ISSN 1883-9606

2015

Vol.131

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2014 ---- March 2015

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2014-March 2015

Introduction
This is volume 131(the edition of year 2015) 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, 2015

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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 Structural Biology ···············································································

2

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

4

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

6

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

8

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

9

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

12

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

14

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

17

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

18

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

21

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

24

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

27

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

28

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

32

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

36

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

37

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

43

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

47

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

48

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

51

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

54

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

55

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

58

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

59

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

65

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

66

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

68

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

71

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

72

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

75

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

99

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

100

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

102

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

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

124

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

146

Department of Infectious Diseases ············································································

150

Department of Stress Sciences and Psychosomatic Medicine ·············································

155

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

157

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.446] )Department of Transfusion Medicine ·········································································

158

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

162

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

163

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

165

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

171

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

173

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

175

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

176

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

181

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

184

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

185

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

189

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

190

Department of Cardiothoracic Surgery ········································································

194

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

199

Hepatobiliary Pancreatic Surgery and Department of Artificial Organ
and Transplantation Surgery Division ·······································································

202

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

204

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

209

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

213

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

216

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

218

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

219

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

223

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

227

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

231

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

237

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

242

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

258

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

259

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

262

Department of Biomedical Ethics & Department of Health Promotion Sciences ·······················

268

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

272

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

273

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

276

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

279

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

283

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

284

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

288

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

291

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

295

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

301

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

302

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

308

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

311

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

312

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

315

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

318

v

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

322

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

324

Department of Biostatistics (See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.262] )Department of Social and Preventive Epidemiology ························································

325

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

328

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

332

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

335

Department of Mental Health(See Department of Mental Health [P.259] )Departments of Health and Social Behavior & Health Education and Health Sociology ··············

336

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.268] )3. Health Services Sciences ·························································································

340

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.102] )Department of Healthcare Informatics (See Department of Medical Informatics and Economics [P.111] )Department of Clinical Information Engineering ····························································

341

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

343

Department of Integrated Traditional Medicine ·····························································

344

Department of Vascular Regeneration (Daiichi Sankyo Co.,Ltd.)(See Department of Oral-Maxillofacial Surgery [P.227] )Department of Bone & Cartilage Regenerative Medicine(See Department of Orthopaedic Surgery [P.231] )Department of Cartilage & Bone Regeneration (Fujisoft)(See Department of Oral- Maxillofacial Surgery [P.227] )Department of Clinical Renal Regeneration(See Central Clinical Facilities Division of Tissue Engineering [P.497] )Department of Clinical Epidemiology and Systems ·························································

347

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

350

Science for joint reconstruction ( See Department of Orthopaedic Surgery [P.231] )Department of Molecular Neuroscience on Neurodegeneration(See Department of Neurology [P.90] )Division of Chronic Kidney Disease (CKD) Pathophysiology··············································

352

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

355

Department of Molecular Vascular Endocrinology ··························································

357

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

359

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

362

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

364

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

366

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

369

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

372

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

374

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

377

Department of Clinical & Molecular Epidemiology ························································

378

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 Ischemic Circulatory Physiology, KAATSU Training ········································

391

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

394

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

396

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

399

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

402

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

405

Department of Health Care Safety Management ·······························································

408

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

413

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

416

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

419

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

422

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

424

Department of Molecular Medicinal Sciences on Metabolic Regulation ·································

427

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

429

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

430

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

433

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

435

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

437

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

440

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

441

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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 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.146] )Infectious Diseases (See Department of Infectious Diseases [P.150] )Neurology (See Department of Neurology [P.90] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.185] )Psychosomatic Medicine(See Department of Stress Sciences and Psychosomatic Medicine [P.155] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.199] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.209] )Hepatobiliary Pancreatic Surgery(See Department of Hepatobiliary Pancreatic Surgery [P.202] )Vascular Surgery (See Department of Vascular Surgery [P.213] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.216] )Artificial Organ and Transplantation Surgery(See Department of Artificial Organ and Transplantation Surgery [P.202] )Cardiovascular Surgery (See Department of Cardiothoracic Surgery [P.194] )Thoracic Surgery (See Department of Thoracic Surgery [P.190] )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.204] )Gynecologic Surgery (See Obstetrics and Gynecology [P.162] )Sensory and Motor System Medicine
Dermatology and Photolaser Medicine (See Department of Dermatology [P.219] )Ophthalmology and Vision Correction (See Department of Ophthalmology [P.237] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.231] )

444

viii

Otorhinolaryngology, and Auditory and Voice Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.242] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.248] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.223] )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.176] )Pediatrics Surgery (See Department of Pediatrics Surgery [P.181] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.163, 165, 171] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.86] )Radiology
Radiology (See Department of Radiology [P.59] )Central Clinical Facilities ···························································································

445

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

446

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

450

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

454

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

456

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.158] )Delivery Unit ·····································································································

460

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

461

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

463

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

465

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

469

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

471

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

473

Department of Hemodialysis & Apheresis ·····································································

477

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

480

ix

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.51] )Department of Planning, Information, and Management(See Department of Medical Informatics and Economics [P.111] )University Hospital Medical Information Network (UMIN) Center ······································

487

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

490

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

492

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

497

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

501

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

505

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

508

Genome Informatics ·····························································································

509

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

511

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

513

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

515

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

523

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

525

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

526

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

530

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

532

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

533

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

536

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

539

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

541

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

545

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

548

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

551

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

554

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

556

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

558

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

560

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

ix

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.

x

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

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.

xi

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

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.

xii

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

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. 131, October 2015

xiii

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

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 ResearchThoracic 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

xiv

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015
Health Sociology
Mental Health
Epidemiology and Preventive Health
Sciences
Health Sciences

Social Gerontology
Health Promotion Sciences
Biostatistics
Biomedical Ethics

Health Sciences andNursing

Advanced Clinical Nursing
Nursing Administration
Preventive and Administrative
Nursing

Family Nursing
Community Health Nursing
Public Health Nursing
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

Health Economics and Epidemiology Research
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

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

xv

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015
Office of International Academic Affairs
Medical Library
Medical Scientist Training Program
Institution

Museum of Health and Medicine
Office for Research Ethics Support
Office for Life Science Research Equipment Supprt
Bone & Cartilage Regenerative Medicine
Cartilarge &Bone Regeneration(Fujisoft)
Immunotherapeutics
Total Renal Care Medicine
Advanced Clinical Science and Therapeutics
Translational Research for Healthcare and Clinical Science
Joint Disease Research
Health Management and Policy
Computational Diagnostic Radiology and Preventive Medicine
Clinical Motor System Medicine
Health Care Safety Management(Tokio Marine & Nichido)
Healthcare Quality Assessment
Anti-Aging Medicine
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 Molecular Psychiatry
Department of Life Support Technology (Molten)
Youth Mental Health
Advanced Nephrology and Regenerative Medicine
Sensory-recognition and Locomotive-function Sciences in the Super-aged Society
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

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

xvi

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

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. 131, October 2015

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

xvii

xviiiThe Tokyo Journal of Medical Sciences. Vol. 131, October 2015
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

xix

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

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

Chiho Watanabe

Director, Medical Library

Tsuyoshi Takato

Director General, University Hospital

Takashi Kadowaki

Director, Center for Disease Biology and Integrative Medicine

Masamitsu Iino

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

Yasushi Miyashita

Professor

Kensaku Mori

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

xx

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

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

Tadashi Iwanaka

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

xxi

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

Department of Vital Care Medicine

Professor

Yoshitsugu Yamada

Professor

Naoki Yahagi

Professor

Norito Kawakami

Professor

Yutaka Matsuyama

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Professor

Hiromi Sanada

Professor

Kiyoko Kamibeppu

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

Department of Preventive and Administrative Nursing

Department of Clinical Nursing

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

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The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

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 Ushida

Laboratory of Clinical Biotechnology

Professor

Kazunori Kataoka

Laboratory of Environmental Health Sciences

Professor

Chiharu Tohyama

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

Masahide Kikkawa

Museum of Health and Medicine

Professor

Kazuhiko Ohe

Office for Research Ethics Support

Professor

Yutaka Yatomi

Department of Bone & Cartilage Regenerative Medicine

Associate professor

Taku Saito

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

Translational Research for Healthcare and Clinical Science

Associate professor

Hiroyuki Morita

Department of Joint Disease Research

Associate professor

Noriko Yoshimura

Health Management and Policy

Professor

Soichi Koike

Associate professor

Ryuichi Yamamoto

Associate professor

Naoto Hayashi

Associate professor

Kansei Uno

Associate professor

Takeharu Yoshikawa

Clinical Motor System Medicine

Associate professor

Shigeyuki Muraki

Healthcare Safety Management (Tokio Marine & Nichido)

Professor

Yasushi Kodama

The Department of Healthcare Quality Assessment

Professor

Hiroaki Miyata

Associate professor

Shun Kohsaka

Anti-Aging Medicine

Professor

Satoshi Inoue

Clinical Epidemiology and Systems

Associate professor

Daisuke Koide

Clinical Trial Data Manegement

Professor

Takuhiro Yamaguchi

Pharmacology and Pharmacokinetics

Associate professor

Masashi Honma

Ubiquitous Preventive Medicine

Associate professor

Yasushi Imai

Division of Research Resources and Support

Faculty of Medicine
Endowed Departments

Computational Diagnostic Radiology and Preventive Medicine

xxiiiThe Tokyo Journal of Medical Sciences. Vol. 131, October 2015

Science for joint reconstruction

Professor

Yoshio Takatori

Associate professor

Toru Moro

Department of Therapeutic Strategy for Heart Failure

Professor

Koichiro Kinugawa

Department of Molecular Structure and Dynamics

Professor

Nobutaka Hirokawa

Department of Medical Genomics

Associate professor

Eirin Sai

Continence medicine

Professor

Yasuhiko Igawa

Department of Molecular Psychiatry

Associate professor

Kazuya Iwamoto

Department of Life Support Technology (Molten)

Associate professor

Taketoshi Mori

Department of Youth Mental Health

Associate professor

Tsuyoshi Araki

Department of Advanced Nephrology and Regenerative Medicine Associate professor

Keiichi Hishikawa

Department of Sensory-recognition and Locomotive-function

Associate professor

Kimihiko Kameyama

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

Professor

Kohjiro Ueki

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

Kazuhiko Koike

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

Sciences in the Super-aged Society

Medicine in Management of Pulmonary Hypertension

musculoskeletal pain
Department of Molecular Science on Diabetes

Social Cooperation Program

University Hospital
Clinical Divisions

xxiv

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

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

Hepatobiliary Pancreatic Surgery

Head

Norihiro Kokudo

Vascular Surgery

HeadToshiaki Watanabe

Breast and Endocrine Surgery

Head

Yasuyuki Seto

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

Tatuya 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

Tadashi Iwanaka

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 Clinical Facilites

xxv

The Tokyo Journal of Medical Sciences. Vol. 131, October 2015

Central 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

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

Tadashi Iwanaka

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

Associate
Haruaki Yanagisawa, Ph. D, Toshiyuki Oda, 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), Yuma Tani, Shohei Fujita,
Itsuki Abe (MSTP students), Akiko Osakaya(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.

clear that flagella/cilia is involved in various
important cell functions.
To study the functions of flagella/cilia, we employ
various imaging techniques, including cryo-electron
microscopy and 3D-tracking microscope incombination with genetic manipulations.
Cryo-electron microscopy and cryo-electron
tomography
One of our strength is in the high-resolution
cryo-electron microscopy (cryo-EM). This techniqueenables preserving biological samples by quickly
freezing them and observing the frozen samples
without staining. Using electron microscopy, we areable
toobtainnano-meter
resolutionofmacromolecular complexes such as axonemes. We
have been developing new techniques, such asasymmetric helical reconstruction and Ruby-Helix
software.

Research activities

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.

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

Model Organism
Our lab currently uses Chlamydomonas as a modelorganism for studying flagella. To identify moleculesthat are involved in regulating dynein, we use various

3

genetic tools, including classical mutagenesis, siRNA.
In addition, we are also developing 3D-tracking
microscopy in collaboration with Dr. Oku in
Department of Engineering. We are trying to track
Chlamydomonas cells and simultaneously record
flagella movement to elucidate the mechanism offlagella regulation.

References
1. Oda T., H. A. Yanagisawa, R. Kamiya, and M
Kikkawa “A molecular ruler determines the repeat
length in eukaryotic cilia and flagella”, Science,
346:857-860, 2014
2. Fujita S., T. Matsuo, M. Ishiura, M. Kikkawa“High-Throughput Phenotyping of Chlamydomonas Swimming Mutants Based on Nanoscale
Video Analysis” Biophysical Journal, 107:336345, 2014
3. Yanagisawa HA, G. Mathis, T. Oda, M. Hirono, E.
A. Richey, H. Ishikawa, W. F. Marshall, M.
Kikkawa, and H. Qin. ”FAP20 is an inner junction
protein of doublet microtubules essential for boththe planar asymmetrical waveform and stability offlagella in Chlamydomonas”. Molecular Biologyof the Cell, 25:1472-1483, 2014
4. Oda T., HA Yanagisawa, T. Yagi, and M. Kikkawa“Mechanosignaling between central apparatus andradial spokes controls axonemal dynein activity”,
Journal of Cell Biology, 204:807-819, 2014
5. Takarada O., N. Nishida, M. Kikkawa, and I.
Shimada “Backbone and side-chain 1H, 15N and
13C resonance assignments of the microtubulebinding domain of yeast cytoplasmic dynein in thehigh and low-affinity states” Biomolecular NMR
Assignments, 8:372-382,

4

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 24 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

5

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

Publications
1. Isshiki, M. and Okabe, S.
Evaluation of cranial window types for in vivo
two-photon imaging of brain microstructures.
Microscopy(Oxf)., Feb;63(1):53-63., 2014
2. Dai, X., Iwasaki, H., Watanabe, M. and Okabe, S.
Dlx1 transcription factor regulates dendritic
growth and postsynaptic differentiation throughinhibition of neuropilin-2 and PAK3 expression.
Eur J Neurosci., Feb;39(4):531-47., 2014
3. Ito-Ishida, A., Kakegawa, W., Kohda, K., Miura,
E., Okabe, S. and Yuzaki, M.
Cbln1 downregulates the formation and functionof inhibitory synapses in mouse cerebellar
Purkinje cells.
Eur J Neurosci., Apr;39(8):1268-80., 2014
4. Okabe, S.
Life science and microscopy in 2014.
Microscopy(Oxf)., Feb;63(1):1., 2014
5. Ebrahimi, S. and Okabe, S.
Structural dynamics of dendritic spines: molecularcomposition, geometry and functional regulation.
Biochim Biophys Acta., Oct;1838(10):2391-8.,
2014
6. Isshiki, M., Tanaka, S., Kuriu, T., Tabuchi, K.,
Takumi, T. and Okabe, S.
Enhanced synapse remodelling as a common
phenotype in mouse models of autism.
Nat Commun., Aug 21;5:4742., 2014

6

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7molecular genetics and X-ray crystallography.

References1.

Kanai Y., D. Wang, and N. Hirokawa. KIF 13b
enhances the endocytosis of LRP1 by recruiting
LRP1 to caveolae. J. Cell Biol. 204: 395-408,
2014.

2.

Yang W., Y. Tanaka, M. Bundo, and N. Hirokawa.
Antioxidant signaling involving the microtubulemotor KIF12 is an intracellular target of nutrition excess in beta cells. Dev Cell 31 : 202–214,
2014.

3.

Morikawa, M., H. Yajima, R. Nitta, S. Inoue, T.
Ogura, C. Saito, and N. Hirokawa.

X-ray and

Cryo-EM structures reveal mutual conformationalchanges of Kinesin and GTP-state microtubules
upon binding. EMBO J. 34: 1270-1286, 2015.
4.

Farkhondeh, A., S. Niwa, Y. Takei, and N. Hirokawa. Characterizing KIF16B in neurons reveals anovel intramolecular "stalk inhibition" mechanismthat regulates its capacity to potentiate the selective
somatodendritic localization of early endosomes. J.
Neurosci. 35 : 5067–5086, 2015.

5.

Hirokawa. N.

Introduction to the ECR Special

Issue on Molecular Motors. Exp Cell Res 334: 1,
2015.
6.

Hirokawa, N. and Y. Tanaka. Kinesin superfamily
proteins (KIFs): Various functions and their relevance for important phenomena in life and diseases.
(Review Article) Exp Cell Res 334: 16-25, 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.

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
was a pioneer in glycolipid research and discovered
the involvement of sialic acid in the ABO blood typeantigens.
Professor Masami Muramatsu graduated from the
University of Tokyo Faculty of Medicine in 1955. He10began studies at the Department of Internal Medicine,and then went to Baylor College of Medicine to study
under Dr. H. Busch. After coming back to Japan, hetook a position at the Cancer Institute and the took up
a professorship at Tokushima University School of
Medicine. In 1982, he succeeded Professor Yamakawa.
He studied ribosomal RNA and cloned interferon andp450 genes.
Professor Hiroto Okayama graduated from Kumamoto
University School of Medicine in 1973. After taking a
Ph.D. degree at Kyoto University School of Medicine,
he went to Stanford University to study under Dr. P.
Berg. After working at the NIH, USA, he became
Professor of Molecular Genetics, at Osaka University
Institute for Infectious Diseases. In 1993 he succeeded
Professor Muramatsu. At Stanford and the NIH, hestudied gene cloning and developed a full length
cDNA cloning method and a cDNA expression
cloning vector system, and, after returning to Japan,
he studied cell cycle control and cancer.
Professor Noboru Mizushima graduated from Tokyo
Medical and Dental University, Faculty of Medicine in
1991. After receiving Ph.D., he studied at National
Institute for Basic Biology in Okazaki and started
works on autophagy in yeast and mammals at Dr.
Yoshinori Ohsumi’s laboratory. Taking a position as a
PI at the Tokyo Metropolitan Institute of Medical
Science in 2004, he started studies on physiologicalroles of autophagy. He was promoted to Professor of
Physiology and Cell Biology, in Graduate School andFaculty of Medicine at Tokyo Medical and Dental
University in 2006, and succeeded Professor Okayama
in 2012.

Research Activities
Our current study focuses on the understanding of themolecular mechanism and physiological roles of
autophagy.
1. Molecular mechanism of autophagy
Autophagy is one of the major degradation
pathways in the cell (1). In autophagy,
intracellular components are sequestered by
autophagosomes and then degraded upon fusion
with lysosomes. Yeast genetic studies haveidentified more than 30 autophagy-related (ATG)

genes (2). Many of these genes are conserved inhigher eukaryotes, which allow us to performgenetic analysis of autophagy in mammals.
We are currently addressing some of thecentral questions remaining the autophagy field
and trying to elucidate the mechanisms of (1)regulation of autophagy, (2) initiation of
autophagosome formation, (3) elongation of the
autophagic membrane, (4) fusion between the
autophagosome and lysosome, and (5) recognitionof selective substrates.
We identified the autophagosomal SNARE
syntaxin 17 (STX17) and found that it is required
for the autophagosome-lysosome fusion throughinteraction with SNAP29 and VAMP8 (Itakura etal. 2012). We also found that STX17 interacts
with HOPS, which has been known to beimportant for the endosome-lysosome fusion, andshowed that HOPS also acts as a tethering
complex essential for the autophagosomelysosome fusion (Jiang et al. 2014). We are further
investigating the spatiotemporal regulation of the
autophagosome-lysosome fusion.
Although the hierarchical relationships of
ATG proteins have been investigated, howindividual ATG proteins or their complexes
contribute to the organization of the autophagic
membrane remains largely unknown. We
performed systematic ultrastructural analysis ofmouse embryonic fibroblasts (MEFs) and HeLa
cells deficient in various ATG proteins andrevealed function of these ATG factors inmembrane organization. We also found thatferritinclusters
accumulatedattheautophagosome formation site together with p62(also known as SQSTM1) in autophagy-deficient
cells, suggesting that ferritin is a novel autophagy
substrate (Kishi-Itakura 2014).
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. We
also identified a human neurodegenerative disease
termed SENDA/BPAN, in which one of the core
autophagy genes WIPI4/WDR45 is mutated(Saitsu et al. 2013). Thus, autophagy plays
important roles in various physiological andpathological 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.

2.

3.

4.

5.

Lin, H.H., Lin, S.M., Chung, Y., Vonderfecht, S.,
Camden, J.M., Flodby, P., Borok, Z., Limesand,
K.H., Mizushima, N., Ann, D.K. Dynamic
involvement of ATG5 in cellular stress responses.
Cell Death Dis. 5:e1478 (2014).
Udagawa, O., Ishihara, T., Maeda, M., Matsunaga,Y., Tsukamoto, S., Kawano, N., Miyado, K.,
Shitara, H., Yokota, S., Nomura, M., Mihara, K.,
Mizushima, N., Ishihara, N. Mitochondrial
Fission Factor Drp1 Maintains Oocyte Quality
via Dynamic Rearrangement of Multiple
Organelles. Curr. Biol. 24:2451-8 (2014).
Kishi-Itakura, C, Koyama-Honda, I., Itakura, E.,
Mizushima, N. Ultrastructural analysis of
autophagosome organization using mammalian
autophagy-deficient cells. J. Cell Sci. 127:40894102 (2014).
Ogasawara, Y., Itakura, E., Kono, N., Mizushima,N., Arai, H., Nara, A., Mizukami, T., Yamamoto,
A. Stearoyl-CoA Desaturase 1 Activity Is
Required for Autophagosome Formation. J. Biol.
Chem. 289:23938-50 (2014).
Yamamoto, A., Mizushima, N., Tsukamoto, S.
Fertilization-Induced Autophagy in Mouse

6.

7.

8.

9.

10.

11.

12.

13.

Embryos Is Independent of mTORC1. Biol.
Reprod. 91:7, 1–7 (2014).
Jiang, P., Nishimura, T., Sakamaki, Y., Itakura, E.,
Hatta, T., Natsume, T., Mizushima, N. The HOPS
complex mediates autophagosome-lysosome
fusion through interaction with syntaxin 17. Mol.
Biol. Cell. 25:1327-1337 (2014).
Watanabe-Asano, T., Kuma, A., Mizushima N.
Cycloheximide
inhibits
starvation-induced
autophagythrough
mTORC1
activation.
Biochem. Biophys. Res. Commun. 445:334-339(2014)
Sahani, M.H., Itakura, E., Mizushima, N.
Expression of the autophagy substrate SQSTM1/
p62 is restored during prolonged starvation
depending on transcriptional upregulation andautophagy-derived amino acids. Autophagy. 10:
431-441 (2014)
Mizushima, N. Sugar modification inhibits
autophagosome-lysosome fusion. Nat. Cell Biol.
16:1132-1133 (2014).
Galluzzi, L., et al. Essential versus accessory
aspects of cell death: recommendations of the
NCCD 2015. Cell Death Differ. 22:58-73 (2014).
Mizushima, N., Sahani, M.H. ATG8 localizationin apicomplexan parasites: Apicoplast and more?
Autophagy. 10:1487-1494 (2014).
Shen, H.M., Mizushima, N. At the end of the
autophagic road: an emerging understanding oflysosomal functions in autophagy. Trends
Biochem. Sci. 39:61-71 (2014).
Jiang, P., Mizushima, N. Autophagy and humandiseases. Cell Res. 24:69-79 (2014).

12

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

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

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

Homepage

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

Introduction and Organization
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, three
postdoctoral fellows, three research fellows, four
graduates, two undergraduates, four researchtechnicians and two secretaries belong to ourdepartment. We are also in a tight collaboration with
Department of Medical Genomics.
Dr. Motonao Nakamura left our Department tobecome the Professor at Laboratory of Cellular
Signaling, Department of Life Science, Okayama
University of Science at April 2014, and Dr. Yoshihiro
Yamashita joined Department of Cellular Signaling at
September 2014 as Associate Professor.

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, suchtechnology is theoretically unable to capture
oncogenes whose promoter/enhancer is silent inrecipient cells. To make every gene expressedsufficiently in recipient cells, we here developed ahighly efficient retrovirus–mediated cDNA expression
library system. Our system enables to make a librarywith high complexity (containing millions of
independent cDNA clones) even from < 104 of cells.
(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

13laboratories, 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 mainly use HiSeq2500 and
HiSeq2000 systems for NGS, and have developed inhouse computational pipelines for detecting somatic
single nucleotide variations, insertions/deletions, andchromosomal rearrangemetns.
By coupling such approaches, we have obtained
following findings this year.
An individual with acute myeloid leukemia(AML) underwent peripheral blood stem cell (PBSC)
transplantation but subsequently experienced relapse.
Whole-exome sequencing of bone marrow cells fromthis patient at different disease stages as well as of
PBSCs from the donor revealed that the
posttransplantation AML was not a regrowth of theoriginal leukemic clones but rather donor cellleukemia (DCL). Importantly, oncogenic mutations of
IDH2 and DNMT3A detected in DCL were alreadypresent at a low frequency in the donor PBSCs.
Targeted deep sequencing of these genes confirmed
this observation and revealed that the emergence ofadditional oncogenic mutations triggered leukemic
evolution.

References
1. Nakamura Y, Taniguchi H, Mizoguchi K, Ikeda T,
Motoshima K, Yamaguchi H, Nagashima S,
Nakatomi K, Soda M, Mano H, Kohno S.
“Secondary EML4-ALK-positive lung adenocarcinoma in a patient previously treated for acutelymphoblastic leukemia in childhood: a casereport” Jpn J Clin Oncol 44:593-596, 2014.
2. Yasuda T, Ueno T, Fukumura K, Yamato A, Ando
M, Yamaguchi H, Soda M, Kawazu M, Sai E,
Yamashita Y, Murata M, Kiyoi H, Naoe T, Mano

H. “Leukemic evolution of donor-derived cells
harboring IDH2 and DNMT3A mutations after
allogeneic stem cell transplantation” Leukemia
28:426-428, 2014.
3. Yoshimi A, Toya T, Kawazu M, Ueno T,
Tsukamoto A, Iizuka H, Nakagawa M, Nannya Y,
Arai S, Harada H, Usuki K, Hayashi Y, Ito E,
Kirito K, Nakajima H, Ichikawa M, Mano H,
Kurokawa M. “Recurrent CDC25C mutations
drive malignant transformation in FPD/AML” Nat
Commun 5:4770, 2014.

14

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

Lecturer
Yukiko Kurihara, M.D.

Research Associate
Kouichi Nishiyama, M.D.

Associate
Yasunobu Uchijima, Ph.D.

URL http://bio.m.u-tokyo.ac.jp/home-j.html
Introduction and Organization

Research Activities

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, 5 graduate students, 2technical staffs and 1 secretary.

1. Developmental Biology and Medicine(1) Neural crest and craniofacial development
We have investigated the role of endothelin-1(ET-1) signaling in neural crest and craniofacial
development and identified the ET-1/ETA-receptor
to Dlx5/6 pathway in the dorsoventral axis
patterning of crest-driven branchial arch structures.
To further clarify the underlying mechanism, we
have established mice in which gene cassettes canbe efficiently knocked-in into the Ednra locus using
recombinase-mediated cassette exchange (RMCE)
based on the Cre-lox system. Using this system,
we have demonstrated that the dorsoventral axis
patterning of pharyngeal arches is regulated by the
ETA-receptor-selective, Gq/G11-dependent signaling,
while the formation of the distal pharyngeal regionis under the control of a Gq/G11-independent
signaling. We also identified Calpain6 as a downstream molecule of the ET-1 pathway and its
biological function in cytoskeletal organization andcell motility. We further identified TAZ as a proteinthat binds to and coactivates Pax3, a key transcription factor in neural crest development and its rolein the organogenesis of the kidney and lung as

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.

15

revealed by gene knockout.
(2) Preimplantation development
We characterized the role of sirtuins, NAD+
-dependent protein deacetylases, in mouse preimplantation development under in vitro culture
conditions. Among all sirtuins (Sirt1-7), which are
expressed in eggs and early embryos, Sirt3 proved
to play a protective role against oxidative stressduring preimplantation development. Sirt3 inactivation increased mitochondrial ROS production,
leading to the upregulation of p53 and changes indownstream gene expression. p53 inactivation
improved developmental outcome of Sirt3knockdown embryos, indicating that the ROS-p53
pathway is responsible for the developmental
defects. These findings may contribute to theunderstanding of preimplantation biology and givea clue to the better outcome of assisted reproductive
technologies.
(3) Angiogenesis
We found that Id1 confers in vivo angiogenic
property to human vascular endothelial cells via
angiopoietin-1 upregulation, which may give a clue
to novel strategy for therapeutic angiogenesis. We
also found that the function of Id1 is controlled byprotein kinase A through nucleoplaasmic shuttling.

3.

4.

5.

6.
2. Mouse Genetics
Collaborative works as follows are going on byusing gene manipulation approach in mice.
(1) Physiological roles of vasoactive peptides(2) Pathophysiological roles of defensin(3) Developmental roles of non-coding RNA

References
1.

2.

Arima Y, Miyagawa-Tomita S, Maeda K, Asai R,
Seya D, Minoux M, Rijli FM, Nishiyama K, Kim
KS, Uchijima Y, Ogawa H, Kurihara Y, Kurihara
H. Preotic neural crest cells contribute tocoronary artery smooth muscle involving
endothelin signalling. Nat. Commun. 3:1267,
2012.
Minamiyama M, Katsuno M, Adachi H, Doi H,
Kondo N, Iida M, Ishigaki S, Fujioka Y,
Matsumoto S, Miyazaki Y, Tanaka F, Kurihara H,
Sobue G. Naratriptan mitigates
CGRP1-

7.

associated motor neuron degeneration caused by
an expanded polyglutamine repeat tract. Nat.
Med. 18:1531-1538, 2012.
Nakatsu Y, Otani Y, Sakoda H, Zhang J, Guo Y,
Okubo H, Kushiyama A, Fujishiro M, Kikuchi T,
Fukushima T, Ohno H, Tsuchiya Y, Kamata H,
Nagamachi A, Inaba T, Nishimura F, Katagiri H,
Takahashi S, Kurihara H, Uchida T, Asano T.
Role of pin1 protein in the pathogenesis of
nonalcoholic steatohepatitis in a rodent model. J.
Biol. Chem. 287:44526-44535, 2012.
Yamanishi Y, Takahashi M, Izawa K, Isobe M, Ito
S, Tsuchiya A, Maehara A, Kaitani A, Uchida T,
Togami K, Enomoto Y, Nakahara F, Oki T,
Kajikawa M, Kurihara H, Kitamura T, Kitaura J.
A soluble form of LMIR5/CD300b amplifies
lipopolysaccharide-induced lethal inflammationin sepsis. J. Immunol. 189:1773-1779, 2012.
Kushiyama A, Okubo H, Sakoda H, Kikuchi T,
Fujishiro M, Sato H, Kushiyama S, Iwashita M,
Nishimura F, Fukushima T, Nakatsu Y, Kamata H,
Kawazu S, Higashi Y, Kurihara H, Asano T.
Xanthine oxidoreductase is involved inmacrophage
foam
cell
formationandatherosclerosis
development.
Arterioscler.
Thromb. Vasc. Biol. 32:291-298, 2012.
Iwashita M, Sakoda H, Kushiyama A, Fujishiro
M, Ohno H, Nakatsu Y, Fukushima T, Kumamoto
S, Tsuchiya Y, Kikuchi T, Kurihara H, Akazawa
H, Komuro I, Kamata H, Nishimura F, Asano T.
Valsartan, independently of AT1 receptor or
PPARgamma, suppresses LPS-induced macrophage activation and improves insulin resistancein cocultured adipocytes. Am. J. Physiol.
Endocrinol. Metab. 302:E286-2E96, 2012.
Kushiyama A, Sakoda H, Oue N, Okubo M,
Nakatsu Y, Ono H, Fukushima T, Kamata H,
Nishimura F, Kikuchi T, Fujishiro M, Nishiyama
K, Aburatani H, Kushiyama S, Iizuka M, Taki N,
Encinas J, Sentani K, Ogonuki N, Ogura A,
Kawazu S, Yasui W, Higashi Y, Kurihara H,
Katagiri H, Asano T. Resistin-like molecule β isabundantly expressed in foam cells and is
involved in atherosclerosis development.
Arterioscler. Thromb. Vasc. Biol. 33:1986-1993,
2013.

16

8.

9.

Zhang J, Nakatsu Y, Shinjo T, Guo Y, Sakoda H,
Yamamotoya T, Otani Y, Okubo H, Kushiyama A,
Fujishiro M, Fukushima T, Tsuchiya Y, Kamata H,
Iwashita M, Nishimura F, Katagiri H, Takahashi
S, Kurihara H, Uchida T, Asano T. Par14 protein
associates with insulin receptor substrate 1(IRS-1), thereby enhancing insulin-induced
IRS-1 phosphorylation and metabolic actions. J.
Biol. Chem. 288:20692-20701, 2013.
Kim K-S, Arima Y, Kitazawa T, Nishiyama K,
Asai R, Uchijima Y, Sato T, Levi G, Kitanaka S,
Igarashi T, Kurihara Y, Kurihara H. Endothelin
regulates neural crest deployment and fate toform great vessels through Dlx5/Dlx6independent mechanisms. Mech. Dev. (in press)

Functional Biology
1. Physiology

18

Department of Integrative
Physiology
Professor
Yasushi Miyashita, Ph.D.

Lecturer
Toshiyuki Hirabayashi, Ph.D.

Project Lecturer
Masaki Takeda, Ph.D., Yohei Ohashi, M.D., Ph.D.

Research Associate
Yusuke Adachi, Ph.D., Kenji Koyano, Ph.D., Keita Tamura, Ph.D.

Homepage

http://www.physiol.m.u-tokyo.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 (Drs. A. Nambu, S. Sugiura, H. Yamamotoand S. Nakanishi) take part in giving lectures andlaboratory courses to the undergraduate students of theMedical School. The lectures are aimed at providing aclear understanding of the hierarchical functionalorganizations of living systems. The curriculum is
updated every year. For example, a new electrocardio-

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

19

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 English seminar, in which the graduate
students learn how to give presentations and holddiscussions and debates in English.

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system :(1) higher functions of vision and memory, (2)non-invasive measurements of human brain activitiesand (3) non-invasive functional measurements ofmonkey brain activities that links above (1) and (2).
The results of such research have been published infirst-rate journals, as listed in the reference. A briefsummary of each topic follows:(1) In the primate, visual information processing in
the cerebral cortex proceeds along the neuralpathway originating from the primary visual areain the occipital lobe to the anterior part of thetemporal association cortex. Our laboratory
discovered several classes of important memoryneurons electrophysiologically in the temporal
lobe of the monkey. In the inferotemporal cortex,
which we propose to be the storehouse of visual
long-term memory, we discovered a group of
neurons which encode object-object association.
We found that the backward signal from themedial temporal lobe to the inferotemporal cortex
mediates formation of the mnemonic neuralcircuits for the association. Recently we also
found that the top-down signal from the prefrontal
cortex to the inferotemporal cortex plays a central
role in retrieval of the mnemonic associative
neural code stored in the inferotemporal cortex.
Since association is a basic mechanism forconstructing the human memory-based knowledge
system, our finding provides a key to understanding the basic organization of the primate
cerebral cortex.
(2) The recent explosion of new technologies for noninvasive measurements of human brain activities,
especially of functional magnetic resonanceimaging (fMRI), allows us to observe parallel

activation of functional brain modules in humans
engaged in various mental tasks. We contributed
to development of a new method called “eventrelated fMRI”, which enables to utilize the time
resolution of fMRI. We applied this “event-related
fMRI” method to the analysis of human cognition,and identified several functional centers in thehuman prefrontal cortex in cognitive tasks such as
the Wisconsin Card Sorting Task.
(3) Recently, we successfully applied fMRI method tomacaque monkeys performing highly intelligent
cognitive tasks. These fMRI studies were done inultra-high field MRI scanner at 4.7 Tesla,
successfully providing much higher spatial
resolution than in a conventional clinical MRI
scanner. This approach provides us a new
approach that bridges a gap between the humannon-invasive studies and the various invasive
studies in animals, including intra-corticalelectrical microstimulation and reversiblefunctional inactivation with GABA agonist drug
injections.

References
1.

2.

3.

4.

Hirabayashi, T., Takeuchi, D., Tamura, K., andMiyashita, Y.:
Microcircuits for Hierarchical Elaboration of
Object Coding Across Primate Temporal Areas.
Science 341, 191-195, 2013
Miyamoto, K., Osada, T., Adachi, Y., Matsui, T.,
Kimura, H.M., Miyashita, Y.:
Functional Differentiation of Memory Retrieval
Network in Macaque Posterior Parietal Cortex.
Neuron 77, 787-799, 2013
Watanabe, T., Hirose, S., Wada, H., Imai, Y.,
Machida, T., Shirouzu, I., Konishi, S., Miyashita,
Y. and Masuda, N. :A pairwise maximum entropy model accurately
describes resting-state human brain networks.
Nat. Commun. 4:1370, 2013.
Yaguchi M., Ohashi Y., Tsubota T., Sato A.,
Koyano W.,K., Wang N., and Miyashita Y.:
Characterization of the Properties of Seven
Promoters in the Motor Cortex of Rats andMonkeys after Lentiviral Vector-Mediated Gene
Transfer.

20

Human Gene Therapy Methods 24, 333-344,
2013
5. Watanabe T, Abe O, Kuwabara H, Yahata N,
Takano Y, Iwashiro N, Natsubori T, Aoki Y,
Takao H, Kawakubo Y, Kamio Y, Kato N,
Miyashita Y, Kasai K, and Yamasue H. :Mitigation of Sociocommunicational Deficits ofAutism Through Oxytocin-Induced Recovery ofMedial Prefrontal Activity : A Randomized Trial.
JAMA Psychiatry (formerly Archives of General
Psychiatry). 71, 166-175, 2013
6. Watanabe T, Hanajima R, Shirota Y, Ohminami S,
Tsutsumi R, Terao Y, Ugawa Y, Hirose S,
Miyashita Y, Konishi S, Kunimatsu A, andOhtomo K. :Bidirectional effects on inter-hemisphericresting-state functional connectivity induced byexcitatory and inhibitory repetitive transcranial
magnetic stimulation.
Human Brain Mapping 35, 1896-1905, 2013
7. Tsubota,T., Ohashi, Y.,Tamura, K.:
Optogenetics in the cerebellum: Purkinje cellspecific approaches for understanding local
cerebellar functions.
Behavioural Brain Research 255, 226-34, 2013.
8. Hirabayashi, T., Takeuchi, D., Tamura, K., andMiyashita, Y. :Functional microcircuit recruited during retrievalof object association memory in monkey
perirhinal cortex.
Neuron 77, 192-203, 2013.
9. Watanabe T., Hirose S., Wada H., Imai Y.,
Machida T., Shirouzu I., Konishi S., Miyashita Y.
and Masuda N.:
Energy landscapes of resting-state brain networks
Front. Neuroinform. 8: 12, 2014
10. Hirabayashi, T. and Miyashita, Y.:
Computational principles of microcircuits forvisual object processing in the macaque temporal
cortexTrends in Neurosci. 37, 178-187, 2014
11. Miyamoto, K., Adachi, Y., Osada, T., Watanabe,T., Kimura, H.M., Setsuie, R. and Miyashita, Y.:
Dissociable memory traces within the macaquemedial temporal lobe predict subsequent
recognition performance.
J. Neurosci. 34, 1988-1997, 201412. Hirabayashi, T., Tamura, K., Takeuchi, D.,
Takeda, M., Koyano, W.,K., and Miyashita, Y.:
Distinct Neuronal Interactions in Anterior
Inferotemporal Areas of Macaque Monkeys
during Retrieval of Object Association Memory.
J. Neurosci. 34, 9377-9388, 2014
13. Watanabe, T., Takezawa, M., Nakawake, Y.,
Kunimatsu, A., Yamasue, H., Nakamura, M.,
Miyashita, Y. and Masuda N. :Two distinct neural mechanisms underlying
indirect reciprocity
Proc. Natl. Acad. Sci. U.S.A. 111, 3990-3995,
2014

21

Department of Cellular andMolecular Physiology
Professor
Kensaku Mori, Ph.D.

Lecturer
Masahiro Yamaguchi, M.D., Ph.D.

Research Associate
Hiroyuki Manabe, Ph.D., Hiromi Naritsuka, Ph.D., Koshi Murata, Ph.D.

Homepage

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

Introduction

Research

The Department of Cellular and Molecular
Physiology succeeded the former ‘Second Departmentof Physiology’, and belongs to the Department of
Physiology. We participate in the teaching ofphysiology at undergraduate school and graduate
school.
The present members include the above stuffs, 2
postdoctoral researchers, 1 visiting scientist, 3
graduate students and 1 secretary stuff.

Using multidisciplinary approaches including
electrophysiology, optical imaging, molecular andcellular biology, molecular genetics and behavioral
analysis, we at the Department of Cellular andMolecular Physiology aim at understanding neuronal
circuit mechanisms for the translation of olfactory
sensory information to a variety of behavioral andemotional responses in the mammalian brain. Our
recent focus includes the functional and spatialorganization of the odor maps in the olfactory bulb,
parallel mitral and tufted cell pathways from olfactory
bulb to olfactory cortex, gamma oscillation couplings
among olfactory bulb, olfactory cortex, and olfactory
cortical mechanisms for the recognition of odor
objects. We study also behavioral state-dependentchange in the information processing mode in theolfactory bulb and olfactory cortex, focusing on theexperience-dependent reorganization of neuronal
circuitry in the olfactory cortex and bulb during
postprandial slow-wave sleep.

Education
The department provides lectures and practice inphysiology for undergraduate students. We teachelectrophysiological methods and cellular andmolecular physiology methods for free quarter
students. The department provides also lectures andinstructions for laboratory research for graduate andundergraduate students in the fields of sensory
physiology and molecular and cellular neurobiology.
Seminars, progress reports, and journal club forgraduate students are routinely provided. Monthly
joint seminars (Functional Biology Seminars and
RIKEN BSI Group Seminars) are also provided for
graduate students.

Granule cells in the olfactory bulb continue to begenerated in adulthood, with nearly half incorporated
and remainder eliminated into or from the neuronal
circuit of the olfactory bulb. We have been investigating the neuronal mechanisms during olfactory
experience and those during postprandial sleep for the22sensory-experience dependent incorporation and/or
elimination of adult-born granule cells into or fromthe pre-existing neuronal circuit in the olfactory bulb.
Currently we are focusing on the following topics.
(1) Parallel mitral and tufted cell pathways to theolfactory cortex.
Odor signals are conveyed from the olfactory
bulb to the olfactory cortex by mitral cells andtufted cells. Whether and how the two types ofprojection neurons differ in function and axonal
connectivity is still poorly understood. Odor
responses and axonal projection patterns werecompared between mitral cells and tufted cells inmice by visualizing axons of electrophysiologically identified single neurons. Tufted cells
demonstrated shorter onset latency for reliable
responses than mitral cells. The shorter latency
response of tufted cells was maintained in a wide
range of odor concentrations, whereas mitral cells
responded only to strong signals. Furthermore,individual tufted cells projected densely to focal
targets only in anterior areas of the olfactorycortex, whereas individual mitral cells dispersedly
projected to all olfactory cortex areas. In theanterior areas of the olfactory cortex, the two cell
types projected to segregated subareas. These
results suggest that mitral cells and tufted cells
transmit temporally distinct odor information todifferent olfactory cortex targets.
(2) Olfactory cortex generates synchronized top-down
inputs to the olfactory bulb during slow-wave
sleep.
The olfactory cortex is functionally isolated
from the external odor world during slow-wave
sleep. However, the neuronal activity pattern in theolfactory cortex and its functional roles duringslow-wave sleep are not well understood. Here, we
demonstrate in freely behaving rats that theanterior piriform cortex, a major area of theolfactory cortex, repeatedly generates sharp waves
that are accompanied by synchronized discharges
of numerous cortical neurons. Olfactory cortex

sharp waves occurred relatively independently ofhippocampal sharp waves. Current source density
analysis showed that sharp wave generation
involved the participation of recurrent association
fiber synapses to pyramidal cells in the olfactorycortex. During slow wave sleep, the olfactory bulb
showed sharp waves that were in synchrony witholfactory cortex sharp waves, indicating that theolfactory cortex sharp waves drove synchronized
top-down inputs to the olfactory bulb. Based onthese results, we speculate that the olfactory cortex
sharp waves play a role in the reorganization of
bulbar neuronal circuits during slow-wave sleep.
(3) Sniff rhythm-paced fast andoscillations in the olfactory bulb

slow

gamma

Oder signals are conveyed from the olfactory
bulb to the olfactory cortex by two types ofprojection neurons, tufted cells and mitral cells,
which differ in signal timing and firing frequency
in response to odor inhalation. Whereas tufted
cells respond with early-onset high frequency
burst discharges starting at the middle of theinhalation phase of sniff, mitral cells show odor
responses with later-onset lower frequency burst
discharges. Since odor inhalation induces
prominent gamma oscillations of local fieldpotentials in the olfactory bulb during thetransition period from inhalation to exhalation that
accompany synchronized spike discharges oftufted cells and mitral cells, we addressed thequestion of whether the odor-induced gamma
oscillations encompass two distinct gamma
oscillatory sources, tufted cell-circuits and mitralcell-circuits, by simultaneously recording the sniff
rhythms and local field potentials in the olfactory
bulb of freely behaving rats. We observed that
individual sniffs induced nested gamma oscillations with two distinct parts during theinhalation-exhalation transition period: early-onset
fast gamma oscillations followed by later-onset
slow gamma oscillations. These results suggestthat tufted cells carry odor signals with early-onset
fast gamma synchronization at the early phase ofsniff, whereas mitral cells send them withlater-onset slow gamma synchronization. We also

23

observed that each sniff typically induced both fastand slow gamma oscillations during awake
whereas respiration during slow-wave sleep andREM sleep failed to induce these oscillations.
These results suggest that behavioral states
regulate the generation of sniff rhythm-paced fastand slow gamma oscillations in the olfactory bulb.

Publications (2013~)
1. Manabe H and Mori K Sniff rhythm-paced fastand slow gamma oscillations in the olfactory
bulb: relation to tufted and mitral cells andbehavioral states J Neurophysiol. 110: 15931599 (2013)
2. Yamaguchi M, Manabe H, Murata K, and Mori K
Reorganization of neuronal circuits of the central
olfactory system during postprandial sleep Front.
Neural Circuits 7: 132 (2013)
3. Mori K, Manabe H, Narikiyo K, and Onisawa N
Olfactory consciousness and gamma oscillation
couplings across the olfactory bulb, olfactorycortex and orbitofrontal cortex
Front.
Psychology 4: 743 (2013)
4. Narikiyo K, Manabe H, and Mori K Sharp
wave-associated synchronized inputs from thepiriform cortex activate olfactory tubercle neurons
during slow-wave sleep
J Neurophysiol. 111:
72-81 (2014)
5. Mori K Piriform Cortex and Olfactory Tubercle
In: Mori K (Ed) The Olfactory System, Springer,
Tokyo, pp 161-176. (2014)
6. Nagayama S, Igarashi KM, Manabe H, and Mori
K Parallel Tufted Cell and Mitral Cell Pathways
from the Olfactory Bulb to the Olfactory Cortex
In: Mori K (Ed) The Olfactory System, Springer,
Tokyo, pp 133-160. (2014)
7. Yamaguchi M
Interneurons in the Olfactory
Bulb: Roles in the Plasticity of Olfactory
Information Processing In: Mori K (Ed) The
Olfactory System, Springer, Tokyo, pp 97-132.
(2014)
8. Mori K Odor Maps in the Olfactory Bulb In:
Mori K (Ed) The Olfactory System, Springer,
Tokyo, pp 59-70. (2014)
9. Mori K and Manabe H Unique Characteristicsof the Olfactory System In: Mori K (Ed) The

Olfactory System, Springer, Tokyo, pp 1-18.
(2014)
10. Sakamoto M, Ieki N, Miyoshi G, Mochimaru D,
Miyachi H, Imura T, Yamaguchi M, Fishell G,
Mori K, Kageyama R, Imayoshi I. Continuous
postnatal neurogenesis contributes to formation of
the olfactory bulb neural circuits and flexible
olfactory associative learning. J Neurosci. 34:
5788-99.(2014)
11. Yamaguchi M, Mori K. Critical periods in adultneurogenesis and possible clinical utilization of
new neurons Front. Neuroscience 8:177 (2014)
12. Komano-Inoue S., Manabe H., Ota M.,
Kusumoto-Yoshida I., Yokoyama T. K., Mori K.,
and Yamaguchi M. Top-down inputs from theolfactory cortex in the postprandial period
promote elimination of granule cells in theolfactory bulb Eur. J. Neurosci. (in press)

24

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

Associate Professor
Kazuo Kitamura, Ph.D.

Research Associate
Naofumi Uesaka, 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, associate professor, 2research associate, project research associate), 5
postdoctoral fellows, 12 graduate students, 5undergraduate students and 5 technicians. We teachneurophysiology for medical undergraduates and forstudents in the Master and Ph.D. courses. Our researchaims at elucidating cellular and molecular mechanisms
underlying regulation of synaptic transmission andpostnatal 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. Students also learn how
functional neural circuits in the brain are formed andmatured during postnatal development. In the practicalcourses, students perform two types of classicalexperiments of neurophysiology. First, students makeintracellular recording from frog skeletal muscle
fibers and examine the endplate potential forunderstanding
basic
properties
ofsynaptictransmission. Second, students record electromyogram(EMG) from human gastrocnemius muscles and learn
how the stretch reflex works.
We accept Free-Quarter students. Students areencouraged to experience patch-clamp recordings
from neurons either in brain slices or in dissociatedculture, or to experience recordings of neuronal
activities from living animals.
For the training of Master and Ph.D. course students,
we have a weekly conference for discussing current
research activities. A laboratory member summarizes
his/her recent experimental data or presents papers
closely related to his/her research. Moreover, formutual communication between the laboratories withsimilar interests in neuroscience, we have a weekly
joint seminar with Department of Cellular
Neurobiology, Division of Structural Physiology 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,
morphology, and genetic engineering of mouse. We
particularly focus on observing neuronal activities in25real 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.

(2)

(3)

(4)

(5)

(6)

(7)

(8)

References(1) Tada M, Takeuchi A, Hashizume M, Kitamura K,
Kano M: A highly sensitive fluorescent indicator
dye for calcium imaging of neural activity invitro and in vivo. Eur J Neurosci 39:1720-(9)

1728, 2014.
Kassai H, Sugaya Y, Noda S, Nakao K, Maeda T,
Kano M, Aiba A:
Selective activation ofmTORC1 signaling recapitulates microcephaly,tuberous sclerosis and neurodegenerative
diseases. Cell Reports 7: 1626–1639, 2014.
Uesaka N, Uchigashima M, Mikuni T, Nakazawa
T, Nakao H, Hirai H, Aiba A, Watanabe M, Kano
M: Retrograde semaphorin signaling regulates
synapse elimination in the developing mousebrain. Science 344: 1020-1023, 2014.
Petrenko A B, Yamazaki M, Sakimura K, Kano M,
Baba H: Augmented tonic pain-related behavior
in knockout mice lacking monoacylglycerol
lipase, a major degrading enzyme for theendocannabinoid 2-arachidonoylglycerol. Behav
Brain Res 271: 51-58, 2014.
Kawata S, Miyazaki T, Yamazaki M, Mikuni T,
Yamasaki M, Hashimoto K, Watanabe M,
Sakimura K, Kano M:
Global scaling-down of
excitatory postsynaptic responses in cerebellar
Purkinje cells impairs developmental synapse
elimination. Cell Reports 8: 1119-1129, 2014.
Otsu Y, Marcaggi P, Feltz A, Isope, P, Kollo M,
Nusser Z, Mathieu B, Kano M, Tsujita M,
Sakimura K, Dieudonné S:
Activity-dependent
gating of calcium spikes by A-type K+ channels
controls climbing fiber signaling in Purkinje cell
dendrites. Neuron 84: 137-151, 2014.
Piochon C, Kloth AD, Grasselli G, Titley HK,
Nakayama H, Hashimoto K, Wan V, Simmons
DH, Eissa T, Nakatani J, Cherskov A, Miyazaki T,
Watanabe M, Takumi T, Kano M, Wang S S-H,
Hansel C:
Cerebellar plasticity and motor
learning deficits in a copy number variation
mouse model of autism. Nat Commun 5: 5586,
2014.
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 novel high-affinity, ultrafast,
red calcium indicator R-CaMP2. Nat Methods
12: 64-70, 2015.
Tsutsumi S, Yamazaki M, Miyazaki T, Watanabe
M, Sakimura K, Kano M, Kitamura K: Structurefunction relationships between aldolase C/zebrin
II expression and complex spike synchrony in the

26

cerebellum. J Neurosci 35:843-852 2015.
(10) 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.
(11) Ohno-Shosaku T, Kano M:
Endocannabinoidmediated retrograde modulation of synaptictransmission. Curr Opin Neurobiol 29: 1–8,
2014.
(12) Kano M: Control of synaptic function by
endocannabinoid-mediated retrograde signaling.
Proc Japan Acad Ser B 90: 235-250, 2014.
(13) Kawaguchi Y, Kano M: Neural circuits: Japan.
Front Neural Circuits 8:135. 2014.
(14) Uesaka N, Uchigashima, M, Mikuni T, Hirai H,
Watanabe M, Kano M: Retrograde signaling for
climbing fiber synapse elimination. Cerebellum
14: 4-7, 2015.

Functional Biology
2. Pharmacology

28

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 Molecular
Neurobiology and Pharmacology in the education ofundergraduate 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
eight outside expert lecturers to cover rapidly
developing fields in pharmacology and related
medical sciences. The laboratory courses include bothtraditional and advanced pharmacological experiments.
A new intensive laboratory course for medical
students started in the year 2001, and we participatedin the program. We also give lectures for graduate
students including master course students and Ph.D.
candidates.

Research activities
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 regulation

29

of IP3R via the Ca2+ sensor of IP3R indeed plays
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
ERandmitochondrial
Ca2+
dynamics
2+
simultaneously with cytosolic Ca concentrationand other cellular 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, andtranslocates 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 have30

been found to be regulated by Ca2+ signals, not all
the Ca2+-dependent cell functions have been
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-regulationinduces
reciprocal
up-regulation of N-cadherin after brain injury.
When the N-cadherin gene is disrupted in
astrocytes, injury-induced astrogliosis andneuroprotection were attenuated. These results
clarified the molecular 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 inNO-dependent neuronal cell death after brainischemia. This finding suggests that NICR can bea 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.
4) Cell-to-cell variability in Ca2+ signals
Cell-to-cell phenotypic variability within clonal
populations has attracted considerable attention.
We found that human embryonic kidney 293 cells
exhibit all-or-none phenotypic variability in Ca2+

31

response upon agonist application: only
approximately 40% of the cells respond to caffeine.
Using a systems-biological approach thatcombines time-lapse Ca2+ imaging and mathematical modeling, we analyzing the basis of thecell-to-cell variability. We found that the balance
between Ca2+ release and uptake is enhanced by
the positive feedback property of the Ca2+ relase to
generate the all-or-none propety of the Ca2+ relase.
Furthermore, individual cells switched between
the caffeine-sensitive and caffeine-insensitive
states with an average transition time of
approximately 65 h, suggestive of temporalfluctuation in endogenous protein expression
levels associated with caffeine response. Thus, thestudy provides a conceptual basis of the cellto-cell phenotypic variability in mammalian cells.

References
1.

2.

3.

4.

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, and local
activity of astrocytes using an ultrasensitive Ca2+
indicator. Cell Rep. 10, 311-318, 2014. doi:
10.1016/j.celrep.2014.05.056.
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.
Kanemaru, K., Kubota, J., Sekiya, H., Hirose, K.,
Okubo, Y. and Iino, M. Calcium-dependentN-cadherin up-regulation mediates reactive
astrogliosis and neuroprotection after brain injury.
Proc Natl Acad Sci USA 110, 11612– 11617,
2013.
Yano, F., Saito, T., Ogata, N., Yamazawa, T., Iino,

M., Chung, U.I. and Kawaguchi, H. β-catenin
regulates PTH/PTHrP receptor signals andchondrocyte hypertrophy through binding to its
intracellular C-terminal region. Arthritis Rheum.
65, 429-435, 2013.
Kakizawa, S., Yamazawa, T. and Iino, M. Nitricoxide-induced calcium release: activation of type1 ryanodine receptor by endogenous nitric oxide.

6.

Channels 7, 1–5, 2013
Iino, M. Synaptic function monitored using
chemobiomolecular indicators. In Chembiomolecular Science: At the Frontier of Chemistry
and Biology. pp. 207–215, 2013.

