,
Watanabe R, Oike T, Nakamura M, Matsumoto M,

Toyama Y, Miyamoto T. Hif1α is required forosteoclast activation and bone loss in maleosteoporosis. Biochem Biophys Res Commun.
2016 Feb 5;470(2):391-6.
7. Suzuki S, Fujita N, Hosogane N, Watanabe K,
Ishii K, Toyama Y, Takubo K, Horiuchi K,
Miyamoto T, Nakamura M, Matsumoto M.
Excessive reactive oxygen species are therapeutictargets for intervertebral disc degeneration.
Arthritis Res Ther. 2015 Nov 5;17:316.
8. Kanemoto S, Kobayashi Y, Yamashita T,
Miyamoto T, Cui M, Asada R, Cui X, Hino K,
Kaneko M, Takai T, Matsuhisa K, Takahashi N,
Imaizumi K. Luman is involved in osteoclastogenesis through the regulation of DC-STAMP
expression, stability and localization. J Cell Sci.
2015 Dec 1;128(23):4353- 65.
9. Kanagawa H, Masuyama R, Morita M, Sato Y,
Niki Y, Kobayashi T, Katsuyama E, Fujie A, Hao
W, Tando T, Watanabe R, Miyamoto K, Morioka
H, Matsumoto M, Toyama Y, Saya H, Miyamoto
T. Methotrexate inhibits osteoclastogenesis bydecreasing RANKL-induced calcium influx into
osteoclast progenitors. J Bone Miner Metab.
2016 Sep;34(5):526-31. doi:10.1007/s00774-0150702-2.
10. Hao W, Tashiro S, Hasegawa T, Sato Y,
Kobayashi T, Tando T, Katsuyama E, Fujie A,
Watanabe R, Morita M, Miyamoto K, Morioka H,
Nakamura M, Matsumoto M, Amizuka N,
Toyama Y, Miyamoto T. Hyperglycaemia
promotes Schwann cell de-differentiation andde-myelination via sorbitol accumulation and Igf1
downregulation. J Biol Chem. 2015 Jul 10;
290(28):17106-15.
11. 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. Genomewide
comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKL-induced
osteoclastogenesis. J Bone Mineral Res. 2015
May;30(5):869-77. doi: 10. 1002/jbmr.2418.
12. Hikita A, Iimura T, Oshima Y, Saitou T,
Yamamoto S, Imamura T. Analysis of bonemodeling and remodeling using in vitro recon-

493

stitution system with two-photon microscopy.
Bone 2015 Jul;76:5-17. doi:10.1016/j.bone. 2015.
02.030.
13. Tsubakihara Y, Hikita A, Yamamoto S, Imamura T.
Arkadia enhance BMP signaling throughubiquitylation and degradation of Smad6. J
Biochem. 2015 Jul;158(1):61-71. doi:10.1093/ jb/
mvv 024.

494

Department of Clinical Research
GovernanceDirector & Professor (From April, 2015 to July, 2015)
Masaomi Nangaku M.D.,Ph.D.
(Vice Director of the University of Tokyo Hospital, Director of Department of Research
Support)Director & Project Professor (From August, 2015 ~)Takashi Moritoyo, M.D.,Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/about/ichiran/#02

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 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 the governance function
within the hospital.
The following activities are carried out by the
Office of TR Strategy Promotion: (1) the formulationof comprehensive strategies for research anddevelopment at the University of Tokyo Hospital; (2)playing the role of administrative headquarters whenpublicly applying for large-scale research projects; (3)serving as a liaison for consultations regarding theacquisition of research funds and intellectual
properties; (4) examination of financial self-reliancestrategies of the clinical research base; (5) discoveryof needs and seeds in clinical practice; (6)investigation of research activities at the University ofTokyo Hospital and the creation of a database; (7)collection of clinical research information fromexternal organizations; (8) activities related toconflicts of interest at the University of Tokyo
Hospital; (9) clerical work related to the Advanced
Medicine
Development
SupportManagement
Committee; and (10) clerical work related to theSpecial 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 of495

a quality assurance system; (3) reliability-related
guidance, advice and consultation; (4) support for
responding to compliance reviews, etc., of clinical
trials and clinical studies conducted by the Universityof Tokyo Hospital, as well as the centralized
management of results; (5) the centralized
management of audit results; and (6) confirmation of
the implementation of corrective and preventive
measures from 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 2016. The
Department of Quality Assurance under the directcontrol of the Director of the Clinical Research
Support Center was established in December 2014,
with one staff member (project specialist). However,the department was reorganized as the Office ofClinical Quality Assurance & Compliance under the
Department of Clinical Research Governance. Twostaff members joined in May and August, 2015.

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, andpreparation of an application for the approval ofclinical research at core hospitals under the Medical
Service Law (approved on March 25, 2016).
2) Activities related to conflict-of-interest management: 3 consultations regarding research administrative structures, management of conflict-of-interest
documents for 225 studies (total number), and 329
consultations regarding the completion of theself-declaration form for conflict-of-interest (total
number).
3) Intellectual property-related activities: evaluationof intellectual properties for network programs foraccelerating the work of bridging research, and 3
consultations regarding intellectual properties (3patent 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, holding of the“Forum for Development of Seeds for Advanced
Medicine, 2016” (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 begun 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 5 cases were audited.
Regarding 2 investigator-initiated clinical trials (amulti-center clinical trial and a trial for a medical
device) at other university hospitals, 3 cases wereaudited. 2. Regarding clinical research, 2 cases ofclinical research at other university hospitals wereaudited. Regarding clinical research at the Universityof Tokyo Hospital, the audit procedures and protocols
for 3 clinical studies were prepared. The members of
the office attended the start-up meeting and explained
the audit schedule and contents, etc. Preparations forother audits have also been initiated.
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. For
inspections by the FDA, the members advised two
imitation audits conducted by pharmaceuticalcompanies.
3) Educational activities:1. A “Lecture Series” wasnewly introduced by the clinical research support
center. The office was involved in making programs,
inviting lecturers, and conducting the seminar. 2.
Supervisions of quality assurance were conducted formembers 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496

discussion on quality assurance. 3. The office’s
experience conducting academic audits was presented
at a symposium of the Japan Society of Quality
Assurance and the Japan Society of Clinical Trials andResearch, and the establishment of a structure for
quality assurance was reported at the Japan Society ofClinical Trials and Research.

References
1. Moritoyo T. Accelerating Regulatory Science
Initiatives for the Development of Drugs for
Alzheimer's Disease in Japan. Clin Ther.
2015;37(8):1622-1626.
2. Moritoyo T, Kameyama Y, Ihara R, Ishii S,
Kawarazaki S, Kirihara K, Murata C, Nakane T.
Bioequivalence study of AMVALO TABLETS「 NICHIIKO 」 on healthy adults. Jpn J Med
Pharm Sci. 2015;72(10):1763-1772. Japanese.

497

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

Assistant professor
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 to 3
professors 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 2015, the Department of Child
Psychiatry consisted of 13 psychiatrists and 8
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 2015 was 239 andslightly larger than to that in 2014. A large part of the
new patients consisted of patients with ASD, tic
disorder or ADHD. Sixty-eight patients were aged
11-15 years old, and 60 patients were aged 6-10 years
old. In other words, more than half of the patients are
students of primary school or junior high school.
Thirty-one patients were younger than 6 years old, and51 patients were older than 20 years old, suggesting
steady needs for assessment and treatment of bothpreschoolers and adults with developmental disorders.
The follow-up clinic consisted of general clinic andspecial clinic (Tic/OCD clinic). At the general clinic, a498

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,
group therapy consisting of biweekly 10 sessions wasprovided in first half year. Intensive individualized
therapy consisting of weekly 10 sessions started in last
half year.
Parent-training for parents with ADHD children,which started in 2011, was provided. This program
aimed that the parents learn deeper understanding ofdifficult children and appropriate strategy of copingwith them.
In addition to these outpatient services, “inpatient
assessment on developmental disorders” program
started in 2010. This program is provided in theinpatient ward of neuropsychiatry for adolescents oradults who have mental problems such as depression
and wish a detailed examination about possibility ofhidden developmental disorders including ASD and
ADHD.

We also focus on psychiatric liaison activity withother departments in the University hospital,
especially pediatrics.

Education
Undergraduates of the University of Tokyo haveopportunities to participate in an assessment anddiagnosis session at the general first visit outpatient
clinic and intervention for preschool children.
Graduate students in clinical psychology course fromthe University of Tokyo participate in intervention forpreschoolers also.
One month training course is offered to juniorresidents especially in pediatric specialty course. This
course includes intake interview of first visit patients,
observation of assessment and treatment for follow-up
patients and intervention for preschoolers, and visit tocommunity hospital and intervention/guidance
facilities for child and adolescent mental health. For
general psychiatrists including senior residents of the
Department of Neuropsychiatry, round for developmental disorders and an inpatient program of assessment about developmental disorders are provided asopportunity to get knowledge and experience ofdevelopmental disorders.
In response to the increasing interest to adults with
developmental disorders, a seminar of developmental
disorders was held in July 2015, and about 180
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

499

ASD the revised program is investigated in arandomized 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.
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.

2.

3.

4.

5.
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.
6.
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.

7.

References
1. Kuwabara H, Araki T, Yamasaki S, Ando S, Kano
Y, Kasai K. Regional differences in post-traumatic

8.

stress symptoms among children after the 2011
tsunami in Higashi-Matsushima, Japan. Brain Dev.
37(1): 130-136, 2015.
Kano Y, Matsuda N, Nonaka M, Fujio M,
Kuwabara H, Kono T. Sensory phenomena in
relation to tics, obsessive-compulsive symptoms,
and global functioning in patients with Tourette
syndrome. Compr Psychiatry. 62: 141-146, 2015.
Nonaka M, Matsuda N, Kono T, Fujio M, Scahill
L, Kano Y. Preliminary study of behavioral
therapy for Tourette Syndrome patients in Japan.
Children’s Health Care. 44(3): 293-306, 2015.
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. 25(6):256-258, 2015.
Ishii-Takahashi A, Takizawa R, Nishimura Y,
Kawakubo Y, Hamada K, Okuhata S, Kawasaki S,
Kuwabara H, Shimada T, Todokoro A, Igarashi T,
Watanabe K, Yamasue H, Kato N, Kasai K, Kano
Y. Neuroimaging-aided prediction of the effect of
methylphenidate in children with attention deficit
hyperactivity disorder： A randomized controlled
trial. Neuropsychopharmacology. 40(12): 26762685, 2015.
Inada N, Ito H, Yasunaga K, Kuroda M, Iwanaga
R, Hagiwara T, Tani I, Yukihiro R,Uchiyama T,
Ogasahara K, Hara K, Inoue M, Murakami T,
Someki F, Nakamura K, Sugiyama T, Uchida H,
Ichikawa H, Kawakubo Y, Kano Y, Tsujii M.
Psychometric properties of the Repetitive
Behavior Scale-Revised for individuals with
autism spectrum disorder in Japan. Res Autism
Spectr Disord. 15-16: 60-68, 2015.
Aoki Y, Watanabe T, Abe O, Kuwabara H, Yahata
N, Takano Y, Iwashiro N, Natsubori T, Takao H,
Kawakubo Y, Kasai K, Yamasue H. Oxytocin's
neurochemical effects in the medial prefrontal
cortex underlie recovery of task-specific brain
activity in autism: a randomized controlled trial.
Mol Psychiatry. 20(4): 447-453, 2015.
Watanabe T, Kuroda M, Kuwabara H, Aoki Y,
Iwashiro N, Tatsunobu N, Takao H, Nippashi Y,
Kawakubo Y, Kunimatsu A, Kasai K, Yamasue H.

500

Clinical and neural effects of six-weekadministration of oxytocin on core symptoms ofautism. Brain. 138(Pt 11): 3400-3412, 2015.
9. Kinoshita A, Takizawa R, Koike S, Satomura Y,
Kawasaki S, Kawakubo Y, Marumo K, Tochigi M,
Sasaki T, Nishimura Y, Kasai K. Effect of
metabotropic glutamate receptor-3 variants on
prefrontal brain activity in schizophrenia: An
imaging genetics study using multi-channel nearinfrared spectroscopy. Prog Neuropsychopharmacol Biol Psychiatry. 62: 14-21, 2015.
10. Matsuda N, Kono T, Nonaka M, Fujio M, Kano Y.
Self-initiated coping with Tourette’s syndrome:
Effect of tic suppression on QOL. Brain Dev. (inpress).
11. Okada N, Takahashi K, Nishimura Y, Koike S,
Ishii-Takahashi A, Sakakibara E, Satomura Y,
Kinoshita A, Takizawa R, Kawasaki S, Nakakita
M, Ohtani T, Okazaki Y, Kasai K. Characterizing
prefrontal cortical activity during inhibition task
in methamphetamine-associated psychosis versus
schizophrenia: a multi-channel near-infrared spectroscopy study. Addict Biol. (in press).
12. 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 of autism
spectrum disorder in the East Asian populations.
Autism Res. (in press).