32

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 threetechnological challenges; 1) next-generation mouse
genetics, where we can produce genetically modified
mice in a high-throughput fashion, 2) system-level
identification and analysis of cellular circuits in thewhole-organ (especially, the whole-brain) andwhole-body, where we can identify individual cells or
cellular circuits in the whole-organ and whole-body,and 3) non-invasive observation/perturbation ofsystem dynamics, where we can observe or perturb the
specific cells or neurons in organisms in a
non-invasive manner. Combined with these techniques,
we investigate how the average (diurnality or
nocturnality), the dispersion (the length of sleepingtime), and the amount (insomniac or hypersomniac
responces) 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 mouse genetics
In the conventional method for production ofgenetically-modified mice, a single line of

33gene-targeted 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 togenerate the desired genetically modified mouse strain,
which typically takes from 9 months to several years.
To develop a high-throughput method of mouse
genetics (next-generation mouse genetics), we aretrying to 1) shorten the process by realizing F0
phenotyping with ~100% ES cell-derived mice (thesame generation at which chimeras are typically
produced) to skip the mating procedures, and 2)
parallelize the process by simultaneous preparation ofmultiple lines of ES cell clones. We aim to use thisnovel high-throughput method to produce hundreds ofstrains of genetically modified ~100% ES cell-derived
mice. Currently, we are developing high-throughput
TALEN- and CRISPER/Cas9-based genome engineering method.
2) System-level identification and analysis of cellular
circuits in the whole-organ and whole-body
To highlight the regulatory cellular networks in thesleep/wake rhythm, we facilitate an identification of
sleep/wake generating cells in the whole-brain in ahighly parallelized manner. A concerted effort has
been made especially in the brain, as scientists areaiming to clarify how neural activity is translated into
consciousness and other complex brain activities. One
example of the technologies needed is whole-brain
imaging at single-cell resolution. This imaging
normally involves preparing a highly transparent
sample that minimizes light scattering and thenimaging neurons tagged with fluorescent probes atdifferent slices to produce a 3D representation.
However, limitations in current methods prevent
comprehensive study of the relationship. A new
high-throughput method, CUBIC (Clear, Unobstructed
Brain Imaging Cocktails and Computational Analysis),published in Cell, is a great leap forward, as it offers
unprecedented rapid whole-brain imaging at single
cell resolution and a simple protocol to clear andtransparentize the brain sample based on the use ofaminoalcohols (Susaki et al., Cell, 2014). In
combination with light sheet fluorescence microscopy,
CUBIC was tested for rapid imaging of a number ofmammalian systems, such as mouse and primate,showing its scalability for brains of different size.
Additionally, it was used to acquire new
spatial-temporal details of gene expression patterns in
the hypothalamic circadian rhythm center. Moreover,by combining images taken from opposite directions,
CUBIC enables whole brain imaging and directcomparison of brains in different environmental
conditions. CUBIC overcomes a number of obstacles
compared with previous methods. One is the clearing
and transparency protocol, which involves seriallyimmersing fixed tissues into just two reagents for a
relatively short time. Second, CUBIC is compatible
with many fluorescent probes because of low
quenching, which allows for probes with longer
wavelengths and reduces concern for scattering when
whole brain imaging while at the same time inviting
multi-color imaging. Finally, it is highly reproducible
and scalable. While other methods have achieved
some of these qualities, CUBIC is the first to realize
all. CUBIC provides information on previously
unattainable 3D gene expression profiles and neuralnetworks at the systems level. Because of its rapid andhigh-throughput imaging, CUBIC offers extraordinary
opportunity to analyze localized effects of genomic
editing. It also is expected to identify neuralconnections at the whole brain level.
To comprehensively understand dynamic andcomplicated phenomena in organism-level, it is alsoessential to quantify the cellular dynamics with highly
time resolution. We are developing absolute,continuous, and highly sensitive quantification
methods of biomolecules secreted from specific region
in the brain. Currently, we have already succeeded in
the absolute quantification of peptides and proteinseven at the ato-mole level by using the mass
spectrometry. By further developing the method suchas on-line connection of microdialysis system withmass spectrometry, we address the establishment of
absolute quantification of various kinds of
biomolecules including neuropeptide, neurotransmitter,
and
other
unidentified
secretions
withacomprehensive, sensitive, and high time resolution
manner. Through these methods, we are also
developing clinical applications such as exploration ofnovel diagnostic markers.

343) Non-invasive observation/perturbation of system
dynamics
Currently, we have already developed anon-invasive sleep/wake analytical system based onhigh-sensitive
respiratory
analyzer
unlikeconventional electroencephalography (EEG) andelectromyogram (EMG), which are high-invasive,labor-intensive, and high cost phenotyping methods.
Furthermore, we have also devised automaticallystaging system to classify sleep and awake state fromlongitudinal data (Sunagawa et al, Genes to Cells
2013). Combined with these techniques, we achieved
automatic phenotyping of sleep and awake state only
by housing mice in the devised chamber for
respiratory analysis in a high-throughput fashion.
In another approach, we are developing noninvasive quantification system of important biomolecules such as monoamine determining cellularstates in whole-brain scale. Although molecular
probes for monoamine detectable in MRI have beenreported, any groups have not succeeded in thevisualization of monoamine dynamics in the wholebrain by using molecular probe knock-in mice.
Through above mentioned next-generation mouse
genetics, we will construct mutant mice expressing
molecular probes in the whole-brain (or specifictissues), and establish non-invasive quantification
platform for biologically important molecules. As forcontactless perturbation of cellular state, we aredeveloping chemical genetics, where mutant miceexpressing foreign artificial receptor in neuron are
perturbed by the corresponding artificial ligand suchas DREADDs (designer receptors exclusively
activated by designer drugs) and PSAMs. For example,
we construct mutant mice expressing active hM3Dq
receptor or inactive hM4Di in specific neurons, andperturb the neurons without contact by oral administration of triggering CNO. Alternatively, we are also
developing novel optogenetics where mutant micelacking all of photoreceptors but expressing artificial
infrared photoreceptors in specific neurons could be
perturbed by contactless infrared photoirradiation(without implanting optical fibers in the brain).
Understanding of hourglass mechanism of sleep, ahomeostatic dependent regulation of sleep amount andtimingIn the brain, there are multiple states such as awake,
NREM-sleep, and REM-sleep, and each state istransferred to each other without remaining in one
state. The underlying mechanism how these multiple
states are produced and what determine the amount ofeach state has been unknown yet. Initially, we are
identifying sleep-related molecules and genes throughthe next-generation mouse genetics. Especially, we arefocusing on wake-promoting genes such as monoamine and acetylcholine (neural circuits hypothesis),
synaptic plasticity-related genes such as receptors ofglutamate and GABA, and modification enzymes(synaptic plasticity hypothesis), and excitatory genes
determining membrane potential such as ion pumps
and ion channels (neural excitability hypothesis). We
elucidate what kinds of genes determine the sleep
amount and timing through non-invasive sleep/wakephenotyping system. Furthermore, we clarify where
sleep-regulating genes are distributed in the brain andhow neural circuits are constructed through wholebrain imaging with single-cell resolution. We also
elucidate how parameters in dynamic homeostasis
relating to the sleep amount and timing are determinedthrough non-invasive perturbation system. Finally, we
are aiming at our understanding of dynamic
homeostasis in the organism.

References
1. Tainaka K, Kubota SI, Suyama TQ, Susaki EA,
Perrin D, Ukai-Tadenuma M, Ukai H, Ueda HR.
Whole-Body Imaging with Single-Cell Resolution
by Tissue Decolorization. Cell 2014; 159(4):911–924.
2. Susaki EA, Tainaka K, Perrin D, Kishino F,
Tawara T, Watanabe TM, Yokoyama C, Onoe H,
Eguchi M, Yamaguchi S, Abe T, Kiyonari H,
Shimizu Y, Miyawaki A, Yokota H, Ueda HR.
Whole-brain imaging with single-cell resolution
using chemical cocktails and computational
analysis. Cell 2014;157(3):726-39.
3. Ikeda S, Tainaka K, Matsumoto K, Shinohara Y,
Ode KL, Susaki EA, Ueda HR. Non-enzymaticDNA
cleavagereaction
inducedby
5-ethynyluracil in methylamine aqueous solution
and application to DNA concatenation. PLOS
ONE 2013:9(3):e92369.

35

4. Tsujino K, Narumi R, Masumoto KH, Susaki EA,
Shinohara Y, Abe T, Iigo M, Wada A, Nagano M,
Shigeyoshi Y, Ueda HR. Establishment of TSH
β real-time monitoring system in mammalianphotoperiodism. Genes Cells 2013:18(7):575-88.
5. Sunagawa GA, Sei H, Shimba S, Urade Y, Ueda
HR. FASTER: an unsupervised fully automatedsleep staging method for mice. Genes Cells 2013:18(6):502-18.
6. Sasagawa Y, Nikaido I, Hayashi T, Danno H, Uno
KD, Imai T, Ueda HR. Quartz-Seq: a highly
reproducible and sensitive single-cell RNA-Seq
reveals non-genetic gene expression heterogeneity.
Genome Biology 2013:14(4):R31.

Pathology, Immunology andMicrobiology
1. Pathology

37

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.*

Lecturer (Hospital)
Masako Ikemura, M.D., Ph.D.*
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.,

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

Akimasa Hayashi M.D., Ph.D.*,
Ryu Miyagawa, Ph.D. (Cancer Professional Training Program)Technical Support Specialist
Yasuyuki Morishita, M.T.,

Homepage

Shinichi Harada,

Kei Sakuma

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”.
Dr. Maeda moved to Department of Cellular andOrgan Pathology, Akita University, as associate
Professor. Dr. Hayashi started his career as one of

Associates from April, and Dr. Tajima from September.
Dr. Shinozaki-Ushiku became Lecturer (Hospital) on
December. Dr. Shintani learned cardiovascularpathology and took a part in the research project ofprognostic markers for predicting heart failure at Prof.
James Stone’s laboratory, Cardiovascular Pathology,
Massachusetts General Hospital from 11, Nov. to 12,
Dec.
Three postgraduate students (Ando, Funata, andTanei) finished the course and received Ph.D. In the
new fiscal year, 2015, six new students will enter the
postgraduate course, and there will be 17

38

postgraduates.
We are responsible for the pathology practice of
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. A position of associate professor has been
approved by the University headquarter for“Promotion of CPC Education and General Integrative
Medicine” from next fiscal year. Dr. Ikemura will beassigned as Lecturer for this position.
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). The mission of the Center is toinvestigate basic technologies for tissue banking, andto hold seminars for doctors and technicians.

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, skin and GI tract.
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. Dr. Abe, as one of delegates ofJapanese Society of Pathology (JSP), was sent to
Department of Pathology, Semmelweiss University,
Hungary from August 11 to 15, to evaluate whether
their Training Course for Autopsy Pathology is
feasible as training for Japanese pathologists. Basedon their reports, the course was decided to be includedin the JSP-official training program for Pathology
specialty.
A model project for the survey analysis of deaths
related to medical treatment (DRMT) has been in
operation since September 2005, and we continue tobe a member of the autopsy inspection of the project(Dr. Shibahara).

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 one, three and one students of
M0, M1 and M2, 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”.

39

Research activities

References

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
EBV-associated GC in addition to its DNA
methylation abnormality. Professor Fukayama
presented the data as an invited lecture of 98th
Congress of German Society of Pathology (June 12-14,
Berlin, Germany). The Cancer Genome Atlas (TCGA)
group published the results of comprehensive
molecular analyses on July, 2014 (Nature 513:202), in
which EBV-associated gastric cancer is classified as
one of four subtypes 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). We
identified RHOA mutation in diffuse type of gastriccancer with Prof. Shumpei Ishikawa (Tokyo Medical
Dental University) and Prof. Aburatani (RCAST) (ref.
12, http://www.m.u-tokyo. ac.jp/news/admin/release_20140513.pdf). We also found high frequencies oftelomerase gene mutation and Japanese-specificmutation signatures in hepatocellular carcinoma(HCC) in collaboration with Prof. Shibata (National
Cancer Center, Medical Institute of University ofTokyo) and Prof. Aburatani (ref.38).
The third theme is to re-evaluate the disease
entities and tumor entities from the standpoint ofclassical histopathology. Dr. Sibahara extracted a
subgroup of HCC which showed histological featuresof steatohepatitis (steatohepatitic HCC), and clarified
its clinicopathological features (ref.37, 37). Dr.
Ushiku classified extrapapillary duodenal adenomas
into gastric and intestinal subtypes, and each subtype
is related with gastric or intestinal dyaplasia,
respectively (ref.40).
The research works closely related withpathology practice are described in Diagnostic
Pathology Division.

(including those of Diagnostic Pathology Division)
Case reports are listed in the section of Diagnostic
Pathology Division.
(1) Fantozzi A, Gruber DC, Pisarsky L, Heck C,
Kunita A, Yilmaz M, Meyer-Schaller N, Cornille
K, Hopfer U, Bentires-Alj M, Christofori G.
VEGF-Mediated Angio- genesis Links EMTInduced Cancer Stemness to Tumor Initiation.
Cancer Res. 2014 Mar; 74(5):1566-75.
(2) 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. A (90)Y-labelled antiROBO1 monoclonal antibody exhibits antitumour
activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy. EJNMMI Res. 2014 Jun; 4:29.
(3) Haraguchi H, Saito-Fujita T, Hirota Y, EgashiraM, Matsumoto L, Matsuo M, Hiraoka T, Koga K,
Yamauchi N, Fukayama M, Bartos A, Cha J, Dey
SK, Fujii T, Osuga Y. MicroRNA-200a locallyattenuates progesterone signaling in the cervix,
preventing embryo implantation. Mol Endocrinol.
2014 Jul;28(7):1108-17.
(4) Hayashi A, Yamauchi N, Shibahara J, Kimura H,
Morikawa T, Ishikawa S, Nagae G, Nishi A,
Sakamoto Y, Kokudo N, Aburatani H, Fukayama
M. Concurrent activation of acetylation and trimethylation of H3K27 in a subset of hepatocellular carcinoma with aggressive behavior.
PLoS One. 2014 Mar; 9(3):e91330(5) Hayashi A, Morikawa T, Kawai T, Kume H,
Ishikawa

S,

Homma

Y,

Fukayama

M.

Clinicopathological and prognostic significanceof EZH2 expression in upper urinary carcinoma.
Virchows Arch. 2014 Apr; 464(4):463-71.
(6) Ibrahim R, Matsubara D, Osman W, Morikawa T,
Goto A, Morita S, Ishikawa S, Aburatani H, Takai
D, Nakajima J, Fukayama M, Niki T, Murakami Y.
Expression of PRMT5 in lung adenocarcinoma
and its significance in epithelial-mesenchymaltransition. Hum Pathol. 2014 Jul; 45(7):1397-405.

40(7) Ichimura T, Morikawa T, Kawai T, Nakagawa T,

105 predicts a favorable prognosis for patients

Matsushita H, Kakimi K, Kume H, Ishikawa S,

with urinary bladder cancer treated with radical

Homma Y, Fukayama M. Prognostic significancecystectomy. Mol Clin Oncol. 2014 Jan;2(1):38-42

of CD204-positive macrophages in upper urinary(14) Kiga K, Mimuro H, Suzuki M, Shinozaki-Ushiku

tract cancer. Ann Surg Oncol. 2014 Jun; 21(6):A, Kobayashi T, Sanada T, Kim M, Ogawa M,

2105-12.

Iwasaki YW, Kayo H, Fukuda-Yuzawa Y, Yashiro(8) Ichinose J, Watanabe K, Sano A, Nagase T,

M, Fukayama M, Fukao T, Sasakawa C.

Nakajima J, Fukayama M, Yatomi Y, Ohishi N,

Epigenetic silencing of miR-210 increases the

Takai

is

proliferation of gastric epithelium during chronic

associated with lower expression of PABPN1 andHelicobacter pylori infection. Nat Commun. 2014

poor prognosis in non-small cell lung cancer.

Sep 4; 5:4497.

D.

Alternativepolyadenylation

Cancer Sci. 2014 Sep;105(9):1135-41.

(15) Kikuchi Y, Kunita A, Iwata C, Komura D,(9) Ishida M, Gonoi W, Hagiwara K, Okuma H,

Nishiyama T, Shimazu K, Takeshita K, Shibahara

Shintani Y, Abe H, Takazawa Y, Ohtomo K,

J, Kii I, Morishita Y, Yashiro M, Hirakawa K,

Fukayama M. Fluid in the airway of nontraumatic

Miyazono K, Kudo A, Fukayama M, Kashima TG.

death on postmortem computed tomography:

The niche component periostin is produced byrelationship with pleural effusion and postmortem

cancer-associated fibroblasts, supporting growthelapsed time. Am J Forensic Med Pathol. 2014of gastric cancer through ERK activation. Am J

Jun; 35(2):113-7.

Pathol. 2014 Mar; 184(3):859-70(10) Ishizawa T, Masuda K, Urano Y, Kawaguchi Y,(16) Li T, Liao X, Lochhead P, Morikawa T, Yamauchi

Satou S, Kaneko J, Hasegawa K, Shibahara J,

M, Nishihara R, Inamura K, Kim SA, Mima K,

Fukayama M, Tsuji S, Midorikawa Y, Aburatani

Sukawa Y, Kuchiba A, Imamura Y, Baba Y, Shima

H, Kokudo N. Mechanistic background andK, Meyerhardt JA, Chan AT, Fuchs CS, Ogino S,

clinicalgreen

Qian ZR. SMO expression in colorectal cancer:

fluorescence imaging of hepatocellular carcinoma.

associations with clinical, pathological, and

Ann Surg Oncol. 2014 Feb; 21(2):440-8(11) Ito S, Takao M, Hatsuta H, Kanemaru K, Arai T,
Saito Y, Fukayama M, Murayama S.Alphasynuclein immunohistochemistry of gastrointestinal and biliary surgical specimens fordiagnosis of Lewy body disease.Int J Clin Exp
Pathol 2014 March;7(4):1714-23

molecular features. Ann Surg Oncol. 2014 Dec;

applicationsof

indocyanine(12) Kakiuchi M, Nishizawa T, Ueda H, Gotoh K,
Tanaka A, Hayashi A, Yamamoto S, Tatsuno K,
Katoh H, Watanabe Y, Ichimura T, Ushiku T,
Funahashi S, Tateishi K, Wada I, Shimizu N,
Nomura S, Koike K, Seto Y, Fukayama M,
Aburatani H, Ishikawa S. Recurrent gain-offunction mutations of RHOA in diffuse-type
gastric carcinoma. Nat Genet. 2014 Jun; 46(6):583-7.
(13) Kawai T, Enomoto Y, Morikawa T, Matsushita H,
Kume H, Fukayama M, Yamaguchi H, Kakimi K,
Homma Y. High expression of heat shock protein

21(13):4164-73.
(17) Maekawa S, Suzuki M, Arai T, Suzuki M, Kato M,
Morikawa T, Kasuya Y, Kume H, Kitamura T,
Homma Y. TMPRSS2 Met160Val polymorphism:
significant association with sporadic prostatecancer, but not with latent prostate cancer inJapanese men. Int J Urol. 2014 Dec; 21(12):1234-8.
(18) Mehta RS, Song M, Bezawada N, Wu K,
Garcia-Albeniz X, Morikawa T, Fuchs CS, Ogino
S, Giovannucci EL, Chan AT. A prospective studyof macrophage inhibitory cytokine-1 (MIC-1/
GDF15) and risk of colorectal cancer. J NatlCancer Inst. 2014 Apr; 106(4):dju016.
(19) Miyata A, Ishizawa T, Kamiya M, Shimizu A,
Kaneko J, Ijichi H, Shibahara J, Fukayama M,
Midorikawa

Y,

Urano

Y,

KokudoN.

41

Photoacoustic tomography of human hepatic

Tanuma J, Uehira T, Hagiwara S, Yajima K,

malignancies using intraoperative indocyanine

Koizumi Y, Shirasaka T, Kojima Y, Nagai H,

green fluorescence imaging.PLoS One. 2014

Yokomaku Y, Shiozawa Y, Koibuchi T, Iwamoto

Nov; 9(11):e112667.

A, Oka S, Hasegawa H, Okada S, Katano H.

(20) Miyazaki H, Yoshimatsu Y, Akatsu Y, Mishima K,

Classification of AIDS-related lymphoma cases

Fukayama M, Watabe T, Miyazono K. Expression

between 1987 and 2012 in Japan based on theof platelet-derived growth factor receptor β is

WHO classification of lymphomas, fourth edition.

maintained by Prox1 in lymphatic endothelial

Cancer Med. 2014 Feb;3(1):143-53.

cells and is required for tumor lymphangiogenesis.
Cancer Sci. 2014 Sep;105(9):1116-23.

(27) Ozawa T, Kazama S, Akiyoshi T, Murono K,
Yoneyama S, Tanaka T, Tanaka J, Kiyomatsu T,(21) Miyagawa R, Mizuno R, Ijiri K, Fujii S

Kawai K, Nozawa H, Kanazawa T, Yamaguchi H,

Formation of Klotho Granules in Oxidative

Ishihara S, Sunami E, Kitayama J, Morikawa T,

Stress-induced Human Cancer Cells. Bioimages.

Fukayama M, Watanabe T. Nuclear Notch3

2014; 22:17-21.

expression is associated with tumor recurrence in(22) Nakai Y, Isayama H, Chang KJ, Yamamoto N,

patients with stage II and III colorectal cancer.

Hamada T, Uchino R, Mizuno S, Miyabayashi K,

Ann Surg Oncol. 2014 Aug; 21(8):2650-8.

Yamamoto K, Kawakubo K, Kogure H, Sasaki T,(28) Panthee N, Ono M, Morota T, Tanaka T, Itoda Y,

Hirano K, Tanaka M, Tada M, Fukayama M,

Ikemura M, Yamamoto T, Suzuki H, Saito A,

Koike K. Slow pull versus suction in endoscopic

Motomura N. Paraphegia prevention by oral

ultrasound-guidedofpretreatment with memantine in a rabbit model. J

pancreatic solid masses. Dig Dis Sci. 2014 Jul;

Thorac Cardiovasc Surg. 2014 Oct; 148(4):59(7):1578-85.

1732-8.

fine-needle

aspiration(23) Nakaya T, Ogawa S, Manabe I, Tanaka M,(29) Pusztaszeri MP, Sadow PM, Ushiku A, Bordignon

Sanada M, Sato T, Taketo MM, Nakao K, Clevers

P, McKee TA, Faquin WC. MYB immunostaining

H, Fukayama M, Kuroda M, Nagai R. KLF5

is a useful ancillary test for distinguishingregulates the integrity and oncogenicity of

adenoid cystic carcinoma from pleomorphic

intestinal stem cells. Cancer Res. 2014 May;

adenoma74(10):2882-91.

specimens. Cancer Cytopathol. 2014 Apr; 122(4):(24) Okuma H, Gonoi W, Ishida M, Shirota G,
Shintani Y, Abe H, Fukayama M, Ohtomo K

infine-needle

aspiration

biopsy257-65.
(30) RaginC,

FukayamaM(15/40),etal.

Comparison of attenuation of striated muscle

HPV-associated lung cancers: an inter- national

between postmortem and antemortem computed

pooled analysis. Carcinogenesis. 2014 Jun; 35(6):tomography: results of a longitudinal study. PLoS

1267-75.

One. 2014 Nov; 9(11):e111457.

(31) Saito Y, Ebihara Y, Ushiku T, Omura G,(25) Okuma H, Gonoi W, Ishida M, Shintani Y,

Kobayashi K, Ando M, Sakamoto T, Negative

Takazawa Y, Fukayama M, Ohtomo K. Greater

human papillomavirus status and excessive

thickness of the aortic wall on postmortem

alcohol consumption are significant risk factors

computedwithfor second primary malignancies in Japanese

antemortem computed tomography: the first

patients with oropharyngeal carcinoma. Jpn J Clin

longitudinal study. Int J Legal Med. 2014 Nov;

Oncol.2014 Jun; 44(6):564-9.

tomography

compared128(6):987-93.
(26) Ota Y, Hishima T, Mochizuki M, Kodama Y,
Moritani S, Oyaizu N, Mine S, Ajisawa A,(32) Sasaki Y, Sasaki T, Kawai T, Morikawa T,
Matsusaka K, Kunita A, Kume H, Aoki I,
Homma

Y,

Fukayama

M.

HER2

protein42

overexpression and gene amplification in upper

17-N-allylamino- 17-demethoxy geldanamycin

urinary tract urothelial carcinoma-an analysis of(17-AAG) synergizes with cisplatin and induces

171 patients. Int J Clin Exp Pathol. 2014 Jan;

apoptosis7(2):699-708.

squamous cell carcinoma cell lines via the Akt/(33) Sato Y, Maekawa S, Ishii R, Sanada M, Morikawa
T, Shiraishi Y, Yoshida K, Nagata Y, Sato-Otsubo

incisplatin-resistantesophageal

XIAP pathway. Oncol Rep. 2014 Feb;31(2):619-24.

A, Yoshizato T, Suzuki H, Shiozawa Y, Kataoka(40) Ushiku T, Arnason T, Fukayama M, Lauwers GY.

K, Kon A, Aoki K, Chiba K, Tanaka H, Kume H,

Extra-ampullary duodenal adenocarcinoma. Am J

Miyano S, Fukayama M, Nureki O, Homma Y,

Surg Pathol. 2014 Nov; 38(11):1484-93.

Ogawa S. Recurrent somatic mutations underlie(41) Wu RC, Ayhan A, Maeda D, Kim KR, Clarke BA,

corticotropin-independent Cushing's syndrome.

Shaw P, Herman Chui M, Rosen B, Shih IM,

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Wang TL. Frequent somatic mutations of the(34) Sato YT, Fukuhara H, Suzuki M, Fujimura T,

telomerase reverse transcriptase promoter in

Nakagawa T, Nishimatsu H, Kume H, Morikawa

ovarian clear cell carcinoma but not in otherT, Fukayama M, Homma Y. Long-term results ofmajor types of gynecologic malignancies. J

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Pathol. 2014 Mar;232(4):473-81.

androgen deprivation therapy for pT3N0 prostatecancer. BMC Urol. 2014 Jan;14(1):13(42) Yamamoto K, Tateishi K, Kudo Y, Sato T,
Yamamoto S, Miyabayashi K, Matsusaka K,(35) Seki Y, Yoshida Y, Ishimine H, Shinozaki-Ushiku

Asaoka Y, Ijichi H, Hirata Y, Otsuka M, Nakai Y,

A, Ito Y, Sumitomo K, Nakajima J, Fukayama M,

Isayama H, Ikenoue T, Kurokawa M, Fukayama

Michiue T, Asashima M, Kurisaki A.

LipaseM, Kokudo N, Omata M, Koike K. Loss ofmember H is a novel secreted protein selectively

histone demethylase KDM6B enhances aggres-upregulated in human lung adeno- carcinomas

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43

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 Professor
Caname Iwata, M.D., Ph.D.

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 2014, Dr.
Shogo Ehata, an assistant professor, was promoted a
project lecturer of GPLLI (Graduate Program for
Leaders in Life Innovation). In March 2015, theDepartment consists of a professor, an associate
professor, a project lecturer, an assistant professor,
technical assistants, and some research fellows,
including 8 graduate students, 2 master course
students, and 4 post-doctoral fellows.

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 webelieve it very 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.
Our research projects are supported by KAKENHI(Innovative Area on “Integrative research on cancer
microenvironment network”) from the Ministry of
Education, Culture, Science, Sports and Technology(MEXT) (http://cancer-microenvironment.jp) since2010, and we are studying the effects of TGF-β family
proteins on cancer microenvironment.
We have been doing collaboration with the Ludwig
Institute for Cancer Research, Uppsala, Sweden for
more than 15 years, and the collaborations between
Sweden, the Netherlands, and Japan are currently
supported by the Core-to-Core Program “Cooperative
International Framework in TGF-β Family Signaling”
of Japan Society for the Promotion of Science (JSPS)(http://c2ctgfb.umin.jp/). We have annual TGF-β
meeting in Sweden or in the Netherlands every year,

44

and four graduate students participated in the TGF-β
meeting in Leiden in 2014. At the 4th internationalcore-to-core symposium held in Tsukuba, Dr.
Koinuma presented his data by oral presentation, and14 presented their data at the poster session.
In 2014, the 18th International Vascular Biology
Meeting was held from April 14 to 17 in Kyoto, andProf. Kohei Miyazono served as one of the organizersof the meeting.
Four of our graduate students are supported by the
GPLLI 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 transforming growth factor-β (TGF-β)family transduce signals, and how they regulate
growth, differentiation, and apoptosis of various cells.
We are also interested in the regulation ofangiogenesis and lymphangiogenesis using various
vascular endothelial cells and lymphatic endothelial
cells (LECs).
A Smad3 and TTF-1/NKX2-1 complex regulates
Smad4-independent gene expression: Thyroidtranscription factor-1 (TTF-1, also known as NKX2-1)
is a tissue-specific homeobox transcription factor
expressed in lung, bronchi, thyroid grand, andforebrain. TTF-1 is expressed in more than 75% oflung adenocarcinoma patients, and patients with
TTF-1-positive cancer show better prognosis thanthose with TTF1-negative cancer.
TGF-β is a multifunctional cytokine withbidirectional roles in the progression of cancer.
Induction of epithelial-to-mesenchymal transition(EMT) is one of the most important mechanisms for
pro-tumorigenic effects of TGF-β. Although TTF-1
inhibits the EMT induced by TGF-β in lungadenocarcinoma cells (Saito et al. Cancer Res. 2009),
the mechanism through which TTF-1 inhibits thefunctions of TGF-β is largely unknown.
We have shown that TTF-1 regulates TGF-β-Smadsignaling by competing with Smad4 and disrupting the
Smad3-Smad4 complex without affecting the nuclear
localization of phospho-Smad3. Genome-wide
analysis by chromatin immunoprecipitation followed
by sequencing (ChIP-seq) revealed that TTF-1
colocalizes with Smad3 on chromatin and modulates
Smad3-binding profiles throughout the genome. We
have also found that TTF-1 generally inhibits Smad4
binding to chromatin. Moreover, Smad3 binds tochromatin together with TTF-1, but not with Smad4,
at some Smad3-binding regions, including LMO3 gene,when TGF-β signaling is absent. LMO3 is known to
induce cell survival downstream of TTF-1. Silencing
the Smad4 expression does not reduce Smad3 binding
in these regions.
Taken together, we have shown that TTF-1
regulates TGF-β-Smad signaling by competing with
Smad4, and that Smad3 acts with TTF-1 to regulate
certain genes, e.g. LMO3, in a Smad4-independent
manner. These findings provide a new model ofregulation of TGF-β-Smad signaling by TTF-1(Isogaya et al. Cell Res. 2014).
Smad4 decreases the population of pancreaticcancer-initiating cells (CICs) through transcriptional
repression of ALDH1A1: Recent studies have shownthat cancer progression involves a rare population ofundifferentiated CICs, which have stem cell-like
properties for self-renewal capacity and hightumorigenic activity. It is currently believed that
understanding and targeting CICs are essential for
improving the efficacy of cancer treatment.
Pancreatic cancer is one of the most aggressive
cancers, and is most commonly diagnosed when it isalready at an advanced stage of either metastatic or
locally advanced cancer. We investigated how
maintenance of pancreatic CICs is regulated by
Smad4, which is a downstream signaling componentof TGF-β and bone morphogenetic protein (BMP),
and is frequently deleted or mutated in pancreaticcancers cells. Silencing of Smad4 expression
increased the expression of the mRNA of aldehyde
dehydrogenase 1A1 (ALDH1A1), an enzyme thatoxidizes retinal to retinoic acid, and is responsible forresistance against anti-cancer drugs, such as
cyclophosphamide. Forced expression of Smad4 inpancreatic cancer cells reduced the expression of
ALDH1A1 mRNA. Smad4 and ALDH1 expression

45

reciprocally correlated in some human clinicalpancreatic adenocarcinoma tissues, suggesting that
ALDH1 in pancreatic cancer cells was associated withdecreased Smad4 expression.
We also examined whether ALDH1 functions as amarker of pancreatic CICs. Pancreatic cancer cells
contained ALDH1hi cells in 3-10% of total cells, withhigh tumorigenic potential. We then investigated theregulatory mechanism of ALDH activity by TGF-β
and BMPs. Treatment with TGF-β decreased thenumber of ALDH1hi cells in several pancreatic cancer
cells, while BMP-4 was not as potent as TGF-β.
Molecular biological experiments demonstrated that
TGF-β regulated the transcription of ALDH1A1
mRNA through binding of Smad4 to its regulatory
sequence.
It thus appears that TGF-β negatively regulates
ALDH1 expression in pancreatic cancer cells in a
Smad-dependent manner, and it in turn impairs theactivity of pancreatic CICs. Our model predicts that
this regulatory mechanism might be disrupted bymutations and deletions that occur in SMAD4 in
human pancreatic cancer cells (Hoshino et al. Am. J.
Pathol. 2015).
Expression of platelet-derived growth factor
receptor β (PDGFRβ) is maintained by Prox1 inlymphatic endothelial cells and is required for tumor
lymphangiogenesis: Lymphatic vessels play importantroles in the maintenance of fluid homeostasis underphysiological conditions, and inflammation and cancer
metastasis under pathological conditions. Therefore,
understanding of the molecular mechanisms
underlying lymphatic vessel formation is crucial.
Previous studies have reported that proliferation andmigration of LECs are activated by various signals
induced by tyrosine kinase receptors such as vascularendothelial growth factor receptor (VEGFR) 3. In
addition, we have recently found that BMP-9 and its
specific type I serine/threonine kinase receptor activin
receptor-like kinase 1 (ALK-1) inhibit lymphatic
vessel formation in vitro and in vivo, while they
induceblood
endothelial
cellproliferation(Yoshimatsu et al., Proc Natl Acad Sci USA 2013).
Signals mediated by PDGFRβ have been shown to
be involved in lymphangiogenesis. However, themechanisms of how the expression of PDGFRβ isregulated in LECs remain to be elucidated. We havedemonstrated that PDGFRβ expression in LECs is
maintained by Prox1, a master transcription factor for
the function of LECs. Knockdown of the expressionof Prox1 in human dermal LECs reduced theexpression of PDGFRβ, resulting in decreased
migration of human dermal LECs towards PDGF-BB,
a ligand for PDGFRβ.
Moreover, we have found that PDGF signals play
an important role in inflammatory lymphangiogenesis
in a chronic aseptic peritonitis model. Blockade of the
PDGFRβ signals by intraperitoneal administration of
imatinib (Gleevec), or transduction of PDGFRβ/Fc
chimeric protein by an adenoviral vector, suppressed
inflammatory
lymphangiogenesis
inducedbythioglycollate in mice. We have also found that theexpression of PDGFRβ/Fc inhibited the tumor
lymphangiogenesis in a cancer xenograft model using
BxPC3 human pancreatic cancer cells.
These findings suggest that PDGFRβ is one of the
key mediators of lymphatic vessel formation acting
downstream of Prox1 (Miyazaki et al. Cancer Sci.
2014).

References
1. Arase, M., Horiguchi, K., Ehata, S., Morikawa,M., Tsutsumi, S., Aburatani, H., Miyazono, K.,
and Koinuma, D. (2014) Transforming growth
factor-β-induced
lncRNA-Smad7
inhibits
apoptosis of mouse breast cancer JygMC(A) cells.
Cancer Sci. 105 (8), 974-982.
2. Miyazaki, H., Yoshimatsu, Y., Akatsu, Y.,
Mishima, K., Fukayama, M., Watabe, T., andMiyazono, K. (2014) Expression of plateletderived growth factor receptor β is maintained by
Prox1 in lymphatic endothelial cells and isrequired for tumor lymphangiogenesis. Cancer Sci.
105 (9), 1116-1123.
3. Isogaya, K., Koinuma, D., Tsutsumi, S., Saito,
R.A., Miyazawa, K., Aburatani, H., and Miyazono,
K. (2014) A Smad3 and TTF-1/NKX2-1 complex
regulates Smad4-independent gene expression.
Cell Res. 24 (8), 994-1008.
4. Kikuchi, Y., Kunita, A., Iwata, C., Komura, D.,
Nishiyama, T., Shimazu, K., Takeshita, K.,
Shibahara, J., Kii, I., Morishita, Y., Yashiro, M.,
Hirakawa, K., Miyazono, K., Kudo, A., Fukayama,

46

5.

6.

7.

8.

M., and Kashima, TG. (2014) The nichecomponent periostin is produced by cancerassociated fibroblasts, supporting growth ofgastric cancer through ERK activation. Am. J.
Pathol. 184 (3): 859-870.
Tanaka, M., Suzuki, H.I., Shibahara, J., Kunita, A.,
Isagawa, T., Yoshimi, A., Kurokawa, M.,
Miyazono, K., Aburatani, H., Ishikawa, S., andFukayama, M. (2014) EVI1 oncogene promotes
KRAS pathway through suppression of
microRNA-96 in pancreatic carcinogenesis.
Oncogene 33 (19): 2454-2563.
Itoh, F., Watabe, T., and Miyazono, K. (2014) Rolesof TGF-β family signals in the fate determination ofpluripotent stem cells. Sem. Cell Dev. Biol. 32, 98106.
Sun, B., Kawahara, M., Ehata, S., and Nagamune,
T. (2014) AAG8 promotes carcinogenesis byactivating STAT3. Cell. Signal. 26 (9), 18631869.
Lou, C., Takahashi, K., Irimura, T., Saiki, I., andHayakawa, Y. (2014) Identification of Hirustine asan anti-metastatic phytochemical by targeting
NF-κB activation. Int. J. Oncol. 45 (5), 20852091.

Pathology, Immunology andMicrobiology
2. Microbiology

48

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

Lecturer
Naoko Kamiya, Ph.D.

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

Homepage

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

Introduction and Organization

Research activities

Professor emeritus Akio Nomoto who had been thechief of the Department retired in 2008 and moved to
Microbial Chemistry Research Foundation as the
Chairman of Board. From 2009, new Department ofMicrobiology started with Professor Masanori
Hatakeyama as the new chief. The present Department
consists of 24 members; 1 professor (Dr. Hatakeyama),
1 lecturer (Dr. Kamiya), 2 assistant professor (Drs.
Takahashi and Hayashi), 2 project assistant professor(Drs. Fujii and Nishikawa), 3 technical staffs (Ms.
Kashiba, Kanemitsu, Okabe), 14 graduate school
students (Ms. and Mrs. Yanagiya, Kikuchi, Nagase,
Saju, Senda, Hashi, Bingo, Noda, Tajiri, Nojima, Ben,
Lu, Tang, Knight), 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.

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

49

1. Regulation of nuclear SHP2 function by Hippo
signaling targets YAP/TAZ
Gain-of-function mutation of SHP2 tyrosine
phosphatase is a major cause of Noonan syndrome, acongenital malformation syndrome with cancer
predisposition, and is associated with a variety of
sporadic cancers. SHP2 is required for full activationof RAS-ERK signaling in the cytoplasm and is alsopresent in the nucleus, where it promotes Wnt target
gene activation through dephosphorylation of parafibromin. However, molecular mechanisms throughwhich SHP2 undergoes nuclear translocalization
remain poorly understood.
The mammalian Hippo pathway, a cascade ofserine/threonine kinases, controls cell proliferation
and apoptosis by sensing high cell density. When the
Hippo signal is off, YAP (Yes-associated protein) andTAZ (transcriptional co-activator with PDZ-binding
motif) undergo nuclear translocalization. In the
nucleus, YAP/TAZ interact with the TEA-domain(TEAD) family of transcription factors and function astranscriptional coactivators of TEADs, causing
induction of TEAD-dependent genes that are involvedin promitogenic and prosurvival programs of cells.
Activation of the Hippo signal in response to high celldensity triggers a serine/threonine kinase cascade
comprising MST1/2 and LATS1/2, which results inthe phosphorylation of YAP/TAZ. Phosphorylated
YAP/TAZ are sequestered in the cytoplasm, where
they undergo proteasomal degradation, making
YAP/TAZ unavailable in the nucleus. Malfunctioningof the Hippo pathway abolishes contact inhibitionin vitro and organ size control in vivo, causing tissue
overgrowth and predisposition to cancer development
We found that SHP2 was distributed both to thecytoplasm and nucleus at low cell density but is
excluded from the nucleus at high cell density.
Furthermore, SHP2 physically interacted with YAP/
TAZ. Through the interaction, nonphosphorylated
YAP/TAZ promoted nuclear translocalization of
SHP2, which in turn stimulated TCF/LEF- andTEAD-regulated genes via parafibromin dephosphorylation. Conversely, YAP/TAZ phosphorylated by
Hippo signaling sequestered SHP2 in the cytoplasm,
thereby preventing nuclear accumulation of SHP2.
Hence, YAP/TAZ serve as a rheostat for nuclear

SHP2 function, which is switched off by the Hippo
signal.
2. Oncogenic potential of the natural variant
CagA derived from Helicobacter pylori v225d
strainUpon 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.
Tyrosine-phosphorylated CagA acquires the ability to
specifically bind to and aberrantly activate SHP2
tyrosine phosphatase, thereby activating mitogenic
signalingandinducing
cell
morphologicaltransformation (hummingbird phenotype). CagA also
binds to partitioning-defective 1 (PAR1)/microtubule
affinity-regulating kinase (MARK) via the CagA
multimerization (CM) sequence in a tyrosine
phosphorylation-independent manner, resulting in
induction of junctional and polarity defects.
Furthermore, CagA-PAR1 interaction stabilizes the
CagA-SHP2 complex. The CagA C-terminal region,
which contains EPIYA motif and CM sequence,
displays a large diversity among H. pylori strains.
Previous studies have also shown that the diversity in
the C-terminal region of CagA influences its binding
ability to SHP2 and PAR1.
H. pylori v225d strain was isolated from a gastricantral biopsy specimen obtained from a patient with
Piaroa Amerindian acute superficial gastritis.
H. pylori v225d-derived CagA (v225d CagA) does notpossess a canonical CM sequence. Furthermore, noneof the reported CagA has a C-terminal region that isclosely related to v225d CagA. Accordingly, weinvestigated the pathobiological activity of v225d
CagA by focusing on its functions related to theunique C-terminal region.
We found that v225d CagA interacts with SHP2 but
not PAR1. Furthermore, SHP2-binding activity ofv225d CagA was much lower than that of CagA of
H. pylori isolated from Western countries (Western
CagA). v225d CagA also displayed a reduced ability
to induce the hummingbird phenotype than that ofWestern CagA. Given that perturbation of PAR1 and
SHP2 by CagA underlies the oncogenic potential of
CagA, the v225d strain is considered to be less

50

oncogenic than other well-studied cagA-positive
H. pylori strains.
3. Elucidation of the three-dimensional structureof Helicobacter pylori CagA
Upon delivery into gastric epithelial cells via the typeIV secretion system, CagA localizes to the inner faceof the plasma membrane and then interacts with anumber of host proteins, such as SHP2 and PAR1,
thereby deregulating multiple cell signaling pathways.
CagA has been under intense study in the field of
molecular and cellular biology, but has never been
resolved in the field of structural biology.
CagA is an approximately 130-kDa protein
consisting of approximately 1200 amino acids, which
does not share sequence homology with any of the
known proteins. In this study, we elucidated thetertiary structure of CagA by X-ray crystallographic
analysis and NMR analysis. We found that CagA
consists of a N-terminal region (~70% of the entire
protein) and C-terminal region (~30% of the entire
protein) in which both EPIYA motif and CM sequence
are involved. NMR analysis revealed that the CagA
C-terminal region is intrinsically disordered andtherefore lacks a solid structure. Intrinsicallydisordered regions are gaining significant attention
due to its structural flexibility. The intrinsicallydisordered nature of C-terminal CagA enables
versatile protein interactions because of its structural
flexibility. X-ray crystallographic analysis revealed
that N-terminal CagA consists of three domains,termed Domains I-III. Domain II contains a basic
amino-acid cluster (basic patch) that provides a
positive electrostatic surface potential. CagA is
tethered to the inner face of the plasma membrane
through interaction between the basic patch andmembrane phosphatidylserine. Domain III interacts
intramolecularly with the intrinsically disordered
C-terminal region. This intramolecular interaction
potentiates the pathogenic scaffold/hub function of
CagA. Our study provides a tertiary-structural basis
for the pathophysiological/oncogenic action of H.
pylori CagA.

References
1. Hatakeyama, M. Helicobacter pylori CagA andgastric cancer: a paradigm for hit-and-run
carcinogenesis. Cell Host Microbe 15(3): 306-316(2014)
2. Hashi, K., Murata-Kamiya, N., Varon, C.,
Megraud, F., Domiguez-Bello, M.G., Hatakeyama,
M. A natural variant of the Helicobacter pylori
CagA oncoprotiein that lost the ability to interact
with PAR1. Cancer Sci. 105(3): 245-251 (2014)
3. Bessède, E., Staedel, C., Acuña Amador, L.A.,
Nguyen, P.H., Chambonnier, L., Hatakeyama, M.,
Belleannée, G., Mégraud, F., Varon, C.
Helicobacter pylori generates cells with cancer
stem cell properties via epithelial-mesenchymaltransition-like changes. Oncogene 33(32): 41234131 (2014)

51

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

LectureShu Okugawa, M.D., Ph.D.

Research Associate
Keita Tatsuno, M.D., Ph.D.
Masashi Suzuki, M.D., Ph.D.
Kazuhito Yuhashi, MD., Ph.D.
Mahoko Ikeda, MD., Ph.D.

Homepage http://www.cc.h.u-tokyo.ac.jp/mulins/kansen/index.html(inside the hospital only)※ The following information is the same as that of the previous year for certain reasons.

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.

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

52

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 activities
We have been mainly studying on following subjects:
Several studies are now going with the members of
department of parmacy 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 microorganisms

References
1.

2.

Nukui Y, Nakamura H, Ishioka H, Miyamoto H,
Okamoto A, Kazumi Y, Yotsuyanagi H, Moriya K,
Hatakeyama S. Synovitis of the wrist caused by
Mycobacterium florentinum. Infection. 42:437440, 2014.
Uranbileg B, Enooku K, Soroida Y, Ohkawa R,
Kudo Y, Nakagawa H, Tateishi R, Yoshida H,
Shinzawa S, Moriya K, Ohtomo N, Nishikawa T,
Inoue Y, Tomiya T, Kojima S, Matsuura T, Koike
K, Yatomi Y, Ikeda H. High ubiquitous
mitochondrial creatine kinase expression in
hepatocellular carcinoma denotes a poor
prognosis with highly malignant potential. Int J
Cancer. 134:2189-2198, 2014.

3.

Kishii K, Kikuchi K, Yoshida A, Okuzumi K,
Uetera Y, Yasuhara H, Moriya K. Antimicrobial
susceptibility profile of Acinetobacter species
isolated from blood cultures in two Japanese
university hospitals. Microbiol Immunol. 58:
142-146, 2014.
4. Saito R, Takahashi R, Sawabe E, Koyano S,
Takahashi Y, Shima M, Ushizawa H, Fujie T,
Tosaka N, Kato Y, Moriya K, Tohda S, Tojo N,
Koike R, Kubota T. First report of KPC-2
carbapenemase-producing Klebsiella pneumoniae
in Japan. Antimicrob Agents Chemother. 58:
2961-2963, 2014.
5. Kishii K, Kikuchi K, Matsuda N, Yoshida A,
Okuzumi K, Uetera Y, Yasuhara H, Moriya K.
Evaluation of matrix-assisted laser desorption
ionization-time of flight mass spectrometry forspecies identification of Acinetobacter strains
isolated from blood cultures. Clin Microbiol
Infect. 20:424-430, 2014.
6. Nguyen T, Xu J, Chikuma S, Hiai H, Kinoshita K,
Moriya K, Koike K, Marcuzzi GP, Pfister H,
Honjo T, Kobayashi M. Activation-induced
cytidine deaminase is dispensable for virusmediated liver and skin tumor development inmouse models. Int Immunol. 26;397-406, 2014.
7. Yamada N, Shigefuku R, Sugiyama R, Kobayashi
M, Ikeda H, Takahashi H, Okuse C, Suzuki M,
Itoh F, Yotsuyanagi H, Yasuda K, Moriya K,
Koike K, Wakita T, Kato T. Acute hepatitis B of
genotype H resulting in persistent infection.
World J Gastroenterol. 20:3044-3049, 2014.
8. Horiuchi Y, Takagi A, Kobayashi N, Moriya O,
Nagai T, Moriya K, Tsutsumi T, Koike K,
Akatsuka T. Effect of the infectious dose and thepresence of hepatitis C virus core gene on mouse
intrahepatic CD8 T cells. Hepatol Res. 44;240252, 2014.
9. Suzuki M, Koyano S, Okugawa S, Okazaki M,
Seki G, Moriya K. Diversity of vancomycinresistant enterococci in a low endemicity area.
Journal of Global Antimicrobial Resistance.
2;115-118, 2014.
10. 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

53

11.

12.

13.

14.

15.

16.

17.

peritransplant period: first reported case inallogeneic hematopoietic stem cell transplant.
Leuk Lymphoma. 27:1-3, 2014.
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. 108:45-48,
2015.
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. 282:237-243,
2014.
Koyano S, Tatsuno K, Okazaki M, Ohkusu K,
Sasaki T, Saito R, Okugawa S, Moriya K.
A Case of Liver Abscess with Desulfovibrio
desulfuricans Bacteremia. Case Rep Infect Dis.
2015:354168, 2015.
Misawa Y, Yoshida A, Okugawa S, Moriya K.
First reported case of Staphylococcus condimenti
infection associated with catheter-related
bacteraemia. New Microbes New Infect. 3:
18-20, 2014.
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:
comparison of genotypes and NS3 resistanceassociated variants between HCV/HIV coinfected
hemophiliacs and HCV monoinfected patients inJapan. PLoS One. 10:e0119145, 2015
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. 462:332-338, 22015.
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 ofhepatocellular carcinoma after hepatitis C virus
eradication in patients. Medicine (Baltimore).

94:e901, 2015.
18. 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. doi: 10, 2015.
19. 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. 15:25, 2015.
20. 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. 4:213-218,
2015.

Pathology, Immunology andMicrobiology
3. Immunology

55

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
Takako Negishi-Koga, Ph.D.; 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
cutting-edge, internationally recognized research in
the field of immunology especially cytokine systems
in the context of the regulation of immunity andoncogenesis. Dr. Taniguchi’s major achievements
were the discovery of interferon-β and a new familyof 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 2014, 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. Hitoshi Sakano(Prof. of Fukui Univ.), and Dr. Tadatsugu Taniguchi(Prof. of the Univ. of Tokyo).

56

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,. broadly covered
within these 4 subjects.
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 osteoclastgenesis (Shinohara et al.,Cell. 2008; Shinohara et al., Bone. 2014). We alsostudied in detail about cytosolic calcium and identified
Tmem64 as a key transmembrane protein for
osteoclastgenesis (Kim et al., Cell Metab., 2013.
Furthermore, we revealed roles of Semaphorin4D on
osteoblast differentiation (Negishi-Koga et. al., NatureMed., 2011) and Semaphorin3A on inhibition of boneabsorption as well as promotion of bone formation(Hayashi et. al., Nature 2012).
Recently, using ChIP-seq analysis for methylated
histone and RNA sequencing analysis, we showed thatthe protocadherin-7 (Pcdh7) gene is epigeneticallyregulated during osteoclastogenesis and is essential
for cell-cell fusion of osteoclasts (Nakamura et al.,Biochem Biophys Res Commun. 2014). We also foundthat immune complexes in serum activate
osteoclastogenesis and cause bone loss throughbinding to Fcγ receptors (Negishi-Koga et al., Nat
Commun. 2015). Furthermore, in collaboration with
Dr. Ishii in Osaka University, we identified the DNA
methyltransferase 3a (Dnmt3a) as a novel factor that
regulates differentiation and metabolic changes ofosteoclasts (Nishikawa et al., Nat Med. 2015). We aretrying to identify new cellular and molecular insights
into the bone-immune interactions, to further advancethe field of osteoimmunology (Takayanagi, Nat Rev
Rheumatol. 2015).
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 intocytoplasm for agonistic selection of T cells especiallyregulatory T cells and iNKT cells (Oh-hora et al.,Immunity. 2013). The microenvironment of thethymus is mainly composed of thymic epithelial cells(TEC) that regulate selections of developing T cells(Nitta et al., Adv Immunol. 2008; Nitta et al.,Immunity 2010). Using a newly established mousemodel of TEC deficiency, we showed the significant
role of thymic epithelial cells in development, not57

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
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). Now we are keen to understandmolecular mechanism in which Foxp3+T cells convert
to Th17 lineage in inflammatory condition. Our final
goal in this project is to develop new therapeuticstrategies for human autoimmune diseases.

3.

4.

5.

6.

7.

8.

References
1. Negishi-Koga T, Gober HJ, Sumiya E, Komatsu N,
Okamoto K, Sawa S, Suematsu A, Suda T, Sato K,
Takai T, Takayanagi H. Immune complexes regulate bone metabolism through FcRγ signaling. Nat
Commun. 6, 6637 (2015)
2. Nitta T, Muro R, Shimizu Y, Nitta S, Oda H, Ohte
Y, Goto M, Yanobu-Takanashi R, Narita T, Takayanagi H, Yasuda H, Okamura T, Murata S, Suzuki H. The thymic cortical epithelium determines

the TCR repertoire of IL-17-producing γδT cells.
EMBO Rep. 2015 Mar 13. [Epub ahead of print]
Nishikawa K, Iwamoto Y, Kobayashi Y, Katsuoka
F, Kawaguchi S, Tsujita T, Nakamura T, Kato S,
Yamamoto M, Takayanagi H, Ishii M. DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine–
producing metabolic pathway. Nat Med. 23 February 2015 [Epub ahead of print]
Nakamura H, Nakashima T, Hayashi M, Izawa N,
Yasui T, Aburatani H, Tanaka S, Takayanagi H.
Global epigenomic analysis indicates protocadherin-7 activates osteoclastogenesis by promoting
cell–cell fusion. Biochem Biophys Res Commun.
455, 305-311 (2014)
Omata Y, Yasui T, Hirose J, Izawa N, Imai Y,
Matsumoto T, Masuda H, Tokuyama N, Nakamura
S, Tsutsumi S, Yasuda H, Okamoto K, Takayanagi
H, Hikita A, Imamura T, Matsuo K, Saito T, Kadono Y, Aburatani H, Tanaka S. Genome-wide
comprehensive analysis reveals critical cooperation between Smad and c-Fos in RANKL-induced
osteoclastogenesis. J Bone Miner Res. 30, 869877 (2014)
Okura H, Sato S, Kishikawa S, Kaneto S,
Nakashima T, Yoshida N, Takayanagi H, Kiyono
H. Runx2-I Isoform Contributes to Fetal Bone
Formation Even in the Absence of Specific
N-Terminal Amino Acids. PLoS One. 9(9):e108294 (2014)
Komatsu N, Okamoto K, Sawa S, Nakashima T,
Oh-Hora M, Kodama T, Tanaka S, Bluestone JA,
Takayanagi H. Pathogenic conversion of Foxp3+
T cells into TH17 cells in autoimmune arthritis.
Nat. Med. 20, 62-8. (2014)
Shinohara M, Chang BY, Buggy JJ, Nagai Y, Kodama T, Asahara H, Takayanagi H. The orally
available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss. Bone.
60, 8-15 (2014)

Radiology and Biomedical
Engineering
1. Radiology

59

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.,

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.,

Noriyasu Sekiya, M.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

60

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
clinicalresearch,
animalexperiments
anddevelopment of instruments as well as computer-based
new technology. 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.

61

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.

2.

3.

4.

5.

6.

References
1. 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 A, Kasai K, Yamasue H.
Oxytocin improves behavioural and neural
deficits in inferring others' social emotions in
autism.

7.

8.