501

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 2015, thenumber achieved to more than total 800 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 team-502

conference on weekdays.
1) Palliative care training program
The training course (selection) for two months ( or *for one month )･ Program to acquire basic knowledge and practice ofpalliative care for targeting all junior residents. *Only in "Comprehensive Internal Medicine”
selection.
The training course (selection) for four or eightmonths･ Program to acquire basic knowledge, practice, andskills of communication for doctors who need to beclinical oncologists or pain and palliative carespecialists.
2) CurriculumContents of training･ All junior residents are assigned to the pain andpalliative care team. They chiefly participate inpalliative care practice as a member of the team.
･ In the course for four and eight months, they learn
to make palliative care plans for inpatients, discuss
palliative care of the cases with patients’ attending
doctors, ward staff, and execute these palliative careplans.
Goal to attain･ Palliative care for inpatients (around 40 cases aday): They acquire the outline of control of physicaland psychiatric symptoms of the patients with
common diseases in our country such as digestivecancers. They also learn the outline of spiritual andfamily care.
･ Cancer registry: In The University of Tokyo
Hospital, it is not unusual that the patient whom thepain and palliative care team treats is often in an
end stage, and his or her condition changes
physically and mentally day by day. Residents
should input the clinical data about palliative careof such patients concisely to the database. Theyacquire the outline of data management of thepalliative care connected directly to a clinicalresearch.
･ Communicative competence: The clinician often
has to break "Bad news" to his patients time after
time along the course of their illness. It is very
difficult for the clinician to provide the appropriate

information about diagnoses, recurrence, progression and prognosis of illness to his patients.

The oncologist has to deal with patients’ strong grief
and feeling of loss when their illness is obviously
progressive as well as has to manage both 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.

503

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. Obuchi M, Sumitani M, Shin M, Ishii K, Kogure
T, Miyauchi S, Yamada Y. Spinal cord stimulation
ameliorates neuropathic pain-related sleep disorders: a case series. Neuromodulation 2015; 18:
191-3
2. Natori A, Ogata T, Sumitani M, Kogure T,
Yamauchi T, Yamauchi H. Potential role of pNF-H,
a biomarker of axonal damage in the central
nervous system, as a predictive marker ofchemotherapy-induced cognitive impairment. Clin
Cancer Res 2015; 21:1348-52
3. Suka M, Odajima T, Okamoto M, Sumitani M,
Igarashi A, Ishikawa H, Kusama M, Yamamoto M,
Nakayama T, Sugimori H. Relationship between
health literacy, health information access healthbehavior and health status in Japanese people.

Patient Education Counsel 2015; 98: 660-8
4. Yokota J, Fujiu K, Tanimoto H, Nebiya H,
Kashiwa K, Kinoshita O, Nawata K, Kimura M,
Stasu T, Chou K, Sumitani M, Ono M, Komuro I.
Electromagnetic interference between continuousflow left ventricular assist device and cardiac
resynchronization therapy defibrillator due to an
unrecognized mechanism. Intl J Cardiol 2015;
179: 510-3
5. Sumitani M, Misaki M, Kumagaya S, Yozu A,
Otake Y, Osumi M, Miyauchi S. Internallyrepresented space and its mirror-reveresed imageof the visuospatial representation: a possible
association. Medical Hypotheses 2015; 85: 500-5
6. Osumi M, Sumitani M, Wake N, Sano Y, Ichinose
A, Kumagaya S, Kuniyoshi Y, Morioka S.
Structured movement representations of aphantom limb associated with phantom limb pain.
Neuroscience Letters 2015; 605: 7-11
7. Matsubayashi Y, Takeshita K, Sumitani M,
Oshima Y, Tonosu J, Kato S, Ohya J, Oichi T,
Okamoto N, Tanaka S. Psychometric validation of
the Japanese version of the Neuropathic Pain
Symptom Inventory. Plos One 2015; 10:e0143350
8. Hashimoto T, Yoshiuchi K, Inada S, Shirakura K,
Wada N, Takeuchi K. Matsushita M. Physicalactivity of elderly patients with rheumatoid
arthritis and healthy individuals: an actigraphy
study. Biopsychosoc Med 2015; 9: 19
9. Iwase S, Kawaguchi T, Tokoro A, Yamada K,
Kanai Y, Matsuda Y, Kashiwaya Y, Okuma K,
Inada S, Ariyoshi K, Miyaji T, Azuma K, Ishiki H,
Unezaki S, Yamaguchi T. Assessment of CancerRelated Fatigue, Pain, and Quality of Life inCancer Patients at Palliative Care Team. Referral:
A Multicenter Observational Study (JORTC
PAL-09). PLOS One 10: e0134022
10. Iwase S, Kawaguchi T, Tokoro A, Yamada K,
Kanai Y, Matsuda Y, Kashiwaya Y, Okuma K,
Inada S, Ariyoshi K, Miyaji T, Azuma K, Ishiki H,
Unezaki S, Yamaguchi T. Assessment of CancerRelated Fatigue, Pain, and Quality of Life inCancer Patients at Palliative Care Team Referral:
A Multicenter Observational Study (JORTC
PAL-09). Plos One 2015; 10: e0134022 (And, 29Japanese articles)504

Department of Clinical Molecular
Medicine
Chief
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 as well as
residents in neighboring communities with the aim ofleading them to appropriate departments and facilities.

Medical Services
Provision of information if patient contracts cancer
If a person gets cancer, the first thing they need to do
is collect information on cancer. The Cancer
Counseling and Support Center provides information
and booklets on different types of cancer. Furthermore,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 their doctors’ 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.

505

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. Cover makeup improved cancer
patients’ Quality of Life. Multinational Association of Supportive Care in Cancer
2. Takako W. The effect of cover makeup for visual
skin changes caused by cancer therapy. The 53rd
Annual Meeting of Japan Society of ClinicalOncology (JSCO)
3. Takako W, Otomo E, Takeda A, Nomura S. The
service for patients’ appearance care in the Tokyo
University Hospital. The 53rd Annual Meeting ofJapan Society of Clinical Oncology (JSCO)506

Genome Informatics
Director & Professor
Takashi Kadowaki, M.D., Ph.D.

1. Organization
The Department of Genome Informatics started asa special unit conducting research on clinical epidemiology and human genetics in 2003. Our section
functions as the unit to establish/support clinical andepidemiological data sampling/management and toaccomplish an appropriate and efficient applicationof results of recently advanced human genetics andgenomics. In addition, as the unit of training andeducating specialists of clinical epidemiology andhuman genetics. It consists of one professor anddifferent specialties participating in the department.
They include cardiologists, diabetologists, epidemiologists, and statisticians. Our section also supported
designing of clinical / genetic studies and provided
services of anonymizing clinical data / samples
derived from study participants.

2. Activities
In collaboration with RIKEN, we explored thecomprehensive catalog of genomic variations provided by the 1000 Genomes Project phase 1 to identify
variations conferring susceptibility to T2D in theJapanese population that were not detected in theprevious scans. We imputed 7,521,072 variants in
23,399 cases and 31,722 controls genotyped by 610K
single-nucleotide polymorphism (SNP) array. We
tested associations for T2D before and after adjusting for age, sex, and body mass index. We found thatin addition to variants of the previously reported loci,there were 7 loci harboring multiple variants
possibly associated with T2D , rs1116357 near
CCDC85A, rs147538848 in FAM60A, rs1575972
near DMRTA1, rs9309245 near ASB3, rs67156297
near ATP8B2, rs7107784 near MIR4686 andrs67839313 near INAFM2. Of these, the associationsof 5 loci (FAM60A, DMRTA1, ATP8B2, INAFM2,

MIR4686) with T2D are replicated in multi-ethnic
populations other than Japanese. The associations of
2 loci (CCDC85A, ASB3) with T2D are notreplicated in multi-ethnic populations other thanJapanese. These findings highlight the usefulness ofconducting GWAS to clarify the genetic predisposition to T2D in East Asians as well as inEuropean-origin populations (up to 65,936 T2Ds and
158,030 controls, P＜0.007).
While searching for potential drug targets for T2D
using a systematic bioinformatics approach (Nature
20, 376-381, 2014), overlapping genes wereidentified. 40 genes included in the T2D risk lociwere scored by adopting selection criteria including,T2D risk missense variants, monogenic diabetes, andknockout mouse phenotypes. We identified two
genes, GSK3B and JUN, which directly interact withmultiple biological T2D susceptibility genes.
We also took part in the Asian Genetic
Epidemiology Network (AGEN) consortium which
conducted a large-scale GWAS with several transethnic consortium and found novel loci associatedwith fasting plasma glucose.
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 daily
practice to gain insight into a larger clinical picture.
Thus, we designed and developed a coronary
angiography and intervention reporting system(CAIRS) to collect data and analyze outcomes ofcoronary intervention. The resulting advanced
CAIRS can record detailed data on coronary
angiographic and interventional procedures. We havealso implemented the same system at otherinstitutions and sampled larger-scale CAD patients.
Implementing the same system at more institutions
and analyzing data collected in the same scheme will

507

provide detailed and timely insight into the 'realworld' of coronary atherosclerotic diseases and theirclinical outcome.
Concerning genetic analysis of monogenic
diseases, our department has provided service ofgenetic analysis of Marfan syndrome (MFS), one of
the representative connective tissue diseases. We
performed mutational analysis using a highthroughput microarray-based resequencing system.

3．References
1. Hwang JY, Sim X, Wu Y, Liang J, Tabara Y, Hu
C, Hara K, Tam CH, Cai Q, Zhao Q, Jee S,
Takeuchi F, Go MJ, Ong RT, Ohkubo T, Kim YJ,
Zhang R, Yamauchi T, So WY, Long J, Gu D,
Lee NR, Kim S, Katsuya T, Oh JH, Liu J,
Umemura S, Kim YJ, Jiang F, Maeda S, Chan JC,
Lu W, Hixson JE, Adair LS, Jung KJ, Nabika T,
Bae JB, Lee MH, Seielstad M, Young TL, Teo
YY, Kita Y, Takashima N, Osawa H, Lee SH,
Shin MH, Shin DH, Choi BY, Shi J, Gao YT,
Xiang YB, Zheng W, Kato N, Yoon M, He J,
Shu XO, Ma RC, Kadowaki T, Jia W, Miki T, Qi
L, Tai ES, Mohlke KL, Han BG, Cho YS, Kim
BJ, Genome-wide association meta-analysis
identifies novel variants associated with fasting
plasma glucose in East Asians. Diabetes. 2015;
64(1): 291-298
2. Hirokawa M, Morita H, Tajima T, Takahashi A,
Ashikawa K, Miya F, Shigemizu D, Ozaki K,
Sakata Y, Nakatani D, Suna S, Imai Y, Tanaka T,
Tsunoda T, Matsuda K, Kadowaki T, Nakamura
Y, Nagai R, Komuro I, Kubo M. A genomewide association study identifies PLCL2 andAP3D1-DOT1L-SF3A2 as new susceptibilityloci for myocardial infarction in Japanese. Eur J
Hum Genet. 2015 :23:374-380
3. Genome-wide association studies in the Japanese
population identify seven novel loci for type 2
diabetes. 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. Nat Commun. (in press)

508

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 ofrecently advanced human genetics and genomics toclinical practice in the hospital and as the unit oftraining and educating specialists of human genetics
practice. It consists of one professor and manydifferent specialties participate in the department.
They include pediatricians, obstetricians, internist(cardiologists, diabetologists, and neurologists),surgeons, and staffs of the Departments of ClinicalLaboratory 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 we started pharmacogenetics tests in2006. Those include tests for proton inhibitor,
warfarin, irinotecan, and tacrolimus.

Publications
1. Ishiura H and Tsuji S. Epidemiology andmolecular mechanism of frontotemporal lobar
degeneration/amyotrophic lateral sclerosis withrepeat expansion mutation in C9orf72. Neurogenet 29: 85-94, 2015. (DOI: 10.3109/01677063.
2015.1085980)
2. Mitsui J, Matsukawa T, Sasaki H, Yabe I,
Matsushima M, D?rr A, Brice A, Takashima H,
Kikuchi A, Aoki M, Ishiura H, Yasuda T, Date H,
Ahsan B, Iwata A, Goto J, Ichikawa Y, Nakahara
Y, Momose Y, Takahashi Y, Hara K, Kakita A,
Yamada M, Takahashi H, Onodera O, Nishizawa
M, Watanabe H, Ito M, Sobue G, Ishikawa K,
Mizusawa H, Kanai K, Hattori T, Kuwabara S,
Arai K, Koyano S, Kuroiwa Y, Hasegawa K,
Yuasa T, Yasui K, Nakashima K, Ito H, Izumi Y,
Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi
M, Kondo T, Murayama S, Hattori N, Yamamoto
M, Murata M, Satake W, Toda T, Filla A,
Klockgether T, W?llner U, Nicholson G, Gilman
S, Tanner CM, Kukull WA, Stern MB, Lee VMY, Trojanowski JQ, Masliah E, Low PA,
Sandroni P, Ozelius LJ, Foroud T, and Tsuji S.
Variants associated with Gaucher disease inmultiple system atrophy. Ann Clin Transl Neurol.
2: 417-426, 2015. (DOI: 10.1002/acn3.185)
3. Ozaki K, Doi H, Mitsui J, Sato N, Iikuni Y,
Majima T, Yamane K, Irioka T, Ishiura H, Doi K,

509

Morishita S, Higashi M, Sekiguchi T, Koyama K,
Ueda N, Miura Y, Miyatake S, Matsumoto N,
Yokota T, Tanaka F, Tsuji S, Mizusawa H, andIshikawa K. A Novel Mutation in ELOVL4
Leading to Spinocerebellar Ataxia (SCA) With
the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34.
JAMA Neurol. 72:797-805, 2015. (DOI: 10.
1001/jamaneurol.2015.0610)

510

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 Bioscience RS II, one
Illumina MiSeq, and one Roche GS Junior. Robotics
for preparation of samples has also been installed.
Computer servers for processing of massive amountof genome data have been installed in the serverroom, 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
outside of 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 hereditary spinocerebellar atrophy(SCA34), a case report of SCA23, BoucherNeuhäuser syndrome, and adult-onset vanishingwhite matter disease.

Publications
1. Koh K, Kobayashi F, Miwa M, Shindo K,
Isozaki E, Ishiura H, and Tsuji S. Novelmutations in the PNPLA6 gene in BoucherNeuh?user syndrome. J Hum Genet 60: 217-20,

2015. (DOI 10.1038/jhg.2015.3)
2. Mitsui J, Matsukawa T, Sasaki H, Yabe I,
Matsushima M, D?rr A, Brice A, Takashima H,
Kikuchi A, Aoki M, Ishiura H, Yasuda T, Date H,
Ahsan B, Iwata A, Goto J, Ichikawa Y, Nakahara
Y, Momose Y, Takahashi Y, Hara K, Kakita A,
Yamada M, Takahashi H, Onodera O, Nishizawa
M, Watanabe H, Ito M, Sobue G, Ishikawa K,
Mizusawa H, Kanai K, Hattori T, Kuwabara S,
Arai K, Koyano S, Kuroiwa Y, Hasegawa K,
Yuasa T, Yasui K, Nakashima K, Ito H, Izumi Y,
Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi
M, Kondo T, Murayama S, Hattori N, Yamamoto
M, Murata M, Satake W, Toda T, Filla A,
Klockgether T, W?llner U, Nicholson G, Gilman
S, Tanner CM, Kukull WA, Stern MB, Lee VMY, Trojanowski JQ, Masliah E, Low PA,
Sandroni P, Ozelius LJ, Foroud T, and Tsuji S.
Variants associated with Gaucher disease inmultiple system atrophy. Ann Clin Transl Neurol.
2: 417-426, 2015. (DOI: 10.1002/acn3.185)
3. Ozaki K, Doi H, Mitsui J, Sato N, Iikuni Y,
Majima T, Yamane K, Irioka T, Ishiura H, Doi K,
Morishita S, Higashi M, Sekiguchi T, Koyama K,
Ueda N, Miura Y, Miyatake S, Matsumoto N,
Yokota T, Tanaka F, Tsuji S, Mizusawa H, andIshikawa K. A Novel Mutation in ELOVL4
Leading to Spinocerebellar Ataxia (SCA) With
the Hot Cross Bun Sign but Lacking
Erythrokeratodermia: A Broadened Spectrum of
SCA34. JAMA Neurol. 72:797-805, 2015. (DOI:
10.1001/jamaneurol.2015.0610)
4. Saigoh K, Mitsui J, Hirano M, Shioyama M,
Samukawa M, Ichikawa Y, Goto J, Tsuji S, andKusunoki S. The first Japanese familial case of

511

spinocerebellar ataxia 23 with a novel mutationin the PDYN gene. Parkinsonism Relat Disord.
21: 332-4, 2015. (DOI: 10.1016/j.parkreldis.
2014.12.028)
5. Watanabe H, Atsuta N, Nakamura R, Hirakawa
A, Watanabe H, Ito M, Senda J, Katsuno M,
Izumi Y, Morita M, Tomiyama H, Taniguchi A,
Aiba I, Abe K, Mizoguchi K, Oda M, Kano O,
Okamoto K, Kuwabara S, Hasegawa K, Imai T,
Aoki M, Tsuji S, Nakano I, Kaji R, and Sobue G.
Factors affecting longitudinal functional decline
and survival in amyotrophic lateral sclerosis
patients. Amyotrophic Lateral Sclerosis &Frontotemporal Degeneration. 16:230-6, 2015.
(DOI: 10.3109/21678421.2014.990036)
6. Yamashita S, Mori A, Nishida Y, Kurisaki R,
Tawara N, Nishikami T, Misumi Y, Ueyama H,
Imamura S, Higuchi Y, Hashiguchi A, Higuchi I,
Morishita S, Yoshimura J, Uchino M, Takashima
H, Tsuji S, and Ando Y. Clinicopathologicalfeatures of the first Asian family having vocal
cord and pharyngeal weakness with distal
myopathy due to a MATR3 mutation. Neuropathol Appl Neurobiol. 41: 391-8, 2015. (DOI:
10.1111/nan.12179)

512

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/※ The following information is the same as that of the previous year for certain reasons.

Introduction and Organization
The application of an advanced bioscience to a newtechnical development of clinical medicine has
become an important subject for research in the 21st
century. We’ve established Cooperative Unit ofMedicine and Engineering Research at The Universityof Tokyo Hospital to create a new research andeducation center, which cross-sectionally unites
medicine with engineering research for the development of a next generation medical technology.
2002 June. The establishment of Cooperative Unitof Medicine and Engineering Research was approvedby a hospital administration committee as a special
practice unit that belongs to The University of Tokyo
Hospital.
2002 September. A steering committee of Cooperative Unit of Medicine and Engineering Research

was organized by representative members of relevant
clinical departments. The committee made a decisionof the following basic principles; recruitment for theparticipation to this unit should be, as a general rule,
an open call for a joint project of clinical department
and engineering or pharmaceutical research group in
The University of Tokyo, an equipment/administration
expense of a laboratory should be a responsibility of
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

513

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

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

Laboratory of Medical Ultrasound with Microbubbles in Oncology
Department of Mechanical Engineering, Fluids
Engineering Laboratory
Department of Surgical Oncology
To develop easy, precise, non-invasive systems to treat
human disease. To devise a method to induce
microbubbles effectively to treat human tumors indeep situ. To make a precise assessment on tumor

Development of Advanced Stereotactic Radiation
Cancer Therapy System
Department of Radiology
Nuclear Professional School, Department of Nuclear
Engineering and Management
Department of Chemical System Engineering
High Precision Stereotactic X-ray Cancer Therapy

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.

514

invasion in μm order by injecting microbubbles into
tumor arteries. To develop a non-invasive treatment
system using HIFU devise and microbubble contrast
agents.
Research and development of micro-neurosurgicalrobotic systems
Department of Neurosurgery, The University of Tokyo
Hospital
Mitsuishi-Sugita
Laboratory,
DepartmentofMechanical 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
Department of Clinical Epidemiology & Systems
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.
Surgical Robot System Lab.
Robotics, Dynamics, and Control Laboratory
Department of Mechano-Informatics
University of Tokyo
Development of motion synchronization technology
for in-vivo molecular imaging of small animals, basedon robot systems for endoscopic cardiac surgery.

Neuro-musculo-skeletal model and its parameter
identification for diagnosis and rehabilitation ofneuromuscular disorders.
Vascular Biomedical Engineering Laboratory
Department of Vascular Surgery
Department of Tissue Engineering, The University ofTokyo Hospital
Bio-Medical Precision Engineering Laboratory,
Department of Precision Engineering, Medical Device
Development and Regulation Research Center, The
University of Tokyo
Development of minimally invasive diagnostic andtherapeutic technologies for vascular surgery throughcollaboration research.
Orthopedic clinical biomechanics laboratory
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.
To develop a new method for evaluation of fracture
healing by echo tracking.
To develop a non-invasive method for morphologicalevaluation of articular cartilage.
To develop a device for assisting in fracture reduction
and fixation.
Minimally invasive cardiac surgery with the
integral videography system
Department of Cardiothoracic Surgery, Graduate
School of Medicine, University of Tokyo
Advanced Therapeutic and Rehabilitation Engineering
Laboratory, Department of Mechano-Informatics,
Graduate School of Information Science andTechnology, University of Tokyo
To develop: real-time three-dimensional echocardiography, suture device with liner probe, integral
videography, and minimal invasive cardiac surgery
monitored by real-time three-dimensional echocardiography without cardiopulmonary bypass
Division of Neutron Capture Therapy & Immunotherapy for Cancer
Department of Cardiothoracic Surgery, Graduate /515

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 develop more effective immunotherapeutic
approaches.
Molecular Imaging Laboratory, Cooperative Unitof Medicine, Engineering and Pharmaceutical
Research
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.
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.
Laboratory of 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 signal transduction pathways of major adipokines
including adiponectin
Laboratory of Biomaterial Science
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
Molecular and cellular mechanics laboratory forthe development of multi-scale heart simulator
Department of Cardiothoracic Surgery, The Universityof Tokyo Hospital

516

Biomechanics Laboratory, Graduate School of
Frontier Sciences, The University of Tokyo
We are developing multi-scale, multi-physics heart
simulator for the in-silico diagnosis and treatment ofheart diseases by the synergistic effort of cellularphysiology and computational mechanics. For
collecting quantitative data for the simulator,
mechanical analysis of cardiomyocytes is performed.
Laboratory of Hard-Tissue Nanomedicine
Kataoka & Yamasaki Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Department of Cartilage & Bone Regeneration,
Graduate School of Medicine, 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 Oraland 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 gene delivery system bysupramolecular nanotechnology. Development of anon-viral siRNA delivery system by supramolecular
nanotechnology. Production of regenerated cartilage
and bone with high safety and usefulness.
Establishment of practical production and quality
control systems. Promotion of the clinical applicationof regenerated cartilage and bone. Development ofeasy, precise, non-invasive systems to detect
osteoblastic
andchondrocytic
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

Cooperative Unit of Kataoka Laboratory andDepartment of Vascular Surgery
Department of Vascular Surgery, Division of Tissue
Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering,
The University of Tokyo
To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we aredeveloping non-viral gene vectors based on nanoscaled polymer assemblies (polymeric micelles).
Polymeric micelles, which are spontaneously formed
from block copolymers, have a core containing
packaged genes surrounded by biocompatiblepoly(ethylene glycol) (PEG) palisades, and a varietyof pilot molecules can be installed on the surface ofpolymeric micelles. This "virusmimicking" nanoparticles might achieve efficient gene transfer to thetargeted tissues or cells because of protection of theloaded DNA from nuclease attack, their lowered
non-specific interaction with proteins and cells andfacilitated internalization by the targeted cells throughspecific interaction of the pilot molecules. Currently,
our research has been focused on in vivo gene transfer
to artery walls and muscles using polymeric micelles
incorporated genes.
Development of intraoperative navigation system
during rectal cancer surgery
Department of Surgical Oncology
Department of Precision Engineering, Bio-Medical
Precision Engineering Laboratory
Recently, less invasive laparoscopic surgery has
played a central part even in the field of pelvic surgery
including rectal surgery. Therefore, safer and more
effective surgical modalities are needed. In thisresearch department, we aim to develop theintraoperative tracking system corresponding topostural change, and to establish the intraoperative
real-time 3D display system which will enable
surgeons to recognize the location of the forceps
during rectal surgery through the use of preoperative
image information.

517

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17. Yoshii H., Onuma T., Yamazaki T., Watada H.,
Matsuhisa M., Matsumoto M., Kitagawa a K,
Kitakaze M., Yamasaki Y., Kawamori R.: Effectsof Pioglitazone on Macrovascular Events inPatients with Type 2 Diabetes Mellitus at High
Risk of Stroke: The PROFIT-J Study. J
Atheroscler Thromb. 21(6):563-73,2014
18. Lee, S.L., Hashimoto H., Kohro H., Horiguchi H.,
Koide D., Komuro I., Fushimi K., Yamazaki T.,
Yasunaga H.: Influence of Municipality-Level
Mean Income on Access to Aortic Valve
Surgery:A Cross-Sectional Observational Study
under Japan's Universal Health-Care Coverage.
PLOS ONE e111071:9,2014.
19. Ikeda Y., Shimada K., Teramoto T., Uchiyama S.,
Yamazaki T., Oikawa S., Sugawara M., Ando K.,
Murata M., Yokoyama K., Ishizuka N.: Low-Dose
Aspirin for Primary Prevention of Cardiovascular
Events in Japanese Patients 60 Years or Older
With Atherosclerotic Risk Factors. JAMA 312(23):2510-20,2014.
20. Moro T, Takatori Y, Kyomoto M, Ishihara K,
Hashimoto M, Ito H, Tanaka T, Oshima H, Tanaka
S, Kawaguchi H: Long-term hip simulator testingof the artificial hip joint bearing surface graftedwith biocompatible phospholipid polymer. J
Orthop Res 32(3): 369-376, 2014.
21. Moro T, Kyomoto M, Ishihara K, Saiga K,
Hashimoto M, Tanaka S, Ito H, Tanaka T, Oshima
H, Kawaguchi H, Takatori Y: Grafting of poly
(2-methacryloyloxyethyl phosphorylcholine) on
polyethylene liner in artificial hip joints reduces
production of wear particles. J Mechan Behav
Biomed Mater 31: 100-106, 2014.
22. Kyomoto M, Moro T, Yamane S, Watanabe K,
Hashimoto M, Takatori Y, Tanaka S, Ishihara K:
Poly(2-methacryloyloxyethyl phosphorylcholine)
grafting and vitamin E blending for high wear
resistance and oxidative stability of orthopedic
bearings. Biomaterials 35: 6677-6686, 2014.
23. Kyomoto M, Moro T, Yamane S, Hashimoto M,
Takatori Y, Ishihara K: Effect of UV-irradiation
intensityongraft
polymerizationof
2-methacryloyloxyethyl phosphorylcholine on
orthopedic bearing substrate. J Biomed Mater Res
A 102A: 3012–3023, 2014.