Brain 137(11): 3073-86, 2014
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.
A (90) Y-labelled anti-ROBO1 monoclonal
antibody exhibits antitumour activity against
hepatocellular carcinoma xenografts during
ROBO1-targeted radioimmunotherapy.
EJNMMI Res 4: 29, 2014
Furuta T, Kiryu S, Yamada H, Hosoi M,
Kurokawa M, Morikawa T, Shibahara J, Ohtomo
K.
Erdheim-Chester
diseasewithan
18Ffluorodeoxyglucose-avid breast mass and BRAF
V600E mutation.
Jpn J Radiol 32(5): 282-7, 2014
Furuta T, Yamaguchi M, Nakagami R, Akahane M,
Minami M, Ohtomo K, Fujii H.
Delayed hepatic signal recovery on ferucarbotranenhanced magnetic resonance images in a rat
model with regional liver irradiation.
MAGMA 27(6): 501-8, 2014
Goto M, Kunimatsu A, Shojima M, Mori H, Abe
O, Aoki S, Hayashi N, Gonoi W, Miyati T, Ino K,
Yano K, Saito N, Ohtomo K.
Depiction of branch vessels arising fromintracranial aneurysm sacs: Time-of-flight MRangiography versus CT angiography.
Clin Neurol Neurosurg 126: 177-84, 2014
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 thedefault-mode network: utility of volume
standardized with global gray-matter volume for
Alzheimer's disease: a preliminary study.
Radiol Phys Technol 8(1): 64-72, 2015
Hangai M, Kimura Y, Mori H, Yasui K, Tsuchida
S, Takahashi N.
Computed tomography findings of ongoing
subgaleal hemorrhage.
Pediatr Int 56(4): 623-6, 2014
Hashimoto K, Mizuno H, Nakagawa K, Horisaki
R, Iwasaki A, Kannari F, Sakuma I, Goda K.
High-speed multispectral videography with a62periscope array in a spectral shaper.
Opt Lett 39(24): 6942-5, 2014
9. Hirose S, Jimura K, Kunimatsu A, Abe O,
Ohtomo K, Miyashita Y, Konishi S.
Changes in cerebro-cerebellar interaction during
response
inhibition
after
performance
improvement.
Neuroimage 99: 142-8, 2014
10. Ichikawa K, Kashio A, Mori H, Ochi A, Karino S,
Sakamoto T, Kakigi A, Yamasoba T.
A new computed tomography method to identify
meningitis-related cochlear ossification andfibrosis before cochlear implantation.
Otolaryngol Head Neck Surg 150(4): 646-53,
2014
11. Ishida M, Gonoi W, Hagiwara K, Okuma H,
Shintani Y, Abe H, Takazawa Y, Ohtomo K,
Fukayama M.
Fluid in the airway of nontraumatic death on
postmortem computed tomography: relationshipwith pleural effusion and postmortem elapsedtime.
Am J Forensic Med Pathol 35(2): 113-7, 2014
12. Kamiya K, Tanaka F, Ikeno M, Okumura A, AokiS.
DTI tractography of lissencephaly caused by
TUBA1A mutation.
Neurol Sci 35(5): 801-3, 2014
13. Kamiya K, Sato N, Saito Y, Nakata Y ,Ito
K ,Shigemoto Y ,Ota M ,Sasaki M ,Ohtomo K.
Accelerated myelination along fiber tracts inpatients with hemimegalencephaly.
J Neuroradiol 41(3): 202-10, 2014
14. Kamiya K, Hori M, Miyajima M, Nakajima M,
Suzuki Y, Kamagata K, Suzuki M, Arai H,
Ohtomo K, Aoki S.
Axon diameter and intra-axonal volume fractionof the corticospinal tract in idiopathic normalpressure hydrocephalus measured by q-space
imaging.
PLoS One 9(8): e103842, 2014
15. Kanegasaki S, Matsushima K, Shiraishi K,
Nakagawa K, Tsuchiya T.
Macrophage inflammatory protein derivative
ECI301 enhances the alarmin-associated abscopal
benefits of tumor radiotherapy.
Cancer Res 74(18): 5070-8, 2014

16. Katsura M, Hirose S, Sasaki H, Mori H,
Kunimatsu A, Ohtomo K, Jimura K, Konishi S.
Decreased fronto-temporal interaction during
fixation after memory retrieval.
PLoS One 9(10): e110798, 2014
17. Katsura M, Suzuki Y, Hata J, Hori M, Sasaki H,
Akai H, Mori H, Kunimatsu A, Masutani Y, Aoki
S, Ohtomo K.
Non-gaussian diffusion-weighted imaging forassessing diurnal changes in intervertebral discmicrostructure.
J Magn Reson Imaging 40(5): 1208-14, 2014
18. Maeda E, Katsura M, Gonoi W, Yoshikawa T,
Hayashi N, Ohtsu H, Ohtomo K.
Abnormal signal intensities of the seminal
vesicles in a screening population.
J Magn Reson Imaging 39(6): 1426-30, 2014
19. Miyagawa T, Ueda K, Ohtomo R, Sasaki T,
Takahashi M, Momose T, Kurokawa M, Tsuji S.
Treatable chorea associated with polycythemia
vera.
Neurol Clin Neurosci 2(3): 90-1, 2014
20. Miyashita M, Kawakami S, Kato D, Yamashita H,
Igaki H, Nakano K, Kuroda Y, Nakagawa K.
The importance of good death components amongcancer patients, the general population,
oncologists, and oncology nurses in Japan:
patients prefer fighting against cancer.
Support Care Cancer 23(1): 103-10, 2015
21. Nakagawa K, Haga A, Sasaki K, Kida S, Masutani
Y, Yamashita H, Takahashi W, Igaki H, Sakumi A,
Ohtomo K, Yoda K.
Lung tumor motion reproducibility for fivepatients who received four-fraction VMAT
stereotactic ablative body radiotherapy underconstrained breathing conditions: a preliminary
study.
J Radiat Res 55(6): 1199-201, 2014
22. Natsubori T, Hashimoto RI, Yahata N, Inoue H,
Takano Y, Iwashiro N, Koike S, Gonoi W, Sasaki
H, Takao H, Abe O, Kasai K, Yamasue H.
An fMRI study of visual lexical decision inpatients with schizophrenia and clinical high-risk
individuals.
Schizophr Res 157(1-3): 218-24, 2014
23. Natsubori T, Inoue H, Abe O, Takano Y, Iwashiro
N, Aoki Y, Koike S, Yahata N, Katsura M, Gonoi

63

W, Sasaki H, Takao H, Kasai K, Yamasue H.
Reduced Frontal Glutamate + Glutamine and
N-Acetylaspartate Levels in Patients With
Chronic Schizophrenia but not in Those at
Clinical High Risk for Psychosis or With FirstEpisode Schizophrenia.
Schizophr Bull 40(5): 1128-39, 2014
24. Nomura Y, Nemoto M, Masutani Y, Hanaoka S,
Yoshikawa T, Miki S, Maeda E, Hayashi N,
Yoshioka N, Ohtomo K.
Reduction of false positives at vessel bifurcations
in computerized detection of lung nodules.
J Biomed Graph Comput 4(3): 36-46, 2014
25. Nomura Y, Masutani Y, Miki S, Nemoto M,
Hanaoka S, Yoshikawa T, Hayashi N, Ohtomo K.
Performance improvement in computerized
detection of cerebral aneurysms by retrainingclassifier using feedback data collected in routine
reading environment.
J Biomed Graph Comput 4(4): 12-21, 2014
26. Ohgami Y, Kotani Y, Arai J, Kiryu S, Inoue Y.
Facial, verbal, and symbolic stimuli differently
affect the right hemisphere preponderance ofstimulus-preceding negativity.
Psychophysiology 51(9): 843-52, 2014
27. Okuma H, Gonoi W, Ishida M, Shintani Y,
Takazawa Y, Fukayama M, Ohtomo K.
Greater thickness of the aortic wall on
postmortem computed tomography compared withantemortem computed tomography: the firstlongitudinal study.
Int J Legal Med 128(6): 987-93, 2014
28. Okuma H, Gonoi W, Ishida M, Shirota G, Shintani
Y, Abe H, Fukayama M, Ohtomo K
Comparison of attenuation of striated muscle
between postmortem and antemortem computed
tomography: results of a longitudinal study.
PLoS One 9(11): e111457, 201429. Shiraishi K, Futaguchi M, Haga A, Sakumi A,
Sasaki K, Yamamoto K, Igaki H, Ohtomo K, Yoda
K, Nakagawa K.
Validation of planning target volume margins byanalyzing intrafractional localization errors for 14
prostate cancer patients based on threedimensional cross-correlation between theprostate images of planning CT and intrafraction
cone-beam CT during volumetric modulated arc

therapy.
Biomed Res Int 2014: 960928, 2014
30. Takahashi M, Momose T, Koyama K, Ichikawa M,
Kurokawa M, Ohtomo K.
Dynamic Metabolic Changes during the First 3
Months after 90Y-Ibritumomab Tiuxetan Radioimmunotherapy.
ScientificWorldJournal 2014: 368947, 2014
31. Takahashi W, Mori S, Nakajima M, Yamamoto N,
Inaniwa T, Furukawa T, Shirai T, Noda K,
Nakagawa K, Kamada T.
Carbon-ion scanning lung treatment planning withrespiratory-gated phase-controlled rescanning:
simulation study using 4-dimensional CT data.
Radiat Oncol 9(1): 238, 2014
32. Tamamitsu M, Nakagawa K, Horisaki R, Iwasaki
A, Oishi Y, Tsukamoto A, Kannari F, Sakuma I,
Goda K.
Design for sequentially timed all-optical mapping
photography with optimum temporal performance.
Opt Lett 40(4): 633-6, 2015
33. Tomizawa N, Kanno S, Maeda E, Akahane M,
Torigoe R, Ohtomo K.
Minimizing the acquisition phase in coronary CT
angiography using the second generation 320-row
CT.
Jpn J Radiol 32(7): 391-6, 2014
34. Tomizawa N, Kanno S, Maeda E, Akahane M,
Torigoe R, Ohtomo K.
In reply to: minimizing the radiation dose incoronary CT angiography using prospective
ECG-triggering, low tube voltage and iterative
reconstruction technologies.
Jpn J Radiol 33(1): 48-9, 2015
35. Tsukada Y, Nakamura N, Ohde S, Akahane K,
Sekiguchi K, Terahara A.
Factors that delay treatment of symptomatic
metastatic extradural spinal cord compression.
J Palliat Med 18(2): 107-13, 2015
36. Wang F, Akashi K, Murakami Y, Inoue Y, Furuta T,
Yamada H, Ohtomo K, Kiryu S.
Detection of lung tumors in mice using a 1-Tesla
compact magnetic resonance imaging system.
PLoS One 9(4): e94945, 2014
37. Watanabe T, Yahata N, Kawakubo Y, Inoue H,
Takano Y, Iwashiro N, Natsubori T, Takao H,
Sasaki H, Gonoi W, Murakami M, Katsura M,

64

Kunimatsu A, Abe O, Kasai K, Yamasue H.
Network structure underlying resolution of
conflicting non-verbal and verbal social
information.
Soc Cogn Affect Neurosci 9(6): 767-75, 2014
38. Yamaji Y, Isomura Y, Yoshida S, Yamada A,
Hirata Y, Shiraishi K, Kumagai J, Enomoto Y,
Homma Y, Koike K.
A Case of Behcet’s Disease with Radiation
Proctitis Improved by Oral Administration of
Irsogladine.
Gastroenterol Pancreatol Liver Disord 1(2): 1-4,
2014
39. Yamashita H, Onishi H, Matsumoto Y, Murakami
N, Matsuo Y, Nomiya T, Nakagawa K; JapaneseRadiological Society multi-institutional SBRT
study group (JRS-SBRTSG).
Local effect of stereotactic body radiotherapy forprimary and metastatic liver tumors in 130
Japanese patients.
Radiat Oncol 9: 112, 2014
40. Yamashita H, Takahashi W, Haga A, Kida S,
Saotome N, Nakagawa K.
Stereotactic body radiotherapy for small lungtumors in the University of Tokyo Hospital.
Biomed Res Int 2014: 136513, 2014
41. Yamashita H, Takahashi W, Haga A, Nakagawa K.
Radiation pneumonitis after stereotactic radiation
therapy for lung cancer.
World J Radiol 6(9): 708-15, 2014
42. Yamashita H, Omori M, Takenaka R, Okuma K,
Kobayashi R, Ohtomo K, Nakagawa K.
Involved-field irradiation concurrently combinedwith nedaplatin/5-fluorouracil for inoperable
esophageal cancer on basis of (18) FDG-PET
scans: a phase II study.
Radiother Oncol 113(2): 182-7, 2014
43. Yamashita H, Haga A, Takahashi W, Takenaka R,
Imae T, Takenaka S, Nakagawa K.
Volumetric modulated arc therapy for lungstereotactic radiation therapy can achieve highlocal control rates.
Radiat Oncol 9: 243, 2014
44. Yamashita M, Takenaka HY, Nakagawa K.
Semi-radical
chemoradiotherapy
for53
esophageal squamous cell carcinomas withsupraclavicular lymph node metastasis in a single

institutional retrospective study.
Hepatogastroenterology 61(135): 1971-8, 2014
45. Yasaka K, Katsura M, Akahane M, Sato J,
Matsuda I, Ohtomo K.
Dose-reduced CT with model-based iterative
reconstruction in evaluations of hepatic steatosis:
how low can we go?
Eur J Radiol 83(7): 1063-8, 2014
46. Yasutake T, Kiryu S, Akai H, Watadani T,
Akahane M, Tomizawa N, Gonoi W, Ikemura M,
Takahashi M, Matsuoka Y, Ohtomo K.
MR imaging of carcinosarcoma of the liver using
Gd-EOB-DTPA.
Magn Reson Med Sci 13(2): 117-21, 2014
47. 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 inadenocarcinoma of the lung?
Ann Thorac Cardiovasc Surg 21(1): 8-13, 2015
48. Zhou T, Ando T, Nakagawa K, Liao H, Kobayashi
E, Sakuma I.
Localizing fluorophore (centroid) inside ascattering medium by depth perturbation.
J Biomed Opt 20(1): 017003, 2015

Radiology and Biomedical
Engineering
2. Biomedical Engineering

66

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

research under the supervision of our staffs.

The Department 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. Former professor of our laboratory is Prof.
Shogo Ueno, who extensively did the research of
bio-magnetic imaging and magnetoencephalographyof brain functions. After his retirement in 2006, Dr.
Yasuteru Urano took up the post, and the newlaboratory was launched since January of 2010. Dr.
Mako Kamiya joined in May 2010 as an assistantprofessor, and three postdocs, four PhD student, threemaster course students and one technician has joinedby the end of FY2013.

Research activities

Teaching activities
As for under-graduate education, our department takes
a part in medical engineering lectures for the 3rd year
medical students. As for PhD course education, ourdepartment delivers the lecture of fluorescenceimaging for both master and doctor course students.
Our laboratory is also accepting Free Quarter students
every year, and this year we had two 3rd year students
for three weeks. They were trained to synthesize
chemical probes and observe live cells withfluorescent microscopes. Our laboratory is also
accepting three under-graduate students (one in M2
and two in M1) as Medical Scientist Training Programin faculty of medicine. They are doing their own

1. Development of novel fluorescence probes
Two specialized rooms for chemical syntheses weresettled in our department, equipped with various
instruments for chemical syntheses, purification, andcharacterization, i.e., six chemical hoods, six
evaporators, two instruments for the purification ofcompounds based on different chromatographicalmechanisms, three HPLC systems, one HPLC systemfor bulk purification, 400 MHz NMR, ESI-TOF mass,and so on. UV-Vis spectrometers and fluorometers
were also settled in our laboratory. So now, molecular
design,chemical
syntheses,
purification,
characterization of novel probes can be done in our
department.
By using above instruments, we are now conducting
various projects of establishing novel bioimaging
techniques based on the development of new
fluorescence probes. So far, we have succeeded inestablishing rational design strategies of fluorescenceprobes based on photoinduced electron transfer andintramolecular spirocyclization mechanism. In 2013,
we have succeeded to develop various novel
fluorescence probes by utilizing the concept of bothmechanisms.
2. Live imaging of cellular functions and in vivo
tumors by precisely designed fluorescence probes

67

Various instruments for live imaging of cells andanimals were already settled in our laboratory, i.e.,
confocal fluorescence microscope equipped with awhite-light laser, two wide field fluorescencemicroscopes, FACS, two in vivo fluorescent imagers,
in vivo bioluminescent imager, fluorescent endoscope,
etc. Also, instruments for cell culture and DNA work
were also settled in our laboratory.
By using these instruments, we are doing live imaging
of cancer cells and model mice extensively, forelucidating characteristic features of live cancer cells.
Based on the acquired data, we are developing novel
fluorescence probes for detecting tiny tumor sites invivo. Especially, a novel fluorescence probe for
γ-glutamyltranspeptidase which was developed in2011, was applied for various real human resected
tumor samples under several collaborations withsurgeons including those in Tokyo University Hospitalin order to examine the efficiency of the new probe.

References
1. Yamashita S, Sakabe M, Ishizawa T, Hasegawa K,
Urano Y, Kokudo N: Visualization of the leakageof pancreatic juice using a chymotrypsin-activatedfluorescent probe. Br J Surg. 100(9): 1220-1228,
2013. doi: 10.1002/bjs.9185.
2. Terai T, Tomiyasu R, Ota T, Ueno T, Komatsu T,
Hanaoka K, Urano Y, Nagano T: TokyoGreen
derivatives as specific and practical fluorescentprobes for UDP-glucuronosyltransferase (UGT)
1A1.Chem Commun (Camb) 49(30): 3101-3103,
2013. doi: 10.1039/c3cc38810g.
3. Sakabe M, Asanuma D, Kamiya M, Iwatate JR,
Hanaoka K, Terai T, Nagano T, Urano Y:
Rational Design of Highly Sensitive Fluorescence
Probes For Protease and Glycosidase Based on
Precisely Controlled Spirocyclization. J. Am.
Chem. Soc. 135(1): 409-414, 2013. doi: 10.1021/
ja309688m.
4. Kojima R, Takakura H, Ozawa T, Tada Y,
Nagano T, Urano Y: Rational Design andDevelopment of Near-Infrared-Emitting Firefly
Luciferins Available In Vivo. Angew Chem Int
Ed Engl 21;52(4):1175-9, 2013. doi: 10.1002/
anie.201205151.

68

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

Teaching activities

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 the 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 forclinical medicine. With the structural reformation ofFaculty of Medicine, Institute of Medical Electronics
has been shifted to Graduate School of Medicine, andDepartment of Clinical Medicine in the Institute ofMedical Electronics has been reformed to the present
department since April 1, 1997.
The current members include an associate professor, alecturer, a project researcher, 7 graduate students, 14visiting researchers, a senior technical specialist, and a
project academic support stuff.
Our research covers wide area of interdisciplinary andcomprehensive research fields based on the advanced
medical and engineering technologies. We arecooperating with various laboratories. Our doctor
course students can choose to perform their researchworks under the guidance of Prof. Mabuchi at
Department of Information Physics and Computing,
Graduate School of Information Science andTechnology.

We take a part in systematic lectures for the 3rdyear medical students. We also provide practice in the“free quarter” 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 the

69

doctor 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.
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 and developments for driving mechanisms,
energy converters, blood pumps, biomaterials, powertransmissions, measurement techniques, control
methods, anatomical fitting, blood compatibility,
tissue compatibility, computational fluid dynamic(CFD) analysis, physiology, pathology, and so on,
have been studied. All the stuffs and students are inpart participating in the artificial heart project. In
1995, we succeeded to survive a goat for 532 days
with the paracorporeal total artificial heart (TAH) withno anticoagulant, 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 thecomplexed drive shaft mechanism. To improve theproblem of the UPTAH, a new blood pump, named thehelical flow pump (HFP), was invented in ourlaboratory in 2005. The HFP is a novel blood pumphaving a hydrodynamic levitating impeller, which
promises high durability. The animal experiment of thehelical flow TAH (HFTAH) had started in 2011. The
HFTAH could be implanted in the goat successfully
with good anatomical fitting. To date, the goat whoseheart was replaced with the HFTAH survived for 100
days. We are expecting to develop an ideal TAH that
surpass the outcome of the heart transplantation withcombination of the technologies of the physiologicalcontrol and hybrid materials described later.
How to control the output of a TAH is primary interest.
We have developed our original physiological control
method of the TAH, named 1/R control. The 1/R
control was developed with a conductance (1/R:
reciprocal of a resistance) parallel circuit model. At
the present time, the 1/R control is the only reported
method to achieve a physiological control of a TAH,
which can control venous pressure. With the 1/R
control, the particular problems of a TAH such as
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
the problem of instability in the 1/R control, a newcontrol method based on the fluctuation of arterial andvenous pressures (named ΔP control) was developedby reforming 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

70

nonpulsatile flow, which seemed almost identical.
However, under the physiological atrial pressure, thesucking effect of atria was more significant in the
nonpulsatile flow than the pulsatile flow. Therefore,
the nonpulsatile TAH with the 1/R control was
considered to be inadequate, unless some pulsatility
would be introduced to avoid the sucking effect for
ensuring sufficient inflow condition.
Concerning the materials, we have been developing a
new method to develop hybrid materials. In general, it
is not easy to develop mechanical parts for complexed
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 the molding of resin in theindustrial field, was introduced. In this method, themold, in which 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. A new membrane
oxygenator and a new blood pump were designed andintegrated into one piece. An experimental model
exhibited good performance. The improved model ofthe ELSS is under the development to realize severalmonths support. The whole system components will bepacked in a case having 180 mm in diameter and 390

mm in length. The whole weight will be about 20 kg.
Our research of the application of ICT (Informationand communication technology) to medicine has been
focused to the home medical care. The research anddevelopment for monitoring the condition of thepatients living at home has been performed utilizing
the miniaturized wireless ECG (electro cardiogram)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.
Nerve interface will be very important technology fordeveloping control mechanism of artificial organs.
The basic study to develop a multiple interface arrayfor brain machine interface is being studied at thelaboratory of Prof. Mabuchi, Department ofInformation Physics and Computing, Graduate Schoolof Information Science and Technology.

References
1. Hosoda K, Ishii K, Isoyama T, Saito I, Inoue Y,
Ariyoshi K, Ono T, Nakagawa H, Imachi K,
Kumagai H, Abe Y. Computational fluid dynamics
analysis of the pump parameters in the helicalflow pump. J Artif Organs 2014:17; 9-15, DOI
10.1007/s10047-013-0739-8
2. Wu S, Saito I, Isoyama T, Inoue Y, Sato M, Hara S,
Li X, Yurimoto T, Murakami H, Kawase K, Ono T,
Abe Y. Concept of left atrial pressure estimation
using its pulsatile amplitude in the helical flow
total artificial heart. J Artif Organs 2014:17; 301-7,
DOI 10.1007/s10047-014-0788-7

Neuroscience
1. Basic Neuroscience72

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

Lecturer
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 thepathogenesis of Alzheimer’s disease (AD) and related
neurodegenerative conditions (especially, dementia
with Lewy bodies; DLB) by multidisciplinary
approaches, based on histopathology and protein
biochemistry of postmortem human brains. They thenextended the knowledge derived from the humanstudies in a way to establish cellular models and to
elucidate the key steps in the pathological cascade ofneurodegeneration. Thus, Dr. Iwatsubo’s group has
been addressing the pathogenesis of neurodegenerative 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

73

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,

74

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.

References
1) Li Y, Lu SH-J, Tsai, C-J, Bohm C, Qamar S, Dodd
RB, Meadows W, Jeon A, McLeod A, Chen F,
Arimon M, Berezovska O, Hyman BT, Tomita T,
Iwatsubo T, Johnson CN, Farrer LA,
Schmitt-Ulms G, Fraser F, St George-Hyslop P:
Structural interactions between inhibitor andsubstrate docking sites give insight intomechanisms of human PS1 complexes. Structure
22:125-135, 2014
2) Taniguchi A, Shiohara A, Sasaki D, Iwatsubo T,
Tomita T, Sohma Y, Kanai M: Attenuatedaggregation and neurotoxicity of Alzheimer

disease-associated amyloid-β peptide by catalytic
photo-oxygenation.
Angewandte
Chemie53:1382-1385, 2014
3) Doody RS, Thomas RG, Farlow M, Iwatsubo T,
Vellas B, Joffe S, Kieburtz K, Raman R, Sun X,
Aisen PS, for the Alzheimer’s Disease Cooperative
Study Steering Committee and Siemers E,
Liu-Seifert H, Mohs R for the solanezumab Study

Group: Phase three trials of solanezumab for mild
to moderate Alzheimer’s disease. N Eng J Med
370:311-321, 2014
4) Tanaka T, Wakabayashi T, Oizumi H, Nishio S,
Sato T, Harada A, Fujii D, Matsuo Y, Hashimoto T,
Iwatsubo T: CLAC-P/collagen type XXV isrequired for the intramuscular innervation of
motoneurons during neuromuscular development.
J Neurosci 34:1370-1379, 20145) Ohki Y, Shimada N, Tominaga A, Osawa S, Higo T,
Yokoshima S, Fukuyama T, Tomita T, Iwatsubo T:
Binding of longer Aβ to transmembrane domain 1of presenilin 1 impacts on Aβ42 generation. Mol
Neurodegener 9:7, 2014
6) Kanatsu K, Morohashi Y, Suzuki M, Kuroda H,
Watanabe T, Tomita T, Iwatsubo T: Decreased
CALM expression reduces Aβ42 to total Aβ ratio
throughclathrin-mediatedendocytosisofγ-secretase. Nat Commun 5:3386 doi: 10.1038/
ncomms4386, 2014
7) Ito G, Fujimoto T, Kamikawaji S, Kuwahara T,
Iwatsubo T: Lack of correlation between the
kinase activity of LRRK2 harboring kinasemodifying mutations and its phosphorylation at
Ser910, 935, and Ser955. PLOS One 9:e97988,
20148) Yonezawa H, Nishiyama Y, Takeo K, Iwatsubo T,
Tomita T, Yokoshima S, Fukuyama T: New
photocleavable linker: α-Thioacetophenone-type
linker. Bioorg Med Chem Lett 24:2831-2833,
20149) Takeo K, Tanimura S, Shinoda T, Osawa S,
Zahariev I, Takegami N, Ishizuka-Katsura Y,
Shinya N, Takagi-Niidome S, Tominaga A,
Ohsawa N, Kimura-Someya T, Shirouzu M, Yokoshima S, Yokoyama S, Fukuyama T, Tomita T,
Iwatsubo T: Allosteric activation of γ-secretase
processivity by a phenylimidazole- typeγ-secretase modulator. Proc Natl Acad Sci USA
111:10544-10549, 201

75

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 partsof the neurons 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 in August 2001, Associate Professor
Haruhiko Bito was appointed as Head of Department
since January 2003. The Department is located on the

76

6th floor, in the West wing of the third building of theMedical 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 technical assistants and one administrative
assistant.

Teaching activities
The Department’s teaching activities include:
1) Introductory Neuroscience coursework provided to
pre-medical students in the Komaba campus (onehour);
2) Neurochemistry lectures to medical students as partof the “Biochemistry- Molecular BiologyNutrition” core curriculum (two hours);3) Introductory Molecular and Cellular Neuroscience,
and Basic Neurochemistry lectures to first-year
master degree students (three hours);
4) Organization of the lecture course: “Basic Neuroscience” (Molecular and Cellular Neuroscience) (alecture series with fifteen lectures from outstanding
neuroscientists from all over Japan).
Additionally, Neurochemistry Seminars are
frequently and regularly organized that enables direct
exposure of Ph.D. graduate students and postdocs toboth young promising researchers and establishedinvestigators from all over the world.

Research activities
The Department of Neurochemistry currently
focuses its resources into two core projects:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calcium-dependent
synaptic modification, especially during signalingfrom synapse-to-nucleus, and back from nucleus-tosynapses.
Changes in efficacy of synaptic transmission
have been shown to strongly correlate with functional
plasticity of many brain circuits including the
hippocampus, the amygdala, the striatum, theneocortex, the cerebellum or the spinal cord. An earlyphase of long-term synaptic plasticity is induced byvirtue of specific post- and/or presynaptic modifications of the biochemical machinery dedicated tosynaptic release and neurotransmitter recognition. It
then is expressed by bistable mechanisms that arestrongly governed and dictated by the pattern ofsynaptic calcium influxes experienced during theinitial conditioning period. While the molecular
identity of the involved synaptic proteins is now(almost) being solved (or is becoming much lesscontroversial than before), several essential questions
remain unanswered.
The “Old” question was: What are the moleculardeterminants that enable these plastic changes to be
induced and maintained locally? Yet, related issues ofcritical importance that still remain wide open
questions are:1) What are the full-range of calcium-triggered
molecular signaling cascades which are activated atand near the potentiated/depressed synapses? And
how do they influence plasticity per se?
2) What is the contribution of activity-dependent gene
expression in prolongation and consolidation ofsuch synapse-restricted changes?
In order to begin to address these issues, we havebeen investigating in particular the role of several
calcium-calmodulin dependent protein kinases.
We previously showed the critical importanceof a CaMKK/CaMKIV cascade in triggering
synaptically-stimulated nuclear CREB phosphorylation in hippocampal neurons. The extreme
biochemical efficacy and the relative poor frequencydependence of this signaling cascade, in combination
with the robust correlation between prolonged pCREB
response and downstream gene expression led us topropose that CaMKK/CaMKIV/pCREB cascade was
likely to act as a critical temporal integrator for
activity-dependent gene expression in excitatoryneurons (Bito et al., Cell, 1996; Bito et al., Curr. Opin.
Neurobiol., 1997; Bito, Cell Calcium, 1998). Thishypothesis has now been critically tested in various
brain systems and indeed pCREB immunofluorescence is now considered as a universal marker
for integrated synaptic activity that is more sensitive
than that of c-Fos (Nonaka, J. Neurosci. 2009). The
critical function of CaMKK/CaMKIV/pCREB cascadein the expression of long-term synaptic plasticity was
also validated in long-term potentiation in the

77hippocampus (Redondo et al., J Neurosci. 2010).
Furthermore,
CaMKIV-KO,
CaMKK-KO
and
CaMKIV-dominant negative transgenic studies bymany laboratories have confirmed the critical role for
CaMKIV as synaptic activity-triggered CREB kinase.
We subsequently also showed that CaMKIV inthe cerebellar granule cells played a critical role intuning the pCREB response necessary for
depolarization-mediated neuronal survival, and that 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/phosphatasesignaling
responsibleforactivity-dependent 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 ofthis kinase to be properly sorted into specificlipid-restricted membrane microdomains. The
function played by this lipidified, membrane-inserted
CaMK in circuitry formation and maturation was
scrutinized using RNA interference. Along with theidentification of the critical lipid-modifying enzymethat 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 alsosuggest the active contribution of CaMKK cascade inthis process (Ageta-Ishihara et al., J. Neurosci. 2009;
Takemoto-Kimura et al. Eur. J. Neurosci. 2010).
How do these multiple Ca2+-dependent signaling
molecules process each pattern of intracellular Ca2+

78

dynamics to induce a cellular response? Recently, we
have developed a method named dFOMA (dual FRET
imaging with optical manipulation) to simultaneously
measure activities of two distinct signaling moleculesin living neurons. Applying originally developed
FRET probes to dFOMA method enabled us tomeasure activities of CaMKII, calcineurin and Ca2+,
when a neuron received various frequencies ofsynaptic inputs. These experiments provided evidence
that CaMKIIα and calcineurin are fine-tuned to uniquebandwidths and compute input variables in an
asymmetric manner (Fujii et al., Cell Reports 2013).
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 morphologicalcomponent 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
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

79

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 thevoltage-gated calcium channels in its vicinity, theopening of which triggers their release (Kiyonaka etal., Nature Neurosci., 2007).

Publications by lab members(January 2014- December 2014)
1.

2.

3.

4.

Nonaka M, Fujii H, Kim R, Kawashima T, Okuno
H, Bito H. Untangling the two-way signallingroute from synapses to the nucleus, and from thenucleus back to the synapses. Philos Trans R
Soc Lond B Biol Sci. 369: 20130150, 2014
Kawashima T, Okuno H, Bito H. A new era
for functional labeling of neurons: activitydependent promoters have come of age. Front
Neural Circuits., 8: 37, 2014.
Nonaka M, Kim R, Sharry S, Matsushima A,
Takemoto-Kimura S, Bito H. Towards a better
understanding of cognitive behaviors regulated
by gene expression downstream of activitydependent transcription factors. Neurobiol Learn
Mem., 115: 21-29, 2014.
Nonaka M, Kim R, Fukushima H, Sasaki K,
Suzuki K, Okamura M, Ishii Y, Kawashima T,
Kamijo S, Takemoto-Kimura S, Okuno H, Kida S,
Bito H. Region-specific activation of CRTC1CREB signaling mediates long-term fear memory.
Neuron, 84(1):92-106, 2014.

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 generating
fluorescent probes for live cell imaging
Imagingtechniques
whichvisualizesignaling
molecules in living cells is apowerful method tounderstand the mechanism underling physiological
functions. To facilitate this process, we developed ahigh-throughput screening system based on 96-wellplate format protocol. After screening, we obtained
glutamate indicators consisting of many combinationsof the cysteine mutant and the fluorescent dye
showing large fluorescence changes upon glutamate
binding. This result suggests that our screening systemshould be applicable to develop the fluorescentindicator for other signaling molecules as well as forglutamate in short periods.
2) Study of synapse physiology by glutamate
imaging technique
In mammalian central nervous system, direct imagingof neurotransmission should greatly contribute toclarifyexocytosis dynamics at synapses and improve
our understanding of the mechanisms in synaptictransmission. Aiming at imaging glutamate, wedeveloped a novel optical glutamate probe by our
high-throughput screening system. We successfully
visualized 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) Study of regulation mechanism of cell movementby fluorescent imaging of Rho family proteins
We have constructed new fluorescent indicators for
Rho family, including Rho, Rac and Cdc42, whichfunction as molecular switches in many signalingcascades. These indicators revealed spatial-temporal
dynamicsof Rho family proteins activation in
randomly migrating HT1080 cells. In contrast to
previous studies, Rho and Cdc42 were activated inbroad areas of the plasma membrane in motile cells.
Therefore, our probes can be used for more effective
and quantitative study for cell movement. Furthermore,in a central nervous system, Rho family is known as amolecules regulation cell motility of neuronal cells
and synaptic function. We applied our fluorescentprobes to experiments for analysis of these cellfunctions.
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
reportedamethodcalledEPRIL(enzymatic

production of RNAi library) by which shRNA vectors
are produced 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.

Ishino Y, Hayashi Y, Naruse M, Tomita K, Sanbo
M, Fuchigami T, Fujiki R, Hirose K, Toyooka Y,
Fujimori T, Ikenaka K, Hitoshi S. Bre1a, ahistone H2B ubiquitin ligase, regulates the cell
cycle and differentiation of neural precursor cells.
The Journal of Neuroscience 34(8) 3067-78
2014.

2.

3.

4.

Asanuma D, Takaoka Y, Namiki S, Takikawa K,
Kamiya M, Nagano T, Urano Y, Hirose K.
Acidic-pH-Activatable Fluorescence Probes for
Visualizing Exocytosis Dynamics. Angewandte
Chemie International Edition 53(24) Sep-85
2014.
Takikawa K, Asanuma D, Namiki S, Sakamoto H,
AriyoshiT,
KimparaN,
HiroseK.
High-throughput development of a hybrid-type
fluorescent glutamate sensor for analysis ofsynaptic transmission. Angewandte ChemieInternational Edition 53(49) 13439-43 2014.
Isa M, Asanuma D, Namiki S, Kumagai K,
Kojima H, Okabe T, Nagano T, Hirose K.
High-throughput screening system to identify
small molecules that induce internalization anddegradation of HER2. ACS Chemical Biology
9(10) 2237-41 2014.

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 theirdevelopment are emphasized. Especially, as Japan
falls far behind other nations in research andeducation system of child psychiatry, development ofspecialists who can promote research by themselves
and improve quality of diagnosis and treatment basedon their own research are strongly demanded. In
response to these needs, Department of Child
Neuropsychiatry, Graduate School of Medicine wasestablished in April 2010. This is believed to be thefirst Japanese department which works as an actual
department of child psychiatry managed by childpsychiatrist. Based on experience of clinical-based
research as well as medical care and training ofclinicians for decades in child psychiatry division of
Department of Neuropsychiatry and Department ofChild Psychiatry since April 2005, we are developing
new activities. Three professors are administrating
Department of Child Psychiatry, the University
Hospital also, and trying to utilize its clinical activities
for research more effectively.

Research activities

Teaching activities
In the year of 2014, we had 7 graduate students.
In addition to research training, educational program
including full-year lectures of child psychiatry, case

Main subjects of our research are ASD including
autism and Asperger syndrome, ADHD, Tourette
syndrome which is a severe and chronic tic disorder,and child & adolescent obsessive-compulsive disorder(OCD). We are trying to combine scientific analysis ofobjective mental and behavioral indicators withneuropsychological, brain-imaging, and genetic
studies into comprehensive and multidimensional
approach to problems in development of brain andmind. We are applying this comprehensive approach
to intervention studies including pharmacotherapy.
Major research projects with full or preliminary
performance in 2014 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. Takizawa R, Fukuda M, Kawasaki S, Kasai K,
Mimura M, Pu S, Noda T, Niwa SI, Okazaki Y; onbehalf of the Joint Project for PsychiatricApplication of Near-Infrared Spectroscopy (JPSYNIRS) Group (Ishii-Takahashi A). Neuroimagingaided differential diagnosis of the depressive state.
Neuroimage 85 Pt1: 498-507, 2014.
2. 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 Pt1: 518-26, 2014.
3. 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,Ishii-Takahashi
A, Kawakubo Y, Kasai K. Genetic influences on
prefrontal activation during a verbal fluency task
in adults: a twin study based on multichannel
near-infrared spectroscopy. Neuroimage. 85 Pt 1:
508-17, 2014.
4. Watanabe T, Abe O, Kuwabara H, Yahata N,
Takano Y, Iwashiro N, Natsubori T,Aoki Y,
Takao H, Kawakubo Y, Kamio Y, Kato N,
Miyashita Y, Kasai K, Yamasue H. Mitigation ofsociocommunicational deficits of autism throughoxytocin-induced recovery of medial prefrontal
activity: a randomized trial. JAMA Psychiatry.
71(2):166-75, 2014.
5. 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. Social Cognitive and Affective
Neuroscience. 9(6):767-75, 2014.
6. 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 A, Kasai K, Yamasue H. Oxytocin

improves behavioural and neural deficits in
inferring others'social emotions in autism. Brain.
137(Pt 11):3073-86, 2014.
7. Itahashi T, Yamada T, Nakamura M, Watanabe H,
Yamagata B, Jimbo D, Shioda S, Kuroda M,
Toriizuka K, Kato N, Hashimoto R. Linked
alterations in gray and white matter morphology
in adults with high-functioning autism spectrum
disorder: a multimodal brain imaging study.
Neuroimage Clin. 3(7):155-69, 2014.
8. Kamio Y, Inada N, Koyama T, Inokuchi E,
Tsuchiya K, Kuroda M. Effectiveness of Using theModified Checklist for Autism in Toddlers in
Two-Stage Screening of Autism Spectrum
Disorder at the 18-Month Health Check-Up in
Japan. Journal of Autism and Developmental
Disorder. 44(1):194-203,2014.
9. Kuwabara H, Araki T, Yamasaki S, Ando S, Kano
Y, Kasai K. Regional differences in post-traumaticstress symptoms among children after the 2011
tsunami in Higashi-Matsushima, Japan. Brain Dev.
(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.

Noriyuki Hayashi, M.D.

Katsuhisa Yamada, M.D.

Tomoko Ando, M.D.

Yosuke Kumakura, M.D.

Mao Fujioka, M.D.

Homepage

http://npsy.umin.jp/

Introduction and Organization
The Department of Neuropsychiatry is the oldest
department of psychiatry in Japan which wasestablished in 1886. "Anti-Psychiatry" movement in
the last 3 decades had brought highly negative impacts
on the progress of all aspects of our activities.
However, in 1994, our department has beennormalized and restarted to play a leading role inpsychiatry in Japan. Since 2005, we have begun tofocus on basic and clinical neuroscience in pervasive
developmental disorders (PDDs). From 2006, we havebeen working in the new closed ward and in the open
ward. Dr. Kiyoto Kasai has been serving as aprofessor since 2008. Now the Department of
Neuropsychiatry is dedicated to high quality clinicalservices, excellent training, education for students andinnovative 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 thepathophysiology 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 Epilepsy, PTSD, autism and schizophrenia.
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 theReferences(1) Iwashiro N, Yahata N, Kawamuro Y, Kasai K,
Yamasue H. Aberrant interference of auditory
negative words on attention in patients withschizophrenia. PLoS ONE. 2013; 8:e83201(2) Ishii-Takahashi A, Takizawa R, Nishimura Y,
Kawakubo Y, Kuwabara H, Matsubayashi J,
Hamada K, Okuhata S, Yahata N, Igarashi T,
Kawasaki S, Yamasue H, Kato N, Kasai K, Kano
Y. Prefrontal activation during inhibitory control
measured by near-infrared spectroscopy for
differentiating between autism spectrum disorders
and attention deficit hyperactivity disorder in
adults. Neuroimage Clin. 2013 4: 53-63(3) Koike S, Nishimura Y, Takizawa R, Yahata N,
Kasai K. Near-infrared spectroscopy inschizophrenia: A possible biomarker forpredicting clinical outcome and treatment
response. Front Psychiatry 2013 14 4:145.
(4) Nagai T, Tada M, Kirihara K, Araki T, Jinde S andKasai K. Mismatch negativity as a “translatable”
brain marker toward early intervention for psychosis: a review. Front. Psychiatry 2013 4:115:
1-10.
(5) Kuwabara H, Yamasue H, Koike S, Inoue H,
Kawakubo Y, Kuroda M, Takano Y, Natsubori T,
Aoki Y, Kano Y, Kasai K Altered metabolites in
the plasma of autism disorder: a capillary electrophoresis time-of-flight mass spectroscopy study.
PLoS ONE. 2013 8: e73814(6) Sumiyoshi C, Uetsuki M, Suga M, Kasai K,
Sumiyoshi T Development of brief versions of theWechsler Intelligence Scale for schizophrenia:
considerations of the structure and predictabilityof intelligence. Psychiatry Res. 2013 210:773-779(7) Ando S, Nishida A, Koike S. A pilot retrospective
cohort study on the effectiveness of a multidisciplinary team intervention for first-episodepsychosis in Japan. Psychiatr Serv. 2013 64(9):932-3.
(8) Natsubori T, Inoue H, Abe O, Takano Y, Iwashiro
N, Aoki Y, Koike S, Yahata N, Katsura M, Gonoi

88W, 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. 2013
(9) Kinou M, Takizawa R, Marumo K, Kawasaki S,
Kawakubo Y, Fukuda M, Kasai K Differential
spatiotemporal characteristics of the prefrontal
hemodynamic response and their association withfunctional impairment in schizophrenia and major
depression. Schizophr Res. 2013 150:459-467(10) Nagai T, Tada M, Kirihara K, Yahata N,
Hashimoto R, Araki T, Kasai K Auditory
mismatch and P3a in resonse to duration andfrequency changes in the early stages ofpsychosis. Schizophr Res. 2013 150:547-554(11) Ikegame T, Bundo M, Sunaga E, Asai T,
Nishimura F, Yoshikawa A, Kawamura Y, Hibino
H, Tochigi M, Kakiuchi C, Sasaki T, Kato T,
Kasai K, Iwamoto K DNA methylation analysis
of BDNF gene promoters in peripheral blood
cells of schizophrenia patients. Neurosci Res.
2013 77:208-214(12) 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 Association of decreased
prefrontal hemodynamic response during a verbal
fluency task with EGR3 gene polymorphism inpatients with schizophrenia and in healthy
individuals. NeuroImage. 2013 85:527-534(13) 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.
2013(14) Ando S, Matsumoto T, Kanata S, Hojo A, Yasugi
D, Eto N, Kawanishi C, Asukai N, Kasai K
One-year follow up after admission to an
emergency department for drug overdose in Japan.
Psychiatry Clin Neurosci. 2013 67(6):441-450(15) Asai T, Bundo M, Sugawara H, Sunaga F, Ueda J,
Tanaka G, Ishigooka J, Kasai K, Kato T, Iwamoto
K Effect of mood stabilizers on DNA methylationin human neuroblastoma cells. Int J Neuro-

psychopharmacol. 2013 16(10):2285-2294(16) Aoki Y, Inokuchi R, Nakao T, Yamasue H. Neuralbases of antisocial behavior: a voxel-based
meta-analysis. Soc Cogn Affect Neurosci. 2013(17) Sugawara H, Bundo M, Ishigooka J, Iwamoto K,
Kato T. Epigenetic regulation of serotonintransporter in psychiatric disorders. Journal of
Genetics and Genomics 2013 40:325-329(18) Ando S, Kasai K, Matamura M, Hasegawa Y,
Hirakawa H, Asukai N Psychosocial factors
associated with suicidal ideation in clinicalpatients with depression. J Affect Disord. 2013
151(2):561-5(19) Aoki Y, Abe O, Nippashi Y, Yamasue H
Comparison of white matter integrity between
autism spectrum disorder subjects and typicallydeveloping individuals: a meta-analysis ofdiffusion tensor imaging tractography studies.
Mol Autism. 2013 2;4(1):25(20) Aoki Y, Inokuchi R, Suwa H Reduced
N-acetylaspartate in the hippocampus in patientswith fibromyalgia: a meta-analysis. Psychiatry
Res. 2013 213(3):242-8(21) Brigman JL, Daut RA, Wright T, Gunduz-Cinar O,
Graybeal C, Davis MI, Jiang Z, Saksida LM,
Jinde S, Pease M, Bussey TJ, Lovinger DM,
Nakazawa K, Holmes A. GluN2B in
corticostriatal circuits governs choice learningand choice shifting. Nat Neurosci. 2013 16:11011110(22) Noda Y, Nakamura M, Saeki T, Inouke M,
Iwanari H, Kasai K Potentiation of quantitativeelectroencephalograms
following
prefrontal
repetitive transcranial magnetic stimulation inpatients with major depression. Neurosci Res.
2013;77:70-77(23) Sato H, Yahata N, Funane T, Takizawa R, Katura
T, Atsumori H, Nishimura Y, Kinoshita A,
Kiguchi M, Koizumi H, Fukuda M, Kasai K A
NIRS–fMRI investigation of prefrontal cortex
activity during a working memory task.
Neuroimage. 2013 83:158-173(24) Koike S, Takizawa R, Nishimura Y, Kinou M,
Kawasaki S, Kasai K Reduced but broader
prefrontal activity in patients with schizophrenia
during n-back working memory tasks: amulti-channel near-infrared spectroscopy study. J

89

Psychiatr Res. 2013 47(9):1240-1246(25) Ikegame T, Bundo M, Murata Y, Kasai K, Kato T,
Iwamoto K. DNA methylation of the BDNF geneand its relevance to psychiatric disorders. Journalof Human Genetics 2013 58:434-438.
(26) Aoki Y, Inokuchi R, Suwa H, Aoki A. Age-relatedchange of neurochemical abnormality inattention-deficit hyperactivity disorder: a metaanalysis. Neurosci Biobehav Rev. 2013 37(8):1692-701(27) Yamaguchi S, Wu SI, Biswas M, Yate M, Aoki Y,
Barley EA, Thornicroft G Effects of short-term
interventions to reduce mental health-related
stigma in university or college students: asystematic review. J Nerv Ment Dis. 2013 201(6):490-503(28) Koike S, Sasaki R. Multi-modal brain imaging
showing brain damage to the orbitofrontal cortex
and left hemisphere, in a case of prolonged
hypoglycemia-induced
transienthemiplegia
followed by persistent encephalopathy. Psychiatry
Clin Neurosci. 2013 67(5):360-2.
(29) Aoki Y, Orikabe L, Takayanagi Y, Yahata N,
Mozue Y, Sudo Y, Ishii T, Itokawa M, Suzuki M,
Kurachi M, Okazaki Y, Kasai K, Yamasue H
Volume reductions in frontopolar and left
perisylvian cortices in methamphetamine induced
psychosis. Schizophr Res. 2013 147(2-3): 355361(30) Furukawa M, Tochigi M, Otowa T, Arinami T,
Inada T, Ujike H, Watanabe Y, Iwata N, Itokawa
M, Kunugi H, Hashimoto R, Ozaki N, Kakiuchi C,
Kasai K, Sasaki T An association analysis of the
cardiomyopathy-associated 5 (CMYA5) genewith schizophrenia in a Japanese population.
Psychiatr Genet. 2013 23(4):179-180(31) Araki T, Niznikiewicz M, Kawashima T, Nestor
PG, Shenton ME, McCarley RW Disruption offunction-structure coupling in brain regions
sub-serving self monitoring in schizophrenia.
Schizophr Res 2013 146: 336-343(32) Takizawa R, Nishimura Y, Yamasue H, Kasai K
Anxiety and performance: the disparate roles ofprefrontal
subregions
under
maintained
psychological stress. Cereb Cortex. 2013(33) Jinde S, Zsiros V, Nakazawa K. Hilar mossy cell
circuitry controlling dentate granule cell

excitability. Front Neural Circuits. 7:14 2013(34) Ando S, Yamasaki S, Shimodera S, Sasaki T,
Oshima N, Furukawa TA, Asukai N, Kasai K,
Mino Y, Inoue S, Okazaki Y, Nishida A A greaternumber of somatic pain sites is associated withpoor mental health in adolescents: a crosssectional study. BMC Psychiatry. 2013 13:30(35) Nishioka M, Bundo M, Koike S, Takizawa R,
Kakiuchi C, Araki T, Kasai K, Iwamoto K
Comprehensive DNA methylation of peripheral
blood cells derived from patients with firstepisode schizophrenia. J Hum Genet. 2013 58(2):91-97"(36) Koike S, Takano Y, Iwashiro N, Satomura Y, Suga
M, Nagai T, Natsubori T, Tada M, Nishimura Y,
Yamasaki S, Takizawa R, Yahata N, Araki T,
Yamasue H, Kasai K A multimodal approach toinvestigate biomarkers for psychosis in a clinicalsetting: the integrative neuroimaging studies inschizophrenia targeting for early intervention andprevention (IN-STEP) project. Schizophr Res.
2013 143(1): 116-124(37) Nishioka M, Shimada T, Bundo M, Ukai W,
Hashimoto E, Saito T, Kano Y, Sasaki T, Kasai K,
Kato T, Iwamoto K Neuronal cell-type specific
DNA methylation patterns of the Cacna1c gene.
Int J Dev Neurosci. 2013 31(2):89-95

90

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

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

Lecturer
Jun Shimizu, M.D. , Ph.D.
Yasuo Terao, 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., Toshihiro Hayashi, 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 the patients withhighly advanced clinical practice as well as on clinicalactivities connected to postgraduate education of
Neurology.
We have outpatient clinics covering the broad fields
of Neurology. Furthermore, we also provide clinics
specialized to movement disorders and dementia(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.
Clinical trials including that for polyglutamine
disease.

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.
For training of board-certified Neurologists, we91

offer the excellent program including patients’care,training in Neurophysiology and Neuropathology,
consultation for Neurology, and supervising of juniortrainees. This program is integrated with clinicalpractice at the affiliated hospitals where richexperience is obtained for numerous cases in Clinical
Neurology.
In Graduate School, we offer highly advanced
research activities based on the interest of graduate
students.

Research activities
Our research field covers broad fields related toneurological diseases, with the goals to elucidate themechanisms of neurological diseases, and to eventually develop new therapeutic strategies. Our research
activities include molecular genetics, developmental
biology, cell biology, pharmacology, pathology, andphysiology. We aim to integrate these broad research
fields to better contribute to clinical neurology.
In the field of molecular genetics, we havedeveloped Medical Genome Center, and introduced
next-generation sequencers to conduct comprehensive
genome analyses to elucidate molecular bases ofneurological diseases. Applying massively parallel
sequencing technologies, we found mutations in
COQ2 in familial as well as sporadic multiple system
atrophy. Based on these discoveries, we are in theprocess of setting up an investigator-initiated clinical
trial using coenzyme Q10 for patients with multiple
system atrophy. Employing comprehensive mutational
analyses, we also elucidated the molecularepidemiology of hereditary spastic paraplegia in theJapanese population and further broadened themutational and clinical spectra of hereditary spastic
paraplegia. Collaborative researches have achieved
multiple accomplishments including development ofcomputational procedures for detecting and locating
long short tandem repeats promptly by using thefrequency distribution of all short tandem repeats andpaired-end read information, identification of thecausative gene for Kenny-Caffey syndrome type 2,
and elucidation of genotype-phenotype correlations inalternating hemiplegia of childhood. Application ofnext generation sequencers for molecular diagnosis
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.)
The human neurophysiology section has been
studying normal function of the human brain andpathophysiology for neurological disorders using
several non-invasive physiological methods, such as
TMS, EEG, MEG, fMRI, NIRS and EOG. Our final
goal is to develop new therapeutic methods for
intractable disorders. One of them is deep brain
stimulation (DBS) which has been partly established.
We began a physiological approach to elucidate thetherapeutic mechanisms for DBS in the patients. We
have also recently developed a new, highly effective
TMS method to induce long-term effects on thehuman brain using repetitive, monophasic magnetic
stimuli (quadripulse stimulation). We have just started
a project to treat patients with movement disorders,intractable pain, epilepsy and so on using that newtreatment. (Terao, Y., Hamada, M., Okabe, S., Terada,
S., , Tokushige, S., and Sasaki, T.)
In the field of neuromuscular diseases, we provide
pathological diagnosis of biopsied materials frompatients with myopathy or neuropathy. We also
provide autoantibody testing for anti-ganglioside antibodies, muscle specific antibodies and paraneoplastic
neurological antibodies. In research field, using
biopsied muscles and collected serum samples, wehave been studying the mechanisms of inflammatory
myopathies from the view points of pathologicalchanges, myositis specific autoantibodies, serum
cytokines, and expression profiling of muscle samples.
Our aim is to increase understanding of the etiology
and pathogenesis of neuromuscular diseases. (Shimizu,J., Maeda M., Kadoya M., Ikenaga C., Uchio N., TairaK.).
Biochemistry lab is currently working on neuroepigenetics using post-mortem brains. Research ofinterest includes Alzheimer’s disease, Lewy bodydisease, multiple system atrophy and amyotrophic
lateral sclerosis. Among them, abnormal CpG
methylation in Alzheimer’s disease has been published.
Other research area includes HDAC3 function in
Huntington’s disease. We also work on molecularpathology of chronic ischemia using mouse models.
We newly developed a confocal laser Raman
microspectroscopy and determined polyglutamine

92

specific vibrational spectra within inclusion bodies.
This is a universal methodology in order to observe
non-labeled aggregating proteins within physiologicalcondition. Clinical study includes preclinical sporadic
Alzheimer’s disease cohort and familial Alzheimer’s
disease (DIAN-J) and clinical trial of florbetapir.
(Iwata, Nagashima, Miyagawa, Ohtomo, Mano(T),Bannai, Tsuchida, Hamada, Mano(K))

Publication
1. Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M,
Doyu M, Hamada C, Kondo K, Yoneoka T,
Akimoto M, Yoshino H; Edaravone ALS Study
Group. Confirmatory double-blind, parallel-group,
placebo-controlled study of efficacy and safety ofedaravone (MCI-186) in amyotrophic lateralsclerosis patients. Amyotroph Lateral Scler
Frontotemporal Degener. 15:610-7 2014.
2. Doi H, Ushiyama M, Baba T, Tani K, Shiina M,
Ogata K, Miyatake S, Fukuda-Yuzawa Y, Tsuji S,
Nakashima M, Tsurusaki Y, Miyake N, Saitsu H,
Ikeda S, Tanaka F, Matsumoto N, Yoshida K.
Late-onset spastic ataxia phenotype in a patientwith a homozygous DDHD2 mutation. Sci Rep.
4:7132, 2014.
3. Doi K, Monjo T, Hoang PH, Yoshimura J, Yurino
H, Mitsui J, Ishiura H, Takahashi Y, Ichikawa Y,
Goto J, Tsuji S, Morishita S. Rapid detection of
expanded short tandem repeats in personal
genomics
usinghybridsequencing.
Bioinformatics. 30:815-22, 2014.
4. Meral Güneş A, Sezgin Evim M, Baytan B, Iwata
A, Hida A, Avcı R. Aceruloplasminemia in a
Turkish adolescent with a novel mutation of
ceruloplasmine gene: The first diagnosed casefrom Turkey. J Pediat Hematol Oncol. 36, e423-5.
2014
5. Hanajima R, Terao Y, Shirota Y, Ohminami S,
Tsutsumi R, Shimizu T, Tanaka N, Okabe S, Tsuji
S, Ugawa Y. Triad-conditioning transcranial
magnetic stimulation in Parkinson's disease.
Brain Stimul. 7:74-9, 2014.
6. Ishiura H, Takahashi Y, Hayashi T, Saito K,
Furuya H, Watanabe M, Murata M, Suzuki M,
Sugiura A, Sawai S, Shibuya K, Ueda N, Ichikawa
Y, Kanazawa I, Goto J, Tsuji S. Molecularepidemiology and clinical spectrum of hereditary
spastic paraplegia in the Japanese population
based on comprehensive mutational analyses. J
Hum Genet. 59:163-72, 2014.
7. 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 type 2. J Bone Miner
Res. 29:992-8, 2014.
8. Ito H, Fujita K, Tagawa K, Chen X, Homma H,
Sasabe T, Shimizu J, Shimizu S, Tamura T,
Muramatsu S, Okazawa H. HMGB1 facilitates
repair of mitochondrial DNA damage and extends
the lifespan of mutant ataxin-1 knock-in mice.
EMBO Mol Med. 7: 78-101. 2014
9. Iwata A. Asymmetry of symptoms and signs in
multiple system atrophy. Int J Neurol Brain
Disord. 1, 1-2, 2014
10. Iwata A, Nagata K, Hatsuta H, Takuma H, Bundo
M, Iwamoto K, Tamaoka A, Murayama S, Saido T,
Tsuji S. Altered CpG methylation in sporadic
Alzheimer's disease is associated with APP and
MAPT dysregulation. Hum Mol Genet. 3:648-56,
2014.
11. Kiga K, Fukuda-Yuzawa Y, Tanabe M, Tsuji S,
Sasakawa C, Fukao T. Comprehensive silencingof target-sharing microRNAs is a mechanism for
SIRT1 overexpression in cancer. RNA Biol. 11:
1347-54, 2014.
12. Koh K, Ishiura H, Miwa M, Doi K, Yoshimura J,
Mitsui J, Goto J, Morishita S, Tsuji S andTakiyama Y. Exome sequencing shows a novel denovo mutation in ATL1. Neurol Clin Neurosci. 2:
1-4, 2014
13. Mano T, Suzuki T, Tsuji S, Iwata A. Differential
effect of HDAC3 on cytoplasmic and nuclear
huntingtin aggregates. PLoS One. 9:e111277,
2014.
14. Matsuda S, Matsumoto H, Furubayashi T, Fukuda
H, Emoto M, Hanajima R, Tsuji S, Ugawa Y,
Terao Y. Top-down but not bottom-up visualscanning is affected in hereditary pure cerebellar
ataxia. PLoS One. 9:e116181, 2014.
15. Mitsui J, Tsuji S. Genomic aspects of sporadic
neurodegenerative diseases. Biochem Biophys
Res Commun. 452:221-5, 2014.