24. Kyomoto M, Moro T, Yamane S, Watanabe K,
Takatori Y, Tanaka S, Ishihara K: Smart PEEK
modified by self-Initiated surface graft polymerization for orthopedic bearings. Reconstructive
Review 4(3): 36-45, 2014.
25. Ichikawa Y, Kamiya M, Obata F, Miura M, Terai T,
Komatsu T, Ueno T, Hanaoka K, Nagano T, Urano
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Y, Tobita S, Urano Y, A spontaneously blinking
fluorophore based on intramolecular spirocyclization for live-cell super-resolution imaging.
Nat Chem, 6(8): 681-689, 2014.
27. Fujii T, Kamiya M, Urano Y, In Vivo Imaging of
Intraperitoneally Disseminated Tumors in Model
Mice by Using Activatable Fluorescent SmallMolecular Probes for Activity of Cathepsins.
Bioconjug Chem, 25:1838-1846, 2014.
28. Umeda N, Takahashi H, Kamiya M, Ueno T,
Komatsu T, Terai T, Hanaoka K, Nagano T, Urano
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29. Yoshida M, Kamiya M, Yamasoba T, Urano Y, A
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30. Akihiro Haga, Taiki Magome, Shigeharu Takenaka,Toshikazu Imae, Akira Sakumi, Akihiro Nomoto,
Hiroshi Igaki, Kenshiro Shiraishi, Hideomi
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32. Hideomi Yamashita, Wataru Takahashi, Akihiro
Haga, Satoshi Kida, Naoya Saotome, and Keiichi
Nakagawa, “Stereotactic Body Radiotherapy for
Small Lung Tumors in the University of Tokyo
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Volume 2014, Article ID 136513, 13 pages.
33. Akihiro Haga, Keiichi Nakagawa, Calvin Maurer,
Ken Ruchala, Edward Chao, Dylan Casey, Satoshi
Kida, Dousatsu Sakata, Masahiro Nakano, Taiki
Magome and Yoshitaka Masutani, “Reconstructionof the treatment area by use of sinogram in helicaltomotherapy”, Radiation Oncology, 9:252, 2014.
34. Yanagie H, Higashi S, Seguchi K, Ikushima I,
Fujihara M, Nonaka Y, Oyama K, Maruyama S,
Hatae R, Suzuki M, Masunaga S, Kinashi T,
Sakurai Y, Tanaka H, Kondo N, Narabayashi M,
Kajiyama T, Maruhashi A, Ono K, Nakajima J,
Ono M, Takahashi H, Eriguchi M. : Pilot clinicalstudy of boron neutron capture therapy for recurrent hepatic cancer involving the intra-arterial
injection of a (10) BSH-containing WOW
emulsion. Appl Radiat Isot. 2014 Jun;88:32-7.
35. Qiang G, Nakajima J. Simultaneous Stapling of
Pulmonary Vein and Bronchus in Video-Assisted
Thoracic Surgery Lobectomy. Ann Thorac
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Anraku M, Murakawa T, Nakajima J. Results ofbony chest wall reconstruction with expanded
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Cartwright, Junko Maeda,Colleen A. Brents,
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Uesaka, “Monoglucosyl-rutin as a possible
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39. Junko Maeda, Eruca J. Roybal, Colleen A. Brents,
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520

Department of Disaster Medical
Management
Professor
Masaomi Nangaku, 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 post as the first General Managerof the Department of Disaster Medical Management.
Also, in March 2013, Dr. Jun Tomio was assigned as
the Vice Manager of the Department of Disaster
Medical Management. Afterwards, in January 2015,
Professor Dr. Tadashi Iwanaka, the Hospital Vice
Director, was assigned post as the second General
Manager, and also Lecturer Dr. Masataka Gunshin, theEmergency Medicine Center Vice Director, wasassigned post as the second Vice Manager. Then, in
April 2015, Professor Dr. Masaomi Nangaku, theHospital Vice Director in charge of crisis managementand disaster prevention, was assigned post as the third
General Manager of the Department of Disaster
Medical Management and was appointed as thechairman 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. In
the year 2015, drills of launching a new earthquake
early warning system, building hospital headquarterfor disaster control, reporting in-hospital damage
situation, establishing triage and casualty clearing
station, triage and rescue mass casualties, andfirefighting, were performed with cooperation of the
University of Tokyo, the Metropolitan Tokyo Fire
Department, and the Japan DMATs dispatched by the
Ministry of Health Labor and Welfare.

Teaching activities
We have started “General Emergency and Disaster
Medicine Lecture” on a weekly basis for personnel
and junior residents and student physicians of thisuniversity hospital with cooperation of Emergency

521

Medicine Center and General Clinical Education
Center since January 2015.
As educational activities outside of the University,
we are teaching in the Japan DMAT workshops, AHA
life support courses, and NAEMT life support courses
for national and public universities to cooperate with
their development.

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 participating in outside
research groups and cooperating for mental healthcare at the time of disaster and establishment ofemergency medical system.

References
1. Inokuchi R, Gunshin M, et al: “Impact of a New
Medical Record System for Emergency Departments Designated to Accelerate Clinical Documentation: A Crossover Study.” Medicine. 7; 94:865. 2015
2. Inokuchi R, Gunshin M, et al: “Comparison of
intranasal and intravenous diazepam on statusepilepticus in stroke patients: a retrospective
study.” Medicine. 2; 94: 555. 2015
3. Wada T, Gunshin M, et al: “Effectiveness ofsurgical fixation on prolonged mechanical ventilation in patients with traumatic rib fracture: A
propensity score-matched analysis.” J Crit Care.
12; 30: 1227-31. 2015

522

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 in November, 2012 as asignificant step forward in enhancing The Universityof Tokyo Hospital’s development as an international
hub. Designated director position has been assigned
starting June 2013.

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. For example, amultilingual website has been opened since the end of
the fiscal year 2013 and there have been over 80,000
hits from 175 countries so far. Clinical trials ofmachine translation system have been also conducted.
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.

523

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

partial 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

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 was officiallyoutsourced to a foundation.
In 1957, the first nationwide meeting of nationaluniversity-hospital head dietitians was held at the
University of Tokyo with the aim of improving
patients’ diets.
In 1958, the complete food service was abolished.
Implementation of a standard food service and staffing
with a dietitian became required conditions, and thefood service section was staffed by a part-time section
chief and a dietitian. In 1962, a request from thenationwide meeting of national-university-hospitalhead dietitians, which primarily conducted its
activities at the University of Tokyo, was realized, andthe managerial dietitian system was established by a
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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 March 2015.

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, and whenever necessary members from other fields (pharmacists, medical technologists, physical therapists)
joined, and they held a hospital ward meeting once a
week. In 2010, an NST committee was created as aresult of the establishment of charges for NSTs. The
NST director up until that time became a member ofthe committee and played an active role as the centerof in-hospital NST activities. The addition of 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

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
131 guidance sessions in 2015.
In April 2014, the department started calculating
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of nutritional management procedure. The ratio ofcompletion reached 99.0% in March 2016.

charges for NST and counted 1261 instances in thefirst fiscal year, which reached 1529 instances in
2015.
In November 2014, the procedure manual of nutritional management was revised and an original twostep nutritional screening by physicians, managerial
dietitians, nurses and pharmacists was introduced. In
this system, the high-risk patients of malnutrition are
now screened through the common criteria in our
hospital and monitored by the medical team. The
high-risk patients picked up through this two-stepscreening are weekly referred to the NST of each floor.
In the fiscal year of 2015, 8923 instances weremonitored 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.

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 assessment inesophageal 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”

・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 aretrainees 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 Doctorin-training and Clinical Nutrition Seminar throughout
the year. The department also organizes NST
Conference and Joint Conference of Team Medicine
for case discussions to facilitate cooperation with eachfloor NST and other medical teams. In 2015, thedepartment
started“Nutritional
Management
e-learning” for all employee to learn basic knowledge

References<Publications (English)>
1. Takahara N, Isayama H, Nakai Y, Sasaki T, Saito
K, Hamada T, Mizuno S,Miyabayashi K, Mohri D,
Kogure H, Matsubara S, Yamamoto N, Hirano K,
Ijichi H, Tateishi K, Tada M, Koike K. Pancreaticcancer with malignant ascites: clinical featuresand outcomes. Pancreas. 2015 Apr;44(3):380-5.
2. Nakai Y, Isayama H, Sasaki T, Takahara N, Saito
K, Ishigaki K, Hamada T,Mizuno S, Miyabayashi
K, Yamamoto K, Mohri D, Kogure H, Yamamoto
N, Ijichi H,Tateishi K, Tada M, Koike K. The
inhibition of renin-angiotensin system in advanced pancreatic cancer: an exploratory analysis in
349 patients. J Cancer Res Clin Oncol. 2015 May;
141(5):933-9.
3. Asaoka Y, Ijichi H, Koike K. PD-1 Blockade in
Tumors with Mismatch-Repair Deficiency. N
Engl J Med. 2015 Nov 12;373(20):1979.
4. Hashimoto S, Kubota N, Sato H, Sasaki M,
Takamoto I, Kubota T, Nakaya K, Noda M, Ueki
K, Kadowaki T: Insulin Receptor Substrate-2(Irs2) in Endothelial Cells Plays a Crucial Role inInsulin Secretion. Diabetes 64(3):876-86, 2015
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Sentani, Naohide Oue, Wataru Yasui, Hideki
Ohdan: The generation of colorectal cancer mousemodel based on microsatellite instability and theidentification of transforming growth factor-beta
signal target.
3. AACR 106th Annual Meeting 2015, Philadelphia,
USA, 2015.4
Koji Miyabayashi, Hideaki Ijichi, Ryota
Takahashi, Keisuke Yamamoto, Yoshinari Asaoka,
Keisuke Tateishi, Yousuke Nakai, Hiroyuki
Isayama, Harold L Moses, Kazuhiko Koike: A
role of bone morphogenetic protein signaling inpancreatic cancer.
4. Digestive Disease Week 2015; Washington D.C.,
USA, 2015. 4
Sozaburo Ihara, Yoshihiro Hirata, Takako
Serizawa, Nobumi Suzuki, Hiroto Kinoshita,
Hayato Nakagawa, Hideaki Ijichi, Kazuhiko
Koike: Signaling Crosstalk Between TGF-β/Notch
on Dendritic Cells Governs Colonic Homeostasis
by Controlling Epithelial Differentiation andLuminal Microbiota.
5. Digestive Disease Week 2015; Washington D.C.,
USA, 2015. 4
Yoshihiro Hirata, Nobumi Suzuki, Hiroto
Kinoshita, Hideaki Ijichi, Kosuke Sakitani,
Sozaburo Ihara, Takako Serizawa, Hayato
Nakagawa, Kazuhiko Koike: Role of CDH1,
TGFβR2, and KRAS Mutations in the Carcinogenesis of Stomach.
6. The 16th congress of parenteral and enteralnutrition society of Asia; Nagoya, Japan, 2015.7
Kaori Kitakubo, Ai Otani: The roles of medical
staff in nutrition support.
7. Keystone Symposia on Molecular and Cellular
Biology, Diabetes: New Insights into Molecular
Mechanisms and Therapeutic Strategies (T2);
Kyoto, Japan, 2015.10
Tetsuya Kubota, Naoto Kubota, Mariko Inoue,
Iseki Takamoto, Toshimasa Yamauchi, Kohjiro
Ueki,
Takashi
Kadowaki:
Pioglitazone
ameliorates cuff-Induced neointimal formation byboth adiponectin-dependent and -independent
pathways.
8. 7th AASD Scientific Meeting and Annual Scientific
Meeting of the Hong Kong Society of
Endocrinology, Metabolism and Reproduction;

5. Nakatsu D, Horiuchi Y, Kano F, Noguchi Y,
Sugawara T, Takamoto I, Kubota N, Kadowaki T,
Murata M: L-cysteine reversibly inhibits glucoseinduced biphasic insulin secretion and ATP
production by inactivating PKM2. Proc Natl Acad
Sci U S A. 112(10): E1067-76, 2015
6. Katsuyama H, Kubota N, Kubota T, Haraguchi M,
Obata A, Takamoto I, Shigematsu K, Miyata T,
Ueki K, Kadowaki T: Effects of beraprost sodium,an oral prostacyclin analog, on insulin resistancein patients with type 2 diabetes. Diabetol. Int. 6:
39-45, 2015
7. Shibata S, Tada Y, Hau CS, Mitsui A, Kamata M,
Asano Y, Sugaya M, Kadono T, Masamoto Y,
Kurokawa M, Yamauchi T, Kubota N, Kadowaki
T, Sato S: Adiponectin regulates psoriasiform skininflammation by suppressing IL-17 production
from γδ-T cells. Nat Commun 6: 7687, 2015
8. Motonishi S, Nangaku M, Wada, T,Ishimoto Y,
Ohse T, Matsusaka T, Kubota N, Shimizu A,
Kadowaki T, Tobe K, Inagi R: Sirtuin1 Maintains
Actin Cytoskeleton by Deacetylation of Cortactin
in Injured Podocytes. J Am Soc Nephrol, 26(8):
1939-59, 2015
9. 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(3): 1029-42, 2016
<Academic meeting presentations (International).>1. The 3rd JSGE International Topic Conference inthe 101st Japanese Society of Gastroenterology
Annual Meeting. Tokyo, Japan, 2015.4
Hideaki Ijichi, Koji Miyabayashi, Ryota
Takahashi, Dai Mohri, Harold L Moses, Kazuhiko
Koike: Translational research of pancreatic cancer
using genetically-engineered mouse models.
2. AACR 106th Annual Meeting 2015, Philadelphia,
USA, 2015.4
Masashi Miguchi, Takao Hinoi, Manabu
Shimomura, Tomohiro Adachi, Yasufumi Saito,
Hiroaki Niitsu, Masatoshi Kochi, Yusuke
Sotomaru, Hideaki Ijichi, Tsuneo Ikenoue,
Kunitoshi Shigeyasu, Kohji Tanakaya, Kazuhiro
526

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Hong Kong, China, 2015.11
Naoto Kubota: Clarification of molecularmechanisms of type 2 diabetes using genetic
engineering techniques in mice.
＜Academic meeting presentations (Japan), etc＞
54 presentations in 2015
＜Publications (Japanese)＞
26 publications in 2015

527

Center for Disease Biology andIntegrative Medicine

529

Laboratory of Molecular
Biomedicine for Pathogenesis
Professor
Toru Miyazaki, M.D., Ph.D.

Associate Professor
Satoko Arai, Ph.D.

Assistant Professor
Daiji Sakata, 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-

530

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
Taiwan-Japan Joint Meeting was held at the Taipei
International Convention Center. Almost 40 participants including teaching staffs, graduate students,
undergraduates and researchers from three labs in
National Taiwan University, National Yang-Ming
University and Tokyo University attended to themeeting. Mainly young researcher and students madeoral and poster presentations on the latest researchfindings in their labs and then discussed their researchcontents. Having had the opportunity to makepresentations and have discussions on findings or theirwork in English, they were able to realize theimportance and pleasure of communication in the fieldof scientific research.
The CREST meeting, jointly-hosted by Kumamoto
University and Tokyo University was held in two
consecutive years.Teaching staffs, graduate students,
researchers from the two Universities participated in
the meeting and graduate students of Kyusyu Univ.
also participated in it for the first year only. All theparticipants have had a fulfilling time with substantial
presentations and lively discussions during the several
days meeting.
Those fruitful meetings were great opportunities for
all the participants, for they were able to experience
what they can rarely experience in other meetings.
They could build relationships for their future research,through participating dinners and get-togethers as well

as research sessions.
We plan to hold this kind of joint meetings
continuously, in future.
Seminar hosted by our lab (co-sponsorship: MPUTC)
Title: Regulation of Pathogen Survival and Immune
Responses through Coronin 1-MediatedActivation of Cell Surface Signaling ／ Jean
Pieters（Professor, Biozentrum, University ofBasel,Switzerland）
On January 2015, we organized an invited lecture by
Prof. Jean Pieters introducing his latest findings andfollowed by discussions with graduate students in ourlaboratory.
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 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.

531

DBELS WORKSHOPIn 2007, we had a workshop at Unzen, a great resort
place in Nagasaki prefecture. Along the policy for
DBELS, we invited 8 top scientists from Kyoto,
Tokyo, Hokkaido, Okinawa, and Boston as lecturers,
and many young participants as audiences. Staying ina beautiful resort hotel, we all had a scientifically andculturally fruitful time. The next workshop is
scheduled to be held in Switzerland, probably in 2010
summer.
Music and Science
On Jun 6, 2006, to commemorate the foundation of
our lab, we organized an invited recital by Mr Maestro
Krystian Zimerman, a world-famous pianist, followed
by a debate session on music and science between Mr.
Zimerman and Professor Miyazaki at Yasuda
Auditorium with more than 800 audiences.
Visiting Professors
We welcomed Prof. Wakeland from Southwestern
Medical Center at The University of Texas in fiscal
2006, 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
1. Miyazaki, T., Arai, S. Tricking an ancient immune
function to eradicate hepatocellular carcinomaMol Cell Oncol. 2, e985915 (2015).
2. Miyazaki, T., Arai, S. A defense system against
multiple diseases via biological garbage clearance
mediated by soluble scavenger proteins- Inflamm
Regen. 35, 203-209 ( 2015).

532

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Lecturers
Noriko Takahashi, M.D., Ph.D., Akiko Hayahsi-Takagi

Research Associates
Jun Noguchi, Ph.D., 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. 6) of this year in somedetail.

Teaching activities
We have 1 master course and 5 doctor course
students in 2015. 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).

533

Optogenetic probes can be used to manipulate
neuronal activity using light, but their targeting
resolution is limited to entire neurons or bundles ofprojections. Uncaging techniques can target individual
dendritic spines, but they cannot be used in vivo. We
have developed a probe for manipulating specificsubsets of dendritic spines in vivo. This technique willallow researchers to causally link experiencedependent changes in spines with behavior, elucidating subcellular mechanisms of learning and allowing
for manipulation of specific memories.
The probe is a modification of a photoactivatable formof the Rac1 small GTPase known as PaRac1. We took
advantage of PaRac1 because the prolonged activationof Rac1 could induce spine shrinkage. We fused
PaRac1 to an inactive membrane protein that localizes
to the post-synapse. They also added a targeting
element from Arc mRNA, which leads to selective
dendritic localization and translation of the mRNA in
response to NMDA glutamate receptor activation.
We demonstrated the utility of their probe inhippocampal slice cultures, confirming that it was
expressed specifically in spines activated by glutamate
uncaging or by other means. Once induced, probe
expression was maintained for about 2 days.
For us, the real impetus to develop this probe was tolook at the role of spines in behavior which we did inmice trained in a motor task known as the rotarod.
Learning the rotarod induces formation of new
dendritic spines in motor cortex and requires Arc. We
virally expressed the probe in the motor cortex andmonitored spine dynamics with two-photon imaging
through a cranial window, confirming that learning
induced the formation of new spines.
One day after training, photoactivation of PaRac1 with
an optical fiber through the cranial window led to
selective shrinkage of newly-formed spines. This
optical erasure of newly-formed spines in motor
cortex was sufficient to block motor improvement due
to training in subsequent behavioral tests. Re-training
in the same task (after optical erasure of spines) led tore-potentiation of the same ensemble of spines,
suggesting that the spines involved in rotarod training

were consistent over time.
Even more impressively, we were able to demonstrate
the specificity of spine ensembles to a particularbehavioral task. We sequentially trained mice on two
different motor tasks, the rotarod and beam, which led
to the activation of two partially overlapping
ensembles of spines. Optical erasure of spines
potentiated in beam training (once PaRac1 expression
in rotarod-potentiated spines had dissipated)
selectively disrupted performance on the beam, but
not the rotarod.
Dysfunctions in dendritic spines have been observedin numerous psychiatric disorders, but ascribing a
causal role to spine changes in disease
pathophysiology has been difficult. No matter how
well we would reveal the property of the dendritic
spines in some psychiatric disease model mice, thesestudies would not increase our understanding between
the spine and disease pathophysiology. That was
why we launched the project to manipulate the spines
systematically to challenge the causal relationship. We
plan to use their probe to investigate the role of spine
defects in post-traumatic stress disorder.

References
1. Hayashi-Takagi, A., Araki, Y., Nakamura, M.,
Vollrath, B., Duron, S.G., Yan, Z., Kasai, H.,
Huganir, R.L., Campbell, D.A., Sawa, A. (2014)
PAKs inhibitors ameliorate schizophreniaassociated dendritic spine deterioration in vitro
and in vivo during late adolescence. Proc. Natl.
Acad. Sci. U.S.A. 111, 6461-6.
2. Miyazaki, J., Tsurui, H., Hayashi-Takagi, A.,
Kasai, H. & Kobayashi, T. (2014). Sub-diffraction
resolution pump-probe microscopy with shotnoise limited sensitivity using laser diodes. Opt
Express 22:9024-32.
3. Boinapally, S., Huang, B., Abe, M., Katan, C.,
Noguchi, J., Watanabe, S., Kasai, H., Xue, B. &Kobayashi, T. (2014) Caged Glutamates with
π-Extended 1,2-Dihydronaphthalene Chromophore: Design, Synthesis, Two-Photon Absorption Property, and Photochemical Reactivity. J.
Organic Chemistry 79: 7822-7830.

534

4. Takehara, H. *, Nagaoka, A. *, Noguchi, J., Akagi,T., Kasai, H. & Ichiki, T. (2014). Lab-on-a-brain:
Implantable micro-optical fluidic devices forneural cell analysis in vivo. Scientific Report 4:6721.
5. Yagishita, S., Hayashi-Takagi, A., Ellis-Davies,
G.C.R., Urakubo, H., Ishii, S. & Kasai, H. (2014).
A critical time window for dopamine action on the
structural plasticity of dendritic spines. Science,
345:1616-1620.
6. 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.
7. 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.
8. 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.
Chemical Communications 52: 331-334.

535

Laboratory of Regenerative
Medical Engineering
Professor
Takashi Azuma, Ph.D.

Associate Professor
Taichi Ito, Ph.D.

Lecturer
Takayuki Akimoto, Ph.D.

Homepage

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

Introduction and Organization

Research activities

The Division is composed of two laboratories, Ushidalaboratory and Ito Laboratory. The Division tightly
collaborates with Faculty of Engineering. Prof. Ushidais also charged at Department of MechanicalEngineering, where the laboratory members include
Assistant Professor, two Associates and 15 graduate
students. Prof. Ito charged at Department of Chemical
System Engineering. The current laboratory members
include one JSPS postdoctoral fellow, and 12 graduate
students from Department of Chemical System
Engineering, Graduate School of Engineering.

Prof. Ushida’s laboratory aims to establish key
technologies for regenerative medicine. One of the
projects of our research targets the hard tissue
regeneration, such as cartilage or bone by tissue
engineering technology. Hard tissue engineering
requires the control of its shape in addition to the cell
accumulation and scaffold play a key role in meeting
this requirement. We focus on the development of
biocompatible materials such as synthetic polymer orinorganic materials combined with stem cell biotechnology. Secondly, we try to elucidate mechanismsof cellular responses to physical stimulations such ashydrostatic pressure, shear stress, stretch, throughobserving intracellular signaling, and to adopt thoseeffects to tissue engineering.
1) Tissue engineering of cartilage or bone defect- Design and development of biocompatible materials
for cartilage or bone using synthetic polymer,
inorganic materials or those combination.
- Development of osteoinductive biomaterials
hybridized with bioactive substances.
- Order made shaping of scaffolds by router system
according to the graphical images of tissue defects- Establishment of vascular rich graft bed bybiomaterials that spur new blood vessel growth.

Teaching activities
Prof. Ushida and Prof. Ito are sharing duties forundergraduate and graduate students of both Graduate
School of Medicine and Graduate School of Engineering. They give lectures on biomedical engineering at
Graduate School of Medicine. Prof. Ushida has also
lectures on tissue engineering, advanced biomaterials
and biomechanics at Graduate School of Engineering.
Prof. Ito gives a lecture concerning biosystemengineering, separation technology, and biotechnology
at the Chemical System Engineering course and Bioengineering course at Graduate School of Engineering
School.