93

16. Mitsui J, Tsuji S. Mutant COQ2 in multiplesystem atrophy. N Engl J Med. 371:82-3, 2014.
17. Miyagawa T, Sasaki T, Ueda K, Takahashi M,
Momose T and Tsuji S. Treatable chorea
associated with polycythemia vera. Neurol Clin
Neurosci. 2: 90-91, 2014
18. Miyazaki H, Oyama F, Inoue R, Aosaki T, Abe T,
Kiyonari H, Kino Y, Kurosawa M, Shimizu J,
Ogiwara I, Yamakawa K, Koshimizu Y, Fujiyama
F, Kaneko T, Shimizu H, Nagatomo K, Yamada K,
Shimogori T, Hattori N, Miura M, Nukina N.
Singular localization of sodium channel beta4
subunit in unmyelinated fibres and its role in the
striatum. Nat Commun. 5: 5525. 2014
19. Ohtomo R, Matsukawa T, Tsuji S, Iwata A.
Abadie's sign in adrenomyeloneuropathy. J
Neurol Sci. 340:245-6, 2014.
20. Ohtomo R, Iwata A, Tsuji S. Unilateral opercularinfarction presenting with Foix-Chavany-Marie
Syndrome. J Stroke Cerebrovasc Dis. 23:179-81,
2014.
21. Ohtomo R, Shirota Y, Iwata A, Shimizu J, Tsuji S.
Cerebral microbleeding in varicella-zoster viralmeningitis: an early sign of vasculopathy?
Neurology. 82:814-5, 2014.
22. Sasaki M, Ishii A, Saito Y, Morisada N, Iijima K,
Takada S, Araki A, Tanabe Y, Arai H, Yamashita S,
Ohashi T, Oda Y, Ichiseki H, Hirabayashi S,
Yasuhara A, Kawawaki H, Kimura S, Shimono M,
Narumiya S, Suzuki M, Yoshida T, Oyazato Y,
Tsuneishi S, Ozasa S, Yokochi K, Dejima S,
Akiyama T, Kishi N, Kira R, Ikeda T, Oguni H,
Zhang B, Tsuji S, Hirose S. Genotype-phenotype
correlations in alternating hemiplegia ofchildhood. Neurol. 82:482-90, 2014.
23. Sawamura H, Yamamoto T, Ohtomo R, Bannai T,
Wakakura M, Tsuji S. Anti-NMDA receptor
encephalitis associated with transient cerebral
dyschromatopsia, prosopagnosia, and lack ofstereopsis. J Neuroophthalmol. 34:144-8, 2014.
24. Shimazaki H, Honda J, Naoi T, Namekawa M,
Nakano I, Yazaki M, Nakamura K, Yoshida K,
Ikeda S, Ishiura H, Fukuda Y, Takahashi Y, Goto J,
Tsuji S, Takiyama Y. Autosomal-recessive
complicated spastic paraplegia with a novel
lysosomal trafficking regulator gene mutation. J
Neurol Neurosurg Psych. 85: 1024-8, 2014.

25. Tezenas du Montcel S, Durr A, Bauer P, Figueroa
KP, Ichikawa Y, Brussino A, Forlani S, Rakowicz
M, Schöls L, Mariotti C, van de Warrenburg BP,
Orsi L, Giunti P, Filla A, Szymanski S,
Klockgether T, Berciano J, Pandolfo M, Boesch S,
Melegh B, Timmann D, Mandich P, Camuzat A;
Clinical Research Consortium for Spinocerebellar
Ataxia (CRC-SCA); EUROSCA network, Goto J,
Ashizawa T, Cazeneuve C, Tsuji S, Pulst SM,
Brusco A, Riess O, Brice A, Stevanin G.
Modulation of the age at onset in spinocerebellar
ataxia by CAG tracts in various genes. Brain.
137:2444-55, 2014.
26. Tokushige S, Mitsui J, Goto R, Hatano K, Terao Y,
Kanda T, Nakano R and Tsuji S. Sensorimotor
neuropathy in late-onset Krabbe diseaseprogressing over 40 years after onset. Neruol Clin
Neurosci. 2:114–116, 2014
27. Tsutsumi R, Hanajima R, Terao Y, Shirota Y,
Ohminami S, Shimizu T, Tanaka N, Ugawa Y.
Effects of the motor cortical quadripulse
transcranial magnetic stimulation (QPS) on thecontralateral motor cortex and interhemisphericinteractions. J Neurophysiol. 111:26-35, 2014.
28. Watanabe T, Hanajima R, Shirota Y, Ohminami S,
Tsutsumi R, Terao Y, Ugawa Y, Hirose S,
Miyashita Y, Konishi S, Kunimatsu A, Ohtomo K.
Bidirectional
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1896-905, 2014.
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Taguchi Y, Takashima S, Tanaka K, Touge T,
Hatsuta H, Murayama S, Hayashi Y, Kaneko M,
Ishiura H, Mitsui J, Atsuta N, Sobue G,
Shimozawa N, Inuzuka T, Tsuji S, Hozumi I.
Evaluation of SLC20A2 mutations that cause
idiopathic basal ganglia calcification in Japan.
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M, Onodera O, Koyano S, Isozaki E, Sawai S,
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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
Kazuhiko Ishii, M.D., Ph.D., 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.,
Shunya Hanakita, M.D., Ph.D., Hirotaka Hasegawa, M.D.

Homepage

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

Introduction and Organization
The Department of Neurosurgery at the Universityof Tokyo Hospital consists of 14 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research and education. The staffs
include a professor/chairman, an associate professor,
four lecturers and eight associates.
Clinical ward for Neurosurgery in our university
hospital was founded in 1951 as the first
Neurosurgical clinic in Japan. Dr. Keiji Sano, as thefounding professor, established the Department of
Neurosurgery in 1962. Dr. Kintomo Takakura and Dr.
Takaaki Kirino served as the second and the third
professor. 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 lesion,functional disorders, head trauma, etc.

Clinical activities
General and specialized outpatient clinics are open
three days a week (Monday, Wednesday and Friday).

New patient are accepted two days a week (Tuesday
and Thursday). Specialized outpatient clinics are open
for patient with brain tumors, pituitary disease, spinal
disease, cerebrovascular disease, endovascular intervention, epilepsy, and gamma knife treatment. From
April 2013 to March 2014, 15,652 patients weretreated at the outpatient clinics.
The Neurosurgery Ward has about 40 beds on theseventh floor of the new hospital building opened in
Sept. 2001. In 2014, 748 patients were admitted to the
Neurosurgical Ward. 428 surgical procedures were
performed with 105 gamma knife procedures in 2014.
Our practice covers a wide variety of neurosurgicaldiseases including malignant and benign brain tumors,hemorrhagic and occlusive cerebrovascular diseases,
spinal disorders, epilepsy, pain and movement
disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional mapping in epilepsy surgery are frequently used topreserve brain function as much as possible. State-ofthe-art techniques including intraoperative computer-95

aided 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.

Teaching activities
Medical students take lectures of clinicalneurosurgery in their second year. Clinical casestudies and bedside teaching are scheduled in the thirdand fourth years. The lecturers introduce general
neurosurgery as well as the state-of-art neurosurgicalpractice to the students. At the bedside teaching andclinical clerkship, they are offered opportunities tolearn clinical management of neurosurgical patients in
the hands-on style, and also are exposed to practice invarious subspecialties in neurosurgery through special
seminars given by experts in the fields.
We accepted 14 residents in 2015 as a neurosurgicalresidency program. These residents are trained in theuniversity hospital and affiliated hospitals toexperience every aspects of neurosurgical practice forfive years in average. Our residency training is
finalized after the sixth year, when the finishingresidents serve as senior residents at the university
hospital for 6 months. Academic training is provided
through numerous intramural clinical and research
conference, journal clubs seminars as well as quarterly
regional meeting of Japan Neurosurgical Society.
After the residents finish their training, or during
training, they can choose to be admitted into the Ph.D.
course at the graduate school of Medicine, Universityof Tokyo, to be involved in advanced basic research
activities for 4 year. After complete training, our
graduates stay in the department to be an associate in
our or other university hospitals or become clinicalstaff in our affiliated hospitals.

Research activities
Clinical research in these two years have mainly
focused on treatment of acoustic neurinoma
techniques of skull base surgery, treatment ofmalignant brain tumors, radiosurgery and epilepsy
surgery. The results were presented at domestic andinternational meetings including Annual Meetings of
the Japan Neurosurgical Society and Annual Meetingsof American Association of Neurological Surgeons. .
Our department has been keeping prominent basic
research activities as well. The fields of our current
research are as follows
1) Pathogenesis of cerebral ischemia and neuronal
regeneration after ischemic brain damage
One of the major topics in recent basic science is toregenerate the brain with endogenous neuralprogenitors. Our laboratory has started basic research
to regenerate neurons in vivo following ischemic
insult. We have demonstrated that the 40% of the lost
neurons could be regenerated by administration of
growth factors. We also succeeded in regeneration of
striatal neurons. Molecular mechanisms of adultneurogenesis are currently investigated using various
models to enhance post-ischemic regeneration. By
extending the research into primate model, we are
pursuing clinical application in the future.
2) Development of New Therapeutic Modalities for
Malignant Brain Tumors
Despite advances in microsurgical techniques, thepoor prognoses of malignant glioma patients have not
improved for decades. We develop a new strategy byusing replication-competent herpes simplex viruses(HSV) that are genetically engineered to replicate in
and kill tumor cells but not normal cells. Using athird-generation oncolytic HSV, we are currently
conducting a clinical trial on patients with progressive
glioblastoma. We are also conducting clinical research
for immunotherapy with human umbilical vein
endothelial cell (HUVEC) as a vaccine.To develop
novel strategy for the treatment of malignant gliomas,
we have isolated brain tumor initiating cells (BTICs),
which are supposed to be responsible for resistance toconventional therapy, from surgical specimens, andwe are studying specific targeting therapy against
BTICs.
We also practice optimized therapy based on the
results of genetic analyses routinely performed ontumor specimens obtained from glioma patients.

963) 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) 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.
6) Clinical applications of the functional brain
imaging and operative simulation using threedimensional computer graphics for neurosurgery
Our department intensively utilizes various kinds offunctional and metabolic imaging modalities including
magnetoencephalography, functional MRI, and diffusion tensor imaging-based tractography for presurgicalbrain mapping. Combining the results of 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.

References (2014)
1. Inoue T., Tamura A., Saito I., Tsutsumi K., Saito N.
Response to "Role of surgical versus endovascularembolectomy for the treatment of acute large
vessel occlusion". Br J Neurosurg 28(3):431-432,
2014
2. Aihara K., Mukasa A., Gotoh K., Saito K., Nagae
G., Tsuji S., Tatsuno K., Yamamoto S., Takayanagi
S., Narita Y., Shibui S., Aburatani H., Saito N.
H3F3A K27M mutations in thalamic gliomas
from young adult patients. Neuro Oncol 16(1):140-146, 2014
3. Johnson B. E., Mazor T., Hong C., Barnes M.,

97

Aihara K., McLean C. Y., Fouse S. D., Yamamoto
S., Ueda H., Tatsuno K., Asthana S., Jalbert L. E.,
Nelson S. J., Bollen A. W., Gustafson W. C.,
Charron E., Weiss W. A., Smirnov I. V., Song J. S.,
Olshen A. B., Cha S., Zhao Y., Moore R. A.,
Mungall A. J., Jones S. J., Hirst M., Marra M. A.,
Saito N., Aburatani H., Mukasa A., Berger M. S.,
Chang S. M., Taylor B. S., Costello J. F.
Mutational analysis reveals the origin andtherapy-driven evolution of recurrent glioma.
Science 343(6167):189-193, 2014
4. Igaki H., Sakumi A., Mukasa A., Saito K.,
Kunimatsu A., Masutani Y., Hanakita S., Ino K.,
Haga A., Nakagawa K., Ohtomo K. Corticospinal
tract-sparing intensity-modulated radiotherapy
treatment planning. Rep Pract Oncol Radiother19(5):310-316, 2014
5. Takami H., Hanakawa K., Sato H., Tsutsumi K.,
Murao M., Ide T. Contralateral hyperacuteintracerebral hemorrhage after carotid arterystenting with contralateral internal carotid artery
occlusion. J Vasc Surg 59(3):821-824, 2014
6. Miyawaki S., Maeda K. Surgical treatment for
cervical carotid artery stenosis in the elderly:
importance of perioperative management ofischemic cardiac complications. Neurol Med
Chir (Tokyo) 54(2):120-125, 2014
7. Miyawaki S., Maeda K. A comparative study ofrisk factors and the occurrence rate of coronary
atherosclerosis in extra- and intracranial
atherosclerotic lesions. J Stroke Cerebrovasc Dis23(3):516-519, 2014
8. Miyamoto S., Yoshimoto T., Hashimoto N., Okada
Y., Tsuji I., Tominaga T., Nakagawara J.,
Takahashi J. C., Investigators J. T. Effects ofextracranial-intracranial bypass for patients withhemorrhagic moyamoya disease: results of theJapan Adult Moyamoya Trial. Stroke 45(5):14151421, 2014
9. Majima K., Matsuo T., Kawasaki K., Kawai K.,
Saito N., Hasegawa I., Kamitani Y. Decoding
visualobjectcategories
fromtemporalcorrelations of ECoG signals. Neuroimage 90:
74-83, 2014
10. Kunii N., Kawai K., Kamada K., Ota T., Saito N.
The significance of parahippocampal high gamma
activity for memory preservation in surgicaltreatment of atypical temporal lobe epilepsy.
Epilepsia 55(10):1594-1601, 2014
11. Hanakita S., Koga T., Shin M., Igaki H., Saito N.
Application of single-stage stereotactic radiosurgery for cerebral arteriovenous malformations>10 cm3. Stroke 45(12):3543-3548, 2014
12. Amemiya S., Kunimatsu A., Saito N., Ohtomo K.
Cerebral hemodynamic impairment: assessmentwith resting-state functional MR imaging.
Radiology 270(2):548-555, 2014
13. Hirohata T., Ishii Y., Matsuno A. Treatment of
pituitary carcinomas and atypical pituitaryadenomas: a review. Neurol Med Chir (Tokyo)
54(12):966-973, 2014
14. Fukushima Y., Imai H., Yoshino M., Kin T.,
Takasago M., Saito K., Nakatomi H., Saito N.
Ptosis as partial oculomotor nerve palsy due tocompression by infundibular dilatation ofposterior communicating artery, visualized withthree-dimensional computer graphics: case report.
Neurol Med Chir (Tokyo) 54(3):214-218, 201415. Sato I., Higuchi A., Yanagisawa T., Murayama S.,
Kumabe T., Sugiyama K., Mukasa A., Saito N.,
Sawamura Y., Terasaki M., Shibui S., Takahashi J.,
Nishikawa R., Ishida Y., Kamibeppu K. Impact oflate effects on health-related quality of life insurvivors of pediatric brain tumors: motility
disturbance of limb(s), seizure, ocular/visual
impairment, endocrine abnormality, and higher
brain dysfunction. Cancer Nurs 37(6):E1-E14,
2014
16. Wakimoto H., Tanaka S., Curry W. T., Loebel F.,
Zhao D., Tateishi K., Chen J., Klofas L. K., Lelic
N., Kim J. C., Dias-Santagata D., Ellisen L. W.,
Borger D. R., Fendt S. M., Vander Heiden M. G.,
Batchelor T. T., Iafrate A. J., Cahill D. P., Chi A. S.
Targetable signaling pathway mutations areassociated with malignant phenotype in IDHmutant gliomas. Clin Cancer Res 20(11):28982909, 2014
17. Takami H., Mizutani T., Ota T., Yuyama R.
Spontaneous regression of restenosis after CEA:
significance of preoperative plaque characteristics
under duplex ultrasound; clinical investigation.
Acta Neurochir (Wien) 156(1):63-67, 201418. Hanakita S., Koga T., Shin M., Takayanagi S.,
Mukasa A., Tago M., Igaki H., Saito N. The

98long-term outcomes of radiosurgery for
intracranial hemangioblastomas. Neuro Oncol 16(3):429-433, 201419. Echizen K., Nakada M., Hayashi T., Sabit H.,
Furuta T., Nakai M., Koyama-Nasu R., NishimuraY., Taniue K., Morishita Y., Hirano S., Terai K.,
Todo T., Ino Y., Mukasa A., Takayanagi S., OhtaniR., Saito N., Akiyama T. PCDH10 is required forthe tumorigenicity of glioblastoma cells. Biochem
Biophys Res Commun 444(1):13-18, 2014
20. Takai H., Masuda K., Sato T., Sakaguchi Y.,
Suzuki T., Koyama-Nasu R., Nasu-Nishimura Y.,
Katou Y., Ogawa H., Morishita Y., Kozuka-Hata
H., Oyama M., Todo T., Ino Y., Mukasa A., Saito
N., Toyoshima C., Shirahige K., Akiyama T.
5-Hydroxymethylcytosine plays a critical role inglioblastomagenesis by recruiting the CHTOPmethylosome complex. Cell Rep 9(1):48-60, 2014
21. Takami H., Asai A., Ohshige H., Uesaka T.,
Takeda J., Yoshimura K., Uemura Y., Kawamoto
K. Fat necrosis appearing as intraorbital tumour:case report. Br J Neurosurg 28(4):525-527, 201422. Shinozaki M., Nakamura M., Konomi T.,
Kobayashi Y., Takano M., Saito N., Toyama Y.,
Okano H. Distinct roles of endogenous vascularendothelial factor receptor 1 and 2 in neuralprotection after spinal cord injury. Neurosci Res
78:55-64, 2014
23. Takayanagi S., Ochi T., Hanakita S., Suzuki Y.,
Maeda K. The safety and effectiveness of
low-dose recombinant tissue plasminogenactivator (0.6 mg/kg) therapy for elderly acuteischemic stroke patients (≥ 80 years old) in the
pre-endovascular era. Neurol Med Chir (Tokyo)
54(6):435-440, 201424. Hirohata T., Miyawaki S., Mizutani A., IwakamiT., Yamada S., Nishido H., Suzuki Y., Miyamoto
S., Hoya K., Murakami M., Matsuno A.
Subarachnoid hemorrhage secondary to a ruptured
middle cerebral aneurysm in a patient withosteogenesis imperfecta: a case report. BMC
Neurol 14:150, 2014
25. Koyama-Nasu R., Haruta R., Nasu-Nishimura Y.,
Taniue K., Katou Y., Shirahige K., Todo T., Ino Y.,
Mukasa A., Saito N., Matsui M., Takahashi R.,
Hoshino-Okubo A., Sugano H., Manabe E.,
Funato K., Akiyama T. The pleiotrophin-ALK

axis is required for tumorigenicity of glioblastoma
stem cells. Oncogene 33(17):2236-2244, 2014
26. Sato I., Higuchi A., Yanagisawa T., Mukasa A.,
Ida K., Sawamura Y., Sugiyama K., Saito N.,
Kumabe T., Terasaki M., Nishikawa R., Ishida Y.,
Kamibeppu K. Cancer-specific health-related
quality of life in children with brain tumors. Qual
Life Res 23(4):1059-1068, 2014
27. Goto M., Kunimatsu A., Shojima M., Mori H.,
Abe O., Aoki S., Hayashi N., Gonoi W., Miyati T.,
Ino K., Yano K., Saito N., Ohtomo K. Depictionof branch vessels arising from intracranial
aneurysm sacs: Time-of-flight MR angiography
versus CT angiography. Clin Neurol Neurosurg
126:177-184, 2014
28. Fukushima S., Otsuka A., Suzuki T., YanagisawaT., Mishima K., Mukasa A., Saito N., Kumabe T.,
Kanamori M., Tominaga T., Narita Y., Shibui S.,
Kato M., Shibata T., Matsutani M., Nishikawa R.,
Ichimura K., Consortium) I. G. C. T. G. A. C. i.
Mutually exclusive mutations of KIT and RAS areassociated with KIT mRNA expression andchromosomal instability in primary intracranial
pure germinomas. Acta Neuropathol 127(6):911925, 201429. Saito K., Mukasa A., Narita Y., Tabei Y., ShinouraN., Shibui S., Saito N. Toxicity and outcome ofradiotherapy with concomitant and adjuvanttemozolomideinelderlypatients
withglioblastoma: a retrospective study. Neurol Med
Chir (Tokyo) 54(4):272-279, 2014
30. Inoue T., Ohwaki K., Tamura A., Tsutsumi K.,
Saito I., Saito N. Subtle structural change
demonstrated on T2-weighted images afterclipping of unruptured intracranial aneurysm:
negative effects on cognitive performance. J
Neurosurg 120(4):937-944, 2014

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

100

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,
includingresearch
fellows,
graduate
andundergraduate 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) Establishment of ex-vivo differentiation system of
myofibroblast.
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
againstcancerandinflammatory diseases.
5) Application of humanized anti-CD4 antibody forcancer.

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References
1: 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.
2: 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.
3: 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 andquantification of dendritic cell migration andantigen trafficking between the skin and lymph
nodes. Sci Rep. 2014 Aug 12;4:6030.
4: Yoshie O, Matsushima K. CCR4 and its ligands:
from bench to bedside. Int Immunol. 2015 Jan;27(1):11-20.
5: 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.
6: 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.
7: 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.

8: 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.
9: Shono Y, Shiratori S, Kosugi-Kanaya M, Ueha S,
Sugita J, Shigematsu A, Kondo T, Hashimoto D,
Fujimoto K, Endo T, Nishio M, Hashino S,
Matsuno Y, Matsushima K, Tanaka J, Imamura M,
Teshima T. Bone marrow graft-versus-hostdisease: evaluation of its clinical impact on
disrupted hematopoiesis after allogeneic hematopoietic stem cell transplantation. Biol Blood
Marrow Transplant. 2014 Apr;20(4):495-500.
10: Toda E, Terashima Y, Esaki K, Yoshinaga S,
Sugihara M, Kofuku Y, Shimada I, Suwa M,
Kanegasaki S, Terasawa H, Matsushima K.
Identification of a binding element for thecytoplasmic regulator FROUNT in the membraneproximal C-terminal region of chemokine
receptors CCR2 and CCR5. Biochem J. 2014 Jan
15;457(2):313-22.

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

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

Lecturer
Jun Tomio, M.D., M.Sc., Ph.D. (From June, 2014)

Associate
Fumiaki Nakamura, M.D., Ph.D.

Homepage

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

Introduction and Organization
Modern concepts of public health originated in the
Industrial Revolution era in the UK, and since thendeveloped in Western countries. In Japan, theseconcepts became important and popular in the 1880s,
when the Japan Private (non-governmental)
Association for Hygiene (a synonym of public healthin that age) was established to fight against repeatedoutbreaks of cholera 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 2014, the Department
consists of four faculty members above listed, aproject lecturer (part-time), two project researchers(part-time), two supporting staffs, 16 graduate
students (14 in PhD program and two in MPH
program), 17 part-time lecturers, and 18 visiting
fellows.

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Teaching activities
1) Undergraduate Program (Medical School)
In the winter term of the fourth grade in School of
Medicine (M2), students are provided with thefollowing lectures; current issues of public health,preventive services, epidemiology, evidence based
medicine (EBM), health economics, quality of care,
community medicine, infection and tuberculosis
control, mental health, human ecology, international
health, current health policy and administration in
Japan, and so on. Similarly, in the sixth grade (M4), an
intensive course of public health (e.g., health caresystems, 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”. The
Department also provides a research course forindividual students, in which he or she carries out aspecific research task under the supervision of afaculty member of the Department.

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. We also conduct
research on quality of care (cancer, diabetes, andosteoporosis). These studies have been published inhealth policy and health services research journals. We
have continued 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) assessment of
disclosure risk of privacy in cancer registry database,(2) evaluation of newspaper reporting on hospitalcancer survival, (3) evaluation of disaster preparedness in local communities and healthcare facilities,(4) evaluation of the effectiveness of the Safe

104

Communities model for safety promotion, and (5)epidemiological study on incidence and survival rateof children with cerebral palsy.
In relation to research activities, Associate Professor
Satoshi Toyokawa was awarded the 2014 “Shoreisho”
Award by the Japanese Society of Public Health for
his research on public health researches for physician
supply and access to healthcare.

References
1.

2.

3.

4.

5.

6.

Nakamura F, Higashi T, Saruki N, Fukuhara S,
Sobue T: Understanding by the general public ofnewspaper reports on publicly reported cancer
survival in Japan: a randomized controlled Trial.
Japanese Journal of Clinical Oncology 44(7):651-60, 2014.
Higashi T, Nakamura F, Shibata A, Emori Y,
Nishimoto H: The national database of
hospital-based cancer registries: A nationwide
infrastructure to support evidence-based cancer
care and cancer control policy in Japan. Japanese
Journal of Clinical Oncology 44(1): 2-8, 2014.
Sugiyama T, Tsugawa Y, Tseng CH, Kobayashi Y,
Shapiro MF: Different time trends of caloric and
fat intake between statin users and nonusers
among US adults: Gluttony in the time of statins?
JAMA Internal Medicine 174(7): 1038-1045,
2014.
Maeda E, Ishihara O, Saito H, Kuwahara A,
Toyokawa S, Kobayashi Y: Age-specific cost andpublic funding of a live birth following assisted
reproductive treatment in Japan. Journal of
Obstetrics and Gynaecology Research 40(5):1338-1344, 2014.
Okuyama A, Nakamura F, Higashi T: Prescription
trendsofprophylactic
antiemetics
forchemotherapy-induced nausea and vomiting inJapan. Support Care Cancer 22(7): 1789-95,
2014.
Kondo N, Nakamura F, Yamazaki S, Yamamoto Y,
Akizawa T, Akiba T, Saito A, Kurokawa K,
Fukuhara S: Prescription of potentiallyinappropriate medications to elderly hemodialysis
patients: prevalence and predictors. Nephrology
Dialysis Transplantation doi: 10.1093/ndt/gfu070,

2014.
7. Nishimura K, Nakamura F, Takegami M,
Fukuhara S, Nakagawara J, Ogasawara K, Ono J,
Shiokawa Y, Miyachi S, Nagata I, Toyoda K,
Matsuda S, Kataoka H, Miyamoto Y, Kitaoka K,
Kada A, Iihara K: Cross-sectional survey ofworkload and burnout among Japanese physiciansworking in stroke care: The J-ASPECT Study.
Circulation Cardiovascular Quality and Outcomes
7(3): 414-22, 2014.
8. Iihara K, Nishimura K, Kada A, Nakagawara J,
Ogasawara K, Ono J, Shiokawa Y, Aruga T,
Miyachi S, Nagata I, Toyoda K, Matsuda S,
Miyamoto Y, Suzuki A, Ishikawa K, Kitaoka K
Nakamura F, Kamitani S: Effects of comprehensive stroke care capabilities on in-hospitalmortality of patients with ischemic andhemorrhagic stroke: J-ASPECT Study. PLoS One
9(5):e96819, doi:10.1371/journal.pone.0096819,
2014.
9. Kawada H, Kurita N, Nakamura F, Kawamura J,
Hasegawa S, Kotake K, Sugihara K, Fukuhara S,
Sakai Y: Incorporating apical lymph node status
into the seventh edition of TNM classification
improves prognosis prediction in stage III coloncancer: a multicenter cohort study in Japan.
British Journal of Surgery 101(9): 1143-52, 2014.
10. Iihara K, Nishimura K, Kada A, Nakagawara J,
Toyoda K, Ogasawara K, Ono J, Shiokawa Y,
Aruga T, Miyachi S, Nagata I, Matsuda S,
Ishikawa KB, Suzuki A, Mori H, Nakamura F,
J-ASPECT Study collaborators: The impact ofcomprehensive stroke care capacity on thehospital volume of stroke interventions: A
nationwide study in Japan: J-ASPECT Study.
Journal of Stroke and Cerebrovascular Disease23(5): 1001-18, 2014.
11. Hayashino Y, Jackson JL, Hirata T, Fukumori N,
Nakamura F, Fukuhara S, Tsujii S, Ishii H:
Effects of exercise on C-reactive protein,inflammatory cytokine and adiponectin inpatients with type 2 diabetes: A meta-analysis ofrandomized controlled trials. Metabolism 63(3):431-40, 2014.
12. Noguchi S, Toyokawa S, Miyoshi Y, Suyama Y,
Inoue K, Kobayashi Y: Five-year follow-up studyof the association between periodontal disease

105

and myocardial infarction among Japanese maleworkers: MY Health Up Study. Journal of Public
Health doi:10.1093/pubmed/fdu076, 2014.
13. Aoki Y, Okada M, Inokuchi R, Matsumoto A,
Kumada Y, Yokoyama H, Ishida T, Saito I, Ito H,
Sato H, Tomio J, Shinohara K, Thornicroft G:
Time-related changes in suicide attempts after the
nuclear accident in Fukushima. Social Psychiatry
and Psychiatric Epidemiology l49 (12): 1911-8,
2014.
14. Tomio J, Sato H: Emergency and disaster
preparedness for chronically ill patients: a review
of recommendations. Open Access Emergency
Medicine 6 : 69-79, 2014.
15. Tomio J, Sato H, Matsuda Y, Koga T, Mizumura
H: Household and community disaster
preparedness in Japanese provincial city: A
population-based household survey. Advances in
Anthropology 4: 68-77, 2014.
16. Kamitani S, Nishimura K, Nakamura F, Kada A,
Nakagawara J, Toyoda K, Ogasawara K, Ono J,
Shiokawa Y, Aruga T, Miyachi S, Nagata I,
Matsuda S, Miyamoto Y, Iwata M, Suzuki A,
Ishikawa KB, Kataoka H, Morita K, Kobayashi Y,
Iihara K: Consciousness level and off-hour
admission affect discharge outcome of acutestroke patients: A J-ASPECT study. Journal of
American Heart Association doi: 10.1161/ JAHA.
114.001059, 2014.
17. 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 doi: 10.1002/cam4.379,
2014.
18. Arai K, Maeda E, Iwata T, Tanaka O, Murata K,
Sakamoto M: Impact of dietary behaviors on
dyslipidemia in Japanese male workers. Annals ofTranslational Medicine & Epidemiology 1(1):1003, 2014.
19. Iwamoto M, Nakamura F, Higashi T: Estimatedlife expectancy and risk of death from cancer by
quartiles in the older Japanese population: 2010
vital statistics. Cancer Epidemiology 38(5): 511-4,
2014.
20. Inoue M, Minami M, Yano E: Body mass index,
blood pressure, and glucose and lipid metabolism

among permanent and fixed-term workers in the
manufacturing industry: a cross-sectional study.
BMC Public Health 207(14): 1-8, 2014.

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

107

Department of Forensic Medicine
Professor
Ken-ichi Yoshida, M.D., Ph.D.

Lecturer
Kaori Shintani, Ph.D.

Assistant Professor
Hisashi Nagai, M.D., Ryohei Kuroda, M.D., Ph.D.

Homepage

http://forensicmed.umin.jp

Introduction and Organization
Associate Professor Kuniyoshi Katayama lectured“judicial medicine” in University of Tokyo since 1882
before our department was founded as the firstdepartment of forensic medicine in Japan in 1888. 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.
Ken-ichi Yoshida has been directing our department
since 1999 as the 8th Professor and he has studied themechanism of ischemic heart disease and sudden
cardiac death related to emotional stress, with respect
to gap junction, intracellular signaling, andproteolysis.
The department currently has one professor, one
lecturer, two assistant professor, one associate, two
special technicians, four postgraduate students, andone researcher. Three doctors from this department
have become professors since 1999. It is a nationwide
difficulty to find suitable doctors as forensic
pathologists. However, there are not a few doctors
who want to become the graduate students in our
department. Those who have experience in clinicalpractices, and researchers in biochemistry, physiology,
pathology, and molecular biology are welcome. We
are preparing to teach practice and research for the
future forensic pathologists.

Forensic autopsy
The determination of precise cause of death is themost important mission of our department. We
autopsy about 120 criminal cases in eastern part ofTokyo every year. We have already autopsied more

108

than 11,423 cases since 1897. Some of these cases arevery famous in criminology in Japan.
In forensic autopsy, we examine the pathological,
alcohol, toxicological, and blood type testing of eachcase, 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. We have kept them since first
autopsy case in 1897. We have serious responsibility
in the determination of cause of death.
Since 2005, we also performed autopsies on
medical practice-related deaths (MPAD) in corraboration with Department of Human Pathology. The both
departments lead the pilot study on the investigation
and analysis of MPAD (supported by government).
We also contribute to evolve new way of presenting
expert opinions for the jury courts that has beenenacted in 2009.

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 are based on the autopsy and court
cases for the better understanding of the deathinvestigation and medical law. In the Free Quarter
training course, students experience laboratory
practices (toxicology, DNA typing, histology) or
experiments. In the clinical clerkship, each student
experiences the process from autopsy to presentationof expert opinion. They can also attend the practicesof medical examiner’s activities and the court.
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
Our mission is to determine the cause of death inunnatural deaths through autopsy and various
examinations. We have also tried to find problems inlegal-social systems related to death investigation,

court procedure, and patient safety. To improve deathinvestigation and related legal-social systems, we
conducted variety of researches including cardiovascular basic sciences, legal-social medicine,forensic pathology, toxicology, and DNA polymorphism as described below.
1. Molecular mechanism of myocardial lesions andcell death in ischemia-reperfusion
We autopsy many cases suddenly died inassociation with accidents, violence, restraint, or
medical practices. Particularly, cardiac lesion andarrhythmias related to a brief ischemia andemotional stress respectively are important inforensic practices. The diagnosis and demonstrationof scientific evidence are very difficult in thesecases. We study the mechanism of these phenomenain the models of coronary occlusion, isolated
perfused heart, or cultured cardiomyocytes throughcirculatory physiology, biochemistry, histology, andmolecular biology.
Previously, we reported that calpain (Ca2+-dependent protease) following intracellular Ca2+
overloading contributes to the myocardial injury,
contractile dysfunction and development of infarction in reperfusion via proteolysis of cytoskeletal
proteins. Meanwhile, shortage of sarcoplasmic
reticulum (SR) Ca2+ uptake by the dephosphorylation of phospholamban (PLN) underlies heart
failure, and the blockade of PLN to restore SR Ca2+
uptake has been an important therapeutic target.
Recently, we found that prevention of cytosolic
Ca2+ overloading by the restoration of SR Ca2+
uptake by introduction of anti-PLN antibody in theheart paradoxically promotes myocardial infarction.
The findings led us to find the presence of calpain
in the mitochondria, and the implication of themitochondrial calpain in the development of
myocardial infarction after ischemia-reperfusion.
2. Research on cardiovascular risk and sudden deathin sleep apnea syndrome（SAS）
This is the most challenging theme in the field ofcardiovascular research, but the production of agood animal model has been difficult. We havesuccessfully developed an apparatus for the rat
model of SAS with intermittent hypoxia (IH), and109

have undertaken the investigation on the molecularmechanism on hypertension. We have organizedmulti-facility research groups. We found that IH
induces autophagy, and the inhibition of autophagy
induces heart failure in IH rats. Additionally, we
found that IH induces β-AR-dependent protective
mechanisms against hypoxic pulmonary vasoconstriction, and development of pulmonary hypertension and right ventricular failure. Moreover, wefound the effects of IH in multiple organs
depending on age and diseases such as obesity,
diabetes or ovariectomy.
3. Mechanism of MDMA cardiotoxicity.
3,4-Methylendioxymethyl-amphetamine (MDMA,"ecstasy") abuse often causes sudden death, but themechanism is largely unknown. We found that
MDMA induces activation of autophagy andlysosome, myofibril lysis with proteolysis via
lyososomal protease, and contractile dysfunction.
4. Mechanism of sudden cardiac death in restrain.
Restraint of excited persons cause sudden death,and the restrainer may be accused. We have foundthat restraint can cause sudden death of rats with
inhibition of gap-junction communication of cardiomyocytes that has been known in many heartdiseases. Meanwhile, restraint is known to induce
emotional stress, and emotional stress andcatecholamine overflow induces stress (takotsubo)
cardiomyopathy characterized by transient andregional reduction of wall motion, with takotsubolike ventriculogram. Recently, we found that
α-AR-Gi (inhibitory G protein) coupling underlie
the transient and regional reduction of left
ventricular contraction in restraint.
5. Investigation on the law and social system related
to death investigation, medical safety, and lawsuit.
The disclosure of the information and bereavement
service related to medico-legal autopsy have been
limited by law. Additionally, the information related
to medico-legal autopsy cannot be used for accident
prevention. To find a clue to improve the situations,
we have conducted the conference on the autopsy
cases after emergency medical practices, andpotentially therapeutic deaths, with attendance ofmany emergency doctors, forensic practitioners,
lawyers, prosecutors, and clinical experts (fortherapeutic deaths). The discussion at theconference has disclosed the discrepancy of clinicaland autopsy diagnoses in 30~40% cases, and manycases of overlook of injuries after imaging analyses.
A few cases warranted the attendance of the dangerof misdiagnoses as traumatic or iatrogenic led toguilty or responsible of the suspects, but the discussion at the conference avoided the false accusation.
Moreover, the attendants have learned much fromeach other. The sharing of the experiences between
the attendants will lead to the change in legal
system to take the advantage of death investigationand the conference to the prevention of similar
accidents. .
6. Development of new methods for forensic
examinations
Through the experience in forensic practices, wehave adopted or developed new methodology fortoxicological analyses. Additionally, we developed
new methods for forensic practices such as the
production of distribution map of planktons indifferent river and sea areas.
7. Case studies and forensic pathology.
We have reported rare cases related to clinicalmedicine or potentially therapeutic deaths, for the
training or education of graduate students or young
pathologists. Recently, we reported three cases as
the first autopsy case or new disease modality. We
have published many papers in clinical & pathology
journals.

Publications
1.

2.

3.

Saka K, Kudo K, Hayashida M, Kurisaki E,
Niitsu H, Terada M, Yamaguchi K, Yoshida K.
Relationship between the matrix effect and thephysicochemical properties of analytes in gas
chromatography. Anal Bioanal Chem. 2013;405(30):9879-88.
Kiuchi T, Yoshida K, Kotani H, Tamaki K, Nagai
H, Harada K, Ishikawa H. Legal Medicine
Information System using CDISC ODM. Leg
Med (Tokyo). 2013 ;15(6):332-4.
Kashima J, Shintani-Ishida K, Nakajima M,
Maeda H, Unuma K, Uchiyama Y, Yoshida K.
Immunohistochemical study of the autophagy
marker microtubule-associated protein 1 lightchain 3 in normal and steatotic human livers.

110

Hepatol Res. 2014 ;44(7):779-87.
4. Maeda H, Nagai H, Takemura G, Shintani-Ishida
K, Komatsu M, Ogura S, Aki T, Shirai M,
Kuwahira I, Yoshida K. Intermittent-hypoxia
inducedautophagyattenuates
contractile
dysfunction and myocardial injury in rat heart.
Biochim Biophys Acta. 2013;1832(8):1159-66.
5. Unuma K, Aki T, Funakoshi T, Yoshida K,
Uemura K. Cobalt protoporphyrin accelerates
TFEB activation and lysosome reformation
during LPS-induced septic insults in the rat heart.
PLoS One. 2013;8(2):e56526.
6. Hirose I, Harada K, Kuroda R, Ishii Y, Nakajima
M, Kamei Y, Takazawa Y, Yoshida K. An autopsy
report on a ruptured rudimentary horn (uterine
anomaly) with ectopic pregnancy. Forensic Sci
Int. 2013;224(1-3):e4-6.
7. Unuma K, Aki T, Matsuda S, Funakoshi T,
Yoshida K, Uemura K. Inducer of heme
oxygenase-1 cobalt protoporphyrin accelerates
autophagy and suppresses oxidative damages
during lipopolysaccharide treatment in rat liver.
Hepatol Res. 2013;43(1):91-6.
8. Unuma K, Aki T, Matsuda S, Funakoshi T,
Yoshida K, Uemura K. Elimination and active
extrusion of liver mitochondrial proteins during
lipopolysaccharide administration in rat. Hepatol
Res. 2013 May;43(5):526-34.
9. Hikiji W, Yamaguchi K, Saka K, Hayashida M,
Ohno Y, Fukunaga T. Acute fatal poisoning with
Tolfenpyrad. J Forensic Leg Med. 2013; 20:962-964.
10. Fujii Y, Funakoshi T, Uchida K, Watanabe M,
Saka K, Uemura K. An autopsy case of acutecarbon monoxide poisoning with fatal hypnotic
drugs in the blood. Int Med J. 2013; 20(5):587-588.
11. Kuroda R, Nakajima M, Nagai H, Maeda H,
Kashima J, Saka K, Shintani-Ishida K, Igarashi A,
Yoshida K. Small focal coagulation necrosis in
the myocardium of a young methamphetamineuser. Int J Cardiol. 2013; 164: e5-e6.

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Department of Medical
Informatics and Economics
Professor
Kazuhiko Ohe, M.D., Ph.D.

Associate Professor
Kengo Miyo, R.N, 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.

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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
and passing 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

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format, a web application for browsing the disease
ontology was developed and published on the website; http://lodc.med-ontology.jp/
2) Development of Multi-purpose Clinical 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.
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.

2.

Yamagata Y, Kozaki K, Imai T, Ohe K,
Mizoguchi R.:
An ontological modelingapproach for abnormal states and its applicationin the medical domain.,J Biomed Semantics.
2014;5:23.
Hanatani T, Sai K, Tohkin M, Segawa K, Antoku
Y, Nakashima N, Yokoi H, Ohe K, Kimura M,
Hori K, Kawakami J, Saito Y.: Evaluation of
two Japanese regulatory actions using medical
information databases: a ‘Dear Doctor’ letter torestrict oseltamivir use in teenagers, and labelchange caution against co-administration ofomeprazole with clopidogrel., J Clin Pharm

3.

4.

5.

Ther. 2014 Aug;39(4):361-7.
Sumitani M, Yasunaga H, Uchida K, Horiguchi H,
Nakamura M, Ohe K, Fushimi K, Matsuda S,
Yamada Y.: Perioperative factors affecting theoccurrence of acute complex regional pain
syndrome following limb bone fracture surgery:data from the Japanese Diagnosis Procedure
Combination database., Rheumatology, 2014Jul;
53(7):1186-93.
Waki K, Fujita H, Uchimura Y, Omae K, Aramaki
E, Kato S, Lee H, Kobayashi H, Kadowaki T,
Ohe K.: DialBetics: A Novel Smartphone-based
Self-management Support System for Type 2
Diabetes Patients.,J Diabetes Sci Technol. 2014
Mar 13;8(2):209-215.
Chikuda H, Yasunaga H, Takeshita K, Horiguchi
H, Kawaguchi H, Ohe K, Fushimi K, Tanaka S.:
Mortality and morbidity after high-dose
methylprednisolone treatment in patients withacute cervical spinal cord injury: a propensitymatchedanalysisusinganationwide
administrative database.,Emerg Med J. 2014 Mar;31(3):201-6.

Internal Medicine
1. Medicine Ⅰ

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

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

Ichiro Manabe, M.D., Ph.D.

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

Jiro Andoh, M.D.

Hospital Lecturer
Norihiko Takeda, M.D., Ph.D. (since February, 2015)

Homepage

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

Introduction and Organization

Clinical activities

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.

In 2014, 1,906 patients were newly admitted to our
hospital ward of approximately 50 beds. Cardiovascular angiograms were conducted in 1,765 patients,of which 571 cases were interventional procedures.
CT coronary angiography was examined in 397
patients and cardiovascular MRI in 80. For
arrhythmias, there were 298 cases of catheter ablation,
69 cases of implantation or replacement of apacemaker, and other specialized pacemaker devices
such as 20 cases of implantation or replacement of an
implantable cardioverter-defibrillator (ICD) and 18
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 6 cases in 2014 (total 50 cases).
March 2014, our facility was also authorized for lungtransplantation. Duration of hospitalization is on
average 12.2 days.
Out-patient clinics are available as part of the
Department of Medicine or as a specialized

Staff: one professor (Issei Komuro), 4 lecturers, 1
hospital lecturer, 16 research associates, 11 staff
members, 29 graduate school students.

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department. The profile of diseases includes ischemic
heart disease, 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 221.5 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 (2014)
1. Abe H, Iguchi N, Utanohara Y, Inoue K,
Takamisawa I, Seki A, et al. Non-invasive
diagnosis of coronary artery disease by 123IBMIPP/201TlCl dual myocardial SPECT inpatients with heart failure. Int J Cardiol 2014 Oct
20;176(3):969-74.
2. Akazawa H, Komuro I. Dickkopf-3: a stubborn
protector of cardiac hypertrophy. Cardiovasc Res
2014 Apr 1;102(1):6-8.
3. Amiya E, Watanabe M, Komuro I. The Relationship between Vascular Function and the Autonomic Nervous System. Ann Vasc Dis 2014;7(2):109-19.
4. Amiya E, Watanabe M, Takata M, Nakao T,
Hosoya Y, Watanabe S, et al. Diurnal body temperature rise is reduced in diabetes with autonomic
neuropathy. Clin Auton Res2014 Apr;24(2):95-7.
5. Eguchi K, Manabe I. Toll-like receptor,
lipotoxicity and chronic inflammation: the pathological link between obesity and cardiometabolic
disease. J Atheroscler Thromb2014;21(7):629-39.
6. Fujino T, Kinugawa K, Hatano M, Imamura T,
Muraoka H, Minatsuki S, et al. Low blood pressure,
low serum cholesterol and anemia predict earlynecessity of ventricular assist device implantationin patients with advanced heart failure at the timeof referral from non-ventricular assist device
institutes. Circ J2014;78(12):2882-9.
7. Fujita D, Takeda N, Imai Y, Hirata Y. [Current
status and future perspectives in the research of
Marfan syndrome]. Nihon Rinsho2014 Jun;72(6):1163-71.

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8. Fujita D, Takeda N, Imai Y, Inuzuka R, Komuro I,
Hirata Y. Pathophysiology and Japanese clinicalcharacteristics in Marfan syndrome. Pediatr Int
2014 Aug;56(4):484-91.
9. Hara H, Yamashita H, Nakayama A, Hosoya Y,
Ando J, Iijima K, et al. A rare case of anomalous
origin of the left anterior descending artery fromthe pulmonary artery. Int J Cardiol2014 Mar 1;
172(1):e66-8.
10. Hirakawa H, Zempo H, Ogawa M, Watanabe R,
Suzuki J, Akazawa H, et al. A DPP-4 inhibitor
suppresses fibrosis and inflammation on
experimental autoimmune myocarditis in mice.
PLoS One2014;10(3):e0119360.
11. 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. Eur J Hum
Genet2014 Mar;23(3):374-80.
12. Imamura T, Kinugawa K, Fujino T, Inaba T, Maki
H, Hatano M, et al. Recipients with shorter
cardiopulmonary bypass time achieve improvementof parasympathetic reinnervation within 6 months
after heart transplantation. Int Heart J2014;55(5):440-4.
13. Imamura T, Kinugawa K, Fujino T, Inaba T, Maki
H, Hatano M, et al. Increased urine aquaporin-2
relative to plasma arginine vasopressin is a novel
marker of response to tolvaptan in patients withdecompensated heart failure. Circ J2014;78(9):2240-9.
14. Imamura T, Kinugawa K, Hatano M, Fujino T,
Inaba T, Maki H, et al. Status 2 patients had poor
prognosis without mechanical circulatory support.
Circ J2014;78(6):1396-404.
15. Imamura T, Kinugawa K, Hatano M, Fujino T,
Inaba T, Maki H, et al. Low cardiac output
stimulates vasopressin release in patients with staged heart failure. Circ J2014;78(9):2259-67.
16. Imamura T, Kinugawa K, Hatano M, Fujino T,
Muraoka H, Inaba T, et al. Preoperative betablocker treatment is a key for deciding left
ventricular assist device implantation strategy as abridge to recovery. J Artif Organs2014 Mar;17(1):23-32.

17. Imamura T, Kinugawa K, Kato N, Muraoka H,
Fujino T, Inaba T, et al. Late-onset right ventricular
failure in patients with preoperative small left
ventricle after implantation of continuous flow left
ventricular assist device. Circ J2014;78(3):625-33.
18. Imamura T, Kinugawa K, Minatsuki S, Muraoka H,
Kato N, Inaba T, et al. Urine sodium excretion after
tolvaptan administration is dependent uponbaseline serum sodium levels: a possible explanation for the improvement of hyponatremia withscarce chance of hypernatremia by a vasopressin
receptor antagonist. Int Heart J2014;55(2):131-7.
19. Imamura T, Kinugawa K, Murasawa T, Kagami Y,
Endo M, Muraoka H, et al. Cardiac allograft
vasculopathy can be distinguished from donortransmitted coronary atherosclerosis by opticalcoherence tomography imaging in a hearttransplantation recipient: double layered intimal
thickness. Int Heart J2014;55(2):178-80.
20. Imamura T, Kinugawa K, Ohtani T, Sakata Y,
Higo T, Kinugawa S, et al. Assessment of qualityof life during long-term treatment of tolvaptan inrefractory heart failure: design and rationale of the
AQUA-TLV study. Int Heart J2014;55(3):264-7.
21. Kato N, Jaarsma T, Kinugawa K. Impact ofcomorbidities on economic and health outcomesfor patients with cardiovascular disease. CircJ2014;78(3):588-9.
22. Kato N, Kinugawa K, Teruhiko I, Hironori M,
Hisataka M, Toshiro I, et al. Differential impacts ofachieved heart rate and achieved dose ofbeta-blocker on clinical outcomes in heart failure
with and without atrial fibrillation. Int J Cardiol
2014 May 1;173(2):331-3.
23. Kimura M, Kinoshita O, Nawata K, Nishimura T,
Hatano M, Imamura T, et al. Midterm outcome of
implantable left ventricular assist devices as abridge to transplantation: Single-center experiencein Japan. J Cardiol2014 May;65(5):383-9.
24. Kinugawa K, Nagai R, Inoue H, Atarashi H, Seino
Y, Yamashita T, et al. Impacts of patient characteristics on the effectiveness of landiolol in AF/AFL
patients complicated with LV dysfunction:
Subgroup analysis of the J-Land study. Adv Ther
2014 Apr;31(4):426-39.
25. Kinugawa K, Nguyen-Michel VH, Mariani J.
[Obstructive sleep apnea syndrome: a cause of

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cognitive disorders in the elderly?]. Rev Med
Interne2014 Oct;35(10):664-9.
26. Kinugawa K, Sato N, Inomata T, Shimakawa T,
Iwatake N, Mizuguchi K. Efficacy and safety of
tolvaptan in heart failure patients with volume
overload. Circ J2014;78(4):844-52.
27. Kobayashi N, Suzuki J, Ogawa M, Aoyama N,
Komuro I, Izumi Y, et al. Porphyromonas
gingivalis promotes neointimal formation afterarterial injury through toll-like receptor 2 signaling.
Heart Vessels2014 Jul;29(4):542-9.
28. Kojima T, Imai Y, Komuro I. Giant coronary
arteriovenous fistula between left superior
pulmonary vein and left atrial appendage. Europace
2014 Jan;16(1):39.
29. Kudo-Sakamoto Y, Akazawa H, Ito K, Takano J,
Yano M, Yabumoto C, et al. Calpain-dependentcleavage of N-cadherin is involved in the progression of post-myocardial infarction remodeling. J
Biol Chem2014 Jul 11;289(28):19408-19.
30. Lee SL, Daimon M, Kawata T, Kohro T, Kimura K,
Nakao T, et al. Estimation of right atrial pressure
on inferior vena cava ultrasound in Asian patients.
Circ J2014;78(4):962-6.
31. Lee SL, Hashimoto H, Kohro T, Horiguchi H,
Koide D, Komuro I, et al. Influence ofmunicipality-level mean income on access to aortic
valve surgery: a cross-sectional observational study
under Japan's universal health-care coverage. PLoS
One2014;9(10):e111071.
32. Morita H, Komuro I. Somatic mutations in cerebral
cortical malformations. N Engl J Med2014 Nov 20;371(21):2037.
33. Morita H, Komuro I. The metabolic syndrome and
DYRK1B. N Engl J Med2014 Aug 21;371(8):785.
34. Muraoka H, Higashikuni Y, Ando J, Komuro I.
Cardiac compression by massive mediastinal
haematoma due to bleeding from the ectopic
bronchial artery. Eur Heart J2014 Jun 14;35(23):1567.
35. Myojo M, Nagata D, Fujita D, Kiyosue A,
Takahashi M, Satonaka H, et al. Telmisartan
activates endothelial nitric oxide synthase via
Ser1177 phosphorylation in vascular endothelial
cells. PLoS One2014;9(5):e96948.
36. Nakaya T, Ogawa S, Manabe I, Tanaka M, Sanada
M, Sato T, et al. KLF5 regulates the integrity andoncogenicity of intestinal stem cells. Cancer
Res2014 May 15;74(10):2882-91.
37. 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 Vessels2014
May;30(3):304-8.
38. Nakayama A, Morita H, Miyata T, Hoshina K,
Nagayama M, Takanashi S, et al. Predictors ofmortality after emergency or elective repair ofabdominal aortic aneurysm in a Japanese
population. Heart Vessels2014 Jan;29(1):65-70.
39. Nishihara M, Takeda N, Harada T, Kidoguchi K,
Tatsumi S, Tanaka K, et al. Diagnostic yield andmorbidity by neuronavigation-guided framelessstereotactic biopsy using magnetic resonance imaging and by frame-based computed tomographyguided stereotactic biopsy. Surg Neurol Int2014;
5(Suppl 8):S421-6.
40. Nishimura S, Nagasaki M, Okudaira S, Aoki J,
Ohmori T, Ohkawa R, et al. ENPP2 contributes toadipose tissue expansion and insulin resistance indiet-induced obesity. Diabetes2014 Dec;63(12):4154-64.
41. Nishizaki Y, Shimada K, Tani S, Ogawa T, Ando J,
Takahashi M, et al. Significance of imbalance inthe ratio of serum n-3 to n-6 polyunsaturated fatty
acids in patients with acute coronary syndrome.
Am J Cardiol2014 Feb 1;113(3):441-5.
42. Noda S, Asano Y, Nishimura S, Taniguchi T, Fujiu
K, Manabe I, et al. Simultaneous downregulationof KLF5 and Fli1 is a key feature underlying
systemic sclerosis. Nat Commun2014;5:5797.
43. Nozawa H, Kanazawa T, Tanaka T, Takahashi M,
Ishihara S, Sunami E, et al. Laparoscopic resectionof a gastrointestinal stromal tumor of the lower
rectum in a patient with coronary artery disease
following long-term neoadjuvant imatinib treatment and anticoagulation therapy. World J Surg
Oncol2014;12:211.
44. Odagiri H, Kadomatsu T, Endo M, Masuda T,
Morioka MS, Fukuhara S, et al. The secreted
protein ANGPTL2 promotes metastasis of osteosarcoma cells through integrin alpha5beta1, p38
MAPK, and matrix metalloproteinases. Sci Signal
2014 Jan 21;7(309):ra7.