5362) Cellular signal transduction induced by physicalstimulations- Hydrostatic pressure loading to chondrocytes orarticular cartilage- Shear stress loading to endothelial cells- Stretch loading to endothelial cells, smooth muscle
cells
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 are encapsulated
in various materials which achieve ideal releasekinetics. The functions of these biomaterials andphenomena inside and outside biomaterials in vivo arecomplicated both in terms of chemistry and biology.
Ito Laboratory is trying to design and develop novel
biomaterials for tissue engineering and drug delivery
by the combination of medicine and chemical systemengineering. Especially we focus on hydrogels which
can be utilized for islet regeneration and drug delivery
in peritoneum.
1) Biomaterials- Development of novel in situ crosslinked hydrogels
for a medical use using hyaluronan, chitosan,
dextran and synthetic dendritic polymers
2) Drug delivery- Peritoneal adhesion prevention by hydrogels- Peritoneal dissemination treatment by hydrogels- Hemostat by hydrogels
3) Tissue engineering- Hydrogel scaffolds to control cell development andvascular network constraction- Development of oxygen carriers by membraneemulsification

References(1) N. Syazwani, M. Shafig, T. Ushida, A. Azhim,
Simulation and Experimental Measurement of
Acoustic Intensity on Sonication and Decellularization using Sonication Treatment, Journal of
Signal Processing 19(4)179-182 (2015)(2) Hideyuki Suenaga, Katsuko S. Furukawa, Yukako
Suzuki, suyoshi Takato, Takashi Ushida, Boneregeneration in calvarial defects in a rat model by
implantation of human bone marrow-derived
mesenchymal stromal cell spheroids, J Mater Sci:
Mater Med 26:254-260 (2015)(3) S. Wada, Y. Kato, S. Sawada, K. Aizawa, J. H. Park,
A. P. Russell, T. Ushida, T. Akimoto. MicroRNA23a has minimal effect on endurance exerciseinduced adaptation of mouse skeletal muscle.
Pflügers Archiv, 467(2), 389-398, 2015
(4) Jeonghyun Kim, Kevin Montagne, Takashi Ushida,
Katsuko Furukawa, Enhanced chondrogenesis withupregulation of PKR using a novel hydrostaticpressure bioreactor, Biosci Biotechnol Biochem.,
79(2):239-41 (2015)(5) N. Syazwani, A. Azhim, Y. Morimoto, K. S.
Furukawa, T. Ushida, Decellularization of Aorta
Tissue Using Sonication Treatment as Potential
Scaffold for Vascular Tissue Engineering, Journalof Medical and Biological Engineering, 35(2),258-269 (2015)(6) Yoshiyuki Nakagawa, Yuki Amano, Satoshi
Nakasako, Seiichi Ohta, Taichi Ito “Biocompatible
Star Block Copolymer Hydrogel Cross-linked with
Calcium Ions” ACS Biomaterials Science andEngineering, 2015(1) 914-918(7) Yao-Tong Lai, Seiichi Ohta, Kazuki Akamatsu,
Shin-ichi Nakao, Yasuyuki Sakai, Taichi Ito “Size-dependent interaction of cells and hemoglobinalbumin based oxygen carriers prepared using theSPG
membraneemulsification
technique”
Biotechnology Progress, 2015(31) 1676-1684(8) Seiichi Ohta, Toru Nishiyama, Megumu Sakoda,
Kyoko Machioka, Masaya Fuke, Shigetoshi
Ichimura, Fuyuki Inagaki, Atsushi Shimizu, Kiyoshi
Hasegawa, Norihiro Kokudo, Makoto Kaneko,
Yutaka Yatomi, Taichi Ito “Development of
Carboxymethyl Cellulose Non-Woven Sheets as a
Novel Hemostatic Agent” Journal of Bioscienceand Bioengineering, 2015 119(6) 718-23

537

Laboratory of Clinical
Biotechnology
Professor
Kazunori Kataoka, Ph.D.

Associate Professor
Kanjiro Miyata, Ph.D.

Research Associate Professor
Keiji Itaka, M.D., Ph.D.

Assistant Professor
Yutaka Miura, Ph.D.

Homepage:

http://www.cdbim.m.u-tokyo.ac.jp/english/research/04.php
http://iconm.kawasaki-net.ne.jp/kklab/index-e.html

Introduction and Organization
Laboratory of Clinical Biotechnology in Center for
Disease Biology and Integrative Medicine (CDBIM)
was established in April 2003. This laboratory wishes
to contribute to the development of nanomedicine.
Our laboratory actively collaborates with Graduate
School of Engineering at The University of Tokyo andDivision of Tissue Engineering at The University ofTokyo Hospital. Our laboratory also participates in the
Graduate Program for Leaders in Life Innovation,
which started in 2012, for novel medicine-engineeringinterdisciplinary communication, and tries to produce
medical ventures by promoting liaison with theindustrial sector, and further, professionals who
understand both advanced medicine and nanotechnology. Our laboratory consists of one professor,
two associate professors, one assistant professor, andseveral project staff members.
Our laboratory particularly focuses on the development of nanomedicine. Nanotechnology, which has
been attracting tremendous attention as a leading
scientific field in the 21st century, attempts to process
and assemble materials with precision at the atomic/
molecular level to produce units with sophisticatedfunctionalities. Nanomachines, which are constructedby integrating materials and systems on a nanometerscale, hold the key to realizing the futuristic medical
system that can fulfill the needed function at the righttime and the right place with minimal invasiveness.
Furthermore, nanomachines are expected to become
an important interface between basic biomedical
science and clinical medicine by facilitating thetranslation of basic achievements into clinical applications. Our laboratory wishes to produce innovative
medical nanomachines based on nanotechnology,
spreading the idea of "Nanomedicine" internationally.

Teaching activities
Traditional medicine-engineering interdisciplinary
programs have focused on the exchange of researchers
and the promotion of collaborative researches between
these two different academic areas. However, the next
generation of medicine, such as "minimum-invasive
diagnosis-treatment" and "targeting medical treatment",
and also nanotechnologies are developing rapidly withincreased complexity, and thus scholars in both areasfind it hard to understand each other. This situation
prevents the effective development of revolutionary

538

medical diagnostic and therapeutic inventions. Ourlaboratory intends to provide an optimal milieu where
undergraduate and graduate students from both fieldsof medicine and engineering can study their fusionarea with respect to each other's background in orderto achieve the ultimate goal of developing smart
nanomachines for the futuristic medical system.

Research activities
Drug delivery to the target site of action is strongly
desired to enhance the drug function and minimize theside effects. In this regard, drug delivery systems
based on self-assemblies of block copolymers (i.e.,
polymeric micelles) have drawn much attention as oneof the medical applications of the nanotechnology.
Block copolymers spontaneously form polymeric
micelles, which consist of the core-shell structure withthe size of less than 100 nm, in aqueous media. The
core of the micelles behaves as a nanoreservoir for
drugs, while the coronal shell providing thebiocompatible surface. Polymeric micelles can
incorporate a variety of drugs including hydrophobic
drugs, metal complex drugs, and macromolecular
drugs such as proteins and DNA, and release them in asustained manner or in response to environmental
changes such as pH. The site-specific drug delivery
can be achieved by conjugation of the pilot moleculeson the surface of polymeric micelles. Thus, polymeric
micelles behave as smart chemical nanomachines forthe drug targeting.
The long-circulation of drug carriers is a requisite
for the successful drug targeting. The major obstacles
to long-circulation are considered to be glomerular
excretion in the kidney and recognition by thereticuloendothelial system (RES) located at the liver,spleen, and lung. Polymeric micelles can evade fromthose barriers in the body, resulting in stable blood
circulation. Another advantage of using polymeric
micelles is their preferential accumulation in solid
tumors, probably due to microvascular hyperpermeability and immature lymphatic system in tumor
tissues. We have succeeded in the tumor-selective
delivery of several antitumor drugs including
paclitaxel, cisplatin (CDDP), and oxaliplatin bypolymeric micelles, and observed enhanced antitumor
activity with reduced side effects. These micellar

formulations are currently being tested in clinical
trials.
Recently, plasmid DNA (pDNA), messenger RNA(mRNA), and small interfering RNA (siRNA) arehighlighted as promising tools for the treatment ofgenetic and intractable diseases. One of the major
requirements for therapeutic use of pDNA, mRNA,and siRNA is the development of nanovectors, which
can safely and effectively deliver them into specificcells and regulate their expressions. Recently, we have
prepared polymeric micelles incorporating siRNAthrough the electrostatic interaction between siRNAand positively charged block copolymers. The
polymeric micelles protected the loaded siRNA fromdegradation by nuclease attack and showed efficientgene silencing in a variety of cells. Also, various smart
functionalities, such as targeting ability andenvironmental sensitivity, can be integrated intopolymeric micelles, providing the opportunities todevelop effective synthetic nanovectors resemblingviruses. Thus, polymeric micelles are expected as
useful nanocarriers of nucleic acid drugs for in vivo
application.

References
1. J. Makino, H. Cabral, Y. Miura, Y. Matsumoto, M.
Wang, H. Kinoh, Y. Mochida, N. Nishiyama, K.
Kataoka, cRGD-installed polymeric micellesloading platinum anticancer drugs enable cooperative treatment against lymph node metastasis.
J. Control. Release 220 783-791 (2015)
2. M. Murakami, K. Nishina, C. Watanabe, K. Y.
Tanaka, W. Piao, H. Kuwahara, Y. Horikiri, K.
Miyata, N. Nishiyama, K. Kataoka, M. Yoshida,
H. Mizusawa, T. Yokota, Enteral siRNA delivery
technique for therapeutic gene silencing in theliver via the lymphatic route. Sci. Rep. 5 17035(2015)
3. O. F. Mutaf, A. Kishimura, Y. Mochida, A. Kim,
K. Kataoka, Induction of secondary structure
through micellization of an oppositely charged
pair of homochiral block- and homopolypeptides
in an aqueous medium. Macromol. Rapid
Commun. 36 1958-1964 (2015)
4. Y. Miura, A. B. Tsuji, A. Sugyo, H. Sudo, I. Aoki,
M. Inubushi, M. Yashiro, K. Hirakawa, H. Cabral,

539

N. Nishiyama, T. Saga, K. Kataoka, Polymeric
micelle platform for multimodal tomographic
imaging to detect scirrhous gastric cancer. ACS
Biomater. Sci. Eng. 1 1067-1076 (2015)
5. A. Matsui, S. Uchida, T. Ishii, K. Itaka, K.
Kataoka, Messenger RNA-based therapeutics forthe treatment of apoptosis-associated diseases. Sci.
Rep. 5 15810 (2015)
6. Y. Li, K. Osada, Q. Chen, T. A. Tockary, A.
Dirisala, K. M. Takeda, S. Uchida, K. Nagata, K.
Itaka, K. Kataoka, Toroidal packaging of pDNA
into block ionomer micelles exerting promoted invivo gene expression. Biomacromolecules 16
2664-2671 (2015)
7. K. S. -Kato, K. Nanjo, H. Kusuhara, N.
Nishiyama, K. Kataoka, T. Kawanishi, H. Okuda,
Y. Goda, Effect of knockout of Mdr1a and Mdr1b
ABCB1 genes on the systemic exposure of adoxorubicin-conjugated block copolymer in mice.
Mol. Pharmaceutics 12 19 3175-3183 (2015)
8. T. Okuda, Y. Suzuki, Y. Kobayashi, T. Ishii, S.
Uchida, K. Itaka, K. Kataoka, H. Okamoto,Development of biodegradable polycation-based
inhalable dry gene powders by spray freeze drying.
Pharmaceutics 7 233-254 (2015)
9. K. Nishina, W. Piao, K. Y-Tanaka, Y. Sujino, T.
Nishina, T. Yamamoto, K. Nitta, K. Yoshioka, H.
Kuwahara, H. Yasuhara, T. Baba, F. Ono, K.
Miyata, K. Miyake, P. P. Seth, A. Low, M.
Yoshida, C. F. Bennett, K. Kataoka, H. Mizusawa,
S. Obika, T. Yokota, DNA/RNA heteroduplex
oligonucleotide for highly efficient gene silencing.
Nat. Commun. 6 7969 (2015) (DOI: 10.1038/
ncomms8969)
10. K. Itaka, S. Uchida, A. Matsui, K. Yanagihara, M.
Ikegami, T. Endo, T. Ishii, K. Kataoka, Genetransfection toward spheroid cells on micropatterned culture plates for genetically-modified
cell transplantation. JoVE 101 e52384 (2015)11. S. Uchida, K. Kataoka, K. Itaka, Screening ofmRNA chemical modification to maximize protein expression with reduced immunogenicity.
Pharmaceutics 7 137-151 (2015)12. J. Li, Q. Chen, Z. Zha, H. Li, K. Toh, A. Dirisala,Y. Matsumoto, K. Osada, K. Kataoka, Z. Ge,
Ternary polyplex micelles with PEG shells andintermediate barrier to complexed DNA cores for