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45. Oguri G, Nakajima T, Yamamoto Y, Takano N,
Tanaka T, Kikuchi H, et al. Effects ofmethylglyoxal on human cardiac fibroblast: rolesof transient receptor potential ankyrin 1 (TRPA1)
channels. Am J Physiol Heart Circ Physiol2014
Nov 1;307(9):H1339-52.
46. Oka T, Akazawa H, Naito AT, Komuro I.
Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles inheart failure. Circ Res2014 Jan 31;114(3):565-71.
47. Okuyama Y, Matsuo M, Matsuo H, Sakaguchi Y,
Takai H, Horiguchi Y, et al. Introduction of pointof-care testing in Japanese outpatient clinics is
associated with improvement in time in therapeutic
range in anticoagulant-treated patients. Circ J2014;
78(6):1342-8.
48. Sakamoto A, Ishizaka N, Imai Y, Ando J, Nagai R,
Komuro I. Association of serum IgG4 and solubleinterleukin-2 receptor levels with epicardial
adipose tissue and coronary artery calcification.
Clin Chim Acta2014 Jan 20;428:63-9.
49. Sato G, Sekine K, Matsuda K, Ueeda H, Horii A,
Nishiike S, et al. Long-term prognosis of hearing
loss in patients with unilateral Meniere's disease.
Acta Otolaryngol2014 Oct;134(10):1005-10.
50. Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki
J, Horiuchi M, et al. The Japanese Society ofHypertension Guidelines for the Management ofHypertension (JSH 2014). Hypertens Res2014 Apr;
37(4):253-390.
51. Suzuki J, Aoyama N, Aoki M, Tada Y, Wakayama
K, Akazawa H, et al. High incidence of
periodontitis in Japanese patients with abdominal
aortic aneurysm. Int Heart J2014;55(3):268-70.
52. Suzuki J, Imai Y, Aoki M, Fujita D, Aoyama N,
Tada Y, et al. Periodontitis in cardiovasculardisease patients with or without Marfan
syndrome--a possible role of Prevotella intermedia.
PLoS One2014;9(4):e95521.
53. Suzuki JI, Aoyama N, Aoki M, Tada Y, Wakayama
K, Akazawa H, et al. Incidence of periodontitis inJapanese patients with cardiovascular diseases: acomparison between abdominal aortic aneurysm
and arrhythmia. Heart Vessels2014 Apr 16.
54. Tada Y, Ogawa M, Watanabe R, Zempo H,
Takamura C, Suzuki J, et al. Neovascularizationinduced by hypoxia inducible transcription factor isassociated with the improvement of cardiac dysfunction in experimental autoimmune myocarditis.
Expert Opin Investig Drugs2014 Feb;23(2):149-62.
55. Takahashi M, Myojo M, Watanabe A, Kiyosue A,
Kimura K, Ando J, et al. Effect of purified
eicosapentaenoic acid on red cell distribution widthin patients with ischemic heart disease. Heart
Vessels2014 May 31.
56. Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Takata M, et al. Clinical correlation ofbrachial artery flow-mediated dilation in patientswith systemic sclerosis. Mod Rheumatol2014 Jan;24(1):106-11.
57. Takata M, Amiya E, Watanabe M, Omori K, ImaiY, Fujita D, et al. Impairment of flow-mediateddilation correlates with aortic dilation in patientswith Marfan syndrome. Heart Vessels2014 Jul;29(4):478-85.
58. Wang JH, Eguchi K, Matsumoto S, Fujiu K,
Komuro I, Nagai R, et al. The omega-3
polyunsaturated fatty acid, eicosapentaenoic acid,attenuates abdominal aortic aneurysm development
via suppression of tissue remodeling. PLoS One
2014;9(5):e96286.
59. Watanabe S, Amiya E, Watanabe M, Takata M,
Ozeki A, Watanabe A, et al. Elevated C-reactive
protein levels and enhanced high frequency
vasomotion in patients with ischemic heart diseaseduring brachial flow-mediated dilation. PLoS One
2014;9(10):e110013.
60. Yagi H, Amiya E, Ando J, Watanabe M, Yanaba K,
Ikemura M, et al. In-stent restenosis exacerbated bydrug-induced severe eosinophilia after secondgeneration drug-eluting stent implantation. Am J
Case Rep2014;15:397-400.
61. Yamagata K, Goto Y, Nishimasu H, Morimoto J,
Ishitani R, Dohmae N, et al. Structural basis forpotent inhibition of SIRT2 deacetylase by amacrocyclic peptide inducing dynamic structuralchange. Structure2014 Feb 4;22(2):345-52.

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

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

Associate
Hidenori Kage, M.D.,Ph.D., Akihisa Mitani, M.D.,Ph.D., Osamu Narumoto, M.D.,Ph.D.,
Hirokazu Urushiyama, M.D.,Ph.D., Hiroyuki Tamiya, M.D.,Ph.D., Kousuke Watanabe,
M.D.,Ph.D., Yosuke Amano, M.D.,Ph.D., Satoshi Noguchi, M.D.,Ph.D.

Homepage

http://kokyuki.umin.jp/

Introduction and Organization

Clinical activities

The staff of the Department of Respiratory Medicine,
Graduate School of Medicine, University of Tokyo,
consists of 1 professor, 2 lecturers, and 8 associates. In
the University of Tokyo, affiliated hospitals andforeign institutions, approximately 45 members
belong to the Department. In the University of Tokyo
Hospital, about 15 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,
interstitial pneumonia, respiratory infections, COPD,
pneumothorax and asthma. Many patients withprimary lung cancer also have interstitial pneumonia
or COPD as their back ground pulmonary diseases.
There are many emergency visits and admissions withpneumonia, respiratory failure due to exacerbation of
COPD or interstitial pneumonia, progression of lungcancer, and so on. In cases of severe respiratory
failure such as severe pneumonia and ARDS, we
conduct ventilatory support of such patients incollaboration with ICU staff in an effort to rescue
them. A specialized clinical conference for respiratory
disease has been held once a week since late 1990s,
where staff of our department, department of thoracic
surgery and department of radiology join and discuss
together to make best diagnostic and therapeutic

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approach to individual patients. This conference has
been highly appreciated as prototype of Cancer Boardof the University of Tokyo Hospital, and, is now held
as Respiratory Cancer Board. This conference is still
one of the most frequently held Cancer Board in our
hospital. Our department contributes to the pre- andpost-surgical evaluation of respiratory functions, andalso receives consultation about respiratorycomplications 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 remarkableeffectiveness of molecular-targeted therapies inprimary lung cancer attract much attention in thefields of both basic science and clinical practice.
Respiratory infections are now the 3rd leading cause of
all death and COPD also will be major leading causeof all death in the near future. Among respiratory
diseases, there are several disorders to which noeffective 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 2014
1. Primary lung cancer
342
2. Respiratory Infection48
3. Interstitial pneumonia
42
4. Bronchial asthma
11
5. Sarcoidosis
11
6. Pneumothorax
10
7. COPD
9
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 incollaboration with expert respiratory physicians fromseveral 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 clinicalclerkship and this lecture is highly appreciated by thestudents.
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.

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

tion, 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.

Research activities

References

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.

1. Hasegawa W, Yamauchi Y, Yasunaga H, Sunohara
M, Jo T, Matsui H, Fushimi K, Takami K, Nagase
T: Factors affecting mortality following
emergency admission for chronic obstructive
pulmonary disease. BMC Pulm Med 2014, 14:151.
2. Horie M, Saito A, Noguchi S, Yamaguchi Y,
Ohshima M, Morishita Y, Suzuki HI, Kohyama T,
Nagase T: Differential knockdown of TGF-betaligands in a three-dimensional co-culture tumorstromal interaction model of lung cancer. BMC
Cancer 2014, 14:580.
3. Horie M, Saito A, Yamauchi Y, Mikami Y,
Sakamoto M, Jo T, Nakajima J, Takizawa H,
Nagase T, Kohyama T: Histamine induces humanlung fibroblast-mediated collagen gel contraction
via histamine H1 receptor. Exp Lung Res 2014,40(5):222-236.
4. Ichinose J, Watanabe K, Sano A, Nagase T,
Nakajima J, Fukayama M, Yatomi Y, Ohishi N,
Takai D: Alternative polyadenylation is associatedwith lower expression of PABPN1 and poor
prognosis in non-small cell lung cancer. Cancer
Sci 2014, 105(9):1135-1141.
5. Kage H, Flodby P, Gao D, Kim YH, MarconettCN, DeMaio L, Kim KJ, Crandall ED, Borok Z:
Claudin 4 knockout mice: normal physiologicalphenotype with increased susceptibility to lunginjury. Am J Physiol Lung Cell Mol Physiol 2014,
307(7):L524-536.
6. Li G, Flodby P, Luo J, Kage H, Sipos A, Gao D, Ji
Y, Beard LL, Marconett CN, DeMaio L et al:
Knockout mice reveal key roles for claudin 18 inalveolar barrier properties and fluid homeostasis.

Search for diseases-susceptibility genes andelucidation of their pathophysiological roles in
respiratory diseases.
Analysis of disease-models using geneticallyengineered mice.
Analysis of DNA methylation, histone 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 transi-

Takahide Nagase is GOLD National Leader.

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Am J Respir Cell Mol Biol 2014, 51(2):210-222.
7. Mikami Y, Matsuzaki H, Horie M, Noguchi S, Jo
T, Narumoto O, Kohyama T, Takizawa H, Nagase
T, Yamauchi Y: Lymphotoxin beta receptor
signaling induces IL-8 production in humanbronchial epithelial cells. PLoS One 2014, 9(12):e114791.
8. Noguchi S, Saito A, Horie M, Mikami Y, Suzuki
HI, Morishita Y, Ohshima M, Abiko Y, Mattsson
JS, Konig H et al: An integrative analysis of thetumorigenic role of TAZ in human non-small celllung cancer. Clin Cancer Res 2014, 20(17):4660-4672.
9. Noguchi S, Yamauchi Y, Takizawa H: Noveltherapeutic strategies for fibrotic lung disease: areview with a focus on epithelial-mesenchymaltransition. Recent Pat Inflamm Allergy Drug
Discov 2014, 8(1):9-18.
10. Okazaki H, Ishikawa O, Iijima T, Kohira T,
Teranishi M, Kawasaki S, Saito A, Mikami Y,
Sugiura A, Hashimoto S et al: Novel swine modelof transfusion-related acute lung injury.
Transfusion 2014, 54(12):3097-3107.
11. Tarui M, Shindou H, Kumagai K, Morimoto R,
Harayama T, Hashidate T, Kojima H, Okabe T,
Nagano T, Nagase T et al: Selective inhibitors of a
PAF biosynthetic enzyme lysophosphatidylcholine
acyltransferase 2. J Lipid Res 2014, 55(7):13861396.
12. Yamauchi Y, Hasegawa W, Yasunaga H, Sunohara
M, Jo T, Takami K, Matsui H, Fushimi K, Nagase
T: Paradoxical association between body massindex and in-hospital mortality in elderly patientswith chronic obstructive pulmonary disease inJapan. Int J Chron Obstruct Pulmon Dis 2014, 9:
1337-1346.

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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.

Dai Mohri, M.D., Ph.D.

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

Yosuke Tsuji, 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, 21 associates, 16 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 2014). Number of treatments forhepatocellular carcinoma, represented by percutaneous radiofrequency ablation, exceeded 420
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
for more than 1000 cases each year. The cumulative
number of patients treated for choledocholithiasis withendoscopic papillary balloon dilation method exceeds
1,300, which is possibly the largest in the world.
Recently, EPLBD, which utilizes a larger diameter ofdilation balloon, was also applied, and more than 80
cases with choledocholithiasis are annually treatedendoscopically. Endoscopic placement of a metal stentis an effective palliative care for malignant obstructive
jaundice (about 80 procedures performed every year),and our group is a pioneer of covered metal stents forbiliary obstruction, and is one of the world’s largest
centers using covered metal stents. Pancreaticinterventions such as pancreatic stenting, cystic
drainage, endoscopic stone extraction and lithotripsy
using ESWL (extracorporeal shock-wave lithotripsy)
are performed for many challenging cases. We havealso 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 (350 patients a year). Nonexposedendoscopic wall-inversion surgery (NEWS), whichwasdevelopedwiththeDepartment
ofGastrointestinal Surgery, now expanded its clinicalapplication to the treatment of gastric cancer.
Double-balloon endoscopy and capsule endoscopy
have been introduced recently, which enabled theexamination of whole small intestines (400 cases in2014). 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, gastroduodenal endoscopy
on 9,000, and colonoscopy on 4,500 patients each year,
leading the detection of about 240 cases of gastriccancer and 250 cases of colorectal cancer annually.
About 40 % of them are treated endoscopically, but
we also aim to perform basic studies using specimen,
and turn these efforts to clinical 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
practically. The results are reported to the professor at
the end of the course in the style of oral examination.

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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 1-6 months inrotation 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 may learn advanced techniques ingastroenterology in affiliated hospitals for a few years.
Usually, they will come back to the department afterthat period, and improve their clinical skills still
further while at the education course. The majority ofthem also become graduate student, and starts medical
researches either in a basic or clinical research area.
Currently, the department has 65 students, who were
graduated from more than 30 medical schools inJapan.

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, roleof miRNA in hepatocarcinogenesis, etc.
Various clinical activities are recorded indatabase 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.
The department is dedicated to pursuing bettermedical services from all facets of the subspecialty ofgastroenterology, which is brought about by both basic
and clinical researches.

References
1) Sasaki T, Isayama H, Nakai Y, Ito Y, Yasuda I,
Toda N, Yagioka H, Matsubara S,Hanada K,
Maguchi H, Kamada H, Hasebe O, Mukai T,
Okabe Y, Maetani I, Koike K. Treatment
outcomes of chemotherapy between unresectable
and recurrent biliary tract cancer. World J
Gastroenterol. 2014 Dec 28;20(48):18452-7.
2) Asaoka Y, Tateishi R, Nakagomi R, Kondo M,
Fujiwara N, Minami T, Sato M, Uchino K,
Enooku K, Nakagawa H, Kondo Y, Shiina S,
Yoshida H, Koike K. Frequency of and predictive
factors for vascular invasion after radiofrequency
ablation for hepatocellular carcinoma. PLoS One.
2014 Nov 14;9(11):e111662.
3) 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 canprevent esophageal stricture after endoscopic
submucosal dissection. Endoscopy. 2015 Apr;47(4):336-40.
4) Mochizuki S, Uedo N, Oda I, Kaneko K,
Yamamoto Y, Yamashina T, Suzuki H, Kodashima
S, Yano T, Yamamichi N, Goto O, Shimamoto T,
Fujishiro M, Koike K; SAFE Trial Study Group.
Scheduled second-look endoscopy is notrecommended after endoscopic submucosal
dissection for gastric neoplasms (the SAFE trial):a multicentre prospective randomised controlled
non-inferiority trial. Gut. 2015 Mar;64(3):397-405.
5) Hirano K, Tada M, Isayama H, Koike K.
Intrapancreatic biliary stricture in autoimmune
pancreatitis should not be included in IgG4related sclerosing cholangitis. Pancreas. 2014 Oct;12743(7):1123.
6) Kageyama-Yahara N, Yamamichi N, Takahashi Y,
Nakayama C, Shiogama K, Inada K,
Konno-Shimizu M, Kodashima S, Fujishiro M,
Tsutsumi Y, Ichinose M, Koike K. Gli regulates
MUC5AC transcription in human gastrointestinal
cells. PLoS One. 2014 Aug 28;9(8):e106106.
7) Nakagawa H, Umemura A, Taniguchi K,
Font-Burgada J, Dhar D, Ogata H, Zhong Z,
Valasek MA, Seki E, Hidalgo J, Koike K,
Kaufman RJ, Karin M. ER stress cooperates withhypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014 Sep
8;26(3):331-43.
8) Shibata C, Ohno M, Otsuka M, Kishikawa T, GotoK, Muroyama R, Kato N, Yoshikawa T, Takata A,
Koike K. The flavonoid apigenin inhibits hepatitis
C virus replication by decreasing mature micro
RNA122 levels. Virology. 2014 Aug;462-463:
42-8.
9) Fujiwara N, Tateishi R, Kondo M, Minami T,
Mikami S, Sato M, Uchino K, Enooku K,
Masuzaki R, Nakagawa H, Kondo Y, Asaoka Y,
Shiina S, Yoshida H, Koike K. Cause-specificmortality associated with aging in patients with
hepatocellular
carcinoma
undergoing
percutaneous radiofrequency ablation. Eur J
Gastroenterol Hepatol. 2014 Sep;26(9):1039-46.
10) Ohno M, Otsuka M, Kishikawa T, Shibata C,
Yoshikawa T, Takata A, Muroyama R, Kowatari N,
Sato M, Kato N, Kuroda S, Koike K. Specificdelivery of microRNA93 into HBV-replicating
hepatocytes downregulates protein expression ofliver cancer susceptible gene MICA. Oncotarget.
2014 Jul 30;5(14):5581-90.
11) Sasaki T, Isayama H, Aoki T, Tanaka M, Hamada
T, Nakai Y, Sakamoto Y, Hasegawa K, Morikawa
T, Fukayama M, Kokudo N, Koike K. A R0
resection case of initially unresectable metastatic
pancreatic cancer downstaged by FOLFIRINOX
therapy. Pancreas. 2014 Aug;43(6):972-4.
12) Mizuno S, Nakai Y, Isayama H, Kawahata S, Saito
T, Takagi K, Watanabe T, Uchino R, Hamada T,
Miyabayashi K, Kogure H, Sasaki T, Yamamoto N,
Sasahira N, Hirano K, Tsujino T, Ijichi H, Tateishi
K, Tada M, Koike K. Smoking, family history ofcancer, and diabetes mellitus are associated withthe age of onset of pancreatic cancer in Japanesepatients. Pancreas. 2014 Oct;43(7):1014-7.
13) Yamaji Y, Mitsushima T, Koike K. Pulse-wave
velocity, the ankle-brachial index, and the visceralfat area are highly associated with colorectal
adenoma. Dig Liver Dis. 2014 Oct;46(10):943-9.
14) Yamamoto K, Tateishi K, Kudo Y, Sato T,
Yamamoto S, Miyabayashi K, Matsusaka K,
Asaoka Y, Ijichi H, Hirata Y, Otsuka M, Nakai Y,
Isayama H, Ikenoue T, Kurokawa M, Fukayama
M, Kokudo N, Omata M, Koike K. Loss ofhistone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα. Carcinogenesis. 2014 Nov;
35(11):2404-14.
15) Tateishi R, Okanoue T, Fujiwara N, Okita K,
Kiyosawa K, Omata M, Kumada H, Hayashi N,
Koike K. Clinical characteristics, treatment, andprognosis of non-B, non-C hepatocellular
carcinoma: a large retrospective multicenter
cohort study. J Gastroenterol. 2015 Mar;50(3):350-60.
16) 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, Koike K.
Tumor markers are more useful in patients
undergoing surveillance for hepatocellular
carcinoma
withunreliable
resultsbyultrasonography. Hepatol Res. 2015 Apr;45(4):415-22.
17) Yamamoto N, Isayama H, Sasahira N, Tsujino T,
Nakai Y, Miyabayashi K, Mizuno S, Kogure H,
Sasaki T, Hirano K, Tada M, Koike K. Endoscopic
minor papilla balloon dilation for the treatment ofsymptomatic pancreas divisum. Pancreas.2014
Aug;43(6):927-30.
18) Kakiuchi M, Nishizawa T, Ueda H, Gotoh K,
Tanaka A, Hayashi A, Yamamoto S, Tatsuno K,
Katoh H, Watanabe Y, Ichimura T, Ushiku T,
Funahashi S, Tateishi K, Wada I, Shimizu N,
Nomura S, Koike K, Seto Y, Fukayama M,
Aburatani H, Ishikawa S. Recurrent gain-offunction mutations of RHOA in diffuse-type
gastric carcinoma. Nat Genet. 2014 Jun;46(6):583-7.
19) Nakagomi R, Tateishi R, Shiina S, Imamura J,

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Fujiwara N, Asaoka Y, Kondo Y, Koike K.
Drastically reduced neoplastic seeding related toradiofrequency ablation for hepatocellular
carcinoma. Am J Gastroenterol. 2014 May;109(5):774-6.
20) Kobayashi Y, Yamada A, Watabe H, Takahashi R,
Suzuki H, Hirata Y, Yamaji Y, Yoshida H, Koike K.
Sonographic detection of a patency capsule prior
to capsule endoscopy: case report. J Clin
Ultrasound. 2014 Nov-Dec;42(9):554-6.
21) Hamada T, Isayama H, Nakai Y, Kogure H,
Yamamoto N, Koike K. Tips and troubleshooting
for transpapillary metal stenting for distal
malignant biliary obstruction. J Hepatobiliary
Pancreat Sci. 2014 Mar;21(3):E12-8.
22) Sato M, Kondo M, Tateishi R, Fujiwara N, Kato N,
Yoshida H, Taguri M, Koike K. Impact of IL28B
genetic variation on HCV-induced liver fibrosis,
inflammation, and steatosis: a meta-analysis.
PLoS One. 2014 Mar 17;9(3):e91822.
23) Nakai Y, Isayama H, Kawakubo K, Kogure H,
Hamada T, Togawa O, Ito Y, Matsubara S,
Arizumi T, Yagioka H, Takahara N, Uchino R,
Mizuno S, Miyabayashi K, Yamamoto K, Sasaki T,
Yamamoto N, Hirano K, Tada M, Koike K.
Metallic stent with high axial force as a risk factor
for cholecystitis in distal malignant biliary
obstruction. J Gastroenterol Hepatol. 2014;29(7):1557-62.
24) Uchino R, Sasahira N, Isayama H, Tsujino T,
Hirano K, Yagioka H, Hamada T, Takahara N,
Miyabayashi K, Mizuno S, Mohri D, Sasaki T,
Kogure H, Yamamoto N, Nakai Y, Tada M, Koike
K. Detection of painless pancreatitis by CT inpatients with post-endoscopic retrograde cholangiopancreatography hyperamylasemia. Pancreatology. 2014 Jan-Feb;14(1):17-20.
25) Isomura Y, Yamaji Y, Yamada A, Watanabe Y,
Suzuki H, Kobayashi Y, Yoshida S, Watabe H,
Hirata Y, Yoshida H, Koike K. Irsogladine
improves small-intestinal injuries in regular users
of nonsteroidal anti-inflammatory drugs. Gastrointest Endosc. 2014 Jul;80(1):118-25.
26) Yamamichi N, Shimamoto T, Sakaguchi Y,
Takahashi Y, Kodashima S, Nakayama C,
Minatsuki C, Ono S, Mochizuki S, Matsuda R,
Asada-Hirayama I, Niimi K, Fujishiro M, Tsuji Y,

Takeuchi C, Kakimoto H, Goto O, Mitsushima T,
Koike K. Categorization of upper gastrointestinal
symptoms is useful in predicting backgroundfactors and studying effects and usages ofdigestive drugs. PLoS One. 2014 Feb 5;9(2):e88277.
27) Nakagawa H, Hikiba Y, Hirata Y, Font-Burgada J,
Sakamoto K, Hayakawa Y, Taniguchi K,
Umemura A, Kinoshita H, Sakitani K, Nishikawa
Y, Hirano K, Ikenoue T, Ijichi H, Dhar D, Shibata
W, Akanuma M, Koike K, Karin M, Maeda S.
Loss of liver E-cadherin induces sclerosing
cholangitis and promotes carcinogenesis. Proc
Natl Acad Sci U S A. 2014 Jan 21;111(3):1090-5.
28) Otsuka M, Kishikawa T, Yoshikawa T, Ohno M,
Takata A, Shibata C, Koike K. The role ofmicroRNAs in hepatocarcinogenesis: current
knowledge and future prospects. J Gastroenterol.
2014 Feb;49(2):173-84.
29) Kogure H, Tsujino T, Isayama H, Takahara N,
Uchino R, Hamada T, Miyabayashi K, Mizuno S,
Mohri D, Yashima Y, Kawakubo K, Sasaki T,
Yamamoto N, Nakai Y, Hirano K, Sasahira N,
Tada M, Koike K. Short- and long-term outcomesof endoscopic papillary large balloon dilation withor without sphincterotomy for removal of large
bile duct stones. Scand J Gastroenterol. 2014 Jan;49(1):121-8.
30) Tsuji Y, Ohata K, Gunji T, Shozushima M,
Hamanaka J, Ohno A, Ito T, Yamamichi N,
Fujishiro M, Matsuhashi N, Koike K. Endoscopic
tissue shielding method with polyglycolic acidsheets and fibrin glue to cover wounds aftercolorectal endoscopic submucosal dissection(with video). Gastrointest Endosc. 2014 Jan;79(1):151-5.
31) Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Fushimi K, Koike K. Impact of
hospital volume on outcomes in acute pancreatitis: a study using a nationwide administrative database. J Gastroenterol. 2014 Jan;49(1):148-55.
32) Koike K. The oncogenic role of hepatitis C virus.
Recent Results Cancer Res. 2014;193:97-111.
33) Kawakubo K, Tada M, Isayama H, Sasahira N,
Nakai Y, Takahara N, Uchino R, Hamada T,
Miyabayashi K, Yamamoto K, Mizuno S, Mohri D,

129

Kogure H, Sasaki T, Yamamoto N, Hirano K,
Ijichi H, Tateishi K, Koike K. Disease-specificmortality among patients with intraductal
papillary mucinous neoplasm of the pancreas.
Clin Gastroenterol Hepatol. 2014 Mar;12(3):486-91.
34) Sato M, Tateishi R, Yasunaga H, Horiguchi H,
Yoshida H, Matsuda S, Fushimi K, Koike K.
Acute liver disease in Japan: a nationwide
analysis of the Japanese Diagnosis Procedure
Combination database. J Gastroenterol. 2014 Mar;49(3):547-54.
35) Takahashi Y, Yamamichi N, Shimamoto T,
Mochizuki S, Fujishiro M, Takeuchi C, Sakaguchi
Y, Niimi K, Ono S, Kodashima S, Mitsushima T,
Koike K. Helicobacter pylori infection ispositively associated with gallstones: a large-scalecross-sectional study in Japan. J Gastroenterol.
2014 May;49(5):882-9.
36) Yamada A, Watabe H, Iwama T, Obi S, Omata M,
Koike K. The prevalence of small intestinal
polyps in patients with familial adenomatous
polyposis: a prospective capsule endoscopy study.
Fam Cancer. 2014 Mar;13(1):23-8.
37) Sato M, Kato N, Tateishi R, Muroyama R,
Kowatari N, Li W, Goto K, Otsuka M, Shiina S,
Yoshida H, Omata M, Koike K. IL28B minor
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Apr;49(4):748-54.

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
Seiji Fukumoto, M.D., Ph.D.(〜Nov. 30, 2014), George Seki, M.D., Ph.D.,
Akihiro Tojo, M.D., Ph.D.,

Hospital Lecturer
Takehiko Wada, M.D., Ph.D.

Associate
Katsutoshi Takahashi, M.D.

Manabu Taguchi, M.D., Ph.D.,

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

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 benefits

132of treatment to the patients. We also treat diabetic
patients with proteinuria and end-stage renal failure.
Each staff of our department also works at the
hemodialysis unit, thus we can manage patients inevery stage of renal diseases. In collaboration with
Department of Urology, we are conducting renaltransplantation and promoting peritoneal dialysis.
In the endocrine unit there is a variety of patients
having disorders in thyroid, parathyroid, pituitary,adrenal and gonadal glands. It is also our specialty todiagnose and treat secondary hypertension caused byprimary aldosteronism, Cushing’s syndrome, pheochromocytoma, renal artery stenosis and so on. We
often have consultation from other departments concerning disorders of water and mineral metabolism.

Education
We have responsibility for educating undergraduates, graduate students and residents. Our staffs
take part in several lectures for undergraduate andgraduate students. In addition, our members areactively involved in clinical clerkship 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. Investigationofcausesofatypicalhemolytic-uremic 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 ahemodialysis controlling system is a hub to transfer all
digital and analog data from patients and to monitor
machines, including blood purification machines, tothe host computer in our hospital, centralizing all data
and administering 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.

133

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.
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

3.
4.

5.
6.
7.
8.
9.

pulse hemoglobin meter.
Genome wide association study for Nephrotic
syndrome and those functional analyses.
Reevaluation of screening approaches to Fabry
disease to elucidate the patient cohort; theenzyme-replacement therapy is indispensable.
Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
AKI biomarkers and their clinical significance in
ICU/CCU.
Renal biomarker to determine clinical action
ability in CKD and type-2 DN.
The potentiality of urine biomarker tests fordeveloping country [JICA-JST: Science andTechnology Research Partnership for Sustainable
Development; SATREPS].

Publications(1) 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. Am Soc Nephrol. 2014 Nov
25.
(2) Kawakami T, Mimura I, Shoji K, Tanaka T,
Nangaku M. Hypoxia and fibrosis in chronic
kidney disease: crossing at pericytes. Kidney Int
Suppl (2011). 2014 Nov;4(1):107-112.
(3) 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.
(4) Tanaka S, Tanaka T, Nangaku M. Hypoxia as a
key player in the AKI-to-CKD transition. Am J
Physiol Renal Physiol. 2014 Dec 1;307(11):F1187-95.
(5) Hiruma T., Asada T., Yamamoto M., Inokuchi R.,
Matsubara T., Ishii T., Sumda M., Isshiki R.,
Mayumi K., Noiri E., Nangaku M., Yahagi N.,
Doi K. Mortality prediction by acute kidney

134

injury biomarkers in comparison with serum
creatinine. Biomarkers. 2014 Dec;19(8):646-51.
(6) 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. 2015 Jun;20(3):623-8.
(7) 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.
(8) Ando K, Nitta K, Rakugi H, Nishizawa Y,
Yokoyama H, Nakanishi T, Kashihara N, Tomita
K, Nangaku M, Takahashi K, Isshiki M,
Shimosawa T, Fujita T. Comparison of theantialbuminuric effects of benidipine andhydrochlorothiazide
inRenin-Angiotensin
System (RAS) inhibitor-treated hypertensive
patients with albuminuria: the COSMO-CKD(COmbination Strategy on Renal Function of
Benidipine or Diuretics TreatMent with RAS
inhibitOrs in a Chronic Kidney Disease
Hypertensive Population) study. Int J Med Sci.
2014 Jun 21;11(9):897-904.
(9) Tanaka T, Higashijima Y, Wada T, Nangaku M.
The potential for renoprotection with incretinbased drugs. Kidney Int. 2014 Oct;86(4):701-11.
(10) Furuse SU, Ohse T, Jo-Watanabe A, Shigehisa A,
Kawakami K, Matsuki T, Chonan O, Nangaku M.
Galacto-oligosaccharides attenuate renal injury
with microbiota modification. Physiol Rep. 2014
Jul 3;2(7).
(11) 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-associatedlipocalinmeasurement in patients who undergo left
ventricular assist device implantation surgery.
Circ J. 2014;78(8):1891-9.
(12) Maejima T, Inoue T, Kanki Y, Kohro T, Li G,
Ohta Y, Kimura H, Kobayashi M, Taguchi A,
Tsutsumi S, Iwanari H, Yamamoto S, Aruga H,
Dong S, Stevens JF, Poh HM, Yamamoto K,
Kawamura T, Mimura I, Suehiro J, Sugiyama A,
Kaneki K, Shibata H, Yoshinaka Y, Doi T,

Asanuma A, Tanabe S, Tanaka T, Minami T,
Hamakubo T, Sakai J, Nozaki N, Aburatani H,
Nangaku M, Ruan X, Tanabe H, Ruan Y, Ihara S,
Endo A, Kodama T, Wada Y. Direct evidence forpitavastatin induced chromatin structure change
in the KLF4 gene in endothelial cells. PLoS One.
2014 May 5;9(5):(13) Tanaka T, Nangaku M. ANO1: an additional key
player in cyst growth. Kidney Int. 2014
May;85(5):1007-9.
(14) Inagi R, Ishimoto Y, Nangaku M. Proteostasis inendoplasmic reticulum--new mechanisms inkidney disease. Nat Rev Nephrol. 2014 Jul;10(7):369-78.
(15) Ueda K, Hirahashi J, Seki G, Tanaka M, Kushida
N, Takeshima Y, Nishikawa Y, Fujita T,
Nangaku M. Successful treatment of acute kidney
injury in patients with idiopathic nephrotic
syndrome using human atrial natriuretic Peptide.
Intern Med. 2014;53(8):865-9.
(16) Inoue T, Kohro T, Tanaka T, Kanki Y, Li G, Poh
HM, Mimura I, Kobayashi M, Taguchi A,
Maejima T, Suehiro J, Sugiyama A, Kaneki K,
Aruga H, Dong S, Stevens JF, Yamamoto S,
Tsutsumi S, Fujita T, Ruan X, Aburatani H,
Nangaku M, Ruan Y, Kodama T, Wada Y.
Cross-enhancement of ANGPTL4 transcription
by HIF1 alpha and PPAR beta/delta is the resultof the conformational proximity of two response
elements. Genome Biol. 2014 Apr 10;15(4):R63.
(17) Hanafusa N, Noiri E, Nangaku M. Vascularaccess puncture under ultrasound guidance. Ther
Apher Dial. 2014 Apr;18(2):213-4.
(18) Doi K, Ishizu T, Tsukamoto-Sumida M, Hiruma
T, Yamashita T, Ogasawara E, Hamasaki Y,
Yahagi N, Nangaku M, Noiri E. The
high-mobility group protein B1-Toll-like receptor
4 pathway contributes to the acute lung injury
induced by bilateral nephrectomy. Kidney Int.
2014 Aug;86(2):316-26.
(19) Jo-Watanabe A, Ohse T, Nishimatsu H,
Takahashi M, Ikeda Y, Wada T, Shirakawa J,
Nagai R, Miyata T, Nagano T, Hirata Y, Inagi
R, Nangaku M. Glyoxalase I reduces glycativeand oxidative stress and prevents age-related
endothelial dysfunction through modulation of

135

endothelial nitric oxide synthase phosphorylation.
Aging Cell. 2014 Jun;13(3):519-28.
(20) Sawai T, Nangaku M, Ashida A, Fujimaru R,
Hataya H, Hidaka Y, Kaname S, Okada H, Sato
W, Yasuda T, Yoshida Y, Fujimura Y, Hattori M,
Kagami S. Diagnostic criteria for atypicalhemolytic uremic syndrome proposed by the
Joint Committee of the Japanese Society ofNephrology and the Japan Pediatric Society.
Pediatr Int. 2014 Feb;56(1):1-5.
(21) Ito T, Hanafusa N, Fukui M, Yamamoto H,
Watanabe Y, Noiri E, Iwase S, Miyagawa K,
Fujita T, Nangaku M. Single center experience ofcell-free and concentrated ascites reinfusion
therapy in malignancy related ascites. Ther Apher
Dial. 2014 Feb;18(1):87-92.
(22) Ueda K, Fujiki K, Shirahige K, Gomez-Sanchez
CE, Fujita T, Nangaku M, Nagase M.
Genome-wide analysis of murine renal distal
convoluted tubular cells for the target genes ofmineralocorticoid receptor. Biochem Biophys Res
Commun. 2014 Feb 28;445(1):132-7.
(23) Wada T, Nangaku M, Maruyama S, Imai E, Shoji
K, Kato S, Endo T, Muso E, Kamata K,
Yokoyama H, Fujimoto K, Obata Y, Nishino T,
Kato H, Uchida S, Sasatomi Y, Saito T, Matsuo S.
A multicenter cross-sectional study of circulating
soluble urokinase receptor in Japanese patientswith glomerular disease. Kidney Int. 2014 Mar;85(3):641-8.
(24) Shoji K, Tanaka T, Nangaku M. Role of hypoxia
in progressive chronic kidney disease andimplications for therapy. Curr Opin Nephrol
Hypertens. 2014 Mar;23(2):161-8.
(25) Saito T, Iwano M, Matsumoto K, Mitarai T,
Yokoyama H, Yorioka N, Nishi S, Yoshimura A,
Sato H, Ogahara S, Shuto H, Kataoka Y, Ueda S,
Koyama A, Maruyama S, Nangaku M, Imai E,
Matsuo S, Tomino Y; Refractory Nephrotic
Syndrome Study Group. Significance ofcombined cyclosporine-prednisolone therapy andcyclosporine blood concentration monitoring for
idiopathic membranous nephropathy withsteroid-resistantnephrotic
syndrome:arandomized controlled multicenter trial. Clin Exp
Nephrol. 2014 Oct;18(5):784-94.

(26) Sawai T, Nangaku M, Ashida A, Fujimaru R,
Hataya H, Hidaka Y, Kaname S, Okada H, Sato
W, Yasuda T, Yoshida Y, Fujimura Y, Hattori M,
Kagami S. Diagnostic criteria for atypicalhemolytic uremic syndrome proposed by the
Joint Committee of the Japanese Society ofNephrology and the Japan Pediatric Society. Clin
Exp Nephrol. 2014 Feb;18(1):4-9.
(27) Doi K, Urata M, Katagiri D, Inamori M, Murata
S, Hisagi M, Ono M, Matsubara T, Ishii T,
Yahagi N, Nangaku M, Noiri E. Plasma
neutrophil gelatinase-associated lipocalin in acutekidney injury superimposed on chronic kidneydisease after cardiac surgery: a multicenterprospective study. Crit Care. 2013 Nov 12;17(6):R270.
(28) Doi K, Noiri E, Nangaku M, Yahagi N,
Jayakumar C, Ramesh G. Repulsive guidance cue
semaphorin 3A in urine predicts the progressionof acute kidney injury in adult patients from amixed intensive care unit. Nephrol Dial
Transplant. 2014 Jan;29(1):73-80.

136Department 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
Midori Fujishiro, M.D., Ph.D.,

Iseki Takamoto, M.D., Ph.D.

Assistant Professor
Yoko Iizuka, M.D., Ph.D.,

Hiroaki Okazaki , M.D., Ph.D.,

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

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

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

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

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

Hirotsugu Suwanai, 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 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. Since Dr. Kadowaki was elected as

Director of the University of Tokyo Hospital in 2011,
Dr. Toshimasa Yamauchi has served as Manager of the
Department of Diabetes and Metabolic Diseases
during 2014. Currently, we hold 28 beds mainly on the
12th floor of the North Wing Ward A and the 4th floorof the Ward B of the University of Tokyo Hospital,
and take care of more than 570 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 Assistant Professor, Dr. Masato
Iwabu and Dr. Miki Okada-Iwabu), Department of

137

Translational Systems Biology and Medicine Initiative(Project Assistant Professor, Dr. Takayoshi Sasako),
Division of Biophysics, Center for Disease Biology
and Integrative Medicine (Lecturer, Dr. Noriko
Takahashi), Ubiquitous Health Informatics (Project
Assistant 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 (Project Assistant Professor, Dr. Makoto
Kurano). With all these staffs, we actively instruct andteach the residents and medical school students;
annual evaluation of the teaching skill by the students
always rates our department within the three places of
the top. In addition, there are more than 20 students ofGraduate School in our division. With all these 67
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 44,059 patients per year). On the inpatient ward,
we not only take care of around 30 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 are becoming more prevalent in Japan,
and lead to complications including nephropathy,
retinopathy, neuropathy and cardiovascular diseases.
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 bed-side learning, 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.
Lectures that lead to profound understandings of themetabolic diseases are regularly provided by the staff
physicians.
In clinical clerkship, we arrange the program so thatthe students can experience the clinical practice andlearn the disease itself more profoundly. One faculty
and one senior-resident always instruct one student.
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 otherdepartments, we focus on the molecular mechanismsof the metabolic diseases and the establishment of the

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novel therapeutics.
1) Molecular mechanisms of type 2 diabetes
We have been attempting to elucidate the mechanisms
underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, we are
exploring the signal transduction pathways andphysiological roles of insulin and adipokines invarious tissues and the mechanisms of insulin
secretion under the normal or pathological conditions,such as diabetes and obesity, using a number oftransgenic and knockout animal models, in parallelwith information obtained by whole-genome analysis
of human patients. In particular, we are interested in
the physiological and pathophysiological functions ofadipokines secreted by adipocytes, including
adiponectin, and the signal transduction pathway of
adiponectin through the receptors, AdipoR1 andAdipoR2, that we discovered and characterized. In
addition, we have been successfully unraveling themolecular mechanisms of β cell proliferation andinter-tissue communication of glucose metabolism inobesity and type 2 diabetes. We believe that thesefindings will lead to novel therapeutic strategies fordiabetes 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,
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 theanti-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 vigorously conducting clinical trials andepidemiological studies including “Japan Diabetes
Optimal Integrated Treatment study for 3 major risk

factors of cardiovascular diseases (J-DOIT3)”,“Longitudinal/cross-sectional studies to generate
evidence for diagnosis/management of metabolic
syndrome in governmental health checkup andguidance system (MHLW’s research project)”,
systematic reviews and meta-analyses with a focus on
important issues, and investigator initiated clinical
trials targeting for a new class of anti-diabetic agents.

References
1. Kadowaki T, Yamauchi T, Okada-Iwabu M, Iwabu
M. Adiponectin and its receptors: implications forobesity-associated diseases and longevity. Lancet
Diabetes Endocrinol. 2014 Jan;2(1):8-9.
2. Tanaka S, Uenishi K, Ishida H, Takami Y, Hosoi T,
Kadowaki T, Orimo H, Ohashi Y. A randomized
intervention trial of 24-wk dairy consumption on
waist circumference, blood pressure, and fastingblood sugar and lipids in Japanese men withmetabolic syndrome. J Nutr Sci Vitaminol(Tokyo). 2014;60(5):305-12.
3. Kabeya Y, Kato M, Isogawa A, Takahashi Y,
Matsushita Y, Goto A, Iso H, Inoue M, Mizoue T,
Tsugane S, Kadowaki T, Noda M. Descriptive
epidemiology of diabetes prevalence and HbA1c
distributions based on a self-reported questionnaire and a health checkup in the JPHC diabetes
study. J Epidemiol. 2014;24(6):460-8.
4. Maeda T, Takeuchi K, Xiaoling P, P Zankov D,
Takashima N, Fujiyoshi A, Kadowaki T, Miura K,
Ueshima H, Ogita H. Lipoprotein-associatedphospholipase A2 regulates macrophage apoptosis
via the Akt and caspase-7 pathways. J Atheroscler
Thromb. 2014;21(8):839-53.
5. Hara K, Fujita H, Johnson TA, Yamauchi T,
Yasuda K, Horikoshi M, Peng C, Hu C, Ma RC,
Imamura M, Iwata M, Tsunoda T, Morizono T,
Shojima N, So WY, Leung TF, Kwan P, Zhang R,
Wang J, Yu W, Maegawa H, Hirose H;
DIAGRAM consortium, Kaku K, Ito C, Watada H,
Tanaka Y, Tobe K, Kashiwagi A, Kawamori R, Jia
W, Chan JC, Teo YY, Shyong TE, Kamatani N,
Kubo M, Maeda S, Kadowaki T. Genome-wide
association study identifies three novel loci for
type 2 diabetes. Hum Mol Genet. 2014 Jan 1;
23(1):239-46.

139

6. Yamauchi T, Iwabu M, Okada-Iwabu M,
Kadowaki T. Adiponectin receptors: a review of
their structure, function and how they work. Best
Pract Res Clin Endocrinol Metab. 2014 Jan;28(1):15-23.
7. Fruchart JC, Davignon J, Hermans MP,
Al-Rubeaan K, Amarenco P, Assmann G, Barter P,
Betteridge J, Bruckert E, Cuevas A, Farnier M,
Ferrannini E, Fioretto P, Genest J, Ginsberg HN,
Gotto AM Jr, Hu D, Kadowaki T, Kodama T,
Krempf M, Matsuzawa Y, Núñez-Cortés JM,
Monfil CC, Ogawa H, Plutzky J, Rader DJ,
Sadikot S, Santos RD, Shlyakhto E, Sritara P, Sy
R, Tall A, Tan CE, Tokgözoğlu L, Toth PP, Valensi
P, Wanner C, Zambon A, Zhu J, Zimmet P;
Residual Risk Reduction Initiative (R3i). Residual
macrovascular risk in 2013: what have welearned? Cardiovasc Diabetol. 2014 Jan 24;13:26.
8. Toda G, Fujishiro M, Yamada T, Shojima N,
Sakoda H, Suzuki R, Yamauchi T, Ueki K,
Kadowaki T. Lung abscess without sepsis in apatient with diabetes with refractory episodes of
spontaneous hypoglycemia: a case report andreview of the literature. J Med Case Rep. 2014
Feb 13;8:51.
9. Odawara M, Kadowaki T, Naito Y. Incidence andpredictors of hypoglycemia in Japanese patientswith type 2 diabetes treated by insulin glargine
and oral antidiabetic drugs in real-life: ALOHA
post-marketing surveillance study sub-analysis.
Diabetol Metab Syndr. 2014 Feb 15;6(1):20.
10. DIAbetes Genetics Replication And Meta-analysis(DIAGRAM) Consortium; Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D)
Consortium; South Asian Type 2 Diabetes(SAT2D) Consortium; Mexican American Type 2
Diabetes (MAT2D) Consortium; Type 2 Diabetes
Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES)
Consortium, Mahajan A, Go MJ, Zhang W, Below
JE, Gaulton KJ, Ferreira T, Horikoshi M,,
Kadowaki T,,McCarthy MI, Morris AP. Genomewide trans-ancestry meta-analysis provides insight
into the genetic architecture of type 2 diabetes
susceptibility. Nat Genet. 2014 Mar;46(3):234-44.
11. Takamoto I, Kubota N, Nakaya K, Kumagai K,
Hashimoto S, Kubota T, Inoue M, Kajiwara E,

Katsuyama H, Obata A, Sakurai Y, Iwamoto M,
Kitamura T, Ueki K, Kadowaki T. TCF7L2 inmouse pancreatic beta cells plays a crucial role inglucose homeostasis by regulating beta cell mass.
Diabetologia. 2014 Mar;57(3):542-53.
12. Møller JB, Pedersen M, Tanaka H, Ohsugi M,
Overgaard RV, Lynge J, Almind K, Vasconcelos
NM, Poulsen P, Keller C, Ueki K, Ingwersen SH,
Pedersen BK, Kadowaki T. Body composition is
the main determinant for the difference in type 2
diabetes pathophysiology between Japanese andCaucasians. Diabetes Care. 2014 Mar;37(3):796-804.
13. Sacks FM, Hermans MP, Fioretto P, Valensi P,
Davis T, Horton E, Wanner C, Al-Rubeaan K,
Aronson R, Barzon I, Bishop L, Bonora E,
Bunnag P, Chuang LM, Deerochanawong C,
Goldenberg R, Harshfield B, Hernández C,
Herzlinger-Botein S, Itoh H, Jia W, Jiang YD,
Kadowaki T, Laranjo N, Leiter L, Miwa T,
Odawara M, Ohashi K, Ohno A, Pan C, Pan J,
Pedro-Botet J, Reiner Z, Rotella CM, Simo R,
Tanaka M, Tedeschi-Reiner E, Twum-Barima D,
Zoppini G, Carey VJ. Association between plasma
triglycerides
andhigh-density
lipoproteincholesterol and microvascular kidney disease andretinopathy in type 2 diabetes mellitus: a global
case-control study in 13 countries. Circulation.
2014 Mar 4;129(9):999-1008.
14. Waki K, Fujita H, Uchimura Y, Omae K, Aramaki
E, Kato S, Lee H, Kobayashi H, Kadowaki T,
Ohe K. DialBetics: A Novel Smartphone-based
Self-management Support System for Type 2
Diabetes Patients. J Diabetes Sci Technol. 2014
Mar 13;8(2):209-215.
15. Awazawa M, Futami T, Sakada M, Kaneko K,
Ohsugi M, Nakaya K, Terai A, Suzuki R, Koike M,
Uchiyama Y, Kadowaki T, Ueki K. Deregulationof pancreas-specific oxidoreductin ERO1β in thepathogenesis of diabetes mellitus. Mol Cell Biol.
2014 Apr;34(7):1290-9.
16. Suzuki Y, Shimizu H, Ishizuka N, Kubota N,
Kubota T, Senoo A, Kageyama H, Osaka T,
Hirako S, Kim HJ, Matsumoto A, Shioda S, Mori
M, Kadowaki T, Inoue S. Vagal hyperactivity due
to ventromedial hypothalamic lesions increases
adiponectin production and release. Diabetes.

1402014 May;63(5):1637-48.
17. Kadowaki T, Haneda M, Inagaki N, Terauchi Y,
Taniguchi A, Koiwai K, Rattunde H, Woerle HJ,
Broedl UC. Empagliflozin monotherapy inJapanese patients with type 2 diabetes mellitus: arandomized, 12-week, double-blind, placebocontrolled, phase II trial. Adv Ther. 2014 Jun;
31(6):621-38.
18. Amemiya A, Noguchi H, Oe M, Ohashi Y, Ueki K,
Kadowaki T, Mori T, Sanada H. Elevated plantarpressure in diabetic patients and its relationshipwith their gait features. Gait Posture. 2014 Jul;
40(3):408-14.
19. Ohtomo K, Shigeeda T, Hirose A, Ohno T,
Kinoshita O, Fujita H, Ando J, Nagai R, Takamoto
S, Kadowaki T, Kato S. Silent myocardialischaemia in patients with diabetic retinopathy.
Acta Ophthalmol. 2014 Sep;92(6):e492-3.
20. Inagaki N, Ueki K, Tanizawa Y, Watada H,
Nakamura J, Yamada Y, Shimomura I, Nishimura
R, Yamazaki T, Kadowaki T. Protocol for alarge-scale prospective observational study withalogliptin in patients with type 2 diabetes:
J-BRAND Registry. BMJ Open. 2014 Sep 16;
4(9):e004760.
21. Hara K, Shojima N, Hosoe J, Kadowaki T.
Genetic architecture of type 2 diabetes. Biochem
Biophys Res Commun. 2014 Sep 19;452(2):213-20.
22. Kurano M, Hara M, Tsuneyama K, Sakoda H,
Shimizu T, Tsukamoto K, Ikeda H, Yatomi Y.
Induction of insulin secretion by apolipoprotein M,
a carrier for sphingosine 1-phosphate. Biochim
Biophys Acta. 2014 Sep;1841(9):1217-26.
23. Sekiya M, Yamamuro D, Ohshiro T, Honda A,
Takahashi M, Kumagai M, Sakai K, Nagashima S,
Tomoda H, Igarashi M, Okazaki H, Yagyu H,
Osuga J, Ishibashi S. Absence of Nceh1 augments
25-hydroxycholesterol-induced ER stress andapoptosis in macrophages. J Lipid Res. 2014 Oct;55(10):2082-92.
24. Møller JB, Dalla Man C, Overgaard RV,
Ingwersen SH, Tornøe CW, Pedersen M, Tanaka
H, Ohsugi M, Ueki K, Lynge J, Vasconcelos NM,
Pedersen BK, Kadowaki T, Cobelli C. Ethnic
differences in insulin sensitivity, β-cell function,and hepatic extraction between Japanese andCaucasians: a minimal model analysis. J Clin
Endocrinol Metab. 2014 Nov;99(11):4273-80.
25. Sakai K, Igarashi M, Yamamuro D, Ohshiro T,
Nagashima S, Takahashi M, Enkhtuvshin B,
Sekiya M, Okazaki H, Osuga J, Ishibashi S.
Critical role of neutral cholesteryl ester hydrolase
1 in cholesteryl ester hydrolysis in murine macrophages. J Lipid Res. 2014 Oct;55(10):2033-40.
26. 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. 2014
Nov 25.pii: ASN.2014030289.
27. Nishimura S, Nagasaki M, Okudaira S, Aoki J,
Ohmori T, Ohkawa R, Nakamura K, Igarashi K,
Yamashita H, Eto K, Uno K, Hayashi N,
Kadowaki T, Komuro I, Yatomi Y, Nagai R.
ENPP2 contributes to adipose tissue expansion
and insulin resistance in diet-induced obesity.
Diabetes. 2014 Dec;63(12):4154-64.
28. 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 and dropout from treatment. Obesity(Silver Spring). 2015 Jan;23(1):183-91. Epub
2014 Oct 16.
29. 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 Jan-Feb;
29(1):127-33. Epub 2014 Sep 28.
30. 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,

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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 Jan;64(1):291-8. Epub
2014 Sep 3.
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 Feb 1;115(3):307-15. Epub 2014 Nov 13.
32. 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 andAP3D1-DOT1L-SF3A2 as new susceptibility locifor myocardial infarction in Japanese. Eur J Hum
Genet. 2015 Mar;23(3):374-80. Epub 2014 Jun
11.
33. 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 the increase in plasma lysophosphatidic acid inacute coronary syndrome. Arterioscler Thromb
Vasc Biol. 2015 Feb;35(2):463-70. Epub 2014
Nov 25.
34. 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 Jan
23;290(4):2477-88. Epub 2014 Dec 12.
35. 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 Mar;64(3):876-86. Epub
2014 Oct 2.

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

Lecturer
Yasuhito Nannya, M.D., Ph.D.

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

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

Akihito Shinohara, M.D., Ph.D.

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

Yuki Kagoya, M.D., Ph.D.

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

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

Ryo Nasu, 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, andeducation of undergraduate as well as graduate
students. We are also engaged in continuous educationof post-graduate doctors who develop into
sophisticated hematologists of eminent distinction.
These activities are performed by the united efforts ofall 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 our department consists of two lecturers,
two special lecturer (hospital), and 6 assistantprofessors.

Clinical activities
On the average, 60-70 patients with hematologicaldiseases are treated in the ward. Clinical facilities
include patient rooms with high-efficiency particulate
air filtration and filtrated water supply. Patients whoare eligible for the treatment with high-grade infection
prophylaxis are admitted to the facilities. Patient careis provided by team management. That is, three
doctors (a junior resident, a senior resident, and an
assistant professor) are assigned to a single patient.
Since clinical issues are highly related tohematopoietic stem cell transplantation especially forpatients with hematological diseases, a substantial
portion of our clinical conferences are shared withstaff members of the Department of Cell Therapy andTransplantation Medicine and the Department ofPediatrics (Hematology/Oncology). Many problems
arising in daily clinical practice are discussed in themorning clinical conference held thrice a week.
Diagnostic and therapeutic issues as well as
pathological aspects of indicative and/or educational
cases are discussed in clinical conferences held twicea month.
Outpatient clinical services are provided from
Monday to Friday in the morning and afternoon using
three booths. Approximately 60-65 patients visit our
outpatient clinic every weekday. One of our ultimate
goals in the clinical activities is to cure patients with

143

hematological 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 thetreatment 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 physicalexamination, interpretation of laboratory tests, andpractical 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 achieveknowledge 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. Hangai S, Yoshimi A, Hosoi A, Matsusaka K,
Ichikawa M, Fukayama M, Kurokawa M. An
indeterminate result of QuantiFERON-TB Gold
In-Tube for miliary tuberculosis due to a highlevel of IFN-γ production. Int J Hematol 2014; 99:
523-6.
2. Harada S, Yamazaki S, Nakamura F, Morita K,
Yoshimi A, Shinozaki-Ushiku A, Fukayama M,

144

Kurokawa M. Autoimmune neutropenia preceding
Helicobacter pylori-negative MALT lymphomawith nodal dissemination. Int J Clin Exp Pathol
2014; 7: 6386-90.
3. Honda A, Nakamura F, Nannya Y, Shintani Y,
Fukayama M, Ichikawa M, Kurokawa M.
Pulmonary lymphocyte-rich classical Hodgkin
lymphoma with early response to ABVD therapy.
Ann Hematol 2014; 93: 1073-4.
4. Hosoi M, Kumano K, Taoka K, Arai S, Kataoka K,
Ueda K, Kamikubo Y, Takayama N, Otsu M, Eto
K, Nakauchi H, Kurokawa M. Generation of
induced pluripotent stem cells derived fromprimary and secondary myelofibrosis patient
samples. Exp Hematol 2014; 42: 816-25.
5. Kagoya Y, Yoshimi A, Kataoka K, Nakagawa M,
Kumano K, Arai S, Kobayashi H, Saito T,
Iwakura Y, Kurokawa M. NF-κB/TNF-α positive
feedback loop with active proteasome machinerysupports myeloid leukemia initiating cell capacity.
J Clin Invest 2014; 124: 528-42.
6. Kagoya Y, Yoshimi A, Tsuruta-Kishino T, Arai S,
Satoh T, Akira S, Kurokawa M. JAK2V617Fpositive myeloproliferative neoplasm clones
evoke paracrine DNA damage to adjacent normal
cells through secretion of lipocalin-2. Blood 2014;
124: 2996-3006.
7. Kagoya Y, Nannya Y, Nakamura F, Kurokawa M.
Gene expression profiles of central nervous
system lymphoma predict poor survival inpatients with diffuse large B-cell lymphoma. Br J
Haematol 2014; 166: 794-7.
8. Kobayashi T, Seo S, Morita S, Goto A, Masuda A,
Shimizu N, Nishida M, Nunobe S, Ichikawa M,
Takazawa Y, Seto Y, Fukayama M, Kurokawa M.
Esophageal
intramucosal
hematoma
after
peripheral blood stem cell transplantation: casereport and review of literature. Int J Clin Exp
Pathol 2014; 7: 2690-4.
9. Kogure Y, Nakamura F, Nukina A, Kamikubo Y,
Ichikawa M, Kamikubo Y, Kurokawa M.
Catheter-related septic shock by Micrococcus in
an autologous hematopoietic stem cell transplantation recipient. Am J Infect Control 2014;
42: 87.
10. Kogure Y, Nakamura F, Shinozaki-Ushiku A,
Watanabe A, Kamei K, Yoshizato T, Nannya Y,

Fukayama M, Kurokawa M. Pulmonary
mucormycosis with embolism: two autopsiedcases of acute myeloid leukemia. Int J Clin Exp
Pathol 2014; 7: 3449-53.
11. Nakazaki K, Nannya Y, Kurokawa M.
Distribution of serum erythropoietin levels inlower risk myelodysplastic syndrome cases withanemia. Int J Hematol 2014; 99: 53-6.
12. Nannya Y, Shinohara A, Ichikawa M, Kurokawa
M. Serial profile of vitamins and trace elements
during the acute phase of allogeneic stem celltransplantation. Biol Blood Marrow Transplant
2014; 20: 430-4.
13. Nasu R, Nannya Y, Shinohara A, Ichikawa M,
Kurokawa M. Favorable outcomes of tacrolimus
compared with cyclosporine A for GVHD
prophylaxis in HSCT for standard-risk hematological diseases. Ann Hematol 2014; 93: 1215-23.
14. Nishikawa S, Arai S, Masamoto Y, Kagoya Y,
Toya T, Watanabe-Okochi N, Kurokawa M.
Thrombopoietin/MPL signaling confers growthand survival capacity to CD41-positive cells in amouse model of Evi1 leukemia. Blood 2014; 124:3587-96.
15. Nukina A, Kagoya Y, Watanabe-Okochi N, Arai S,
Ueda K, Yoshimi A, Nannya Y, Kurokawa M.
Single-cell gene expression analysis reveals
clonal architecture of blast-phase chronic myeloid
leukaemia. Br J Haematol 2014; 165: 414-6.
16. Ogura M, Ichikawa M, Masuda A, Kandabashi K,
Nannya Y, Kurokawa M. A mixed-typeautoimmune hemolytic anemia with immune
thrombocytopenia related with myositis andpost-transplantation lymphoproliferative disorder.
Ann Hematol 2014; 93: 869-71.
17. Sato T, Goyama S, Kataoka K, Nasu R,
Tsuruta-Kishino T, Kagoya Y, Nukina A, Kumagai
K, Kubota N, Nakagawa M, Arai S, Yoshimi A,
Honda H, Kadowaki T, Kurokawa M. Evi1
defines leukemia-initiating capacity and tyrosine
kinase inhibitor resistance in chronic myeloid
leukemia. Oncogene 2014; 33: 5028-38.
18. Satoh Y, Masuda A, Jona M, Nannya Y, Yokota H,
Kurokawa M, Yatomi Y. Heparin-mediatedinhibition of PCR in the accelerated phase ofchronic myeloid leukaemia characterized byabundant basophilia. Eur J Haematol 2014; 92:

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456-7.
19. Shinohara A, Imai Y, Nakagawa M, Takahashi T,
Ichikawa M, Kurokawa M. Intracellular reactive
oxygen species mark and influence themegakaryocyte-erythrocyte progenitor fate ofcommon myeloid progenitors. Stem Cells, 2014;
32: 548-57.
20. Takaoka K, Nannya Y, Shinohara A, Arai S,
Nakamura F, Kurokawa M. A novel scoring
system to predict the incidence of invasive fungal
disease in salvage chemotherapies for malignant
lymphoma. Ann Hematol 2014; 93: 1637-44.
21. Toya T, Yoshimi A, Morioka T, Arai S, Ichikawa
M, Usuki K, Kurokawa M. Development of hairycell leukemia in familial platelet disorder withpredisposition to acute myeloid leukemia.
Platelets 2014; 25: 300-2.
22. Tsukamoto A, Nakamura F, Nannya Y, Kobayashi
Y, Shibahara J, Ichikawa M, Fukayama M, Koike
K, Kurokawa M. MALT lymphoma of the small
bowel with protein-losing enteropathy. Int J
Hematol. 2014; 99: 198-201.
22. Tsukamoto A, Yoshiki Y, Yamazaki S, Kumano K,
Nakamura F, Kurokawa M. The significance of
free light chain measurements in the diagnosis of
myelomatous pleural effusion. Ann Hematol
2014; 93: 507-8.
23. Ueda K, Yoshimi A, Kagoya Y, Nishikawa S,
Marquez VE, Nakagawa M, Kurokawa M.
Inhibition of histone methyltransferase EZH2
depletes leukemia stem cell of mixed lineage
leukemia fusion leukemia through upregulation of
p16. Cancer Sci 2014; 105: 512-9.
24. Yamazaki S, Nakamura F, Yoshimi A, Ichikawa M,
Nannya Y, Kurokawa M. Safety of high-dose
micafungin for patients with hematologicaldiseases. Leuk Lymphoma 2014; 55: 2572-6.
25. Yoshimi A, Toya T, Kawazu M, Ueno T,
Tsukamoto T, Iizuka H, Nakagawa M, Nannya Y,
Arai S, Harada H, Usuki K, Hayashi Y, Ito E,
Kirito K, Nakajima H, Ichikawa M, Mano H,
Kurokawa M. Recurrent CDC25C mutations drive
malignant transformation in FPD/AML. Nature
Commun 2014; 5: 4770.

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

Lecturer
Fujio Takeuchi, M.D., Ph.D. (Rheumatology)
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 13 staffs mentioned above, who
preside over 4 medical staff, 22 graduate students for"Doctor of Medical Science" and 1 staff studying
abroad. 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 is situated in
the East Hospital Ward and the research rooms arelocated in the East Hospital Ward, the Central Wardand the Internal Medicine Research Ward.

Education
In regard to undergraduate education, theDepartment is in charge of internal medicine diagnosis
and systemic lectures for M2 students and clinicallectures and bedside education for M3 and M4
students in cooperation with other departments ofinternal medicine. The systemic lectures and clinicallectures covers clinical immunology, connective tissue
diseases and allergy. Bedside education provides
students with a good opportunity to learn about
patients as well as practical knowledge throughnumerous seminars.

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For postgraduate education, internal medicine
trainees are accepted on rotation basis and trained asinternist. Our department accepts students for "Doctorof Medical Science". Our 4-year education covers
clinicalimmunology,
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
autoimmune 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

2014

1. 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;
25:219-23. .Epub 2014 Jul 28
2. Seri Y, Shoda H, Matsumoto I, Sumida T, Fujio K,
Yamamoto K. [Peptidylarginine deiminase type4(PADI4) role in immune system]. Nihon Rinsho
Meneki Gakkai Kaishi. 2014;37:154-9.
3. Inoue M, Shoda H, Seri Y, Kubo K, Kanda H,
Fujio K, Yamamoto K. Three cases of lupus
nephritis patients with serum interleukin-32γ
detection. Lupus. 2014;23:1187-91.
4. Fujio K, Okamura T, Sumitomo S, Yamamoto K.
[The functions of CD4+CD25-LAG3+ regulatory
T cells and Egr2 in the regulation of autoimmunity]. Nihon Rinsho Meneki Gakkai Kaishi.
2014;37:69-73.
5. Shoda H, Sumitomo S, Fujio K, Yamamoto K.
Synovial bursa protruding through the triceps
brachii muscle. Arthritis Rheumatol. 2014;66:1060
6. Sakaue S, Sumitomo S, Kubo K, Fujio K,
Yamamoto K. Tocilizumab-induced leucocytoclastic vasculitis in a patient with rheumatoid
arthritis. Rheumatology (Oxford). 2014;53:152930.
7. Shoda H, Morita K, Kanda H, Fujio K, Yamamoto
K. An elderly woman with peripheral spondyloarthritis with aortitis. Mod Rheumatol. 2014;24(2):353-6.
8. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K,

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Kochi Y, Ohmura K, Suzuki A, Yoshida S,
Graham RR, Manoharan A, Ortmann W, Bhangale
T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD,
Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su
DF, Yang J, Xie G, Keystone E, Westra HJ, Esko T,
Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA,
Diogo D, Cui J, Liao K, Guo MH, Myouzen K,
Kawaguchi T, Coenen MJ, van Riel PL, van deLaar MA, Guchelaar HJ, Huizinga TW, Dieudé P,
Mariette X, Bridges SL Jr, Zhernakova A, Toes
RE, Tak PP, Miceli-Richard C, Bang SY, Lee HS,
Martin J, Gonzalez-Gay MA, RodriguezRodriguez L, Rantapää-Dahlqvist S, Arlestig L,
Choi HK, Kamatani Y, Galan P, Lathrop M; RACI
consortium; GARNET consortium, Eyre S, Bowes
J, Barton A, de Vries N, Moreland LW, Criswell
LA, Karlson EW, Taniguchi A, Yamada R, Kubo
M, Liu JS, Bae SC, Worthington J, Padyukov L,
Klareskog L, Gregersen PK, Raychaudhuri S,
Stranger BE, De Jager PL, Franke L, Visscher PM,
Brown MA, Yamanaka H, Mimori T, Takahashi A,
Xu H, Behrens TW, Siminovitch KA, Momohara
S, Matsuda F, Yamamoto K, Plenge RM. Genetics
of rheumatoid arthritis contributes to biology anddrug discovery. Nature. 2014;506:376-381.
9. Kochi Y, Suzuki A, Yamamoto K. Genetic basis ofrheumatoid arthritis: a current review. Biochem
Biophys Res Commun. 2014;452(2):254-62.
10. Mori T, Iwasaki Y, Seki Y, Iseki M, Katayama H,
Yamamoto K, Takatsu K, Takaki S. Lnk/Sh2b3
controls the production and function of dendritic
cells and regulates the induction of IFN-γproducing T cells. J Immunol. 2014 15;193:172836.
11. Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro
N, Tanaka Y, Eguchi K, Watanabe A, Origasa H,
Iwai K, Sakamaki Y, van der Heijde D, Miyasaka
N, Koike T. Efficacy and safety of certolizumab
pegol without methotrexate co-administration in
Japanese patients with active rheumatoid arthritis:the HIKARI randomized, placebo-controlled trial.
Mod Rheumatol. 2014;24:552-60.
12. Deplus R, Denis H, Putmans P, Calonne E,
Fourrez M, Yamamoto K, Suzuki A, Fuks F.
Citrullination of DNMT3A by PADI4 regulates its
stability and controls DNA methylation. Nucleic
Acids Res. 2014;42:8285-96.

13. Tanaka Y, Yamamoto K, Takeuchi T, Yamanaka H,
Ishiguro N, Eguchi K, Watanabe A, Origasa H,
Shoji T, Miyasaka N, Koike T. Long-term efficacy
and safety of certolizumab pegol in Japaneserheumatoid arthritis patients with an inadequate
response to methotrexate: 52-week results from an
open-label extension of the J-RAPID study. Mod
Rheumatol. 2014;24:734-43.
14. Kimura E, Kanzaki T, Tahara K, Hayashi H,
Hashimoto S, Suzuki A, Yamada R, Yamamoto K,
Sawada T. Identification of citrullinated cellularfibronectin in synovial fluid from patients withrheumatoid arthritis. Mod Rheumatol. 2014 ;24:
766-9.
15. Nakashima R, Imura Y, Hosono Y, Seto M,
Murakami A, Watanabe K, Handa T, Mishima M,
Hirakata M, Takeuchi T, Fujio K, Yamamoto K,
Kohsaka H, Takasaki Y, Enomoto N, Suda T,
Chida K, Hisata S, Nukiwa T, Mimori T. The
multicenter study of a new assay for simultaneous
detection of multiple anti-aminoacyl-tRNA
synthetases in myositis and interstitial pneumonia.
PLoS One. 2014;14;9:e85062.
16. Tanaka Y, Yamamoto K, Takeuchi T, Yamanaka H,
Ishiguro N, Eguchi K, Watanabe A, Origasa H,
Shoji T, Miyasaka N, Koike T. Long-term efficacy
and safety of certolizumab pegol in Japaneserheumatoid arthritis patients who could notreceive methotrexate: 52-week results from an
open-label extension of the HIKARI study. Mod
Rheumatol. 2014 ;24:725-33.
17. Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro
N, Tanaka Y, Eguchi K, Watanabe A, Origasa H,
Shoji T, Sakamaki Y, van der Heijde D, Miyasaka
N, Koike T. Efficacy and safety of certolizumab
pegol plus methotrexate in Japanese rheumatoid
arthritis patients with an inadequate response tomethotrexate: the J-RAPID Mod Rheumatol.
2014 ;24:715-24.
18. Imamura M, Sasaki O, Okunishi K, Nakagome K,
Harada H, Kawahata K, Tanaka R, Yamamoto K,
Dohi M. Perillyl alcohol suppresses antigeninduced immune responses in the lung. Biochem
Biophys Res Commun. 2014 3;443:266-71.
19. Takeuchi T, Kawai S, Yamamoto K, Harigai M,
IshidaK,
Miyasaka
N.
Post-marketingsurveillance of the safety and effectiveness of

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tacrolimus in 3,267 Japanese patients withrheumatoid arthritis. Mod Rheumatol. 2014;24:
8-16.
20. Hara M, Ishiguro N, Katayama K, Kondo M,
Sumida T, Mimori T, Soen S, Nagai K,
Yamaguchi T, Yamamoto K; Iguratimod-ClinicalStudy Group. Safety and efficacy of combination
therapy of iguratimod with methotrexate forpatients with active rheumatoid arthritis with aninadequate response to methotrexate: an openlabel extension of a randomized, double-blind,placebo-controlled trial. Mod Rheumatol. 2014;
24:410-8.

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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

151

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, Yoshitaka
Wakabayashi, Shu Okugawa, Shintaro Yanagimoto,
Keita Tatsuno, Mahoko Ikeda, Hideki Hashimoto,Takeshi Suzuki, Yoshiaki Kanno, Haruka Nakamura,
Daisuke Jubishi,

References
1) Ito K, Yotsuyanagi H, Sugiyama M, Yatsuhashi H,
Karino Y, Takikawa Y, Saito T, Arase Y, Imazeki F,
Kurosaki M, Umemura T, Ichida T, Toyoda H,
Yoneda M, Tanaka Y, Mita E, Yamamoto K,
Michitaka K, Maeshiro T, Tanuma J, Korenaga M,
Murata K, Masaki N, Koike K, Mizokami M;
Japanese AHB and CHB Study Group.
Geographic distribution and characteristics ofgenotype A hepatitis B virus infection inacute andchronic hepatitis B patients in Japan. J Gastroenterol Hepatol. 2015 Jun 25. doi: 10.1111/jgh.
13030. [Epub ahead of print] PubMed PMID:
261103952) 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.
3) 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 Hospitalin Japan. Infect Dis Ther. 2015; 4: 213-8.
4) 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,

152

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. doi: 10.1186/s12876-015-0247-9.
5) 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 Mar 18. doi: 10.1111/
hepr.12517. [Epub ahead of print] PubMed PMID:
25788045.
6) Misawa Y, Yoshida A, Okugawa S, Moriya K.
First reported case of Staphylococcus condimenti
infection associated with catheter-related bacteraemia. New Microbes New Infect. 2014; 3:
18-20.
7) Ogishi M, Yotsuyanagi H, Tsutsumi T, Gatanaga
H, Ode H, Sugiura W, Moriya K, Oka S, Kimura S,
Koike K. Deconvoluting the composition of lowfrequency hepatitis C viral quasispecies:
comparison of genotypes and NS3 resistanceassociated variants between HCV/HIV coinfected
hemophiliacs and HCV monoinfected patients inJapan. PLoS One. 2015; 10: e0119145.
8) Watanabe Y, Yamamoto H, Oikawa R, Toyota M,
Yamamoto M, Kokudo N, Tanaka S, Arii S,
Yotsuyanagi H, Koike K, Itoh F. DNA methylation at hepatitis B viral integrants is associatedwith methylation at flanking human genomic
sequences. Genome Res. 2015; 25: 328-37.
9) 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.
10) Yoshino Y, Wakabayashi Y, Suzuki S, Seo K,
Koga I, Kitazawa T, Okugawa S, Ota Y. Clinicalfeatures of catheter-related candidemia at disease
onset. Singapore Med J. 2014; 55: 579-82.
11) 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.
12) Yamada N, Shigefuku R, Sugiyama R, Kobayashi
M, Ikeda H, Takahashi H, Okuse C, Suzuki M,
Itoh F, Yotsuyanagi H, Yasuda K, Moriya K,
Koike K, Wakita T, Kato T. Acute hepatitis B of
genotype H resulting in persistent infection.
World J Gastroenterol. 2014; 20: 3044-9.
13) Nguyen T, Xu J, Chikuma S, Hiai H, Kinoshita K,
Moriya K, Koike K, Marcuzzi GP, Pfister H,
Honjo T, Kobayashi M. Activation-induced
cytidine deaminase is dispensable for virusmediated liver and skin tumor development inmouse models. Int Immunol. 2014; 26: 397-406.
14) Nukui Y, Nakamura H, Ishioka H, Miyamoto H,
Okamoto A, Kazumi Y, Yotsuyanagi H, Moriya K,
Hatakeyama S. Synovitis of the wrist caused by
Mycobacterium florentinum. Infection. 2014; 42:437-40.
15) Horiuchi Y, Takagi A, Kobayashi N, Moriya O,
Nagai T, Moriya K, Tsutsumi T, Koike K,
Akatsuka T. Effect of the infectious dose and thepresence of hepatitis C virus core gene on mouse
intrahepatic CD8 T cells. Hepatol Res. 2014; 44:
E240-E252.
16) Yoshikawa T, Wada K, Lee JJ, Mitsuda T,
Kidouchi K, Kurosu H, Morisawa Y, Aminaka M,
Okubo T, Kimura S, Moriya K. Incidence rate ofneedlestick and sharps injuries in 67 Japanesehospitals: a national surveillance study. PLoS One.
2013; 8: e77524.
17) Ikeda K, Izumi N, Tanaka E, Yotsuyanagi H,
Takahashi Y, Fukushima J, Kondo F, Fukusato T,
Koike K, Hayashi N, Tsubouchi H, Kumada H.
Discrimination of fibrotic staging of chronic
hepatitis C using multiple fibrotic markers.
Hepatol Res. 2014; 44: 1047-55.
18) Ito K, Yotsuyanagi H, Yatsuhashi H, Karino Y,
Takikawa Y, Saito T, Arase Y, Imazeki F, Kurosaki
M, Umemura T, Ichida T, Toyoda H, Yoneda M,
Mita E, Yamamoto K, Michitaka K, Maeshiro T,
Tanuma J, Tanaka Y, Sugiyama M, Murata K,
Masaki N, Mizokami M; Japanese AHB Study
Group. Risk factors for long-term persistence ofserum hepatitis B surface antigen following acutehepatitis B virus infection in Japanese adults.
Hepatology. 2014 Jan; 59: 89-97.

15319) Kitazawa T, Yoshino Y, Tatsuno K, Ota Y,
Yotsuyanagi H. Changes in the mean plateletvolume levels after bloodstream infection haveprognostic value. Intern Med. 2013; 52: 1487-93.
20) Yotsuyanagi H, Ito K, Yamada N, Takahashi H,
Okuse C, Yasuda K, Suzuki M, Moriya K,
Mizokami M, Miyakawa Y, Koike K. High levelsof hepatitis B virus after the onset of disease leadto chronic infection in patients with acute hepatitis
B. Clin Infect Dis. 2013; 57: 935-42.
21) Higurashi Y, Tatsuno K, Fujimoto F, Kobayashi I,
Ida K, Seto Y, Ohkusu K, Ezaki T, Okugawa S,
Moriya K. Two cases of bacteremia caused by
Leptotrichia trevisanii in patients with febrileneutropenia. J Infect Chemother. 2013;19:1181-4.
22) Koya J, Nannya Y, Kobayashi H, Okugawa S,
Moriya K, Kurokawa M. Simultaneous increase in
1,3-β-D-glucan and procalcitonin levels in
Pseudomonas aeruginosa infection. J Infect. 2013;
67: 164-6.
23) Okazaki T, Yamazaki K, Iwasaki T, Okano T,
Kurosaki Y, Nakamura K, Fujioka T, Yotsuyanagi
H. α2-HS glycoprotein is an essential componentof cryoglobulin associated with chronic hepatitis
C. Clin Chem Lab Med. 2013; 51: e17-8.
24) Nukui Y, Hatakeyama S, Okamoto K, Yamamoto
T, Hisaka A, Suzuki H, Yata N, Yotsuyanagi H,
Moriya K. High plasma linezolid concentrationand impaired renal function affect development oflinezolid-induced thrombocytopenia. J Antimicrob
Chemother. 2013;68:2128-33.
25) Tanaka S, Nagata N, Mine S, Igari T, Kobayashi T,
Sugihara J, Honda H, Teruya K, Kikuchi Y, Oka
S, Uemura N. Endoscopic appearance of AIDSrelated gastrointestinal lymphoma with c-MYC
rearrangements: case report and literature review.
World J Gastroenterol. 2013;19:4827-31.
26) Nagata N, Shimbo T, Sekine K, Tanaka S, Niikura
R, Mezaki K, Morino E, Yazaki H, Igari T,
Ohmagari N, Akiyama J, Oka S, Uemura N.
Alcohol and smoking affect risk of uncomplicatedcolonic diverticulosis in Japan. PLoS One. 2013;
10:e81137.
27) Okamoto K, Brown JD. Hepatosplenic schistosomiasis presenting as spontaneous hemoperitoneumin a Filipino immigrant. Am J Med Sci. 2013;346:
334-7.

28) Thomas BS, Okamoto K, Bankowski MJ, Seto TB.
A lethalcase of Pseudomonas putida bacteremia
due to soft tissue infection. Infect Dis Clin Pract.
2013;21:147-213.
29) Yamaguchi Y, Nukui Y, Kotaki A, Sawabe K,
Saijo M, Watanabe H, Kurane I, Takasaki T,
Tajima S. Characterization of a serine-toasparagine substitution at position 123 in theJapanese encephalitis. J Gen Virol. 2013; 94:
90-96.
30) Nagata N, Shimbo T, Sekine K, Tanaka S, Niikura
R, Mezaki K, Morino E, Yazaki H, Igari T,
Ohmagari N, Akiyama J, Oka S, Uemura N.
Combined endoscopy, aspiration, and biopsy
analysis for identifying infectious colitis inpatients with ileocecal ulcers. Clin Gastroenterol
Hepatol. 2013; 11: 673-80.
31) Nukui Y, Hatakeyama S, Kitazawa T, Mahira T,
Shintani Y, Moriya K. Pandemic 2009 influenza A(H1N1) virus among Japanese healthcare workers:
seroprevalence and risk factors. Infect Control
Hosp Epidemiol. 2012;33:58-62.
32) Goto K, Hatakeyama S, Okamoto K, Kitazawa T,
Abe K, Moriya K, Koike K,Yotsuyanagi H.
Dengue hemorrhagic fever in an adult traveler
returning to Japan. Intern Med. 2012;51:1779-82.
33) Saito N, Hida A, Koide Y, Ichikawa Y, Shimizu J,
Mukasa A, Nakatomi H, Hatakeyama S, Ooka T,
Hayashi T, Tsuji S. Culture-negative brain abscesses with Streptococcus intermedius infection
whose diagnosis was established by direct
analysis of 16s ribosomal DNA fragments. Intern
Med. 2012;51:211-6.
34) Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K,
Yanagimoto S, Okugawa S, Ota Y, Yotsuyanagi H.
Clinical features of Bacteroides bacteremia andtheir association with colorectal carcinoma.
Infection. Infection. 2012;40:63-7.
35) Kitazawa T, Yoshino Y, Tatsuno K, Ota Y,
Yotsuyanagi H. Changes in the mean plateletvolume levels after bloodstream infection haveprognostic value. Intern Med. 2013;52:1487-93.
36) Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K,
Yanagimoto S, Okugawa S, Yotsuyanagi H, Ota Y.
Clostridium difficile flagellin stimulates toll-likereceptor 5, and toxin B promotes flagellin-induced
chemokine production via TLR5. Life Sci. 2013;

154

92:211-7.
37) Yotsuyanagi H, Ito K, Yamada N, Takahashi H,
Okuse C, Yasuda K, Suzuki M, Moriya K,
Mizokami M, Miyakawa Y, Koike K. High levelsof hepatitis B virus after the onset of disease leadto chronic infection in patients with acute hepatitis
B. Clin Infect Dis. 2013;57:935-42.
38) Okuse C, Yotsuyanagi H, Yamada N, Ikeda H,
Kobayashi M, Fukuda Y, Takahashi H, Matsunaga
K, Matsumoto N, Okamoto M, Ishii T, Sato A,
Koike K, Suzuki M, Itoh F. Changes in levels of
hepatitis B virus markers in patients positive forlow-titer hepatitis B surface antigen. Hepatol Res.
2012;42:1236-40.
39) Okazaki T, Yamazaki K, Iwasaki T, Okano T,
Kurosaki Y, Nakamura K, Fujioka T, Yotsuyanagi
H. α2-HS glycoprotein is an essential componentof cryoglobulin associated with chronic hepatitis
C. Clin Chem Lab Med. 2013;51:e17-8.
40) Fukase H, Furuie H, Yasuda Y, Komatsu R,
Matsushita K, Minami T, Suehiro Y, Yotsuyanagi
H, Kusadokoro H, Sawata H, Nakura N, Lattanzi
M. Assessment of the immunogenicity and safetyof varying doses of an MF59-adjuvanted cell
culture-derived A/H1N1 pandemic influenza
vaccine in Japanese paediatric, adult and elderly
subjects. Vaccine 2012;30:5030-7.
41) Goto K, Hatakeyama S, Okamoto K, Kitazawa T,
Abe K, Moriya K, Koike K, Yotsuyanagi H.
Dengue hemorrhagic fever in an adult traveler
returning to Japan. Intern Med. 2012;51:1779-82.
42) Yanagimoto S, Yotsuyanagi H, Kikuchi Y,
Tsukada K, Kato M, Takamatsu J, Hige S,
Chayama K, Moriya K, Koike K. Chronic
hepatitis B in patients coinfected with humanimmunodeficiency virus in Japan: A retrospective
multicenter analysis. J Infect Chemother 2012;
18:883-90.
43) Okazaki T, Yamazaki K, Iwasaki T, Okano T,
Kurosaki Y, Nakamura K, Fujioka T, Yotsuyanagi
H. α2-HS glycoprotein is an essential componentof cryoglobulin associated with chronic hepatitis
C. Clin Chem Lab Med. 2012 Jul 27. doi:pii:/j/cclm.ahead-of-print/cclm-2012-0293/cclm-20120293.xml.10.1515/cclm-2012-0293. [Epub aheadof print]44) Ikeda K, Izumi N, Tanaka E, Yotsuyanagi H,

Takahashi Y, Fukushima J, Kondo F, Fukusato T,
Koike K, Hayashi N, Kumada H. Fibrosis scoreconsisting of four serum markers successfully
predicts pathological fibrotic stages of chronic
hepatitis B. Hepatol Res. 2012 Nov 2. doi:
10.1111/j.1872-034X.2012.01115.x. [Epub aheadof print]45) Okuse C, Yotsuyanagi H, Yamada N, Ikeda H,
Kobayashi M, Fukuda Y, Takahashi H, Matsunaga
K, Matsumoto N, Okamoto M, Ishii T, Sato A,
Koike K, Suzuki M, Itoh F. Changes in levels of
hepatitis B virus markers in patients positive forlow-titer hepatitis B surface antigen. Hepatol Res.
2012;42:1236-1240.
46) Nukui Y, Hatakeyama S, Kitazawa T, Mahira T,
Shintani Y, Moriya K. Pandemic 2009 influenza A(H1N1) virus among Japanese healthcare workers:
seroprevalence and risk factors. Infect Control
Hosp Epidemiol. 2012; 33: 58-62
47) Yamaguchi Y, Nukui Y, Tajima S et al.
Characterization of a serine-to-asparagine substituion at position 123 in the Japanese encephalitis
virus E protein. J Gen Virol. Epub 2012 Oct 1048) Saito N, Hida A, Koide Y, Ooka T, Ichikawa Y,
Shimizu J, Mukasa A, Nakatomi H, Hatakeyama S,
Hayashi T, Tsuji S. Culture-negative brain abscesswith Streptococcus intermedius infection withdiagnosis established by direct nucleotide
sequence analysis of the 16s ribosomal RNA gene.
Intern Med. 2012;51:211-6.
49) Koyano S, Saito R, Nagai R, Tastuno K, Okugawa
S, Okamura N, Moriya K. J Med Microbiol. 2012
Nov 15. [Epub ahead of print]50) Yoshino Y, Okugawa S, Kimura S, Makita E, Seo
K, Koga I, Matsunaga N, Kitazawa T, Ota Y.
Infective endocarditis due to Enterobacter cloacae
resistant to third- and fourth-generation cephalosporins. J Microbiol Immunol Infect. 2012 Sep 24.
doi:pii: S1684-1182(12)00159-4.10.1016/j.jmii.
2012.07.015. [Epub ahead of print]51) Okugawa S, Moayeri M, Pomerantsev AP, Sastalla
I, Crown D, Gupta PK, Leppla SH. Lipoprotein
biosynthesis by prolipoprotein diacylglyceryltransferase is required for efficient spore
germination and full virulence of Bacillus
anthracis. Mol Microbiol. 2012;83:96-109.

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Department of Stress Sciences 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 andPsychosomatic Medicine is one of 11 divisions of the
Department of Internal Medicine, the University ofTokyo. It covers eating disorder, panic disorder, andvarious psychosomatic diseases such as chronicheadache, irritable bowel syndrome, functional
dyspepsia, hypertension, diabetes mellitus, andhyperthyroidism. Our teaching staff consists of one
associate professor, two associates, and 5 adjunctprofessors, and other members are 2 senior residents,
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 2014 January to 2014 December, overall 1,517
patients (58 individuals) were admitted to the ward,
many of whom were eating disorder patients.
Outpatient clinic is attended on every morning andafternoon in three consultation rooms byapproximately fifteen physicians. During 2014
January to 2014 December, the numbers of the new

outpatients and of the overall outpatients in our
department were 210 and 3,035, respectively.

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

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

156

pathology through assessing bio-psycho-behavioral
time-series data, various questionnaire data, andautonomic nervous function. We are also actively
conducting basic as well as clinical research on
eating-related substances.
Some representative research methods are as
follows:
1) Ecological momentary assessment (EMA):
Investigation on neurobehavioral basis of stressrelated diseases such as tension-type headache,eating disorders, insomnia, and panic disorderusing portable computers for real-time assessmentof subjective symptoms in combination withambulatory monitors such as electrocardiogramand actigraphy.
2) Neuroendocrinological and neuroimmunologicalstudies in anorexia nervosa patients: multidisciplinary investigation on energy metabolism
during a refeeding phase; changes in various
substances such as neuropeptides before and after
treatment; relationship between bone metabolism
and various makers; and exploration of biomarkers
for evaluating treatment efficacy.
3) Psycho-oncology: Development of a new questionnaire for evaluating depressive mood in cancer
patients.
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. Takimoto Y, Yoshiuchi K, Ishizawa T, Yamamoto
Y, Akabayashi A. Autonomic dysfunction
responses to head-up tilt in anorexia nervosa.
Clinical Autonomic Research 24:175-181, 2014.
2. Fukui S, Yoshiuchi K, Fujita J, Ikezaki S.
Determinants of financial performance ofhome-visit nursing agencies in Japan. BMC
Health Serv Res 14:11, 2014.

3. Shibayama O, Yoshiuchi K, Inagaki M, Matsuoka
Y, Yoshikawa E, Sugawara Y, Akechi T, Wada N,
Imoto S, Murakami K, Ogawa A, Akabayashi A,
Uchitomi Y. Association between adjuvant
regional radiotherapy and cognitive function inbreast cancer patients treated with conservation
therapy. Cancer Medicine 3:702-709, 2014.
4. Takimoto Y, Yoshiuchi K, Shimodaira S,
Akabayashi A. Diamine oxidase activity levels inanorexia nervosa. Int J Eat Disord 47:203-205,
2014.

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

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

Lecturer
Nelson Hirokazu Tsuno, M.D., Ph.D.

Associate
Toshiyuki Ikeda, M.D., Tomohiko Sato, M.D, Ph.D.

Homepage

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

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 posttransfusional complication, and ex-Professor Yoichi
Shibata contributed enourmously to the field ofplatelet immunology. In 1997, the Department ofTransfusion Medicine was established as a chair of theDivision of Internal Medicine of the Graduate Schoolof 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, immunotherapy of cancer patients, andcollection 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;1592) 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
1) Pre-operative autologous blood collection andpreservation;2) Collection and preservation of peripheral blood
stem cells for transplantation;3) Anti-angiogenic cancer therapy.

Teaching activities
Sixth-year 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 immunotherapy of cancer patients;
11) 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”.
12) One-day visit to the Japanese Red Cross Blood
Center, to learn the general process of blood
donation and transfusion, including the types ofblood products, and their indications.

Research activities
Research on red cells, leukocytes, and platelets, thepost-tranfusional complications, transplantation immunology, immunotherapy, and stem cell biology are
the main themes of the department. Typing of blood
cells is performed by serological and DNA-based
methods. The HLA typing, which was introduced by
ex-Professor Takeo Juji, one of the pioneers of thisfield, is an essential test for hematopoietic stem celland organ transplantations, and still continues as oneof the most important research fields of the department. The mixed-passive hemagglutination (MPHA)
method, the most popular methodology for platelet
serology in Japan, was developed by ex-Professor
Yoichi Shibata and its applicability is now extended
for granulocyte as well as endothelial cell serology.
Transplantation immunology, including stem cellbiology is also an important subject. Also, the roleof pre-storage leukocyte reduction of autologous
blood products, especially focusing on cytokine/
chemokines and bioactive lipids, and the improvements of the preservation methods of autologous
blood are being investigated. Recently, developmentof new materials for medical use is also being
researched. 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.

160

7. Development of a new methodology for evaluationof platelet function.
8. Development of new strategies for the treatment ofcancer patients, by targeting the tumor vasculature.
9. Ex-vivo expansion of hematopoietic stem cells andtheir clinical application.
10. Pathophysiology of TRALI and TACO.
11. Development of new materials for medical use.

References
1. Iida Y, Kawai K, Tsuno NH, Ishihara S,
Yamaguchi H, Sunami E, Kitayama J, Watanabe
T. Proximal shift of colorectal cancer along withaging. Clin Colorectal Cancer. 2014; 13(4):213-8.
2. Okazaki H, Ishikawa O, Iijima T, Kohira T,
Teranishi M, Kawasaki S, Saito A, Mikami Y,
Sugiura A, Hashimoto S, Shimada E, Uchikawa
M, Matsuhashi M, Tsuno NH, Tanaka M,
Kiyokawa N, Fujimoto J, Nagase T, Tadokoro K,
Takahashi K. Novel swine model of transfusionrelated acute lung injury. Transfusion. 2014; 54(12):3097-107.
3. Murono K, Kawai K, Tsuno NH, Ishihara S,
Yamaguchi H, Sunami E, Kitayama J, Watanabe
T. Barium enema and CT volumetry for predicting
pathologic response to preoperative chemoradiotherapy in rectal cancer patients. Dis Colon
Rectum. 2014; 57(6):715-24.
4. Yamamoto Y, Yamashita T, Tsuno NH,
Nagamatsu T, Okochi N, Hyodo H, Ikeda T,
Kawabata M, Kamei Y, Nagura Y, Sone S, Fujii T,
Takahashi K, Kozuma S. Safety and efficacy of
preoperative autologous blood donation for
high-risk pregnant women: experience of a large
university hospital in Japan. J Obstet Gynaecol
Res. 2014; 40(5):1308-16.
5. Kaneko M, Nozawa H, Hiyoshi M, Tada N,
Murono K, Nirei T, Emoto S, Kishikawa J, Iida Y,
Sunami E, Tsuno NH, Kitayama J, Takahashi K,
Watanabe T. Temsirolimus and chloroquine
cooperatively exhibit a potent antitumor effectagainst colorectal cancer cells. J Cancer Res Clin
Oncol. 2014; 140(5):769-81.
6. Tada N, Tsuno NH, Kawai K, Murono K, Nirei T,
Ishihara S, Sunami E, Kitayama J, Watanabe T.
Changes in the plasma levels of cytokines/

chemokines for predicting the response to
chemoradiation therapy in rectal cancer patients.
Oncol Rep. 2014; 31(1):463-71.
7. Matsuhashi M, Tsuno NH, Sone S, Mishima Y,
Nagura Y, Watanabe-Okochi N, Ikeda T,
Kashiwase K, Fukuda S, Iriyama T, Hyodo H,
Yamashita T, Kamei Y, Arai S, Minami M, Fujii
T, Kurokawa M, Tozuka M, Takahashi K, Santoso
S. The role of alloantibodies against humanplatelet antigen-15 in multiply platelet transfused
patients. Transfusion. 2014; 54(4):1093-9.
8. Sone S, Tsuno H, Okazaki H. Management of
massive transfusion - the role of the bloodtransfusion service. Rinsho Byori. 2014; 62(12):1280-5. Review. Japanese.
9. Abe T, Shimada E, Takanashi M, Takamura T,
Motoji K, Okazaki H, Satake M, Tadokoro K.
Antibody against immunoglobulin E contained inblood components as causative factor foranaphylactic transfusion reactions. Transfusion.
2014; 54(8):1953-60.
10. Terada C, Mori J, Okazaki H, Satake M,
Tadokoro K. Effects of riboflavin and ultraviolet
light treatment on platelet thrombus formation oncollagen via integrin αIIbβ3 activation.
Transfusion. 2014; 54(7):1808-16.
11. Maeda T, Noguchi T, Saito S, Yoshioka R, Horibe
E, Miyanaga S, Seguchi S, Kanaumi Y, Kawai T,
Okazaki H, Miyata S: Impact of heparin-induced
thrombocytopenia on acute coronary artery
thrombosis in patients undergoing PCI. Thromb
Haemost 2014; 112(3):624-6.
12. Matsuhashi M, Tsuno N, Iino J, Nagura Y,
Okazaki H, Santoso S. Advances in granulocyte
test methodologies. Vox Sang ISBT Science
Series 2014; 9: 246-252.
13. Tsuno N, Matsuhashi M, Iino J, Nagura Y,
Okazaki H, Santoso S. The importance of platelet
antigens and antibodies in immune-mediatedthrombocytopenia. Vox Sang ISBT Science Series
2014; 9: 104-111.
14. Kaneko M, Wanaka K, Tsuno N, Kanno N,
Nonobe R, Takahashi C, Matsuo T, Okazaki H,
Yatomi Y. The diagnosis and management of
Heparin-Induced Thrombocytopenia in Japan. Vox
Sang ISBT Science Series 2014; 9: 210-216.

161

15. Matsuhashi M, Tsuno N, Takahashi K, Wu GG,
Han KS, Chu CC, Santoso S. Report of the First
Workshop of the ISBT International Platelet
Immunobiology Working Party, Asia Regional.
ISBT Science Series 2014; 9:304-8.

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

163

Department of
Reproductive Endocrinology
Professor
Tomoyuki Fujii

Associate Professor
Kei Kawana

Lecturer
Osamu Hiraike

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, one associate professor
and two 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 nineteen years.
Conventional IVF-ET is mainly indicated to caseswith tubal factor, mild male factor, immunologicalfactor or of unexplained infertility factor. In case of
severe male factor or other fertilization disorderintracytoplasmic sperm injection (ICSI) is performed.
Now we have about 200 OPU cycles of IVF-ET every
year, which conventional IVF-ET and ICSI sharealmost equally. The clinical pregnancy rate of conventional IVF-ET is around 30% per embryo transfer
cycle, which is comparable with that of ICSI. OtherART techniques such as embryo cryopreservation andassisted 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 6) effects of endocrine
disrupters on the reproductive system.

References published in 2014
(1) Fujimoto A, et. al. The outcome of infertility
treatment in patients undergoing assisted
reproductive technology after conservative
therapy for endometrial cancer. J Assist Reprod
Genet. 2014 Sep; 31(9): 1189-94.
(2) Urata Y, et. al. IL-1β increases expression of
tryptophan 2,3-dioxygenase and stimulates
tryptophan catabolism in endometrioma stromal

164

cells. Am J Reprod Immunol. 2014 Nov; 72(5):496-503.
(3) Hirata T, et. al. Efficacy of dienogest in thetreatment of symptomatic adenomyosis: a pilot
study. Gynecol Endocrinol. 2014 Oct; 30(10):726-9.
(4) Fu H, et. al. SIRT3 positively regulates theexpression of folliculogenesis- and luteinizationrelated genes and progesterone secretion by
manipulating oxidative stress in human luteinizedgranulosa cells. Endocrinology. 2014 Aug; 155(8): 3079-87.
(5) Haraguchi H, et. al. MicroRNA-200a locallyattenuates progesterone signaling in the cervix,
preventing embryo implantation. Mol Endocrinol.
2014 Jul; 28(7): 1108-17.
(6) Miyashita M, et. al. Dienogest reduces
proliferation,
aromataseexpression
andangiogenesis, and increases apoptosis in humanendometriosis. Gynecol Endocrinol. 2014 Sep;
30(9): 644-8.
(7) Hirata T, et. al. Concomitant ovarian drilling andoocyte retrieval by laparoendoscopic single-site
surgery led to live birth using in vitro maturationof oocyte and transfer of frozen-thawed
blastocyst in woman with polycystic ovary
syndrome. J Obstet Gynaecol Res. 2014 May;40(5): 1431-5.
(8) Koga K, et. al. Toll-like receptors at thematernal-fetal interface in normal pregnancy andpregnancy complications. Am J Reprod Immunol.
2014 Aug;72(2):192-205.
(9) Akiyama I, et. al. The role of bone morphogenetic
protein 6 in accumulation and regulation ofneutrophils in the human ovary. Reprod Sci. 2014
Jun; 21(6): 772-7.
(10) Taguchi A, et. al. Resveratrol suppresses
inflammatory responses in endometrial stromalcells derived from endometriosis: a possible roleof the sirtuin 1 pathway. J Obstet Gynaecol Res.
2014 Mar; 40(3): 770-8.
(11) Akiyama I, et. al. Bone morphogenetic protein 7
increased vascular endothelial growth factor(VEGF)-a expression in human granulosa cells
and VEGF receptor expression in endothelial
cells. Reprod Sci. 2014 Apr; 21(4): 477-82.
(12) Santoso EG, et. al. Application of detergents orhigh hydrostatic pressure as decellularization
processes in uterine tissues and their subsequenteffects on in vivo uterine regeneration in murine
models. PLoS One. 2014 Jul 24; 9(7): e103201.
(13) Terao M, et. al. Factors that predict poor clinicalcourse among patients hospitalized with pelvic
inflammatory disease. J Obstet Gynaecol Res.
2014 Feb; 40(2): 495-500.
(14) Saito A, et. al. Individualized management ofumbilical endometriosis: a report of seven cases.
J Obstet Gynaecol Res. 2014 Jan; 40(1): 40-5.

165

Department of
Gynecologic Oncology
Professor
Yutaka Osuga

Associate Professor
Kei Kawana

Homepage

Katsutoshi Oda

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 uterine cervicalcancer has been investigated these two decades. To
identify the risk factors for cervical intraepithelial
neoplasia (CIN), we reanalysed the data from ourprevious case-control study by adjusting for humanpapillomavirus (HPV) antibodies. Unlike our previous
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 involvement 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 nonpathological cervix (85.7%) was significantly higher
than in the CIN1 cases (21.5%), the CIN2/3 cases(15.7%), and the cervical cancer cases (0%)(p<0.0001). The regression of the CIN1 lesion 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

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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.
We also investigated interacting proteins with the
HPV E6 protein. Recently, a LAP protein, scribble,
was identified in Drosophila epithelia as a basolateralprotein that controls the apical-basolateral polarity.
Loss of scribble causes disorganisation andovergrowth of the epithelia. Scribble has a humanhomologue, human scribble (hScrib), which is a
substrate of ubiquitin-mediated degradation by humanpapillomavirus E6 and the E6AP ubiquitin-protein
ligase. In the present study, we revealed that hScrib
localised to the basolateral regions of the epithelial
cell line MDCK and human uterine cervical epithelial
tissues by immunofluorescence. Human scribble
colocalised rather with the adherens junction protein
E-cadherin, but not with the tight junction protein
ZO-1. Histochemical analysis showed a dramatic
decrease in the expression of hScrib with theprogression of disease from normal uterine cervicaltissues to invasive cervical cancers through theprecursor lesions. In contrast, the expression of hScrib
was retained in the throughout epithelial layer of the
HPV-negative cervical high-grade squamous intraepithelial lesions (H-SIL). Although quantitative RT-

PCR revealed no significant downregulation of hScribmRNA expression in the H-SIL, it revealed a clear
downregulation in the invasive cancers. These results
suggest the possibility that degradation by HPV E6 is
one of the causal roles for the progressive decrease of
hScrib expression during the disease progression fromlow-grade squamous intraepithelial lesions to H-SIL,
and a cooperative role of downregulation of hScribmRNA expression and ubiquitin-mediated degradationof hScrib by E6 and E6AP led to the complete
decrease of hScrib expression during the process ofcarcinogenesis from H-SIL to invasive cancer. These
data underscore the importance of hScrib in theconstruction of tissue architecture and prevention ofcancer development.
Another basic research is focused on analysis oftumor suppressor genes in gynecological malignancies
as following.
1 Human Scribble
Recently, a LAP protein, scribble, was identified in
Drosophila epithelia as a basolateral protein that
controls the apical-basolateral polarity. Loss ofscribble causes disorganisation and overgrowth of theepithelia. Scribble has a human homologue, humanscribble (hScrib), which is a substrate of ubiquitinmediated degradation by human papillomavirus E6
and the E6AP ubiquitin-protein ligase. In the present
study, we revealed that hScrib localised to thebasolateral regions of the epithelial cell line MDCKand human uterine cervical epithelial tissues byimmunofluorescence. Human scribble colocalised
rather with the adherens junction protein E-cadherin,
but not with the tight junction protein ZO-1.
Histochemical analysis showed a dramatic decrease in
the expression of hScrib with the progression of
disease from normal uterine cervical tissues toinvasive cervical cancers through the precursor lesions.
In contrast, the expression of hScrib was retained in
the throughout epithelial layer of the HPV-negative
cervical high-grade squamous intraepithelial lesions(H-SIL). Although quantitative RT-PCR revealed nosignificant downregulation of hScrib mRNA
expression in the H-SIL, it revealed a clear
downregulation in the invasive cancers. These results
suggest the possibility that degradation by HPV E6 is
one of the causal roles for the progressive decrease of
hScrib expression during the disease progression from167

low-grade squamous intraepithelial lesions to H-SIL,
and a cooperative role of downregulation of hScribmRNA expression and ubiquitin-mediated degradationof hScrib by E6 and E6AP led to the complete
decrease of hScrib expression during the process ofcarcinogenesis from H-SIL to invasive cancer. These
data underscore the importance of hScrib in theconstruction of tissue architecture and prevention ofcancer development.
Drosophila discs large (Dlg) is one of neoplastic
tumor suppressors, which genetically links to scribble.
E6 also targets human Dlg (hDlg) for ubiquitinmediated degradation. Ubiquitin-protein ligase
involved in this process has not been identified thus
far. Here we investigated mechanism underlying
degradation of three target proteins of E6, hScrib,
hDlg, and p53 by using eighteen HPV 16 E6 mutants
with single amino acid substitution. In vitro
degradation ability of each E6 mutant was equivalent
for these tumor suppressors. We investigated whether
E6AP is involved in ubiquitin-mediated degradationof hDlg. In vitro binding assay revealed that hDlg
formed ternary complex with E6-E6AP complex. The
ability of E6 mutants to degrade these tumor
suppressors was correlated with their ability to interact
with E6AP. Furthermore, hDlg was targeted for invitro ubiquitination in the presence of both E6 andE6AP. These data revealed that E6AP is extensively
involved in the ubiquitin-mediated degradation of
E6-dependent substrates as a cellular E3 ubiquitinprotein ligase.
Human Scribble, classified as a LAP protein
containing leucine-rich repeats and PDZ domains,interacts with E6 through its PDZ domains andC-terminal PDZ domain-binding motif of E6 protein.
Interaction between human Discs Large (hDlg), which
is a substrate of E6 for the ubiquitin-mediateddegradation, and adenomatous polyposis coli (APC)
has been shown. Here, we investigated whether hScrib
and APC interact with each other in vitro and in vivo.
Interaction between hScrib and APC is mediated by
the PDZ domains 1 and 4 of hScrib and C-terminal
PDZ domain-binding motif of APC. Human Scribble
co-localized with APC at the synaptic sites ofhippocampal neuron and at the tip of membrane
protrusion in the epithelial cell line. Interference of
the interaction between hScrib and APC caused

disruption of adherens junction. Knockdown of hScrib
expression by RNAi disrupts localization of APC at
the adherens junction. These data suggest that hScrib
may participate in the hDlg-APC complex through its
PDZ domains and regulate cell cycle and neuralfunction by associating with APC.
Drosophila tumor suppressor Scribble has been
identified as an apical-basolateral polarity determinant
in epithelia. A human homolog of Drosophila Scribble,
human Scribble (hScrib), has been identified as aprotein targeted by human papillomavirus E6 for theubiquitin-mediated degradation dependent on E6AP, acellular ubiquitin-protein ligase. Human Scribble isclassified as a LAP protein, having leucine-richrepeats (LRRs) and PDZ domains. We investigatedwhether hScrib, which is thought to have a role inpolarity determination based on the data of its
Drosophila homolog, is involved in cell-cycle
regulation and proliferation control of epithelia.
Transfection of hScrib inhibits cell-cycle progression
from G1 to S phase, and it up- and down-regulates
expression of adenomatous polyposis coli and cyclins
A and D1, respectively. Knockdown of hScrib
expression by siRNA leads to cell-cycle progression
from G1 to S phase. We explored functional domain
mapping to reveal which domains of hScrib are
critical for its cellular proliferation control andlocalization at the basolateral membrane. We foundthat LRRs and PDZ domain 1 are indispensable for
hScrib to inhibit cell growth by blocking cell-cycle
progression and to keep its proper localization. These
data indicate that basolateral membrane localization of
hScrib is closely related to its proliferation control.
Our findings suggest the possibility that hScrib isinvolved in signal transduction to negatively regulate
cell proliferation by localizing at the basolateral
membrane of epithelial cells through LRRs and PDZ
domains.
We also investigated which E3 ubiquitin-protein
ligase is involved in the ubiquitin-mediated degradation of hDlg. Human scribble (hScrib), which was
identified as substrate of human papillomavirus (HPV)
E6 for ubiquitin-mediated degradation dependent on
ubiquitin-protein ligase E6AP, is a human homolog of
Drosophila neoplastic tumor suppressor scribble, inwhich mutation causes loss of polarity and overgrowthof epithelia. Drosophila discs large (Dlg) is one of

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neoplastic tumor suppressors, which genetically links
to scribble. E6 also targets human Dlg (hDlg) for
ubiquitin-mediated degradation. Ubiquitin-protein
ligase involved in this process has not been identified
thus far. Here we investigated mechanism underlying
degradation of three target proteins of E6, hScrib,
hDlg, and p53 by using eighteen HPV 16 E6 mutants
with single amino acid substitution. In vitro
degradation ability of each E6 mutant was equivalent
for these tumor suppressors. We investigated whether
E6AP is involved in ubiquitin-mediated degradationof hDlg. In vitro binding assay revealed that hDlg
formed ternary complex with E6-E6AP complex. The
ability of E6 mutants to degrade these tumor
suppressors was correlated with their ability to interact
with E6AP. Furthermore, hDlg was targeted for invitro ubiquitination in the presence of both E6 andE6AP. These data revealed that E6AP is extensively
involved in the ubiquitin-mediated degradation of E6dependent substrates as a cellular E3 ubiquitin-protein
ligase. hScrib, human homologue of Drosophila
neoplastic tumor suppressor, was identified as a targetof human papillomavirus E6 oncoprotein for theubiquitin-mediated degradation. Here, we report that
hScrib is a novel death substrate targeted by caspase.
Full-length hScrib was cleaved by caspase during
death ligands-induced apoptosis, which generates ap170 C-terminal fragments in Hela cells. In vitro
cleavage assay using recombinant caspases showedthat hScrib is cleaved by the executioner caspases.
DNA damage-induced apoptosis caused loss ofexpression of full-length hScrib, which was recoveredby addition of caspase-3 inhibitor in HaCat cells.
TUNEL positive apoptotic cells, which were identified
4 hours after UV irradiation in HaCat cells, showed
loss of hScrib expression at the adherens junction.
Mutational analysis identified the caspase dependentcleavage site of hScrib at the position of Asp-504.
While MDCK cells transfected with GFP-fused wild
type hScrib showed loss of E-cadherin expression andshrinkage of cytoplasm by UV irradiation, cells
transfected with hScrib with Ala substitution of
Asp-504 showed resistance to caspase dependentcleavage of hScrib and intact expression of E-cadherin.
These results indicate that caspase dependent cleavageof hScrib is a critical step for detachment of cell
contact during process of apoptosis.

2 PTEN
Although the mutation of PTEN, a tumor suppressor, is known to be involved in tumorigenesis ofendometrioid adenocarcinomas of the endometrium
and ovary, the role of PTEN alteration in endometrioid
adenocarcinoma of the cervix remains to be investigated. To elucidate the molecular pathogenesis of
cervicaladenocarcinoma
andadenosquamous
carcinoma, and in particular to examine the potential
role of PTEN mutation in endometrioid-type cancer ofthe cervix, we analyzed 32 cervical adeno- or
adenosquamous carcinomas (8 endometrioid adenocarcinomas, 14 mucinous adenocarcinomas and 10
adenosquamous carcinomas) for PTEN mutations and
HPV infections. PTEN mutation was detected in 2 of
8 (25.0%) endometrioid cases, 2 of 14 (14.3%)
mucinous cases, and none of 10 (0%) adenosquamous
cases. HPV DNA was detected in 11 out of 18 (61.1%)
PTEN wild-type adenocarcinomas and 8 out of 10(80.0%) adenosquamous carcinomas. Among 11
HPV-negative adenocarcinomas, 40.0% (2/5) endometrioid cases and 33.3% (2/6) mucinous cases wereshown to be PTEN mutated, while no cases (0/21)
were PTEN-mutant in the remainder (i.e.
adenosquamous carcinomas and HPV-positive adenocarcinomas). The current observations suggest that
PTEN mutation is frequently detected in HPVnegative adenocarcinomas of the cervix and the mostprevalent occurrence of PTEN mutation in
endometrioid subtype is keeping with endometrial andovarian carcinomas.
Next, we analyzed involvement of PTEN intreatment of endometrial cancer. Young patients withcomplex atypical hyperplasia (CAH) or stage Ia, G1
adenocarcinoma (IaG1) of the endometrium, who
desire to preserve fertility, can select the conservative
therapy by oral progestin, medroxyprogesterone
acetate (MPA). However, conservative treatments
involve potential risks of progression and recurrence.
In an attempt to find out molecular markers forsensitivity to MPA, we performed immunohistochemical analysis of PTEN, phospho-Akt, p53, ER
and PgR in MPA-treated 31 cases with CAH or IaG1.
Eleven of 12 cases (92%) with CAH and 15 of 19
cases (79%) with IaG1 demonstrated an initial
complete response, while five patients underwent
hysterectomy due to no response. Four of 11

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responders (36%) with CAH and five of 15 responders(33%) with IaG1 later developed relapse. Five of ninepatients (56%) with CAH and three of 11 patients(27%) with IaG1 became pregnant after infertility
treatment. Immunohistochemical analysis revealed
that phospho-Akt expression was significantly
decreased by MPA administration (p=0.002). Furthermore, combination of two factors, weak phosho-Akt
or PTEN-null expression, was found to besignificantly associated with receiving hysterectomy(p=0.04), while each factor showed a trend without
statistical significance (p=0.07 and 0.2, respectively).
Strong expression of both ER and PgR significantly
correlated with successful pregnancy after infertility
treatment following complete response to MPA(p=0.02). Our observations in vivo suggest thatanti-tumor action of MPA may be mediated bydephosphorylation of Akt, and that immunohistochemical evaluation of phospho-Akt and PTEN
may be able to predict the outcome of MPA therapy.
3 SFRP1 gene
The SFRP1 gene on chromosome 8p11.2 encodes a
Wnt signaling antagonist, and was recently demonstrated to be a new tumor suppressor that isinactivated by promoter methylation in human coloncancers. Here, we analyzed promoter methylation of
the SFRP1 gene in human ovarian cancers, in whichloss of heterozygosity in 8p is frequently observed andinvolvement of the Wnt signaling pathway has beensuggested. Methylation-specific PCR (MSP) analysis
showed that four of 13 ovarian cancer cell lines andtwo of 17 primary ovarian cancers had methylated
SFRP1, while an immortalized ovarian epithelial cellline, HOSE, and seven ovarian endometrial cyst
samples did not. In the four ovarian cancer cell lines
with the methylation, SFRP1 was not expressed at all
as determined by quantitative RT-PCR analysis. These
results show that SFRP1 is inactivated by promoter
methylation in human ovarian cancers, as well ascolon cancers.
4 hMSH2
The DNA mismatch repair gene is a key regulator in
the elimination of base-base mismatches andinsertion/deletion loops (IDLs). Human MutS
homologue 2 (hMSH2), originally identified as ahuman homologue of the bacterial MutS, is a tumour
suppressor gene frequently mutated in hereditary

non-polyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer is characterised by theearly onset of colorectal cancer and the developmentof extracolonic cancers such as endometrial, ovarian,and urological cancers. Oestrogen receptor (ER) alphaand beta are members of a nuclear receptor (NR)superfamily. Ligand-dependent transcription of ER is
regulated by the p160 steroid receptor coactivatorfamily, the thyroid hormone receptor-associatedproteins/the vitamin D receptor-interacting proteins(TRAP/DRIP) mediator complex, and the TATA boxbinding protein (TBP)-free TBP associated factor
complex (TFTC) type histone acetyltransferase
complex. We identified the interaction between ER
alpha/beta and hMSH2. Immunoprecipitation andglutathione-S-transferase pull-down assay revealed
that ER alpha and hMSH2 interacted in a liganddependent manner, whereas ER beta and hMSH2
interacted in a ligand-independent manner. Oestrogen
receptor alpha/beta bound to hMSH2 through the
hMSH3/hMSH6 interaction domain of hMSH2. In atransient expression assay, hMSH2 potentiated thetransactivation function of liganded ER alpha, but notthat of ER beta. These results suggest that hMSH2
may play an important role as a putative coactivator in
ER alpha dependent gene expression.
(2) Clinical oncology
To compare treatment outcome results of conventional surgery vs. radiotherapy (RT) for carcinomaof the uterine cervix. A retrospective analysis was
conducted of 152 patients with uterine cervical cancer
radically treated with surgery or high dose-rate
intracavitary brachytherapy (HDR-ICBT) with orwithout external RT from June 1991 to May 2004. The
median follow-up time was 43.5 months (range,
1.0-130.0 months). The median age was 53 years(range, 25-81 years). There were 13 patients (9%) instage IA, 52 (34%) in stage IB, 24 (16%) in stage IIA,
and 63 (41%) in stage IIB. The conventional surgery
group included 115 patients (76%) who underwent
hysterectomy with pelvic lymph node dissection. Of
these, 72 (63%) received postoperative radiotherapy.
Thirty-seven patients (24%) were assigned to the RT
group. Of these, 14 (38%) received chemoradiotherapy. Three patients with stage I received
ICBT-alone without external beam irradiation.