efficient systemic gene delivery. J. Control.
Release 209 77-87 (2015)
13. N. Q. Vinh, S. Naka, H. Cabral, H. Murayama, S.
Kaida, K. Kataoka, S. Morikawa, T. Tani,
MRI-detectable polymeric micelles incorporating
platinum anticancer drugs enhance survival in anadvanced hepatocellular carcinoma model. Int. J.
Nanomedicine 10 4137-4147 (2015)14. P. Mi, N. Dewi, H. Yanagie, D. Kokuryo, M.
Suzuki, Y. Sakurai, Y. Li, I. Aoki, K. Ono, H.
Takahashi, H. Cabral, N. Nishiyama, K. Kataoka,
Hybrid calcium phosphate-polymeric micelles
incorporating gadolinium chelates for imagingguided gadolinium neutron capture tumor therapy.
ACS Nano 9 5913-5921 (2015)
15. W. Kawamura, Y. Miura, D. Kokuryo, K. Toh, N.
Yamada, T. Nomoto, Y. Matsumoto, D. Sueyoshi,
X. Liu, I. Aoki, M. R. Kano, N. Nishiyama, T.
Saga, A. Kishimura, K. Kataoka, Density-tunable
conjugation of cyclic RGD ligands with polyion
complex vesicles for the neovascular imaging oforthotopic glioblastomas. Sci. Technol. Adv.
Mater. 16 035004 (2015)
16. L. Cui, K. Osada, A. Imaizumi, K. Kataoka, K.
Nakano, Feasibility of a subcutaneously administered block/homo-mixed polyplex micelle as acarrier for DNA vaccination in a mouse tumor
model. J. Control. Release 206 220-231 (2015)17. H. Cabral, J. Makino, Y. Matsumoto, P. Mi, H.
Wu, T. Nomoto, K. Toh, N. Yamada, Y. Higuchi,
S. Konishi, M. R. Kano, H. Nishihara, Y. Miura,
N. Nishiyama, K. Kataoka, Systemic targeting oflymph node metastasis through the blood vascularsystem by using size-controlled nanocarriers. ACS
Nano 9 4957-4967 (2015)18. H. Ogawa, X. Wu, K. Kawamoto, N. Nishida, M.
Konno, J. Koseki, H. Matsui, K. Noguchi, N.
Gotoh, T. Yamamoto, K. Miyata, N. Nishiyama,
H. Nagano, H. Yamamoto, S. Obika, K. Kataoka,
Y. Doki, M. Mori, H. Ishii, MicroRNAs induce
epigenetic reprogramming and suppress malignant
phenotypes of human colon cancer cells. PLOS
ONE 10 e0127119 (2015)
19. Q. Chen, K. Osada, M. Pennisi, S. Uchida, T. A.
Tockary, A. Dirisala, Y. Li, K. M. Takeda, S.
Oniyanagi, K. Itaka, K. Kataoka, A tadpoleshaped gene carrier with distinct phase segrega-

540

tion in a ternary polymeric micelle. Soft Matter 112718-2722 (2015)
20. M. Baba, K. Itaka, K. Kondo, T. Yamasoba, K.
Kataoka, Treatment of neurological disorders byintroducing mRNA in vivo using polyplex nanomicelles. J. Control. Release 201 41-48 (2015)21. D. R. Christianson, A. S. Dobroff, B. Proneth, A.
J. Zurita, A. Salameh, E. Dondossola, J. Makino,
C. G. Bologa, T. L. Smith, V. J. Yao, T. L.
Calderone, D. J. O'Connell, T. I. Oprea, K.
Kataoka, D. J. Cahill, J. E. Gershenwald, R. L.
Sidman, W. Arap, R. Pasqualini, Ligand-directed
targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis. Proc. Natl.
Acad. Sci. USA. 112 2521-2526 (2015)22. H. Gao, H. Takemoto, Q. Chen, M. Naito, H.
Uchida, X. Liu, K. Miyata, K. Kataoka, Regulated
protonation of polyaspartamide derivatives bearing repeated aminoethylene side chains for
efficient intracellular siRNA delivery with minimal cytotoxicity. Chem. Commun. 51 3158-3161(2015)
23. K. Hayakawa, S. Uchida, T. Ogata, S. Tanaka, K.
Kataoka, K. Itaka, Intrathecal injection of atherapeutic gene-containing polyplex to treat
spinal cord injury. J. Control. Release 197 1-9(2015)
24. J. -Y. Ahn, Y. Miura, N. Yamada, T. Chida, X.
Liu, A. Kim, R. Sato, R. Tsumura, Y. Koga, M.
Yasunaga, N. Nishiyama, Y. Matsumura, H.
Cabral, K. Kataoka, Antibody fragmentconjugated polymeric micelles incorporating
platinum drugs for targeted therapy of pancreaticcancer. Biomaterials 39 23-30 (2015)25. S. Mitragotri, D. G. Anderson, X. Chen, E. K.
Chow, D. Ho, A. V. Kabanov, J. M. Karp, K.
Kataoka, C. A. Mirkin, S. H. Petrosko, J. Shi, M.
M. Stevens, S. Sun, S. Teoh, S. S. Venkatraman,
Y. Xia, S. Wang, Z. Gu, C. Xu, Accelerating thetranslation of nanomaterials in biomedicine. ACS
Nano 9 6644-6654 (2015)
26. K. S. -Kato, N. Nishiyama, M. Kozaki, T.
Nakanishi, Y. Matsuda, M. Hirano, H. Hanada, S.
Hisada, H. Onodera, H. Harashima, Y. Matsumura,
K. Kataoka, Y. Goda, H. Okuda, T. Kawanishi,
General considerations regarding the in vitro andin vivo properties of block copolymer micelleproducts and their evaluation. J. Control. Release
210 76-83 (2015)

541

Laboratory of Environmental
Health Sciences
Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Homepage

http://www.soohsakoss.jp/

Introduction and Organization
Laboratory of Environmental Health Sciences wasestablished as a department of the Center for Disease
Biology and Integrative medicine form January 1th
2005. After 11 years of the laboratory activity in the
research and education in the environmental
toxicology, many staffs left away from this laboratory.
An Associate Professor continues to do research in thesame laboratory with one project researcher, one
doctoral course graduate student, one master course
student, and two visiting undergraduate students.
The laboratory officially belongs to Department ofSocial Medicine and works as cooperation course of
Department of International Health and School of
Public Health.

Research Aims
Several members in the Environmental Health
Science laboratory were transferred from the National
Institute for Environmental Studies about one decadeago. The members have been engaged in research of
the influence on fetal or neonatal low-concentration
exposure to environmental pollution chemical. Such
exposure during the vulnerable developmental time
period occasionally induce the pathogenesis anddevelopmental disorders of adult life. The orthodox
commitment in study to reveal toxic effects are
employed in our group by using animal experimental
models, as well as related molecular mechanisms.
Recently, DOHaD (Developmental Origins of Healthand Disease), the study of academic concept has been
generalized. Chemical exposure is regarded as animportant environmental factor in DOHaD research.
Until now this laboratory, dioxin (TCDD), bisphenol
A (BPA), pesticides, etc., as model compounds which
are exposed non-intentionally from the environment,
were administered to pregnant mice in which the fetus
and pups has been born with adverse effects.
Dioxin issue seems to have subsided bystrengthening installation standards of the incinerator,
however, molecular mechanisms of its various
toxicities are often controversial particularly withregard to endocrine-disrupting mechanism. Also effectof BPA, a plasticizer material used all over the world,on the reproductive function and brain development
has been shown experimentally. In recent years,
Canada, in Europe, regulations are becoming stricter.
Although pesticides neonicotinoids were subjected
regulation it has been pointed out in Europe early is
the cause of colony collapse disorder in order to exert
toxicity to target the bees of the nervous system.
However in Japan, such a regulation is not present
under the present circumstances.
The above-mentioned material is merely an
example. In the world tens of thousands chemical
substances those toxic effects are still unknown, areconstantly emerging, has spread globally. Each timethat regulations have become a necessity of theprocess for modern civilization have a scientific basis.
The mission of this division performs a washout ofcompounds before that occurs the actual damage ofthe ecological impact and health effects. To this aim,
we assess if there is any biological effects of thesechemicals from animal experiments.

542

Research activities
As to the study on epigenetic toxicology, we havebeen studying why mice born to dams that wereadministered dioxin during gestation are prone todevelop cancer. We found that the mice that were
exposed to dioxin in utero had the enhanced
hypomethylated status in CpG as well as histone
modifications in a specific region of the promoter ofa drug metabolizing enzyme Cyp1a1. Moreover we
attempted to utilization of mouse and humanembryonic stem cells (Esc). Here a part of studies
done by a PhD course student, Amenya Hesbon, ispresented below.
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a
potent Ahr ligand, may elicit robust epigenetic
switching at the Ahr target gene Cyp1a1. Given that
epigenetic changes can be stably passed throughmitotic divisions. TCDD-induced epigenetic alterations can be maintained long after TCDD exposure,and these may have a significant impact on Cyp1a1
inducibility.
A single dose of TCDD elicited Cyp1a1transcriptional memory in the adult mouse liver, as
evidenced by a three-fold super-induction of Cyp1a1
in dioxin pre-treated animals. Notably, acute Ahr
activation led to rapid Cyp1a1 promoter DNA
demethylation, increases in H3K4me3, H4ac and aloss of H4K20me3 in Ahr+/+ but not in Ahr-/- mice.
These epigenetic changes persisted to 40 days post
TCDD treatment, and constituted the epigenetic
memory of initial TCDD exposure. In addition, Ahrrecruited thymine DNA glycosylase (Tdg), an active
demethylation factor, to the Cyp1a1 promoter within
24 hrs after dioxin exposure. Further analysis usingsiRNA knockdown revealed that Ahr was requiredalongside the demethylation proteins (ten-eleventranslocation methyldioxygenases) Tet2, Tet3 and Tdg
in the initial Cyp1a1 promoter DNA demethylation.
These results provide novel evidence that Ahr
drives epigenetic modulation and memorization at the
Cyp1a1 promoter and suggests that Cyp1a1 transcriptional memory may play a role in adaptive response todioxin exposure. Maintenance of this hypomethylated
state and open chromatin conformation contributed to
Cyp1a1 transcriptional memory. Therefore, thehistone modifications as well as DNA hypo-

methylation co-existed as epigenetic bookmarks for
Cyp1a1 super-induction in dioxin re-exposed animals.
Transcriptional memory of the Cyp1a1 gene may
imply increased detoxification of endogenous Cyp1a1
substrates or increased activation of procarcinogens tocarcinogenic metabolites. Since Ahr directed theactive DNA demethylation machinery to the Cyp1a1
promoter, it can be anticipated that there is widespread
epigenetic modulation of other Ahr target genes,
although in a cell or tissue specific manner. Taken
together, these findings highlight the importance of
epigenetic mechanisms in downstream Ahr signaling
and target gene regulation and indicate the possibilityof wider roles of epigenetic memory in xenobiotic
tolerance.

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)
Doctor Course in the Graduate School of Medicine:
Environmental Health Sciences (Laboratory Practiceand Seminars)

543

Publications
Invited Presentation:
Seiichiroh Ohsako, Hesbon Amenya, Chiharu
Tohyama. Perinatal exposure to dioxins alters theepigenomic program that influences the susceptibility
to carcinogens exposed in adulthood. The 7thInternational Congress of Asian Society of Toxicology,(2015) June 25th, Jeju International Convention
Center, Jeju, Korea
Patent:Hideko Sone, Seiichiroh Ohsako, Reiko Nagano,
Satoshi Imanishi, and Wataru Miyazaki. Methods forevaluating the impact on fetal programming. Patentpublication number 2010-227079, Patent number
100078662, JP, Acquisition of rights in 2015, Japan544

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.

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 5
teaching staffs, 4 technical support staffs, an assistantmanager of CDBIM, an administrative staff, a project
academic support specialist, 6 assistant laboratory
animal technicians, and 4 assistant clerks. In addition,
about 10 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 661at the end of academic year 2015.
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.

545

1. Generation of mutant marmoset
Common marmoset (Callithrix jacchus) is a nonhuman primate and recently used for humanmodel, especially focusing on brain function. We
have established the techniques for in vitro
fertilization and introducing DNA and/or RNA
into embryos from marmosets. We successfully
introduced mutations for CAMK2A, GAD1 andAAVS1 loci of marmoset embryos using the
CRISPR/Cas system or TALENs. We are currently
generating knock-in marmosets in these loci andthe human disease model marmosets in which
mTOR pathway is constitutively activated.
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 successfully generated knock-in mice by using
microhomology-mediated end joining (MMEJ).
Because he MMEJ system requires only 10-bp
homology arms for 5’ and 3’ of inserted DNA
fragments are required and thus is suitable for rapid
generation of KI mice.
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 founder mice, we are generating Clstn
triple KO mice.