170

RESULTS: The 5-year cause-specific survival (CSS)
rates for surgery and RT were 79.9% and 82.3%,
respectively; the difference between these twotreatments was not statistically significant (P =0.8524). The differences in the survival rates between
the two treatments for each of the stage I or stage II
patients were also not statistically significant (P =0.8407 for stage I and P = 0.6418 for stage II). This
retrospective study suggests that RT results incompatible survival with conventional surgery forpatients with stage I-II cervical carcinoma.

References published in 2014(1) Ikeda Y, et. al. Non-diethylstilbestrol exposed
vaginal clear cell adenocarcinoma has a common
molecular profile with ovarian clear celladenocarcinoma: A case report. Gynecol Oncol
Rep. 2014 Jun 5; 10: 49-52.
(2) Kawana K, et. al. Oral vaccination against HPV
E7 for treatment of cervical intraepithelial
neoplasia grade 3 (CIN3) elicits E7-specificmucosal immunity in the cervix of CIN3 patients.
Vaccine. 2014 Oct 29; 32(47): 6233-9.
(3) Oda K, et. al. Huge pyogenic cervical cyst withendometriosis,
developing
13 years
after
myomectomy at the lower uterine segment: acase report. BMC Womens Health. 2014 Sep 3;
14: 104.
(4) Inoue T, et al. Xanthogranulomatous inflammation of the perimetrium with infiltration into theuterine myometrium in a postmenopausal
woman: a case report. BMC Womens Health.
2014 Jul 15; 14: 82.
(5) Asada K, et. al. Poor prognosis of ovarian cancer
with large cell neuroendocrine carcinoma: casereport and review of published works. J Obstet
Gynaecol Res. 2014 Mar; 40(3): 869-72.
(6) Miyasaka A, et al. Anti-tumor activity of olaparib,a poly (ADP-ribose) polymerase (PARP)
inhibitor, in cultured endometrial carcinoma cells.
BMC Cancer. 2014 Mar 13; 14: 179.
(7) Taguchi A, et. al. Matrix metalloproteinase(MMP)-9 in cancer-associated fibroblasts (CAFs)
is suppressed by omega-3 polyunsaturated fatty
acids in vitro and in vivo. PLoS One. 2014 Feb
27; 9(2): e89605.

(8) Kashiyama T, et. al. Antitumor activity andinduction of TP53-dependent apoptosis towardovarian clear cell adenocarcinoma by the dual
PI3K/mTOR inhibitor DS-7423. PLoS One. 2014
Feb 4; 9(2): e87220.
(9) Inaba K, et. al. High-risk human papillomavirus
correlates with recurrence after laser ablation fortreatment of patients with cervical intraepithelial
neoplasia 3: a long-term follow-up retrospective
study. J Obstet Gynaecol Res. 2014 Feb; 40(2):554-60.
(10)Azuma Y, et. al. Human papillomavirus genotype
distribution in cervical intraepithelial neoplasia
grade 2/3 and invasive cervical cancer inJapanese women. Jpn J Clin Oncol. 2014 Oct;44(10): 910-7.

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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.
Strict measurement 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 havebeen introduced into clinical service. The subjects ofstudies were focused on “fetus” and “ultrasound” inperinatology and medical engineering research group.
Fetal behavior, particularly breathing movements andsleep-wakefulness cycle were studied with ultrasoundin human fetuses. Studies were done to investigate
mechanism of fetal brain damage by repeated cord

occlusion in sheep. The effect of brain damage on
fetal behavior was also studied.
Recurrent spontaneous abortion (RSA) is diagnosed
by a history of three times or more spontaneousabortions in the first trimester. Our “RSA clinic”
opens once a week. About 200 new couples with RSA
visit our hospital in a year. The patients are checked
several risk factors of RSA, such as anatomical,
chromosomal, hormonal, biological, or autoimmune
factors. To RSA patients with autoimmune factors,
especially with antiphospholipid antibodies, anticoagulation therapy is performed. For the low risk
group, low dose aspirin is administered. Heparin
injection is performed for the high risk group, forinstance, patients with successive intrauterine fetal
death during the second or third trimester ofpregnancy, or those with beta-2 glycoprotein I
dependent anticardiolipin antibody. Further to RSA
patients with unknown etiology, the immunotherapy
with her husband’s lymphocyte inoculation had been
indicated. The inoculation was usually performed fourto six times in every two or three weeks. In our clinic,
after the immunotherapy, their pregnancy outcomes
had extremely improved. The successful reproductive
rate had achieved about 75%.

References published in 2014
(1) Toshimitsu M, et. al. Increased risk of pregnancyinduced hypertension and operative delivery afterconception induced by in vitro fertilization/
intracytoplasmic sperm injection in women aged
40 years and older. Fertil Steril. 2014 Oct;102(4): 1065-1070. e1.

172(2) Minakami H, et. al. Guidelines for obstetrical
practice in Japan: Japan Society of Obstetrics andGynecology (JSOG) and Japan Association of
Obstetricians and Gynecologists (JAOG) 2014
edition. J Obstet Gynaecol Res. 2014 Jun; 40(6):1469-99.
(3) Ichinose M, et. al. Hypothermia attenuates
apoptosis and protects contact between myelin
basic protein-expressing oligodendroglial-lineage
cells and neurons against hypoxia-ischemia. J
Neurosci Res. 2014 Oct; 92(10): 1270-85.
(4) Yamamoto Y, et. al. Safety and efficacy of
preoperative autologous blood donation for highrisk pregnant women: experience of a large
university hospital in Japan. J Obstet Gynaecol
Res. 2014 May; 40(5): 1308-16.
(5) Nagamatsu T, et. al. Emerging roles forlysophospholipid mediators in pregnancy. Am J
Reprod Immunol. 2014 Aug; 72(2): 182-91.
(6) Nagamatsu T, et. al. Placental abnormalities
detected by ultrasonography in a case of confinedplacental mosaicism for trisomy 2 with severe
fetal growth restriction. J Obstet Gynaecol Res.
2014 Jan; 40(1): 279-83.

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Department of Molecular andCellular Reproductive Medicine
Professor
Yutaka Osuga

Associate Professor
Kaori Koga

Lecturer
Osamu Hiraike

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
laparoscopically assisted cystectomy or salpingooophorectomy, laparoscopic hysterectomy or laparoscopically assisted vaginal hysterectomy, laparoscopic
or laparoscopically assisted myomectomy, diagnostic
laparoscopy for infertility, laparoscopic surgery forectopic pregnancy, hysteroscopic surgery and so on,which make 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 6) effects of endocrine
disrupters on the reproductive system.

References published in 2014
(1) Fujimoto A, et. al. The outcome of infertility
treatment in patients undergoing assisted reproductive technology after conservative therapy
for endometrial cancer. J Assist Reprod Genet.
2014 Sep; 31(9): 1189-94.
(2) Urata Y, et. al. IL-1β increases expression of
tryptophan 2,3-dioxygenase and stimulates tryptophan catabolism in endometrioma stromal cells.
Am J Reprod Immunol. 2014 Nov; 72(5): 496503.

174(3) Hirata T, et. al. Efficacy of dienogest in thetreatment of symptomatic adenomyosis: a pilot
study. Gynecol Endocrinol. 2014 Oct; 30(10):726-9.
(4) Fu H, et. al. SIRT3 positively regulates theexpression of folliculogenesis- and luteinizationrelated genes and progesterone secretion by
manipulating oxidative stress in human luteinizedgranulosa cells. Endocrinology. 2014 Aug;
155(8): 3079-87.
(5) Haraguchi H, et. al. MicroRNA-200a locallyattenuates progesterone signaling in the cervix,
preventing embryo implantation. Mol Endocrinol.
2014 Jul; 28(7): 1108-17.
(6) Miyashita M, et. al. Dienogest reduces
proliferation,
aromataseexpression
andangiogenesis, and increases apoptosis in humanendometriosis. Gynecol Endocrinol. 2014 Sep;
30(9): 644-8.
(7) Hirata T, et. al. Concomitant ovarian drilling andoocyte retrieval by laparoendoscopic single-site
surgery led to live birth using in vitro maturationof oocyte and transfer of frozen-thawed
blastocyst in woman with polycystic ovary
syndrome. J Obstet Gynaecol Res. 2014 May;40(5): 1431-5.
(8) Koga K, et. al. Toll-like receptors at thematernal-fetal interface in normal pregnancy andpregnancy complications. Am J Reprod Immunol.
2014 Aug;72(2):192-205.
(9) Akiyama I, et. al. The role of bone morphogenetic
protein 6 in accumulation and regulation ofneutrophils in the human ovary. Reprod Sci. 2014
Jun; 21(6): 772-7.
(10) Taguchi A, et. al. Resveratrol suppresses
inflammatory responses in endometrial stromalcells derived from endometriosis: a possible roleof the sirtuin 1 pathway. J Obstet Gynaecol Res.
2014 Mar; 40(3): 770-8.
(11) Akiyama I, et. al. Bone morphogenetic protein 7
increased vascular endothelial growth factor(VEGF)-a expression in human granulosa cells
and VEGF receptor expression in endothelial
cells. Reprod Sci. 2014 Apr; 21(4): 477-82.
(12) Santoso EG, et. al. Application of detergents orhigh hydrostatic pressure as decellularization
processes in uterine tissues and their subsequenteffects on in vivo uterine regeneration in murine
models. PLoS One. 2014 Jul 24; 9(7): e103201.
(13) Terao M, et. al. Factors that predict poor clinicalcourse among patients hospitalized with pelvic
inflammatory disease. J Obstet Gynaecol Res.
2014 Feb; 40(2): 495-500.
(14) Saito A, et. al. Individualized management ofumbilical endometriosis: a report of seven cases.
J Obstet Gynaecol Res. 2014 Jan; 40(1): 40-5.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

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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.,
Motohiro Kato, M.D., Ph.D., (Department of Cell Therapy and Transplantation Medicine)

Associate
Nobutaka Shimizu, M.D., Ph.D., Ken-ichirou Miura, M.D., Haruko Tsurumi, M.D.,Ph.D.,
Mitsuteru Hiwatari, M.D., Ph.D., Hiroyuki Iwasaki, M.D., Hiroki Yasudo M.D., Ph.D.,
Tsuyoshi Isojima, M.D., Takahiro Shindo,M.D., Nagahisa Takahashi, M.D., Konomi
Shimoda, M.D., Yoshinori Aoki, M.D., Yoko Mizuno, M.D., Sayaka Ohta, M.D., Atsushi
Itoh, M.D., Takanobu Inoue, M.D., Yoshihiko Shidara, M.D., Yu Tanaka, M.D, Masahiro
Sekigucho, M.D., Kouta Yoneda, M.D.
(As of March 31, 2015)

Homepage

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

Introduction and Organization
The former Department of Pediatrics developed into
Department of Pediatrics and Department ofDevelopmental Pediatrics, which comprise subgroupsof the Group of Reproductive, Developmental andAging Medicines, Graduate School of Medicine, The
University of Tokyo.
Our staff consists of 1 professor, 3 associate
professors, 5 lecturers, 18 associate professors, 14senior residents, 2 research fellow, and graduate

students on March 31, 2014.
The outpatient clinic of our department is locatedon the second floor of the outpatient clinic building.
The inpatient ward and conference rooms are locatedon the second floor of the inpatient clinic building A.
Offices are on the second and third floors of the East
Research Building. Our laboratories are located on thesecond, third and fourth floors of the Research
Building of Internal Medicine and on the second andthird floors of the East Research Building.

177

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
findings, clinical information, and gene mutations,indicating that this classification would be usefulfor therapeutic strategy. Moreover, epigenetic

178

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
alsoanalyzed
pathological changes in glomerulonephritis, andfound several new molecules which is involved in
the phenotypical changes of mesangial cells.
③ Endocrinology and Metabolism group: We
analyzed genes and mechanisms involved in
endocrinology
andbone
diseases.
We
successfully found the responsible gene of a rarecongenital
diseaseusing
next-generation
sequencing. We found a novel disease entity
caused by LMX1B abnormality. We also
determined two novel genetic mechanisms ofhereditary 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 andepidemiology 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
11. Kato M, Manabe A, Koh K, Inukai T, Kiyokawa
N, Fukushima T, Goto H, Hasegawa D, Ogawa C,

179

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
andasparaginaseasearly
intensification with intermediate-risk pediatricacute lymphoblastic leukemia: Results ofRandomized 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
acute lymphoblastic leukemia: a collaborative
retrospective study of the Tokyo Children’s
Cancer Study Group (TCCSG) and Japan
Association of Childhood 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:
Genome-wide approach to identify second genetargets for malignant rhabdoid tumors using high-180

density oligonucleotide microarrays. Cancer Sci
105: 258-264, 2014
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

181

Department of Pediatric Surgery
Professor
Tadashi Iwanaka, M.D., Ph.D.

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.

Mariko Yoshida, M.D., Ph.D.

Homepage

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

History and organization
In 1951, a pediatric surgical team was established in
the Department of Second Surgery. Subsequently, in
1961, a pediatric surgical research team, which would
eventually research diaphragmatic hernia, wasestablished with a chief, Dr. Ishida, by Professor
Kimoto.
In 1971, it was authorized as the first clinicaldepartment 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. The present staffs are the chief professor,
1 associate professor, 1 lecturer, and 3 research
associates. More than 20 members of our department
shoulder the clinical work as 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 and182

we closely cooperate with pediatricians to diagnose
and treat patients. We also have specialized outpatient
clinics, liver and biliary tract clinics and a tumor clinic.
Recently, a second-opinion clinic 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).
To establish safe endoscopic surgery for low birthweight infants, we investigate effectiveness andproblems of endoscopic surgery for low birth weight
infants by developing animal model for necrotizing
enterocolitis.
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.

183

References
1. Takazawa S, Uchida H, Kawashima H, Tanaka Y,
Sato K, Jimbo T, Deie K, Koiwai K, Nomura K,
Iwanaka T. Massive hemorrhage after Kasai
portoenterostomy in a patient with a congenital
extrahepatic portosystemic shunt, malrotation anda double aortic arch: report of a case. Surg
Today. 44: 1561-4, 2014
2. Takahashi M, Kanamori Y, Takahashi M, Momose
T, Iwanaka T. Detection of a metastatic lesion
and tiny yolk sac tumors in two teenage patientsby FDG-PET: report of two cases. Surg Today.
44: 1962-5, 2014
3. Hatanaka A, Nakahara S, Takeyama E, Iwanaka T,
Ishida K. Management of extremely low birthweight neonates with bowel obstruction within 2
weeks after birth. Surg Today 44: 2269-74, 2014
4. Miyata H, Gotoh M, Hashimoto H, Motomura N,
Murakami A, Tomotaki A, Hirahara N, Ono M,
Ko C, Iwanaka T. Challenges and prospects of aclinical database linked to the board certification
system. Surg Today. 44: 1991-9, 2014
5. Taguchi T, Kobayashi H, Kanamori Y, Segawa O,
Yamataka A, Sugiyama M, Iwanaka T, Shimojima
N, Kuroda T, Nakazawa A, Oda Y, Miyoshi K,
Ieiri S. Isolated intestinal neuronal dysplasia
Type B (IND-B) in Japan: Results from a nationwide survey. Pediatr Surg Int 30: 815-22, 2014.
6. Takazawa S, Uchida H, Kawashima H, Tanaka Y,
Masuko T, Deie K, Amano H, Kobayashi K, Tada
M, Iwanaka T. Urethroscopic holmium: YAG
laser ablation for acquired posterior urethral
diverticulum after repair of anorectal malformation. Pediatr Surg Int 30: 945-9, 2014
7. Takahashi M, Iwanaka T, Kanamori Y, Ishimaru T,
Suzuki K, Kodaka T, Terawaki K, Komura M,
Sugiyama M. Laparoscopic radical nephrectomy
for the management of chromophobe renal cell
carcinoma in a 13-year-old girl. J Pediatr Surg
Case Reports 2: 331-3, 2014
8. 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. 2014, in press

9. Komura M, Komura H, Konishi K, Ishimaru T,
Hoshi K, Takato T, Tabata Y, Iwanaka T.
Promotion of tracheal cartilage growth by intratracheal injection of basic fibroblast growth factor(b-FGF). J Pediatr Surg. 49: 296-300, 2014
10. Tanaka Y, Uchida H, Kawashima H, Masuko T,
Takazawa S, Deie K, Amano H, Iwanaka T.
Laparoscopic partial nephrectomy for thetreatment of large cystic nephroma in children. J
Laparoendosc Adv Surg Tech A. 24: 901-6, 2014
11. Murakami A, Hirata Y, Motomura N, Miyata H,
Iwanaka T, Takamoto S. The national clinicaldatabase as an initiative for quality improvementin Japan. Korean J Thorac Cardiovasc Surg. 47:
437-43, 2014
12. Okubo T, Harada K, Fujii M, Tanaka S, Ishimaru
T, Iwanaka T, Nakatomi H, Sora S, Morita A,
Sugita N, Mitsuishi M. Hand-held multi-DOF
robotic forceps for neurosurgery designed for
dexterous manipulation in deep and narrow space.
Conf Proc IEEE Eng Med Biol Soc. 2014:
6868-71, 2014
13. Fujishiro J, Sugiyama M, Ishimaru T, Uotani T,
Tsuchida S, Takahashi N, Shiozawa R, Takita J,
Iwanaka T. Cyclic fluctuations of blood pressurein neonatal neuroblastoma. Pediatr Int. 56(6):934-7, 2014.

Reproductive, Developmental andAging Sciences
3. Aging Sciences

185

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.

Kenichi Takayama, MD, PhD

Masaki Ishii, MD, PhD.

Yoko Yamada, 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 inJapan.
Since elderly patients tend to have multiple organ
disorders, these patients should be taken cared as awhole from multiple points of view. In addition,
symptoms, signs and responses to the treatment in theelderly patients could be quite different from theyounger counterparts. Specific knowledge on thephysiological and metabolic changes with aging isnecessary when these elderly patients are treated.
Quality of life of the patients is another point of viewwhich should be emphasized. The department belongs
to the division of Internal Medicine. The staff includes
one professor, one associate professor, two lecturers,
and 6 assistant professors.
Our sub-specialty includes pneumology, cardiology,
neurology, hematology, endocrinology, and bonemetabolism, besides geriatrics.
The main objective 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 resident with various procedures. Very
important issues are discussed and decisions are madein weekly professor's round.
Specialized services are provided to out-patients ona daily basis in all areas of internal medicine. 352 newand a total of 18,528 patients visited the out-patient
clinic in the last fiscal year.

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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 the resultsof geriatric assessment is studied through lectures in acase-oriented manner with an emphasis placed on themultidisciplinary basis of geriatric patients.

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 of vascular
calcification
2) Regulation of vascular function by sex hormone
3) Molecular biology for the control of aging:
Association of vascular and neuronal senescenceand the role of Sirt1
4) Molecular biology and treatment of sarcopenia5) Multicenter-investigation of the optimal treatment
strategy for hypertension or lipid disorder in theelderly6) Clinical study on metabolic syndrome in theelderly7) Biomarkers of dementia, caregiver’s stress andgeriatric syndromes8) Research on appropriate healthcare for the elderly
including pharmacotherapy9) Expression and regulation of nuclear receptors inosteoblast and osteoclast10) Molecular mechanism under the treatment of
osteoporosis11) Genetic analysis of osteoporosis and osteoarthritis
12) Identification and functional analysis of the target
gene networks associated with hormone
responsiveness in prostate and breast cancers13) Role of nuclear receptors in senescence andcarcinogenesis14) Molecular mechanism of vitamin K function andits 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. 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.
2. Boele J, Persson H, Shin JW, Ishizu Y, Newie I,
Søkilde R, Hawkins SM, Coarfa C, Ikeda K,
Takayama K, Horie-Inoue K, Ando Y, Burroughs
AM, Sasaki C, Suzuki C, Sakai M, Aoki S, Ogawa
A, Hasegawa A, Lizio M, Kaida K, Teusink B,
Carninci P, Suzuki H, Inoue S, Gunaratne P,
Rovira C, Hayashizaki Y, de Hoon M:
PAPD5-mediated 3' adenylation and subsequentdegradation of oncomiR miR-21 is disrupted inproliferative disease. Proc Natl Acad Sci U S A111, 11467-11472, 2014.
3. Brand JS, Rovers MM, Yeap BB, Schneider HJ,
Tuomainen TP, Haring R, Corona G, Onat A,
Maggio M, Bouchard C, Tong PC, Chen RY,
Akishita M, Gietema JA, Gannagé-Yared MH,
Undén AL, Hautanen A, Goncharov NP, Kumanov
P, Chubb SA, Almeida OP, Wittchen HU, Klotsche
J, Wallaschofski H, Völzke H, Kauhanen J,
Salonen JT, Ferrucci L, van der Schouw YT.
Testosterone, sex hormone-binding globulin andthe metabolic syndrome in men: an individual
participant data meta-analysis of observational
studies. PLoS One. 9:e100409, 2014.
4. Chen LK, Liu LK, Woo J, Assantachai P, Auyeung
TW, Bahyah KS, Chou MY, Chen LY, Hsu PS,
Krairit O, Lee JS, Lee WJ, Lee Y, Liang CK,
Limpawattana P, Lin CS, Peng LN, Satake S,
Suzuki T, Won CW, Wu CH, Wu SN, Zhang T,
Zeng P, Akishita M, Arai H. Sarcopenia in Asia:
consensus report of the asian working group forsarcopenia. J Am Med Dir Assoc. 15:95-101,
2014.
5. Fujimura T, Takahashi S, Urano T, Takayama K,
Sugihara T, Obinata D, Yamada Y, Kumagai J,

187

Kume H, Ouchi Y, Inoue S, Homma Y: Expressionof androgen and estrogen signaling components
and stem cell markers to predict cancer
progression and cancer-specific survival inpatients with metastatic prostate cancer. Clin
Cancer Res 20, 4625-4635, 2014.
6. Iijima K, Ito Y, Son BK, Akishita M, OuchiY.
Pravastatin and Olmesartan SynergisticallyAmeliorate Renal Failure-Induced Vascular
Calcification. J Atheroscler Thromb. 21(9):917929. 2014
7. Ishii S, Tanaka T, Akishita M, Ouchi Y, Tuji T,
Iijima K. Metabolic syndrome, sarcopenia androle of sex and age: cross-sectional analysis of
Kashiwa cohort study. PLosOne. 9:e112718. 2014
8. Ishii S, Tanaka T, Shibasaki K, Ouchi Y, Kikutani
T, Higashiguchi T, Obuchi SP, Ishikawa-Takata K,
Hirano H, Kawai H, Tsuji T, Iijima K.
Development of a simple screening test forsarcopenia in older adults. Geriatr Gerontol Int.
14:93-101, 2014.
9. Ishii S, Kojima T, Yamaguchi K, Akishita M on
behalf of the study group of the Ministry of
Health, Labour and Welfare. Guidance statement
on appropriate medical services for the elderly.
Geriatr Gerontol Int 14: 518–525, 2014.
10. Ishii S, Cauley JA, Greendale GA, Nielson C,
Karvonen-Gutierrez C, Ruppert K, Karlamangla
AS. Pleiotropic effects of obesity on fracture risk:
The Study of Women's Health Across the Nation.
J Bone Miner Res. 29 :2561-70, 2014
11. Ishikawa H, Eto M, Kitamura K, Kiuchi T.
Resident physicians' attitudes and confidence incommunicating with patients: a pilot study at aJapanese university hospital. Patient Educ Couns.
96:361-366. 2014
12. Makita K, Okano H, Furuya T, Urano T,
Hirabayashi H, Kumakubo T, Iwamoto J: Surveyof the utility of once-monthly bisphosphonate
treatment for improvement of medication
adherence in osteoporosis patients in Japan. J
Bone Miner Metab 33, 55-60, 2015.
13. 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 Study of
Women's Health Across the Nation (SWAN).

Bone. 73, 160-6, 2015
14. Obinata D, Ito A, Fujiwara K, Takayama K,
Ashikari D, Murata Y, Yamaguchi K, Urano T,
Fujimura T, Fukuda N, Soma M, Watanabe T,
Nagase H, Inoue S, Takahashi S: Pyrroleimidazole polyamide targeted to break fusion sites
in TMPRSS2 and ERG gene fusion represses
prostate tumor growth. Cancer Sci 105, 12721278, 2014.
15. Sekiyama K, Waragai M, Akatsu H, Sugama S,
Takenouchi T, Takamatsu Y, Fujita M, Sekigawa
A, Rockenstein E, Inoue S, La Spada A, Masliah
E, Hashimoto M: Disease-Modifying Effect of
Adiponectin in Model of α-Synucleinopathie. Ann
Clin Transl Neurol 1, 479-489, 2014.
16. Shiba S, Ikeda K, Azuma K, Hasegawa T,
Amizuka N, Horie-Inoue K, Inoue S: γ-Glutamyl
carboxylase in osteoblasts regulates glucose
metabolism in mice. Biochem Biophys Res
Commun 453, 350-355, 2014.
17. Takayama K, Suzuki T, Tsutsumi S, Fujimura T,
Takahashi S, Homma Y, Urano T, Aburatani H,
Inoue S: Integrative analysis of FOXP1 function
reveals a tumor suppressive effect in prostatecancer. Mol Endocrinol 28, 2012-2024, 2014.
18. Takayama K, Suzuki T, Fujimura T, Urano T,
Takahashi S, Homma Y, Inoue S: CtBP2
modulates the androgen receptor to promote
prostate cancer progression. Cancer Res 74, 65426553, 2014.
19. 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
AR-dependent and -independent prostate cancer.
Oncotarget 6, 2263-2276, 2015.
20. Urano T, Shiraki M, Sasaki N, Ouchi Y, Inoue S:
Large-scale analysis reveals a functional
single-nucleotide polymorphism in the 5'-flanking
region of PRDM16 gene associated with leanbody mass. Aging Cell 13, 739-743, 2014.
21. Urano T, Shiraki M, Saito M, Sasaki N, Ouchi Y,
Inoue S: Polymorphism of SLC25A32, the folatetransporter gene, is associated with plasma folate
levels and bone fractures in Japanese postmenopausal women. Geriatric Gerontol Int 14,
942-946, 2014.

188

22. Yamaga R, Ikeda K, Boele J, Horie-Inoue K,
Takayama K, Urano T, Kaida K, Carninci P,
Kawai J, Hayashizaki Y, Ouchi Y, de Hoon M,
Inoue S: Systemic identification of estrogenregulated genes in breast cancer cells through cap
analysis of gene expression mapping. Biochem
Biophys Res Commun 447, 531-536, 2014.
英文短報
1. Hara H, Yamashita H, Nakayama A, Hosoya Y,
Ando J, Iijima K, Hirata Y, Komuro I. A rare caseof anomalous origin of the left anterior
descending artery from the pulmonary artery
International Journal of Cardiology. Int J Cardiol.
172:e66-8. 2014
2. Ishii S, Tanaka T, Akishita M, Iijima K.
Development of conversion formulae between 4
meter, 5 meter and 6 meter gait speed. Geriatr
Gerontol Int. 15: 233-4, 2015
3. Ishii S, Tanaka T, Akishita M, Iijima K. Re:
Growing research on sarcopenia in Asia. Geriatr
Gerontol Int. 15: 238-9, 2015
4. Umeda-Kameyama Y, Iijima K, Yamaguchi K,
Kidana K, Ouchi Y, Akishita M. Association ofhearing loss with behavioral and psychologicalsymptoms in patients with dementia. Geriatr
Gerontol Int. 14:727-8, 2014.
英文総説
1. Horie-Inoue K, Inoue S: Genomic aspects ofage-related macular degeneration. Special issue
of “Genomic Aspects of Common Diseases”
Biochem Biophys Res Commun 452, 263-275,
2014.
2. Ikeda K, Horie-Inoue K, Inoue S: Identification of
estrogen-responsive genes based on the DNA
binding properties of estrogen receptor using
high-throughput sequencing technology and its
role in breast cancer. Acta Pharmacol Sin 36,
24-31, 2015.
3. Obinata D, Fujiwara K, Yamaguchi K, Takayama
K, Urano T, Nagase H, Inoue S, Takahashi S,
Fukuda N: Perspective of novel therapeutic
medicines targeting androgen signaling pathway
in castration resistance prostate cancer. World J
Clin Urol 3, 264-271, 2014.

4. Urano T, Inoue S: Genetics of osteoporosis.
Special issue of “Genomic Aspects of Common
Diseases” Biochem Biophys Res Commun 452,
287-293, 2014.

Surgical Sciences
1. Surgery

190

Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Murakawa, Tomohiro
Anraku, Masaki

StaffsNitadori, Jun-ichi
Nagayama, Kazuhiro
Konoeda, Chihiro

Homepage

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

History
Clinical and basic researches of the thoracic surgery
have been performed since the prewar era in thisuniversity, when Professor Tsuduki, Masao adopted
the modified Coryllos’s thoracoplasty for the treatment of the pulmonary tuberculosis in 1934. They
initiated thoracoscopy for the treatment of the
tuberculosis in our country. After the successful
application of the antituberculosis drugs, surgicaltreatment of the thoracic malignant neoplasms was the
major concern of the thoracic surgery.
The Department of Cardiothoracic Surgery, The
University of Tokyo, was established in December 15,
1964 as the first department of this field along withthe cardiovascular surgery in the Japanese national
universities. Since then it has played an internationallyleading role and contributed to development of the
field in our country.
Professors and Chairs in the history of thedepartment are as follows: Kimoto, Seiji (1964.12.15~ 1968.3.31), Saigusa, Masahiro (1968.4.1 ~ 1981.
3.31), Asano, Ken-ichi (1981.4.1 ~ 1986.3.31), Furuse,
Akira (1986.4.1 ~ 1997.3.31) and Takamoto, Shinichi(1997.6.1 ~ 2009.3.31). Nakajima, Jun has taken overthe mission of the department since April 2011.

The Department of Cardiothoracic Surgery has been
divided into two departments, Department of
Cardiovascular Surgery and Department of Thoracic
Surgery in 1997.
The mission of the Department of Thoracic Surgery
is to cure the patients with diseases of the thoracic
organs through clinical works, basic and clinicalresearches, and education of the medical students,
postgraduates, and the surgical residents in our
university.

Clinical activities
Five staffs (Nakajima J, Murakawa T, Anraku M,
Nitadori J, and Nagayama K), who are certificated as
members of the Japanese Board of General Thoracic
Surgery, are in charge of the Department of Thoracic
Surgery, University of Tokyo Hospital. They
specialize in surgical treatment for diseases of therespiratory and the mediastinal organs and the chest
wall, except for diseases of the esophagus andmammary glands.
Lung cancer is the leading cause of cancer death inour country: 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

191

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. More than 300
thoracic surgeries are performed in our department in2013.
We have performed the modern-style thoracoscopy
for the diagnosis and treatment of the thoracic disease
with less surgical invasiveness since 1992. We
currently conduct a standard surgery for clinical stage
IA NSCLC, i.e. lobectomy and lymphadenectomy
through thoracoscopy: In 2014, 96% of patients with
NSCLC was the candidate for thoracoscopic surgery
in our department. Researches on less-invasiveness,oncological advantage of the thoracoscopic 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.
We are now preparing for clinical lungtransplantation for the patients suffering fromadvanced stage of diffuse lung diseases that are
refractory to conventional treatments. Our hospital iscertified as a lung transplant centers in March 2014.
We started to register patients who were eligible forlung transplantation.
500
450
400
350
300
250
200
150
100
50
0

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

Academic education
Medical students in the fifth grade have two-weeks’program on the clinical training of the thoracic and the
cardiovascular surgery. They are 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.

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 for192

the 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.

Selected publications
1. Kuwano H, Tsuchiya T, Murayama T, Sano A,
Nagayama K, Yoshida Y, Murakawa T, Nakajima
J. Outcomes of combined modali¬ty therapy forpatients with stage III or IV mediastinal malignant
germ cell tumors. Surg Today. 2014 Mar;44(3):499-504
2. Seki Y, Yoshida Y, Ishimine H, Shinozaki-Ushiku
A, Ito Y, Sumitomo K, Nakajima J, Fukayama M,
Michiue T, Asashima M, Kurisaki A. Lipase
member H is a novel secreted protein selectively
upregulated in human lung adenocarcinomas andbronchi¬oloalveolar
carcinomas.
Biochem
Biophys Res Commun. 2014 Jan 24;443(4):1141-7.
3. Ibrahim R, Matsubara D, Osman W, Morikawa T,
Goto A, Morita S, Ishikawa S, Aburatani H, Takai
D, Nakajima J, Fukayama M, Niki T, Murakami Y
Expression of PRMT5 in lung adeno¬carcinoma
and its significance in epithelial-mesenchymaltransition. Hum Pathol. 2014 Jul;45(7):1397-405.
4. Horie M, Saito A, Yamauchi Y, Mikami Y,
Sakamoto M, Jo T, Nakajima J, Takizawa H,
Nagase T, Kohyama T. Histamine induces humanlung fibroblast-mediated collagen gel contraction
via histamine H1 receptor. Exp Lung Res. 2014
Jun;40(5):222-36
5. Ichinose J, Murakawa T, Hino H, Konoeda C,
Inoue Y, Kitano K, Nagayama K, Nitadori JI,
Anraku M, Nakajima J. Prognostic Impact of theCurrent Japanese Nodal Classification on
Outcomes in Resected Non-Small Cell Lung
Cancer. Chest. 2014 Sep;146(3):644-9
6. Qiang G, Nakajima J. (Correspondence author)
Simultaneous Stapling of Pulmonary Vein and
Bronchus in Video-Assisted Thoracic Surgery
Lobectomy. Ann Thorac Cardiovasc Surg. 2015;21(1):78-80
7. 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 Mar;47(3):567-72
8. Sonoo T, Ohshima K, Kobayashi H, Asada T,
Hiruma T, Doi K, Gunshin M, Murakawa T,
Anraku M, Nakajima S, Nakajima J, Yahagi N.
Acute respiratory distress syndrome (ARDS)
treated successfully by veno-venous extracorporeal membrane oxygenation (ECMO) in anearly drowned patient. J Artif Organs. 2014;
Sep;17(3):281-4.
9. Ichinose J, Watanabe K, Sano A, Nagase T,
Nakajima J, Fukayama M, Yatomi Y, Ohishi N,
Takai D. Alternative polyadenylation isassociated with lower expression of PABPN1 andpoor prognosis in non-small cell lung cancer.
Cancer Sci. 2014 Sep;105(9):1135-41.
10. Karasaki T, Murakawa T, Nagayama K, Nitadori
JI, Anraku M, Kikuchi Y, Shinozaki-Ushiku A,
Igaki H, Nakajima J. New onset of myasthenia
gravis 10 years after proton beam therapy forthymoma. Gen Thorac Cardiovasc Surg. 2014 Oct
10. [Epub ahead of print]
11. Carter BW, Tomiyama N, Bhora FY, Rosado deChristenson ML, Nakajima J, Boiselle PM,
Detterbeck FC, Marom EM. A modern definitionof mediastinal compartments. J Thorac Oncol.
2014 Sep;9(9 Suppl 2):S97-101.
12. Kakimi K, Matsushita H, Murakawa T, Nakajima
J. Gammadelta T cell therapy for the treatment of

193

non-small cell lung cancer. Transl Lung Cancer
Res. 2014 Feb;3(1):23-33
13. Cho BC, Feld R, Leighl N, Opitz I, Anraku M,
Tsao MS, Hwang DM, Hope A, de Perrot M. A
feasibility study evaluating Surgery for
Mesothelioma After Radiation Therapy: the"SMART" approach for resectable malignant
pleural mesothelioma. J Thorac Oncol. 2014 Mar;9(3):397-402
14. Kadota K, Nitadori J, Woo KM, Sima CS, Finley
DJ, Rusch VW, Adusumilli PS, Travis WD.
Comprehensive pathological analyses in lungsquamous cell carcinoma: single cell invasion,
nuclear diameter, and tumor budding are
independent prognostic factors for worse
outcomes. J Thorac Oncol. 2014 Aug;9(8):1126-39

194

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

Lecturer
Yasutaka Hirata, M.D., Kan Nawata, M.D., Mitsutoshi Kimura , M.D.

Associate
Tetsuhiro Takaoka, M.D., Akihiro Masuzawa, M.D. , Haruo Yamauchi, M.D., Osamu
Kinoshita, M.D., Makoto Ohno, M.D., Yoshifumi Itoda, M.D., Shinichi Ozaki, 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 two Lecturer
and eight Associates.

Clinical Activities
Clinical conference starts at 7:15 am in weekdays.
Regular surgery is scheduled on Monday, Wednesday
and Friday. Patient round is on Tuesday. Adult patientsare hospitalized in the South Wing of 5th floor, andpediatric patients in the South Wing of 2nd floor.
Clinics are open Monday through Friday for thefollow-up visit as well as for patient referral.

195

Case volume in recent years has been about 320,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There arenine 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.
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 2014, 53 cases ofheart transplantation and more than 170 cases ofventricular assist device implantation were performedin The University Hospital.

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) development of a newly-designed surgical robotic system,4) application of regenerative medicine to end-stage
heart failure, 5) mechanism analysis of right heart
failure and development of effective pharmacologicaltherapy, 6) development of versatile suture device, 7)
development of new drug for spinal cord ischemia .

References
1. Akai T, Hoshina K, Yamamoto S, Takeuchi H,
Nemoto Y, Ohshima M, Shigematsu K, Miyata T,
Yamauchi H, Ono M, Watanabe T. Biomechanicalanalysis of an aortic aneurysm. model and its
clinical application to thoracic aortic aneurysms

196

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Takata M, Amiya E, Watanabe M, Omori K, ImaiY, Fujita D, Nishimura H, Kato M, Morota T,
Nawata K, Ozeki A, Watanabe A, Kwarasaki S,
Hosoya Y, Nakao T, Maemura K, Nagai R, Hirata
Y, Komuro I. Impairment of flow-mediateddilation correlates with aortic dilation in patientswith Marfan syndrome. Heart Vessels 2014;29
Koizumi N, Oota K, Lee D, Tsukihara H, Nomiya
A, Yoshinaka K, Azuma T, Sugita N, Homma Y,
Matsumoto Y, Mitsuishi M. System Identification
Method for Non-Invasive Ultrasound Theragnostic System Incorporating Mechanical Oscillation
Part. Int. J. of Automation Technology 2014, 8(1)Murakami A, Hirata Y, Motomura N, Miyata H,
Iwanaka T, Takamoto S. The national clinicaldatabase as an initiative for quality improvementin Japan. Korean J Thorac Cardiovasc Surg. 2014
Oct;47(5)Imamura T, Kinugawa K, Hatano M, Fujino T,
Muraoka H, Inaba T, Maki H, Kagami Y, Endo M,
Kinoshita O, Nawata K, Kyo S, Ono M.
Preoperative beta-blocker treatment is a key for
deciding left ventricular assist device implantation
strategy as a bridge to recovery. J Artif Organs
2014; 17: 23-32
Itoda Y, Panthee N, Tanaka T, Ando T, Sakuma I,
Ono M. Development of a suturing device foranastomosis for small caliber arteries. J Artif
Organs 2014; 17: 88-94
Imamura T, Kinugawa K, Kato N, Muraoka H,
Fujino T, Inaba T, Maki H, Kinoshita O, Hatano
M, Kyo S, Ono M. Late-Onset Right Ventricular
Failure in Patients With Preoperative Small Left
Ventricle After Implantation of Continuous Flow
Left Ventricular Assist. Circ J 2014; 78: 625-33.
Kyo S, Ono M, Sawa Y, Nakatani T, Tabayashi K,
Saiki Y, Tominaga Y. HeartMate II Japanese
Clinical Investigators. Results of the prospective
multicenter Japanese bridge to transplant study
with a continuous-flow left ventricular assist
device. J Artif Organs. 2014; 17: 142-8.
Tomotaki A, Miyata H, Hashimoto H, Murakami
A, Ono M. Results of data verification of theJapan congenital cardiovascular database, 2008 to

2009. World J Pediatr Congenit Heart Surg 2014;
5: 47-53.
10. Yanagie H, Higashi S, Seguchi K, Ikushima I,
Fujihara M, Nonaka Y, Oyama K, Maruyama S,
Hatae R, Suzuki M, Masunaga SI, 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 forrecurrent hepatic cancer involving the intraarterial injection of a 10BSH-containing WOW
emulsion. Appl Radiat Isot. 2014; 88: 32-7
11. Kimura M, Kinoshita O, Fujimoto Y, Murakami
A, Shindo T, Kashiwa K, Ono M. Central
extracorporeal membrane oxygenation requiring
pulmonary arterial venting after near-drowning.
Am J Emergency Med 2014; 32: 197. e1-2.
12. Imamura T, Kinugawa K, Murasawa T, Kagami Y,
Endo M, Muraoka H, Fujino T, Inaba T, Maki H,
Hatano M, Kinoshita O, Nawata K, Kyo S,
Komuro I, Ono M. Cardiac allograft vasculopathy
can be distinguished from donor-transmitted
coronary atherosclerosis by optical coherence
tomography imaging in a heart transplantation
recipient: double layered intimal thickness. Int
Heart J. 2014; 55: 178-80
13. 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-AssociatedLipocalin
Measurement in Patients Who Undergo Left
Ventricular Assist Device Implantation Surgery.
Circ J. 2014; 25: 1891-9
14. Date K, Kaneko T, Edure M, Sato Y, Hasegawa Y,
Okada S, Okonogi S, Takihara H, Ono M.
Thoracoabdominal aortic aneurysm repair in apatient with a left ventricular assist device. Ann
Thorac Surg. 2014; 97: 1778-81.
15. Saito S, Yamazaki K, Nishinaka T, Ichihara Y,
Ono M, Kyo S, Nishimura T, Nakatani T, Toda K,
Sawa Y, Tominaga R, Tanoue T, Saiki Y, Matsui
Y, Takemura T, Niinami H, Matsumiya G.
J-MACS Research Group: Post-approval study ofa highly pulsed, low-shear-rate, continuous-flow,
left ventricular assist device, EVAHEART: A
Japanese multicenter study using J-MACS. J
Heart Lung Transplant. 2014; 33: 599-608.

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16. Panthee N, Ono M, Morota T, Tanaka T, Itoda Y,
Ikemura M, Yamamoto T, Suzuki H, Saito A,
Motomura N. Paraplegia prevention by oral
pretreatment with memantine in a rabbit model. J
Thorac Cardiovasc Surg 2014; 148: 1732-8
17. Koyama S, Itatani K, Yamamoto T, Miyazaki S,
Kitamura T, Taketani T, Ono M, Miyaji K.
Optimal bypass graft design for left anterior
descending and diagonal territory in multivessel
coronary disease. Interact Cardiovasc Thorac Surg
2014; 19: 406-13.
18. Miyata H, Gotoh M, Hashimoto H, Motomura N,
Murakami A, Tomotaki A, Hirahara N, Ono M,
Ko C, Iwanaka T. Challenges and prospects of aclinical database linked to the board certification
system. Surg Today 2014; 44: 1991-9.
19. Naito N, Kinoshita O, Ono M. Prolonged left
ventricular assist device support (18 months) inrefractory ventricular fibrillation. J Heart Lung
Transplant 2014; 33: 772-3
20. Imamura T, Kinugawa K, Hatano M, Fujino T,
Inaba T, Maki H, Kinoshita O, Nawata K, Kyo S,
Ono M, Komuro I. Low Cardiac Output
Stimulates Vasopressin Release in Patients With
Stage D Heart Failure. Circ J. 2014; 78: 2259-67.
21. Date K, Nishimura T, Takewa Y, Kishimoto S,
Ono M, Tatsumi E. The comparison between
synchronization and non-synchronization withcardiac beat under the pulsatile mode with arotary LVAD by a native heart load control
system. Int J Artif Organ 2014; 37: 599
22. Imamura T, Kinugawa K, Fujino T, Inaba T, Maki
H, Hatano M, Kinoshita O, Nawata K, Kyo S,
Ono M. Recipients with shorter cardiopulmonary
bypasstimeachieve
improvementofparasympathetic reinnervation within 6 months
after heart transplantation. Int Heart J 2014; 55:
440-444.
23. Nakatani T, Fukushima N, Ono M, Saiki Y,
Matsuda H, Yozu R, Isobe M. The Registry
Report of Heart Transplantation in Japan (1999–2013). Circ J 2014; 78: 2604-9.
24. Fujino T, Kinugawa K, Hatano M, Imamura T,
Muraoka H, Minatsuki S, Inaba T, Maki H,
Kinoshita O, Nawata K, Yao A, Ono M, Komuro I.
Low Blood Pressure, Low Serum Cholesterol andAnemia Predict Early Necessity of Ventricular

Assist Device Implantation in Patients With
Advanced Heart Failure at the Time of Referral
From Non-Ventricular Assist Device Institutes.
Circ J 2014: 78: 2882-2889.
25. Imamura T, Kinugawa K, Hatano M, Fujino T,
Inaba T, Maki H, Kinoshita O, Amiya E, Nawata
K, Yao A, Kyo S, Ono M, Komuro I. Status 2
patients had poor prognosis without mechanicalcirculatory support. Circ J. 2014; 78: 1396-404.
26. Fukushima N, Ono M, Saito S, Saiki Y, Kubota S,
Tanoue Y, Konaka S, Ashikari J. Heart donationin Japan before and after the revision of theJapanese Transplantation Act. Transplant Proc.
2014; 46: 2050-3.
27. 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:
218-26.
28. 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 for endomyocardial biopsy in heart transplant recipients?
Int Heart J. 2015; 56: 67-72.
29. 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 Jan;
179: 510-3.
30. Imamura T, Kinugawa K, Fujino T, Inaba T, Maki
H, Hatano M, Kinoshita O, Nawata K, Kyo S,
Ono M. Lower rotation speed stimulates sympathetic activation during continuous-flow left
ventricular assist device treatment. J Artif Organs.
2015; 18(1): 20-6.
31. Panthee N, Ono M. Spinal cord injury following
thoracic and thoracoabdominal aortic repairs.
Asian Cardiovasc Thorac Ann. 2015 Feb; 23:
235-46.

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32. Akai T, Hoshina K, Yamamoto S, Takeuchi H,
Nemoto Y, Ohshima M, Shigematsu K, Miyata T,
Yamauchi H, Ono M, Watanabe T. Biomechanicalanalysis of an aortic aneurysm model and its
clinical application to thoracic aortic aneurysms
for defining "saccular" aneurysms. J Am Heart
Assoc. 2015 Jan; 4: e001547.
33. 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 Jan; 18: 120-7.
34. 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.

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Department of
Gastrointestinal Surgery
Professor
Yasuyuki Seto MD. PhD.

Associate Professor
Sachiyo Nomura MD. PhD.

Lectuler
Kazuhiko Mori MD. PhD.

Hiroharu Yamashita MD. PhD.

Associates
Masato Nishida MD. PhD.

Susumu Aikou MD. PhD.

Yukinori Yamagata MD. PhD.

Koichi Yagi MD. PhD.

Takashi Kiyokawa MD. PhD

Asami Tanabe MD.

Tomoki Deguchi 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. Aikou S, Aida J, Takubo K, Yamagata Y, Seto Y,
Kaminishi M, Nomura S. Columnar metaplasia ina surgical mouse model of gastro-esophageal
reflux disease is not derived from bone marrowderived cell. Cancer Sci 104(9):1154-61,2013
2. Motoyama S, Mori K, Kamei T, Miura M, Hinai Y,
Sato Y, Yoshino K, Sasaki T, Miyata G, Seto Y,

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3.

4.

5.

6.

7.

8.

9.

Ogawa J. Evaluation of the risk of lymph nodemetastasis using CRP 1846C>T genetic polymorphism in submucosal thoracic esophageal
squamous cell carcinoma. Ann Surg Oncol 20(6):1978-84,2013
Nashimoto A, Akazawa K, Isobe Y, Miyashiro I,
Katai H, Kodera Y, Tsujitani S, Seto Y, Furukawa
H, Oda I, Ono H, Tanabe S, Kaminishi M. Gastriccancer treated in 2002 in Japan: 2009 annual
report of the JGCA nationwide registry. Gastric
Cancer. 16(1):1-27,2013
Nomura S, Terao S, Adachi K, Kato T, Ida K,
Watanabe H, Shimbo T; Research Group for
Establishment of Endoscopic Diagnosis of
Chronic Gastritis. Endoscopic diagnosis of gastricmucosal activity and inflammation. Dig Endosc
25(2): 136-46, 2013
Yamagata Y, Amikura K, Kawashima Y, Yatsuoka
T, Nishimura Y, Sakamoto H, Tanaka Y, Seto Y.
Staging laparoscopy in advanced gastric cancer:
usefulness and issues requiring improvement.
Hepato- gastroenterology 60(124): 751-5, 2013
Mitsui T, Goto O, Shimizu N, Hatao F, Wada I,
Niimi K, Asada-Hirayama I, Fujishiro M, Koike
K, Seto Y.Novel Technique for Full-Thickness
Resection of Gastric Malignancy: Feasibility ofNonexposed Endoscopic Wall-Inversion Surgery(NEWS) in Porcine Models.Surg Laparosc
Endosc Percutan Tech 23(6): e217-21,2013
Mori K, Yamagata Y, Wada I, Shimizu N,
Nomura S, Seto Y. Robotic-assisted totallytranshiatal lymphadenectomy in the middle
mediastinum for esophageal cancer.J Robot Surg
7:385-387,2013
Mitsui T, Fukatsu K, Yanagawa M, Amenomori S,
Ogawa E, Fukuda T, Murakoshi S, Moriya T,
Yasuhara H, Seto Y.Truncal vagotomy
temporarily decreases the pro- and antiinflammatory cytokine levels in the small
intestine. Surg Today. 2013
Shimoyama S.Diabetes mellitus carries a risk ofgastric cancer: a meta-analysis. World J
Gastroenterol 19(40): 6902-10, 2013

202

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

Associate Professor
Kiyoshi Hasegawa, MD.

Yoshihiro Sakamoto, MD.

Lecturers
Junichi Kaneko, MD.

Nobuhisa Akamatsu, MD.

Junichi Arita, MD.

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

1. 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
also are expected to submit a report on a theme of
specific surgical topics.

2. Research
We have published papers on Hepato-BiliaryPancreatic Surgery and liver transplantations 20-30/
year. The ongoing topics involve clinical applicationof ICG fluorescent images, especially for visualizationof biliary trees, hepatic tumors, hepatic hemodynamics, prospective clinical trials of adjuvant

203

chemotherapy for hepatocellular carcinoma, metastatic colorectal cancer, utility of contrast-enhanced
intraoperative ultrasonography, and preoperative
navigation for hepatic surgery.

3. Clinical Activities
Our division deals with patients with hepato-biliarypancreatic malignancies, liver cirrhosis, and HBP
benign diseases. We perform about 200 hepatectomies
for HCC and colorectal mets, 50 Whipples, and 20
liver transplantations, mainly from living donors. The
overall number of operation is about 430/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.

Publications (2014)
1. Omichi K, Inoue Y, Hasegawa K, et al.
Differential diagnosis of liver tumours using
intraoperative real-time tissue elastography. Br J
Surg. 2015;102:246-253.
2. Aoki T, Kokudo N, Komoto I, et al. Streptozocinchemotherapy for advanced/metastatic welldifferentiated neuroendocrine tumors: an analysis
of a multi-center survey in Japan. J Gastroenterol.
2014.
3. Harada N, Ishizawa T, Inoue Y, et al. Acoustic
radiation force impulse imaging of the pancreas
for estimation of pathologic fibrosis and risk of
postoperative pancreatic fistula. J Am Coll Surg.
2014;219:887-894 e885.
4. Mise Y, Hasegawa K, Shindoh J, et al. The
Feasibility of Third or More Repeat Hepatectomy
for Recurrent Hepatocellular Carcinoma. Ann
Surg. 2014.
5. Takemura N, Hasegawa K, Aoki T, et al. Surgicalresection of peritoneal or thoracoabdominal wall
implants from hepatocellular carcinoma. Br J
Surg. 2014;101:1017-1022.
6. Kokudo T, Hasegawa K, Yamamoto S, et al.
Surgical treatment of hepatocellular carcinoma
associated with hepatic vein tumor thrombosis. J
Hepatol. 2014;61:583-588.

7. Yoshioka R, Yasunaga H, Hasegawa K, et al.
Impact of hospital volume on hospital mortality,
length of stay and total costs after pancreaticoduodenectomy. Br J Surg. 2014;101:523-529.
8. Satou S, Aoki T, Kaneko J, et al. Initial
experience of intraoperative three-dimensionalnavigation for liver resection using real-time
virtual sonography. Surgery. 2014;155:255-262.
9. 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 Suppl 3:S348-355.
10. Oba M, Hasegawa K, Matsuyama Y, et al.
Discrepancy between recurrence-free survival andoverall survival in patients with resectable
colorectal liver metastases: a potential surrogate
endpoint for time to surgical failure. Ann Surg
Oncol. 2014;21:1817-1824.
11. Yoshioka R, Hasegawa K, Mise Y, et al.
Evaluation of the safety and efficacy ofsimultaneous resection of primary colorectal
cancer and synchronous colorectal liver
metastases. Surgery. 2014;155:478-485.
12. Ishizawa T, Masuda K, Urano Y, et al.
Mechanistic background and clinical applicationsof indocyanine green fluorescence imaging of
hepatocellular carcinoma. Ann Surg Oncol. 2014;
21:440-448.
13. Kaneko J, Inagaki Y, Ishizawa T, et al.
Photodynamic therapy for human hepatoma-cellline tumors utilizing biliary excretion properties
of indocyanine green. J Gastroenterol. 2014;49:
110-116.
14. Hasegawa K, Makuuchi M, Kokudo N, et al.
Impact of histologically confirmed lymph nodemetastases on patient survival after surgicalresection for hepatocellular carcinoma: report of aJapanese nationwide survey. Ann Surg. 2014;259:
166-170.
15. Aoki T, Kokudo N, Matsuyama Y, et al.
Prognostic impact of spontaneous tumor rupture
in patients with hepatocellular carcinoma: ananalysis of 1160 cases from a nationwide survey.
Ann Surg. 2014;259:532-542.

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Department of Urology
Professor
Yukio Homma, M.D., Ph.D.

Associate Professor
Haruki Kume, M.D., Ph.D.,

Hiroshi Fukuhara, M.D., Ph.D.

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

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

Takeshi Azuma, M.D., Ph.D.,

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

Associate
Yukio Yamada, M.D.,

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

Tomoyuki Kaneko, M.D.

Aya Niimi, M.D.

Yuta Takeshima, M.D., Ph.D.,

Yuta Yamada, M.D.

Toru Sugihara, M.D., Ph.D.,

Akiyoshi Takeuchi, M.D.

Yoichi Fujii, M.D.