4. Selective activation of mTORC1 signaling in thebrain
Mammalian target of rapamycin (mTOR) has been
implicated in human neurological diseases such as
tuberous sclerosis complex (TSC), neurodegeneration
and autism. However, little is known as to when andhow mTOR involved in pathogenesis of these diseases
because of a lack of animal models that directly
increase mTOR activity. We generated transgenic miceexpressing a gain-of-function mutant of mTOR
specifically in cerebellar Purkinje cells in a temporally
controlled manner (L7-mTOR Tg). Activation ofmTORC1 pathway resulted in abnormal tiling of
Purkinje cell dendrites. We are also investigatingnovel mTOR interacting molecules by generation andanalysis of mutant mice lacking these molecules.
5. Role of PKC in mGluR1-inducing melanomas
We previously demonstrated that ectopic expression of
metabotropic glutamate receptor subtype-1 (mGluR1)
induces melanoma formation in mice. We generated
mGluR1 expressed under the control of dopachrome
tautomerase (Dct) promoter (Dct-mGluR1 Tg) andfound all Tg mice generated melanomas. To elucidate
molecular mechanisms underlying mGluR1-induced
melanoma formation, we introduced PKCα mutations
into mGluR1 Dct-mGluR1 Tg. We found that PKCαmutation retarded melanoma formation, suggestingthat the PKCα could be a therapeutic target formelanoma.

References
1. Suzuki W, Yamada A, Aizawa R, Suzuki D,
Nakayama M, Maki K, Takeda S, Yamamoto M,
Aiba A, Baba K, and Kamijo R. Cdc42 is essential
for cartilage development during endochondral
ossification. Endocrinology. 2015 Jan; 156(1):314-322.
2. Mizutani E, Oikawa M, Kassai H, Inoue K, Shiura
H, Hirasawa R, Kamimura S, Matoba S, Ogonuki
N, Nagatomo H, Abe K, Wakayama T, Aiba A andOgura A. Generation of Cloned Mice from Adult
Neurons by Direct Nuclear Transfer. Biol Reprod.
2015 Mar; 92(3):81.
3. Takenaka N, Sumi Y, Matsuda K, Fujita J,
Hosooka T, Noguchi T, Aiba A, and Satoh T.Role

546

for RalA downstream of Rac1 in skeletal muscle
insulin signaling. Biochem J. 2015 Aug; 469(3):445-454.
4. Ayuzawa N, Nagase M, Ueda K, Nishimoto M,
Kawarazaki W, Marumo T, Aiba A, Sakurai T,
Shindo T, and Fujita T. Rac1-Mediated Activationof Mineralocorticoid Receptor in Pressure
Overload-Induced Cardiac Injury. Hypertension.
2015 Dec; 67(1): 99-106.

547

Laboratory of Molecular Radiology
Professor
Kiyoshi Miyagawa, M.D., Ph.D.

Lecturer
Noriko Hosoya, M.D., Ph.D., Atsushi Enomoto, Ph.D.

AssociateShuji Inada, M.D., Ph.D., Takaaki Yasuhara, Ph.D., Claudia Juliane Krause, Ph.D. (Project)

Homepage

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

Introduction and Organization
This laboratory was renamed as the Laboratory of
Molecular Radiology in 2008 to strengthen research
activities. The main duty to support the use ofradioisotope at Graduate School of Medicine has been
also continued. Historically, in 2003, the Departmentof Radiation Oncology and the Radiation ResearchInstitute were joined to form a new department.
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 ourdepartment. This year, the hospital radioisotope
research facility was closed to prepare the opening of
the new facility in CRC.

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
DSBs.
While
nonhomologous
endjoining,
microhomology-mediatedendjoining,andsingle-strand annealing are error-prone repair
pathways, homologous recombination (HR) is an548

error-free pathway in principle using newly replicatedDNA as a template for the repair. There isaccumulating evidence that defective HR plays a rolein tumor development. For example, BRCA1 andBRCA2, tumor suppressors in hereditary breast andovarian cancers, 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. Fukasawa T, Enomoto A, Miyagawa K: SerineThreonine Kinase 38 regulates CDC25A stability
and the DNA damage-induced G2/M checkpoint.
Cell Signal 27:1569-1575, 2015
2. Nagai Y, Yamamoto Y, Yasuhara T, Hata K,
Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T,
Kawai K, Nozawa H, Kazama S, Yamaguchi H,
Ishihara S, Sunami E, Yamanaka T, Miyagawa K,
Watanabe T: High RAD54B expression: an
independent predictor of postoperative distant

549

3.

4.

5.

6.

recurrence in colorectal cancer patients.
Oncotarget 6:21064-21073, 2015
Ito T, Hanafusa N, Iwase S, Noiri E, Nangaku M,
Nakagawa K, Miyagawa K: Effects of cell-freeand concentrated ascites reinfusion therapy(CART) on symptom relief of malignancy-related
ascites. Int J Clin Oncol 20:623-628, 2015
Hosoya N, Miyagawa K: The DNA damage
responses: important determinants of thebiological responses to radiation. J Integ CreatStud 1:01503002, 2015
Miyasaka A, Oda K, Ikeda Y, Sone K, Fukuda T,
Inaba K, Makii C, Enomoto A, Hosoya N,
Tanikawa M, Uehara Y, Arimoto T, Kuramoto H,
Wada-Hiraike O, Miyagawa K, Yano T, Kawana K,
Osuga Y, Fujii T: PI3K/mTOR pathway inhibition
overcomes radioresistance via suppression of the
HIF1-α/VEGF pathway in endometrial cancer.
Gynecol Oncol. 138:174-180, 2015
Morikawa M, Shirai Y, Ochiai R, Miyagawa K:
Barriers to the collaboration between hematologists and palliative care teams on relapse or
refractory leukemia and malignant lymphoma
patients' care: a qualitative study. Am J Hosp
Palliat Care pii: 1049909115611081, 2015

550

Office ofInternational Academic Affairs
HeadYasuyuki Seto

Assistant Professor
Joseph Green
Toshiyuki Maruyama
Christopher Holmes

Homepage

http://koryu.m.u-tokyo.ac.jp/homepage10.html

Status and functions
The Office of International Academic Affairs isunder the direct authority of the Dean of the Facultyof Medicine. Its three most important roles, as definedby the Committee on International Academic Affairs,
are i) international educational exchange, ii)
international contacts in research and scientific fields,
and iii) international cooperation in health care andmedicine.

Activities
This document reports on the office's activities inthese areas over the academic year 2015 (April 1,2015 through March 31, 2016).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2015, there were 102 foreign students (34countries) 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 53 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 2015, at the
Sanjo Kaikan, a reception hall on the Hongo campus.
The annual Ryugakusei Ronbun Contest was first
held in 1999. As in previous years, in the 2015
Contest foreign students gave oral presentations basedon their research papers to interested fellow students
and faculty, and the two best speakers were given
awards.
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 of551

Pennsylvania, 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
University of Tokyo and Johns Hopkins University inDecember 2002. Since the start of the program in
2002, twenty eight University of Tokyo students
visited 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, nineteen University of Tokyo
students have attended clinical electives at the
University of Michigan Medical School, and nine
students from the University of Michigan have taken
clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and Munich University in
February 2005. Since the start of the program in 2005,
fourteen University of Tokyo students visited to attend
research electives at Munich University, and nine
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 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, four University ofTokyo students visited to attend clinical electives at
National Taiwan University and six 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, two University of Tokyo students visited toattend 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 the Sydney Medical School
in June 2015. Since the start of the program in 2015,
three University of Tokyo students visited to attend
clinical electives at Sydney Medical School and three
students from Sydney Medical School have taken
clinical electives at the University of Tokyo.
1.2 Counseling University of Tokyo medical students
and researchers about short-term and longer overseas
study programs
Every year, about 36 requests from students forcounseling regarding pre-graduation or postgraduation studies abroad are received by the Officeof International Academic Affairs. The office
responds to these requests by providing information,
advice, and letters of recommendation.

2. Education and research
3.1 Education
In 2015, 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-levelclasses: International Epidemiology 1 and 2.
Mr. Christopher Holmes taught Medical English 1,
2, and 3, the first two of which are required for all
medical students.
The Office also organized classes in English for the
Health Sciences.
In 2015, Dr. Green and Mr. Holmes led ad hoc
sessions in Oral Presentation Training. These sessions
were open to all students and teaching staff in the
Graduate School of Medicine and the Faculty of
Medicine.
3.2 References
1. Nanishi K, Green J, Taguri M, Jimba M (2015)
Determining a Cut-Off Point for Scores of the552

Breastfeeding Self-Efficacy Scale–Short Form:
Secondary Data Analysis of an Intervention Studyin Japan. PLoS ONE 10(6): e0129698. doi:10.
1371/ journal.pone.0129698 [Published: June 24,
2015]
2. Kojima T, Green J, Barron JP. Conflict-of-interest
disclosure at medical journals in Japan: anationwide survey of the practices of journal
secretariats. BMJ Open 2015;5:e007957. doi:10.
1136/bmjopen-2015- 007957
3. Hongo H, Green J, Nanishi K, Jimba M.
Development of the revised Japanese Maternal
Breastfeeding Evaluation Scale, short version.
Asia Pacific Journal of Clinical Nutrition. doi: 10.
6133/apjcn.032016.08 Published online: March
2016.
4. 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 Nutrition. 2016 May 16:
1-9 [Epub ahead of print]. doi:10.1017/
S136898001600094X. Accepted 30 March 2016.

553

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 90
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 90
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

554

research and courses of medical researchcommunications are held every 1 to 2 weeks. In thejournal club, students are trained to critically readrecent scientific papers published in top journals,
often in the presence of the first authors, if they areavailable. In medical research communications
courses, the students discuss scientific topics andresearch issues with a native English speaker with astrong research background.
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 experience inforeign laboratories
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 2015, a total of 10 students
received the Program’s support for carrying out
research abroad (in US, Europe and Australasia) for
more than a month and to present their researchachievements at international scientific meetings.
2) Organizing an MD scientist training program
retreat
A MDSTP retreat was held on March, 26-27, 2016 topresent ongoing research progress in a closed meeting
among peers. More than 50 participants, mostly
medical school students, but also some medical
interns, graduate students and Program-affiliatedprofessors attended it. Lively discussions among peers
were exciting throughout the meeting and thefeedback from all participants was outstanding andunequivocal in emphasizing the critical importance fora research progress retreat to promote their future
research projects. One important aspect of the retreat
was to provide students, interns and professors to
discuss opportunities in various career paths available
in the basic medical research field.
3) Cooperating with other medical universities acrossJapan
With the availability of governmental support from2011 on, the MDSTP at the University of Tokyo has
been in close touch with sister organizations at Kyoto
University, Osaka University and Nagoya University.
With a view to enhancing collaborative efforts inimproving the basic medical research training at the 4
medical schools, 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 2015, this was held on
August, 17-18 in Tokyo under the auspices of Chiba
University. Around 70 people participated in theretreat and presented their ongoing research progress
and future plans.

Activities (2015)
The number of registered students: 92 (3rd grade: 37,
4th: 17, 5th: 23, 6th: 15)
Lectures for students in Years 1 and 2
Introduction to Medical Biology: 13 lectures
Group reading of Molecular Biology of the Cell: 13
lectures555

Seminar for students (in Year 3 or above)
Journal Club for basic medical research: 9 lectures
Medical Research Communications: 50 lectures
Presentation of research progress: 3 times (including
the retreat of MD scientist training program in the
University of Tokyo)
The number of students receiving travel supports forresearch activities abroad: 10
The number of Year 6 students who passed theirhonors thesis defense: 5 (the Dean’s Prize wasawarded to 2 students)

556

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" and the ninth “theColon” followed.
Since the opening of the Museum, more than
96,047 people had visited by the end of FY2015.

557

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.

558

Office for Research Ethics Support(ORES)
Professor (Director of ORES)
Yutaka Yatomi, M.D., Ph.D.

Professor (Vice Director of ORES)
Akira Akabayashi, M.D., Ph.D.

Lecturer
Yuzaburo Uetake, M.D., Ph.D.

Homepage: http://www.m.u-tokyo.ac.jp/ethics/index.html
Top page of online application system: https://u-tokyo.bvits.com/esct/
Introduction and Organization
The Office for Research Ethics Support (ORES) wasestablished in October 2009 for the advancement ofresearch ethics standards. ORES aims to protect therights, health, and dignity of research participants.
Based on this principle, ORES 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,
ORES 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 and invasive intervention studies),
at Graduate School of Medicine and Faculty of
Medicine, the University of Tokyo and the University of Tokyo Hospital. Correspond in response tovarious 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 2015
・Research Ethics Committee:
341 new applications, 552 minor alterations ofapproved studies, and 76 documentary examinations
・Human Genome, Gene Analysis Research Ethics
Committee:
27 new applications, 153 minor alterations ofapproved studies

559

Department of Biomedical ethics, which is acooperative department.

Though ORES 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.
ORES operates an online application system andcontributes to the convenience of applicants and toenable them to efficiently plan their researchobligations.

Teaching and training activities
ORES 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 2015 with 1411 people attended.
ORES 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.
ORES also aims to advance research ethics standards
by cooperating and consulting with Ethics Consultant
specified by each laboratory.

Research activities
At present, ORES is a business section. For more
information about the research, see the contents of560

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 the instruction
department and the office for student assistance in thefaculty of medicine. The office now consists of ageneral manager (professor), an assistant professor,
and three clerical assistants.

Activities
Before clinical clerkship begins in February 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 a student who has some problems, 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 from
them.

561

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.

562

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. Malathi Srinivasan