Tarou Teshima, 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 1,400 from January 2014 to December 2014.
Elective operations are performed on Tuesday,
Wednesday and Thursday. 1,321 operations were
performed in 2014. The numbers of main operations

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are adrenalectomy 18, nephrectomy 33, partial
nephrectomy 32, nephroureterectomy 27, radical
cystectomy 24, radical prostatectomy 98, transurethralresection of the bladder tumor (TUR-Bt) 164,transurethral resection of the prostate (TUR-P) 4,
laparoscopic surgery 44, and Robot assisted surgery
103.
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 25,000 patientdays from January 2014 to December 2014.

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
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2. 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, 34: 368, 2015
3. 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
4. Arai, E., Sakamoto, H., Ichikawa, H. et al.:Multilayer-omics analysis of renal cell carcinoma,
including the whole exome, methylome andtranscriptome. Int J Cancer, 135: 1330, 2014
5. Fujii, Y., Ikeda, M., Kurosawa, K. et al.: Different
clinicopathological features between patients whodeveloped early and late recurrence following
surgery for renal cell carcinoma. International
journal of clinical oncology: 1, 2014
6. Fujimura, T., Takahashi, S., Urano, T. et al.:Expression of androgen and estrogen signaling
components and stem cell markers to predictcancer progression and cancer-specific survival inpatients with metastatic prostate cancer. Clin
Cancer Res, 20: 4625, 2014
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. Hamasaki, Y., Doi, K., Tanaka, M. et al.:Increased peritoneal permeability at peritoneal
dialysis initiation is a potential cardiovascular riskin patients using biocompatible peritoneal dialysis
solution. BMC nephrology, 15: 173, 2014
9. Hamasuna, R., Tanaka, K., Hayami, H. et al.:Treatment of acute uncomplicated cystitis with

206

faropenem for 3 days versus 7 days: multicentre,
randomized, open-label, controlled trial. J
Antimicrob Chemother, 69: 1675, 2014
10. Hattori, M., Tonooka, A., Zaitsu, M. et al.:Overexpression of aquaporin 1 in the tunica
vaginalis may contribute to adult-onset primaryhydrocele testis. Adv Urol, 2014: 202434, 2014
11. Homma, Y., Fujimura, T.: Linguistic validation of
the English version of the Overactive Bladder
Symptom Score. Int J Urol, 21: 229, 2014
12. Ichimura, T., Morikawa, T., Kawai, T. et al.:Prognostic significance of CD204-positive
macrophages in upper urinary tract cancer. Ann
Surg Oncol, 21: 2105, 2014
13. Igawa, Y., Kumano, S., Aizawa, N. et al.: Changes
in the function and expression of T-type andN-type calcium channels in the rat bladder after
bladder outlet obstruction. J Urol, 191: 1159,
2014
14. 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
15. Iwatsubo, E., Suzuki, M., Igawa, Y. et al.:Individually tailored ultrasound-assisted promptedvoiding for institutionalized older adults withurinary incontinence. Int J Urol, 21: 1253, 2014
16. Kamei, J., Nishimatsu, H., Nakagawa, T. et al.:Risk factors for septic shock in acute obstructive
pyelonephritis requiring emergency drainage ofthe upper urinary tract. Int Urol Nephrol, 46: 493,
2014
17. 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
18. Kawai, T., Enomoto, Y., Morikawa, T. et al.: Highexpression of heat shock protein 105 predicts afavorable prognosis for patients with urinary
bladder cancer treated with radical cystectomy.
Mol Clin Oncol, 2: 38, 2014
19. Koido, S., Enomoto, Y., Apostolopoulos, V. et al.:Tumor regression by CD4 T-cells primed withdendritic/tumor fusion cell vaccines. Anticancer
Res, 34: 3917, 2014
20. Kume, H., Kawai, T., Nagata, M. et al.:Intermittent docetaxel chemotherapy is feasible

for castration-resistant prostate cancer. Mol Clin
Oncol, 3: 303, 2015
21. Maekawa, S., Suzuki, M., Arai, T. et al.:TMPRSS2 Met160Val polymorphism: significant
association with sporadic prostate cancer, but notwith latent prostate cancer in Japanese men. Int J
Urol, 21: 1234, 2014
22. Matsushita, H., Enomoto, Y., Kume, H. et al.: A
pilot study of autologous tumor lysate-loaded
dendritic cell vaccination combined with sunitinib
for metastatic renal cell carcinoma. J Immunother
Cancer, 2: 30, 2014
23. Minagawa, T., Aizawa, N., Igawa, Y. et al.: The
role of transient receptor potential ankyrin 1(TRPA1) channel in activation of single unit
mechanosensitive bladder afferent activities in therat. Neurourol Urodyn, 33: 544, 2014
24. Nakamura, M., Yamazaki, O., Shirai, A. et al.:Preserved Na/HCO3 cotransporter sensitivity toinsulin may promote hypertension in metabolic
syndrome. Kidney international, 87: 535, 2015
25. Niimi, A., Igawa, Y., Fujimura, T. et al.:Midurethral autologous fascial sling surgery withreconstruction of the lower abdominal wall using
the tensor fascia lata muscle flap for posthemipelvectomy stress urinary incontinence. Int J
Urol, 21: 949, 2014
26. Nishimatsu, H., Kitamura, T., Yamada, D. et al.:Improvement of symptoms of aging in males by apreparation LEOPIN ROYAL containing aged
garlic extract and other five of natural medicines comparison with traditional herbal medicines(Kampo). Aging Male, 17: 112, 2014
27. Nose, Y., Ishikawa, A., Taguchi, S. et al.:Pathology-based assessment of the treatment
effect of high intensity focused-ultrasound fororgan-confined prostate cancer. Japanese Journalof Endourology, 27: 207, 2014
28. Obinata, D., Ito, A., Fujiwara, K. et al.: Pyrroleimidazole polyamide targeted to break fusion sites
in TMPRSS2 and ERG gene fusion represses
prostate tumor growth. Cancer Sci, 105: 1272,
2014
29. Sasaki, Y., Sasaki, T., Kawai, T. et al.: HER2
protein overexpression and gene amplification in
upper urinary tract urothelial carcinoma-an

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analysis of 171 patients. Int J Clin Exp Pathol, 7:699, 201430. Sato, Y., Maekawa, S., Ishii, R. et al.: Recurrent
somatic
mutations
underliecorticotropinindependent Cushing's syndrome. Science, 344:
917, 201431. Shirai, A., Yamazaki, O., Horita, S. et al.:Angiotensin II dose-dependently stimulates
human renal proximal tubule transport by thenitric oxide/guanosine 3',5'-cyclic monophosphatepathway. J Am Soc Nephrol, 25: 1523, 201432. Sugihara, T., Yasunaga, H., Horiguchi, H. et al.:Factors affecting choice between ureterostomy,
ileal conduit and continent reservoir after radical
cystectomy: Japanese series. International journalof clinical oncology, 19: 1098, 2014
33. Sugihara, T., Yasunaga, H., Horiguchi, H. et al.:Performance comparisons in major uro ‐oncological surgeries between the USA and Japan.
International Journal of Urology, 21: 1145, 201434. Sugihara, T., Yasunaga, H., Horiguchi, H. et al.:
Does mechanical bowel preparation ameliorate
damage from rectal injury in radical
prostatectomy? Analysis of 151 rectal injury cases.
International Journal of Urology, 21: 566, 201435. Sugihara, T., Yasunaga, H., Horiguchi, H. et al.:Robot ‐ assisted versus other types of radical
prostatectomy: Population‐based safety and costcomparison in Japan, 2012–2013. Cancer science,
105: 1421, 201436. Sugihara, T., Yasunaga, H., Horiguchi, H. et al.:Comparison of Perioperative Outcomes including
Severe Bladder Injury between Monopolar and
Bipolar Transurethral Resection of Bladder
Tumors: A Population Based Comparison. The
Journal of urology, 192: 1355, 201437. Sugihara, T., Yasunaga, H., Yu, C. et al.:Perioperative Outcome Comparisons Between
Open and Laparoscopic Nephroureterectomy
Among a Population-Based Cohort from 2010 to2012. Journal of Endourology, 201438. Sugihara, T., Yu, C., Kattan, M. W. et al.:Long-term survival of extremely advanced
prostate cancer patients diagnosed with prostatespecific antigen over 500 ng/ml. Jpn J Clin Oncol,
44: 1227, 201439. Suzuki, E., Nishimatsu, H., Homma, Y.: Stem celltherapy for erectile dysfunction. World J Clin Urol,
3: 272, 2014
40. Taguchi, S., Fukuhara, H., Azuma, T. et al.:Ultra-early versus early salvage androgendeprivation therapy for post-prostatectomy
biochemical recurrence in pT2-4N0M0 prostatecancer. BMC Urol, 14: 81, 2014
41. Taguchi, S., Fukuhara, H., Kakutani, S. et al.:Risk factors for clinical metastasis in men
undergoing radical prostatectomy and immediateadjuvant androgen deprivation therapy. Asian Pac
J Cancer Prev, 15: 10729, 2014
42. Takagi, T., Sugihara, T., Yasunaga, H. et al.:Cytoreductive nephrectomy for metastatic renal
cell carcinoma: A population‐based analysis ofperioperative outcomes according to clinical stage.
International Journal of Urology, 21: 770, 2014
43. Takahashi, S., Suzuki, M., Kume, H. et al.:Combination
chemotherapyofdocetaxel,
ifosfamide and cisplatin (DIP) in patients withmetastatic urothelial cancer: a preliminary report.
Jpn J Clin Oncol, 35: 79, 2005
44. Takayama, K., Suzuki, T., Tsutsumi, S. et al.:Integrative analysis of FOXP1 function reveals atumor-suppressive effect in prostate cancer. Mol
Endocrinol, 28: 2012, 2014
45. 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
46. Takayama, K.-i., Suzuki, T., Fujimura, T. et al.:CtBP2 modulates the androgen receptor topromote prostate cancer progression. Cancer
research, 74: 6542, 2014
47. Terada, N., Shiraishi, T., Zeng, Y. et al.:Correlation of Sprouty1 and Jagged1 withaggressive prostate cancer cells with different
sensitivities to androgen deprivation. J Cell
Biochem, 115: 1505, 2014
48. Tsurumaki Sato, Y., Fukuhara, H., Suzuki, M. etal.: Long-term results of radical prostatectomy
with immediate adjuvant androgen deprivation
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49. van Koeveringe, G. A., Rademakers, K. L., Birder,
L. A. et al.: Detrusor underactivity: Pathophysiologicalconsiderations,modelsandproposals for future research. ICI-RS 2013.
Neurourol Urodyn, 33: 591, 2014
50. Yamada, D., Matsushita, H., Azuma, T. et al.:Granulocyte macrophage colony-stimulating
factor as a predictor of the response of metastatic
renal cell carcinoma to tyrosine kinase inhibitor
therapy. Mol Clin Oncol, 2: 1023, 2014
51. Yamaguchi, O., Marui, E., Kakizaki, H. et al.:Phase III, randomised, double-blind, placebocontrolled study of the beta3-adrenoceptor agonist
mirabegron, 50 mg once daily, in Japanesepatients with overactive bladder. BJU Int, 113:
951, 2014
52. Yamamoto, S., Kato, M., Tomiyama, Y. et al.:Management of men with a suspicion of prostatecancer after negative initial prostate biopsy results.
Urol Int, 92: 258, 2014
53. Yamanishi, T., Homma, Y., Nishizawa, O. et al.:Multicenter, randomized, sham‐controlled study
on the efficacy of magnetic stimulation for womenwith urgency urinary incontinence. International
Journal of Urology, 21: 395, 2014
54. 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.

Associate professor
Joji Kitayama, M.D., Ph.D.

Lecturer
Eiji Sunami, M.D., Ph.D.,

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

Assistant Professor
Shinsuke Kazama, M.D., Ph.D.

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

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

Keisuke Hata, M.D., Ph.D.

Tomomichi Kiyomatsu M.D., Ph.D.

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

Junichiro Tanaka, M.D., Ph.D.

Takeshi Nishikawa, 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, one Associate Professor,
two Lecturers and nine Assistant Professors. The
outpatient office is located on the third floor of the
Outpatient Building. The ward is situated on theeighth floor of the Ward Building. The administrative
office and research laboratories are located in the
Administration and Research Building. Current
activities of the Department of Surgical Oncology inclinical practice, education, and research aresummarized as follows.

Clinical activities
The Department of Surgical Oncology provides
comprehensive evaluation, diagnosis, treatment andmanagement for adult patients with both general andoncologic surgical problems, in the ambulatory as wellas inpatient setting. In particular, we are trying to
identify the best way to treat each patient with theleast surgical stress by minimally invasive surgery
such as laparoscopic surgery and robotic surgery (daVinci), and preoperative chemoradiotherapy for rectal
cancer. The department is also well known for its
innovative therapy for inflammatory bowel disease.
Department specialists have expertise in biologicalcancer immunotherapy, chemotherapy for a variety ofmalignancies, and radiotherapy for rectal cancer. The
outpatient clinic is open from Monday through Friday,
and twenty-four-hour consultation is available forurgent or emergency problems.
The outpatient clinic is specialized in the lower GI
tract. The Department was responsible for 571
surgically treated inpatients in the year of 2014. 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,

210

research conferences are held every Monday morning.
Each research unit holds its own conference every
week. Over 1200 colonoscopies are performed for ayear. The newest technologies are introduced for
diagnosis and treatment of colon and rectal cancer andlong-term surveillances for inflammatory bowel
disease are performed.

Teaching activities
The Department of Surgical Oncology also offers afellowship in surgical oncology for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in surgicaloncology. The Department of Surgical Oncology has a
Surgical Oncology Training Program and provides
broad reaching experience in technical aspects ofdiagnosis, treatment and management for adultpatients with both surgical and oncologic problems,development of surgical judgment, and increasing
knowledge about routine and complex conditions. In
addition, the dedicated staff allows multiple
opportunities for academic development both along
clinical and basic scientific lines.
In the undergraduate education program, ourdepartment plays a role in the systemic and clinicallectures and the bedside learning program for 3rd year
medical students, in cooperation with other departments of surgery. In the systemic lectures on surgery
for the fiscal year of 2014, various fields were covered
such as surgical oncology and immunology, injury,
somatic reaction to surgery, infectious diseases, shock,pre- and post-surgical management and nutrition. In
the clinical lectures, we presented many diseases suchas colon cancer, colonic polyp, colonic polyposis andulcerative colitis. In the postgraduate education
program, new residents are trained to become
qualified surgeons. In addition to pre- and postsurgery clinical conferences, the residents are
expected to attend research conferences and seminars,
which are held periodically. They are also asked topresent cases at clinical meetings, which are held
locally such as the local meeting of the JapaneseSociety of Gastroenterology.

Research activities
We apply the techniques used in molecular andcellular biology to our research. The following are themajor themes under research.
1) Preoperative radiotherapy in lower rectal cancer
2) Cancer surveillance in ulcerative colitis
3) Carcinogenesis in ulcerative colitis
4) Laparoscopically assisted colon surgery
5) Local immunity in colorectal cancer
6) Genetic analysis of colorectal cancer andadenoma
7) Prognostic factor of early colorectal cancer8) Surveillance program following colectomy forcolorectal cancer
9) The mechanism of liver metastasis of colorectal
cancer10) Dendritic cell Immunotherapy for advanced
cancer11) Cancer Immunotherapy targeting to the tumor
vessels12) Role of LPA S1P and productive enzymes intumor metastasis
13) Lipid metabolism in carcinogenesis and tumor
progression14) Role of peripheral nerve on the growth og
gastrointestinal cancer15) Genetic analysis on sensitivity to chemotherapeutic agents16) Hemostasis and fibrinolysis in Oncology17) Adiponectin and adiponectin receptors in Oncology18) Intraabdominal chemotherapy for peritoneal
metastasis of gastric cancer
19) Pharmacokinetics in intraperitoneal chemotherapy20) Fibroblast Growth Factor (FGF) in inflammatory
bowel disease21) Genetic analysis of undifferentiated colorectal
cancer22) High Frequency Ultrasonography (HIFU) for
solid cancer23) Quantitative analysis of intraperitoneal cancer
cells in peritonitis carcinomatosis24) Immunomodulation in chemoradiotherapy for
locally advanced rectal cancer25) Autophagy in Oncology
26) Robot assisted laparoscopic colorectal surgery (daVinci)

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References
1. Abe S, Yamaguchi H, Murono K, et al. Passage of a
Sigmoid Colon Cast in a Patient With Ischemic
Colitis. Int Surg 2014;99:500-5.
2. Emoto S, Kitayama J, Ishigami H, Yamaguchi H and
Watanabe T. Clinical significance of cytologicalstatus of peritoneal lavage fluid during intraperitoneal chemotherapy for gastric cancer withovert peritoneal dissemination. Ann Surg Oncol
2015;22:780-6.
3. Emoto S, Sunami E, Yamaguchi H, et al. Drugdevelopment for intraperitoneal chemotherapy
against peritoneal carcinomatosis from gastrointestinal cancer. Surg Today 2014.
4. Emoto S, Yamaguchi H, Kamei T, et al.
Intraperitoneal administration of cisplatin via an insitu cross-linkable hyaluronic acid-based hydrogelfor peritoneal dissemination of gastric cancer. Surg
Today 2014;44:919-26.
5. Fujii M and Sato T. Culturing intestinal stem cells:
applications for colorectal cancer research. Front
Genet 2014;5:169.
6. Hata K, Kazama S, Nozawa H, et al. Laparoscopic
surgery for ulcerative colitis: a review of theliterature. Surg Today 2014.
7. Iida Y, Kawai K, Tsuno NH, et al. Proximal shift ofcolorectal cancer along with aging. Clin Colorectal
Cancer 2014;13:213-8.
8. Iida Y, N HT, Kishikawa J, et al. Lysophosphatidylserine stimulates chemotactic migration of colorectal
cancer cells through GPR34 and PI3K/Akt pathway.
Anticancer Res 2014;34:5465-72.
9. Ishihara S, Hayama T, Yamada H, et al. Prognostic
Impact of Primary Tumor Resection and Lymph
Node Dissection in Stage IV Colorectal Cancer with
Unresectable Metastasis: A Propensity Score
Analysis in a Multicenter Retrospective Study. Ann
Surg Oncol 2014;21:2949-55.
10. Ishihara S, Matsuda K, Tanaka T, et al. Patient
Factors Predisposing to Complications Following
Laparoscopic Surgery for Colorectal Cancers. Surg
Laparosc Endosc Percutan Tech 2014.
11. Ishihara S, Nishikawa T, Tanaka T, et al. Prognostic
impact of tumor location in stage IV colon cancer: A
propensity score analysis in a multicenter study. Int J
Surg 2014;12:925-30.

12. Kaneko M, Nozawa H, Hiyoshi M, et al.
Temsirolimus and chloroquine cooperatively exhibit
a potent antitumor effect against colorectal cancer
cells. J Cancer Res Clin Oncol 2014;140:769-81.
13. Kawai K, Ishihara S, Yamaguchi H, et al.
Nomogram Prediction of Metachronous Colorectal
Neoplasms in Patients With Colorectal Cancer. Ann
Surg 2014.
14. Kawai K and Watanabe T. Colorectal cancer andhypercoagulability. Surg Today 2014;44:797-803.
15. Kazama S, Kitayama J, Sunami E, et al. Urethralmetastasis from a sigmoid colon carcinoma: a quiterare case report and review of the literature. BMC
Surg 2014;14:31.
16. Kim HJ, Choi GS, Park JS, et al. ClinicalSignificance of Thrombocytosis Before Preoperative
Chemoradiotherapy in Rectal Cancer: Predicting
Pathologic Tumor Response and Oncologic
Outcome. Ann Surg Oncol 2014.
17. Kitayama J. Intraperitoneal chemotherapy against
peritoneal carcinomatosis: current status and future
perspective. Surg Oncol 2014;23:99-106.
18. Kitayama J, Emoto S, Yamaguchi H, et al. Flowcytometric quantification of intraperitoneal freetumor cells in patients with peritoneal metastasis.
Cytometry B Clin Cytom 2014;86:56-62.
19. Kitayama J, Emoto S, Yamaguchi H, Ishigami H and
Watanabe T. CD90+ mesothelial-like cells inperitoneal fluid promote peritoneal metastasis byforming a tumor permissive microenvironment.
PLoS One 2014;9:e86516.
20. Kitayama J, Emoto S, Yamaguchi H, Ishigami H and
Watanabe T. Intraperitoneal paclitaxel induces
regression of peritoneal metastasis partly bydestruction of peripheral microvessels. Cancer
Chemother Pharmacol 2014;73:605-12.
21. Kitayama J, Emoto S, Yamaguchi H, et al.
CD90(+)CD45(-) intraperitoneal mesothelial-likecells inhibit T cell activation by production ofarginase I. Cell Immunol 2014;288:8-14.
22. Kitayama J, Ishigami H, Yamaguchi H, Emoto S and
Watanabe T. Intraperitoneal Paclitaxel is useful asadjuvant chemotherapy for advanced gastric cancer
with serosal exposure. Case Rep Oncol 2014;7:
58-64.
23. Kitayama J, Ishigami H, Yamaguchi H, et al.
Salvage gastrectomy after intravenous and212

intraperitoneal paclitaxel (PTX) administration withoral S-1 for peritoneal dissemination of advanced
gastric cancer with malignant ascites. Ann Surg
Oncol 2014;21:539-46.
24. Murono K, Kawai K, Tsuno NH, et al. Barium
enema and CT volumetry for predicting pathologic
response to preoperative chemoradiotherapy inrectal cancer patients. Dis Colon Rectum 2014;57:715-24.
25. Murono K, Kazama S, Yamaguchi H, et al.
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 2015;157:322-30.
26. Nirei T, Kazama S, Hiyoshi M, et al. Successfultreatment of rectovaginal fistula complicating
ulcerative colitis with infliximab: a case report andreview of the literature. J Clin Med Res 2015;
7:59-61.
27. Nishikawa T, Sunami E, Tanaka T, et al. Incidence
and prognostic significance of positive peritoneal
lavage in colorectal cancer. Surg Today 2014.
28. Nozawa H, Kanazawa T, Tanaka T, et al.
Laparoscopic resection of a gastrointestinal stromal
tumor of the lower rectum in a patient with coronary
artery disease following long-term neoadjuvant
imatinib treatment and anticoagulation therapy.
World J Surg Oncol 2014;12:211.
29. Ozawa T, Ishihara S, Nishikawa T, et al. Prognostic
Significance of the Lymph Node Ratio in Stage IV
Colorectal Cancer Patients who have Undergone
Curative Resection. Ann Surg Oncol 2014.
30. Ozawa T, Kazama S, Akiyoshi T, et al. Nuclear
Notch3 expression is associated with tumor
recurrence in patients with stage II and III colorectal
cancer. Ann Surg Oncol 2014;21:2650-8.
31. Sunami E and Watanabe T. The laser capture
microdissection cannot be replaced with themacrodissection. Exp Mol Pathol 2014;96:206.
32. Tada N, Tsuno NH, Kawai K, et al. Changes in theplasma levels of cytokines/chemokines forpredicting the response to chemoradiation therapy inrectal cancer patients. Oncol Rep 2014;31:463-71.
33. Tanaka T, Yoshida S, Nishikawa T, et al.
Self-expandable metallic stent placement as a bridgeto laparoscopic or open surgery for obstructive

colorectal cancer: short-term outcomes ofconsecutive nineteen cases. Gastroenterology andHepatology 2014;1:20-5.
34. Watanabe K, Sasaki I, Fukushima K, et al.
Long-term incidence and characteristics of intestinal
failure in Crohn's disease: a multicenter study. J
Gastroenterol 2014;49:231-8.
35. Watanabe T, Kobunai T, Akiyoshi T, et al. Predictionof response to preoperative chemoradiotherapy inrectal cancer by using reverse transcriptase
polymerase chain reaction analysis of four genes.
Dis Colon Rectum 2014;57:23-31.
36. Yamamoto Y, Goto N, Miura K, et al. Developmentof a novel efficient method to construct anadenovirus library displaying random peptides on
the fiber knob. Mol Pharm 2014;11:1069-74.
37. Yamamoto Y, Hiraoka N, Goto N, et al. A targeting
ligand enhances infectivity and cytotoxicity of an
oncolytic adenovirus in human pancreatic cancer
tissues. J Control Release 2014;192:284-93.
38. Yokoyama Y, Kawai K, Kazama S, et al. A case of
extraperitoneal stoma-associated internal hernia
after abdominoperineal resection. World J Surg
Oncol 2014;12:141.
39. Yoshioka R, Hasegawa K, Mise Y, et al. Evaluationof the safety and efficacy of simultaneous resectionof primary colorectal cancer and synchronouscolorectal liver metastases. Surgery 2014;155:478-85.

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

Lecturer
Kunihiro Shigematsu, M.D., Ph.D., 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.,

Ayako Nishiyama, 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, two Associate Professor,
and four Associates. 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. Suzuki JI, Aoyama N, Aoki M, Tada Y, Wakayama
K, Akazawa H, Shigematsu K, Hoshina K, Izumi
Y, Komuro I, Miyata T, Hirata Y, Isobe M. Highincidence of periodonitis in Japanese patients withabdominal aortic aneurysm. Int Heart J 2014 Epubahead of print.
2. Yamamoto S, Hoshina K, Kimura H, Okamoto H,
Shigematsu K, Miyata T, Watanabe T. Clinicalanalysis of non-anastomotic aneurysm of
implanted prosthetic grafts. Surg Today 2014
Epub ahead of print
3. Hoshina K, Hashimoto T, Kato M, Ohkubo N,
Shigematsu K, Miyata T. Feasibility ofendovascular abdominal aortic aneurysm repair
outside of the instructions for use andmorphological changes at 3 years after theprocedure. Ann Vasc Dis 2014;7:34-9.
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 a ruptured abdominal
aortic aneurysm. Heart Vessels 2014 Epub aheadof print

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5. Suzuki JI, Aoyama N, Aoki M, Tada Y, Wakayama
K, Akazawa H, Shigematsu K, Hoshina K, Izumi
Y, Komuro I, Miyata T, Isobe M. Incidence of
periodontitis
inJapanesepatients
withcardiovascular diseases: a comparison between
abdominal aortic aneurysm and arrhythmia. Heart
Vessels 2014 Epub ahead of print
6. Hoshina K, Nemoto M, Shigematsu K, Nishiyama
A, Hosaka A, Miyahara T, Okamoto H, Watanabe
T. The effect of suprarenal aortic cross-clamping:
Juxtarenal versus infrarenal short and/or large
neck abdominal aortic aneurysm. Circ J 2014;78:2219-24.
7. Hosaka A, Miyata T, Nishiyama A, Miyahara T,
Hoshina K, Shigematsu K. Preservation of theaccessary renal arteries after endovascular repairof common iliac artey aneurysm using kissing
stent grafts. J Vasc Surg 2014 Epub ahead of print
8. Akai A, Watanabe Y, Hoshina K, Obitsu Y,
Deguchi J, Sato O, Shigematsu K, Miyata T.
Familiy history of aortic aneurysm is anindependent risk factor for more rapid growth ofsmall abdominal aortic aneurysm in Japan. J Vasc
Surg 2014 Epuf ahead of print
9. Hosaka A, Miyata T, Hoshina K, Okamoto H,
Shigematsu K, Ohshima A. Prognosis of arterial
aneurysm after surgery in patients with Behçet'sdisease. Int Angiol 2014;33:419-25.
10. Hoshina K, Akai T, Shigematsu K, Miyata T,
Watanabe T. Family history of aortic or
intracranial aneurysm is associated withabdominal aortic aneurysm rupture: An
exploratory study. J Vasc Med Surg 2014;2:159.
11. Yamamoto S, Hoshina K, Hosaka A, Shigematsu
K, Watanabe T. Long-term outcomes of surgicaltreatment in patients with popliteal artery
entrapment syndrome. Vascular 2014;Online first,
Nov.
12. Taniguchi R, Hosaka A, Miyahara T, Hoshina K,
Okamoto H, Shigematsu K, Miyata T, Sugiura R,
Yokobori Jr AT, Watanabe T. Viscoelastic
Deterioration of the Carotid Artery Vascular Wallis a Possible Predictor of Coronary Artery Disease.
J Atheroscler Thromb 2014;21:415-23.
13. Taniguchi R, Hoshina K, Hosaka A, Miyahara T,
Okamoto H, Shigematsu K, Miyata T, Watanabe T.

Strain Analysis of Wall Motion in Abdominal
Aortic Aneurysms. Ann Vasc Dis 2014;7:393-8.
14. Haga M, Hosaka A, Miyahara T, Hoshina K,
Shigematsu K, Watanabe T. Penetration of aninferior vena cava filter into the aorta. Ann Vasc
Dis 2014;7:413-6.
15. Akai T, Yamamoto K, Okamoto H, Shigematsu K,
Otsu H, Watanabe T, Miyata T. Usefulness of the
Bollinger scoring method in evaluating peripheralartery angiography with 64-low computed
tomography in patients with peripheral arterial
disease. Int Angiol 2014;33:426-33.
16. Yamamoto S, Hosaka A, Okamoto H, Shigematsu
K, Miyata T, Watanabe T. Efficacy ofrevascularization for critical limb ischemia inpatients with end-stage renal disease. Eur J Vasc
Endovasc Surg 2014;48:316-24.

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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,parathyroid, and adrenal gland. In additional totreatment for malignant cases of these diseases, we
perform surgical procedures for hyperfunctional
diseases. We co-work with the department of
endocrine internal medicine and have about 250
surgical procedures annually in total.

In breast surgery, more than a half of the mammary
cancer patients undergo the breast-preserving surgery.
In addition, sentinel node navigation surgery has been
adopted, resulting in better quality of postoperative
life. Reconstruction surgery for the breast cancer islikely to provide much better QOL. In this field, we
have started collaboration with the Department of
Plastic Surgery. Chemotherapy, hormone therapy andmolecular- targeting therapy play important roles intreatment of the breast cancer. We have accumulated a
lot of experience and achievement in this field.
Our clinical themes are 1) establishment of safe
proceduresfor
endocrine
surgery
without
complications; 2) diagnosis and treatment of microbreast lesions under ultrasonographic guides; 3)preoperative diagnosis for thyroid neoplasmas andbreast tumors based on telomerase activity using
Q-Fish.

Research Acitivities
Our section has been studying about the mostfundamental issues to surgery, i.e., “surgical stress”
which means postoperative physiological andendocrine internal reaction and “nutritional support”
for the postoperative patients. These are subjects to217

reduce the intra- and post-operative stresses thatwould be risky for the patients. Our section is like apioneer for this area in Japan and we establishedJapanese Society for Surgical Metabolism andNutrition in 1965. Graduate students organize main
study group and we have presentations at someinternational conferences each year.
The focus of our research is “surgical metabolism
and nutrition” and “the body’s adaptive responses
during postoperative recovery”. In addition, we havebeen engaged in the project of chemo-sensitivity ofbreast cancer and of treatment for breast tumors byhigh-energy ultrasound. Research details follow.
1) Mechanisms of cross tolerance among different
stresses (endotoxin - hypoxia/ hypoxia - hypoxia)
after surgery
2) Role of IGFR in breast cancer progression3) Bacterial translocation after anti-cancer chemotherapy4) Epigenetic analysis in thyroid cancer tissues5) Detection of circulating tumor cells (CTC) in
breast and thyroid cancer patients
6) Role of oxygen on local and systemic protein
metabolism after major surgery7) Ischemic preconditioning preserves renal dysfunction after ischemia-reperfusion
8) Detection of new tumor suppressor genes in breast
cancer tissues9) Detection of stem cell in breast cancer tisuues10) Chemo-sensitivity test in breast cancer

Publications
1. Kurabayashi R, Takubo K, Aida J, HonmaN, Poon
SSS,Kammori M, Izumiyama-Shimomura N,
Nakamura KI, Tsuji FI, Matsuura M, Ogawa T,
Kaminishi M. Luminal and cancer cells in thebreast show more rapid telomere shortening thanmyoepithelial cells and fibroblasts. Human Pathol
39:1647-1655,2008.
2. 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 18:68-72,2011.

3. Kikuyama M, Takeshima H, Kinoshita T, OkochiTakeda E, Wakabayashi M, Akashi-Tanaka S,
Ogawa T, Seto Y, Ushijima T. Development of anovel approach, the epigenome-based outlier
approach, to identify tumorsuppressor genes
silenced by abrrent DNA methylation. Cancer Let
322:204-212,2012.
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.
International journal of radiation oncology,
biology, physics. 84:331-5(2012). Epub 2012/03/
23.
5. Okubo M, Tada K, Niwa T, Nishioka K, Tsuji E,
Ogawa T, Seto Y. A case of breast cancer in theaxillary tail of Spence - enhanced magnetic
resonance imaging and positron emission
tomography for diagnostic differentiation andpreoperative treatment decision. World journal ofsurgical oncology. 11:217(2013).

Surgical Sciences
2. Sensory and Motor System Medicine

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

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

Takafumi Kadono, M.D., Ph.D

Lecturer
Rei Watanabe, M.D., Ph.D.

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

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

Yoshihide Asano, M.D., Ph.D

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

Zenshiro Tamaki, M.D., Ph.D

Associate
Mayuko Araki, M.D.

Sayaka Shibata, M.D., Ph.D.

Arisa Ito, M.D.

Takuya Miyagawa, 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, four
lecturers, two hospital lecturer and four associatestake part in inpatient and outpatient cares as well as
research and teaching activities. Forty-six doctors who
basically belong to our department are currently out inaffiliated hospitals mainly engaged in clinical works
there. Additionally, seven staff members are abroad atpresent, mainly involved in advanced research
activities in cell biology and molecular biology.

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 seventeen dermatologists who are studyingin the postgraduate course under the guidance of staff
members of our department.
In addition to series of lectures, clinical education isprovided for fifth- and sixth- grade medical students,

220

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. Asahina A, Uno K, Fujita H: Pustular psoriasis ina patient with Turner syndrome: profile of serum
cytokine levels. Int J Dermatol. 2014;53(1):e2932.
2. Kamata M, Sugaya M, Miyagaki T, Sonoda K,
Ichimura Y, Mitsui H, Kamikubo Y, Kurokawa M,
Sato S: A case of CD20-positive peripheral T-cell
lymphoma treated with rituximab and multiagent
chemotherapy. Int J Dermatol. 2014;53(1):e24-6.
3. Suga H, Sugaya M, Miyagaki T, Ohmatsu H,
Fujita H, Sato S: Primary cutaneous γδ T-cell
lymphoma following mycosis fungoides. Int J
Dermatol. 2014;53(2):e82-4.
4. Ohmatsu H, Sugaya M, Fujita H, Kadono T, Sato
S: Primary cutaneous follicular helper T-cell
lymphoma treated with allogeneic bone marrowtransplantation: immunohistochemical comparison with angioimmunoblastic T-cell lymphoma.
Acta Derm-Venereol. 2014;94(1):54-7.
5. Kawaguchi M, Sugaya M, Suga H, Miyagaki T,
Ohmatsu H, Fujita H, Asano Y, Tada Y, Kadono T,
Sato S: Serum levels of angiopoietin-2, but notangiopoietin-1, are elevated in patients witherythrodermic cutaneous T-cell lymphoma. Acta
Derm-Venereol. 2014;94(1):9-13.
6. Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Takata M, Ozeki A, Watanabe A,
Kawarasaki S, Taniguchi T, Ichimura Y, Toyama T,
Watanabe M, Hirata Y, Nagai R, Komuro I, Sato
S: Clinical correlation of brachial artery flow-

mediated dilation in patients with systemicsclerosis. Mod Rheumatol. 2014;24(1):106-11.
7. Ichimura Y, Asano Y, Akamata K, Aozasa N, Noda
S, Taniguchi T, Takahashi T, Toyama T, Sumida H,
Kuwano Y, Yanaba K, Tada Y, Sugaya M, Sato S,
Kadono T: Serum angiopoietin-like protein 3
levels: a possible correlation with progressive skinsclerosis, digital ulcers, and pulmonary vascular
involvement in patients with systemic sclerosis.
Acta Derm-Venereol. 2014;94(2):157-62.
8. Suga H, Sugaya M, Toyama T, Sumida H, Fujita
H, Kogure A, Igarashi A, Sato S: A case of
mycosis fungoides with large cell transformation
associated with infliximab treatment. Acta
Dermato-Venereol. 2014;94(2):233-4.
9. Sugaya M, Tokura Y, Hamada T, Tsuboi R, Moroi
Y, Nakahara T, Amano M, Ishida S, Watanabe D,
Tani M, Ihn H, Aoi J, Iwatsuki K: Phase II studyof intravenous interferon-γ in Japanese patientswith mycosis fungoides. J Dermatol. 2014;41(1):50-6.
10. Miyagaki T, Sugaya M: Immunological milieu inmycosis fungoides and Sézary syndrome. J
Dermatol. 2014;41(1):11-8.
11. Nakao M, Sugaya M, Suga H, Kawaguchi M,
Morimura S, Kai H, Ohmatsu H, Fujita H, Asano
Y, Tada Y, Kadono T, Sato S: Serum autotaxin
levels correlate with pruritus in patients withatopic dermatitis. J Invest Dermatol. 2014;134(6):1745-7.
12. Suga H, Sugaya M, Miyagaki T, Kawaguchi M,
Fujita H, Asano Y, Tada Y, Kadono T, Sato S: The
role of IL-32 in cutaneous T-cell lymphoma. J
Invest Dermatol. 2014;134(5):1428-35.
13. Akamata K, Asano Y, Aozasa N, Noda S,
Taniguchi T, Takahashi T, Ichimura Y, Toyama T,
Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya
M, Kadono T, Sato S: Serum levels of mannosebinding lectin in systemic sclerosis: a possible
contribution to the initiation of skin sclerosis in
the diffuse cutaneous subtype. Eur J Dermatol.
2014;24(1):123-5.
14. Suga H, Sugaya M, Fujita H, Asano Y, Tada Y,
Kadono T, Sato S: TLR4, rather than TLR2,
regulates wound healing through TGF-β andCCL5 expression. J Dermatol Sci. 2014;73(2):117-24.
15. Morimura S, Sugaya M, Kai H, Miyagaki T,
Asano Y, Tada Y, Kadono T, Murakami T, Sato S:
Depsipeptide and roxithromycin induce apoptosisof lymphoma cells by blocking ERK activation. J
Dermatol. 2014;41(1):57-62.
16. Masui Y, Asano Y, Akamata K, Aozasa N, Noda S,
Taniguchi T, Takahashi T, Ichimura Y, Toyama T,
Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya
M, Sato S, Kadono T: Serum resistin levels: apossible correlation with pulmonary vascular

221

involvement in patients with systemic sclerosis.
Rheumatol Int. 2014;34(8):1165-70.
17. Ichimura Y, Asano Y, Akamata K, Takahashi T,
Noda S, Taniguchi T, Toyama T, Aozasa N,
Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya
M, Sato S, Kadono T: Fli1 deficiency contributes
to the suppression of endothelial CXCL5
expression in systemic sclerosis. Arch Dermatol
Res. 2014;306(4):331-8.
18. Kimura T, Hamazaki TS, Sugaya M, Fukuda S,
Chan T, Tamura-Nakano M, Sato S, Okochi H:
Cilostazol Improves Lymphatic Function by
Inducing Proliferation and Stabilization of
Lymphatic Endothelial Cells. J Dermatol Sci.
2014;74(2):150-8.
19. Hasegawa M, Asano Y, Endo H, Fujimoto M,
Goto D, Ihn H, Inoue K, Ishikawa O, Kawaguchi
Y, Kuwana M, Ogawa F, Takahashi H, Tanaka S,
Sato S, Takehara K: Serum adhesion molecule
levels as prognostic markers in patients with earlysystemic sclerosis: a multicentre, prospective,
observational study. PLoS ONE. 2014;9(2):e88150.
20. Saeki H, Hayashi M, Hirota T, Nakagawa H,
Ishiuji Y, Matsuzaki H, Tsunemi Y, Kato T,
Shibata S, Sugaya M, Sato S, Tada Y, Doi S,
Miyatake A, Ebe K, Noguchi E, Ebihara T,
Amagai M, Esaki H, Takeuchi S, Furue M, Tamari
M: Genetic polymorphism in the TRAF3IP2 geneis associated with psoriasis vulgaris in a Japanese
population. J Dermatol Sci. 2014;73(3):264-5.
21. Sugaya M, Suga H, Miyagaki T, Fujita H, Sato S:
Eosinophilic pustular folliculitis associated with
Sezary syndrome. Clin Exp Dermatol. 2014;
39(4):536-8.
22. Saigusa R, Sugaya M, Sunaga S, Sumida H, Suga
H, Fujita H, Yoshimi A, Sunaga S, Sato S: CD8+
aggressive lymphoma in a human T-cellleukaemia virus type-1 carrier. J Dermatol. 2014;41(5):443-4.
23. Tamaki Z, Asano Y, Kubo M, Ihn H, Tada Y,
Sugaya M, Kadono T, Sato S: Effects of theimmunosuppressant rapamycin on the expressionof human alpha2(I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts. J Dermatol Sci. 2014;74(3):251-9.
24. 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. 2014;
192(9):4361-9.
25. Sumida H, Asano Y, Tamaki Z, Aozasa N,
Taniguchi T, Takahashi T, Toyama T, Ichimura Y,
Noda S, Akamata K, Miyazaki M, Kuwano Y,
Yanaba K, Sato S: Successful experience ofrituximab therapy for systemic sclerosisassociated interstitial lung disease withconcomitant systemic lupus erythematosus. J
Dermatol. 2014;41(5):418-20.
26. Bhattacharyya S, Tamaki Z, Wang W, Hinchcliff
M, Hoover M, Getsios S, White ES, Varga J:
FibronectinEDA promotes chronic cutaneous
fibrosis through toll-like receptor signaling. Sci
Transl Med. 2014;6(232):232ra50.
27. Takahashi T, Asano Y, Sunaga R, Ichimura Y,
Taniguchi T, Yamamoto M, Tamaki Z, Takekoshi
T, Mitsui H, Sugaya M, Ohse T, Sato S:
Successful use of intravenous cyclophosphamide
pulse therapy for interstitial lung disease in apatient with systemic sclerosis on hemodialysis. J
Dermatol. 2014;41(6):533-5.
28. Akamata K, Asano Y, Aozasa N, Noda S,
Taniguchi T, Takahashi T, Ichimura Toyama T,
Sato S: Bosentan reverses the pro-fibrotic
phenotype of systemic sclerosis dermal fibroblasts
via increasing DNA binding ability of transcription factor Fli1. Arthritis Res Ther. 2014;16(2):R86.
29. Yamada D, Kadono T, Masui Y, Yanaba K, Sato S:
β7 integrin controls mast cell recruitment,
whereas αE integrin modulates the number andfunction of CD8+ T cells in immune complexmediated tissue injury. J Immunol. 2014;192(9):4112-21.
30. Aasano Y, Ihn H, Jinnin M, Tamaki Z, Tamaki K,
Sato S: Serum levels of matrix metalloproteinase13 in patients with eosinophilic fascitis. J
Dermatol. 2014;41(8):746-8.
31. Ohmatsu H, Humme D, Gulati N, Gonzalez J,
Möbs M, Suárez-Fariñas M, Cardinale I, Mitsui H,
Guttman-Yassky E, Sterry W, Kruger JG:
Interleukin-32 is progressively expressed in
Mycosis Fungoides independent of helper T-cell 2
and helper T-cell 9 polarization. Cancer Immunol
Res. 2014;2(9):890-900.
32. Suga H, Sugaya M, Miyagaki T, Ohmatsu H,
Kawaguchi M, Takahashi N, Fujita H, Asano Y,
Tada Y, Kadono T, and Sato S: Skin Barrier
Dysfunction and Relatively Low Antimicrobial
Peptide Expression in Cutaneous T-cell
Lymphoma. Clin Cancer Res. 2014;20(16):433948.
33. Taniguchi T, Asano Y, Tamaki Z, Takahashi T,
Ichimura Y, Toyama T, Kagami S, Mitsui H, Sato
S: Late-onset anaphylactic reactions following
intravenous cyclophosphamide pulse in a patientwith systemic sclerosis and systemic lupus
erythematosus overlap syndrome. J Dermatol.
2014 ;41(10):912-4.
34. Kimura T, Sugaya M, Suga H, Morimura S, Kai H,
Kagami S, Yanaba K, Fujita H, Asano Y, Tada Y,
Kadono T, Sato S: TARC and I-TAC are sensitive

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markers reflecting pruritus in atopic dermatitis.
Acta Derm-Venereol. 2014;94(3):331-2.
35. Taniguchi T, Asano Y, Tamaki Z, Akamata K,
Aozasa N, Noda S, Takahashi T, Ichimura Y,
Toyama T, Sugita M, Sumida H, Kuwano Y,
Miyazaki M, Yanaba K, Sato S: Histologicalfeatures of localized scleroderma ‘En coup desabre’: a study of 16 cases. J Eur Acad Dermatol
Venereol. 2014;28(12):1805-10.
36. Miyagawa T, Sugaya M, Okada A, Asano Y,
Kadono T, Sato S: Neutrophil-rich anaplastic
large cell lymphoma expressing interleukin-8.
Acta Derm Venereol. 2014;94(6):741-2.
37. Morimura S, Sugaya M, Suga H, Miyagaki T,
Ohmatsu H, Fujita H, Asano Y, Tada Y, Kadono T,
Sato S: TOX expression in different subtypes of
cutaneous lymphoma. Arch Dermatol Res. 2014;
306(9):843-9.
38. Noda S, Asano Y, Nishimura S, Taniguchi T, Fujiu
K, Manabe I, Nakamura K, Yamashita T, Saigusa
R, Akamata K, Takahashi T, Ichimura Y, Toyama
T, Tsuruta D, Trojanowska M, Nagai R, Sato S:
Simultaneous downregulation of KLF5 and Fli1 is
a key feature underlying systemic sclerosis. Nat
Commun. 2014 Dec 12;5:5797 .

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

Lecturer
Kotaro Yoshimura, M.D., Ph.D.

Project Lecturer
Takuya Iida, M.D., Ph.D.

Mitsunaga Narushima, M.D.

AssociateShuji Yamashita, M.D.

Yoko Tomioka, M.D.

Takumi Yamamoto, M.D.

Hisako Hara, M.D.

Shunsuke Tashiro, 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, 1
associate professor, 1 lecturer, 2 project lecturer, 5associates, 6 physicians, and 4 residents. There areabout 100 doctors in the department, but most areserving in rotation at affiliated hospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 20 available beds on the 10th floor in the New
Ward. Our faculty room is located in the Medical
Laboratory Building and laboratory rooms in the East
Laboratory Building.
The present status of the educational, research andclinical activities of the department is as follows.

Clinical Activities
The outpatient clinic is opened every morning from
Monday to Friday. There are several specialized
clinics for 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 Wednesday
morning. Preoperative and postoperative conferences
and seminar that all members of the department
should attend are held on Wednesday evening.
Research conferences are held on every Friday
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 theopportunity of seeing various diseases and disorders in

224

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

drainage.
15) Studies on mechanism of biological effects ofretinoids on epidermis and dermis.
16) Studies on regeneration of peripheral nerves.

References (2013)
1.

2.

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 stromalprogenitor 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

3.

4.

5.

6.

7.

8.

出版物等(2013)
Hara H, Mihara M, Seki Y, Todokoro T, Iida T,
Koshima I. Comparison of indocyanine green
lymphographic findings with the conditions ofcollecting lymphatic vessels of limbs in patientswith lymphedema Plast Reconstr Surg. 2013
Dec;132(6):1612-8.
Kisu I, Mihara M, Banno K, Umene K, Araki J,
Hara H, Suganuma N, Aoki D. Risks for donors
in uterus transplantation. Reprod Sci. 2013 Dec;
20(12):1406-15
Hara H, Mihara M, Seki Y, Koshima I.
Lymphoedema caused by idiopathic lymphatic
thrombus. J Plast Reconstr Aesthet Surg. 2013
Dec;66(12):1780-3.
Mihara M, Hara H, Araki J, Narushima M, Iida T,
Koshima I. Treatment of hand lymphedema withfree flap transfer and lymphangiogenesis analysis
after hand replantation using indocyanine green(ICG) lymphography and histological analysis.
J Plast Reconstr Aesthet Surg. 2013 Nov;66(11):e338-40
Todokoro T, Furniss D, Oda K, Kawana K,
Narushima M, Mihara M, Kikuchi K, Hara H,
Yano T, Koshima I. Effective treatment of pelvic
lymphocele by lymphaticovenular anastomosis.
Gynecol Oncol. 2013 Feb;128(2):209-14
Doi K, Tanaka S, Iida H, Eto H, Kato H, Aoi N,
Kuno S, Hirohi T, Yoshimura K.
Stromalvascular fraction isolated from lipo-aspirates
using an automated processing system: bench andbed analysis J Tissue Eng Regen Med. 2013;
7(11): 864-70
Yamamoto T, Narushima M, Yoshimatsu H,
Yamamoto N, Oka A, Seki Y, Todokoro T, Iida T,
Koshima I. Indocyanine green velocity: lymphtransportation capacity deterioration with progression of lymphedema. Ann Plast Surg. 2013 Nov;
71(5):591-4. doi:10.1097/SAP.0b013e318255168a.
Yamamoto T, Yoshimatsu H, Narushima M,

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Yamamoto N, Koshima I. Split intravascular
stents for side-to-end lymphaticovenular anastomosis. Ann Plast Surg. 2013 Nov;71(5):538-40.
doi: 10.1097/SAP.0b013e318250f0a0.
9. Iida T, Narushima M, Yoshimatsu H, Yamamoto
T, Araki J, Koshima I. A free vascularised iliacbone flap based on superficial circumflex iliac
perforators for head and neck reconstruction.
J Plast Reconstr Aesthet Surg. 2013 Nov;66(11):1596-9. doi:10.1016/j.bjps.2013.03.031. Epub
2013 Apr 19.
10. Narushima M, Iida T, Kadono T, Hara H,
Yamamoto Y, Todokoro T, Mihara M, Koshima I.
Free concha flap for sensitive nasal reconstruction
using the infraorbital artery and nerve as arecipient vessel and a recipient nerve. Microsurgery. 2013 May;33(4):311-4. doi: 10.1002/micr.
22091. Epub 2013 Apr 9.
11. Yamamoto T, Yoshimatsu H, Yamamoto N,
Narushima M, Iida T, Koshima I. Side-to-end
Lymphaticovenular anastomosis through temporary lymphatic expansion. LoS One. 2013;8(3):e59523. doi: 10.1371/journal.pone.0059523. Epub
2013 Mar 25.
12. Yamamoto T, Yamamoto N, Azuma S, Todokoro T,
Koshima I. Handy thermography for bedsideevaluation of pressure ulcer. J Plast Reconstr
Aesthet Surg. 2013 Jul;66(7):e205-6. doi: 10.
1016/j.bjps.2013.02.005. Epub 2013 Mar 6. No
abstract available
13. Azuma S, Yamamoto T, Koshima I. Donor-site
lymphatic function after microvascular lymph
node transfer should be followed using indocyanine green lymphography. Plast Reconstr
Surg. 2013 Mar;131(3):443e-4e. doi: 10.1097/
PRS.0b013e31827c7194. No abstract available.
14. Tashiro K, Mihara M, Todokoro T, Narushima M,
Yamamoto T, Iida T, Araki J, Iwamoto T, Koshima
I. Christmas tree background for supermicrosurgical anastomosis with the presence of avertical interval. J Reconstr Microsurg. 2013
Mar;29(3):205-8. doi: 10.1055/s-0032-1331145.
Epub 2013 Jan 2. No abstract available.
15. Yamamoto T, Yamamoto N, Yoshimatsu H,
Narushima M, Koshima I.
LEC score: ajudgment tool for indication of indocyanine green
lymphography. Ann Plast Surg. 2013 Feb;70(2):227-30. doi: 10.1097/SAP.0b013e3182380861.
16. Yamamoto T, Yoshimatsu H, Narushima M, Seki
Y, Yamamoto N, Shim TW, Koshima I. A
modified side-to-end lymphaticovenular anastomosis. Microsurgery. 2013 Feb;33(2):130-3.
doi: 10.1002/micr.22040. Epub 2012 Sep 14.
17. Iida T, Mihara M, Yoshimatsu H, Narushima M,
Koshima I.
Reconstruction of the external
auditory canal using a super-thin superficial
circumflex iliac perforator flap after tumour
resection. J Plast Reconstr Aesthet Surg. 2013
Mar;66(3):430-3. doi: 10.1016/j.bjps.2012.08.005.
Epub 2012 Sep 10
18. Iida T, Mihara M, Narushima M, Todokoro T,
Hara H, Yoshimatu H, Koshima I, Kadono T.
Dynamic reconstruction of full-thickness abdominal wall defects using free innervated vastus
lateralis muscle flap combined with free anterolateral thigh flap. Ann Plast Surg. 2013 Mar;70(3):331-4. doi:10.1097/SAP.0b013e3182321b64.
19. Yamamoto T, Yamamoto N, Hara H, Mihara M,
Narushima M, Koshima I. Upper extremity
lymphedema index: a simple method for severity
evaluation of upper extremity lymphedema. Ann
Plast Surg. 2013 Jan;70(1):47-9. doi: 10.1097/
SAP.0b013e3182275d23.
20. Eto H, Ishimine H, Kinoshita K, Watanabe-Susaki
K, Kato H, Doi K, Kuno S, Kurisaki A,
Yoshimura K. Characterization of human adipose tissue-resident hematopoietic cell populations reveals a novel macrophage subpopulation
with CD34 expression and mesenchymal multipotency. Stem Cell Dev 22: 985-997, 2013.
21. Inoue K, Yoshimura K.
Isolation andcharacterization of human hair follicle epithelial
cells. Methods Mol Biol 946: 411-421, 2013.
22. Mashiko T, Mori H, Kato H, Doi K, Kuno S,
Kinoshita K, Kunimatsu A, Ohtomo K, Yoshimura
K. Semi-permanent volumization by an absorbable filler: Onlay injection technique to the bone.
Plast Reconstr Surg Glob Open 1: e4, 2013.
23. Bourin P, Bunnell BA, Casteilla L, Domonici M,
Katz AJ, March KL, Redl H, Rubin JP, Yoshimura
K, Gimble JM. Stromal cells from the adipose
tissue derived stromal vascular fraction (SVF) andculture expanded adipose-derived stromal/stem
cells (ASC): a joint statement of IFATS and ISCT.

226

Cytotherapy 15: 641-648, 2013.
24. Inoue K, Yoshimura K.
Skin stem cells.
Methods Mol Biol 989: 305-313, 2013.
25. Yang S, Eto H, Kato H, Doi K, Kuno S, Kinoshita
K, Ma H, Tsai CH, Chou WT, Yoshimura K.
Comparative characterization of stromal vascular
cells derived from three types of vascular wall andadipose tissue. Tissue Eng Part A 19:2724-2734,
2013.
26. Ishimine H, Yamakawa N, Sasao M, Tadokoro M,
Kami D, Komazaki S, Tokuhara M, Takada H, Ito
Y, Kuno S, Yoshimura K, Umezawa A, Ohgushi H,
Asashima M, Kurisaki A. N-Cadherin is a prospective cell surface marker of human mesenchymal stem cells that have high ability for cardiomyocyte differentiation. Biochem Biophys Res
Commun 438: 753-759, 2013

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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.

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

Noriko Hatano, D.D.S., Ph.D.

Madoka Sugiyama, D.D.S.

Yuki Kanno, 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. Abe M, Mori Y, Inaki R, Ohata Y, Abe T, Saijo H,
Ohkubo K, Hoshi K, Takato T. A case ofodontogenic infection by Streptococcus constellatus leading to systemic infection in a Cogan’s
syndrome patient. Case Reports in Dentistry,
2014;2014:793174.
2. Abe M, Mori Y, Kanno Y, Hoshi K, Saijo H, Abe
T, Ohkubo K, Takato T. A case of pleomorphic
adenoma of the parotid gland with multiple local
recurrences through facial to cervical region.
Open Journal of Stomatology, 2014; 4: 441-445.
3. Mori Y, Kanazawa S, Asawa Y, Sakamoto T, Inaki
R, Okubo K, Nagata S, Komura M, Takato T,
Hoshi K. Regenerative cartilage made by fusionof cartilage elements derived from chondrocyte
sheets prepared in temperature-responsive culture
dishes. J Hard Tissue Biol. 2014;23: 101-110.

4. Suenaga H, Unami M, Hoshi K, Mori Y, Takato T.
Rare case of composite embryonal rhabdomyosarcoma and leiomyosarcoma of the tongue of an
adult. J Oral Maxillofac Surg Med Pathol. 2014
Jan;26(1):30-34.
5. Uchiho T, Uzuka K, Suenaga H, Morita T. Quartz
force sensor and facing spiral coils for noncontact
detection. Jpn J Appl Phys. 2014 Jan;53(7S):
07KD09.
6. Kawase-Koga Y, Mori Y, Saijo H, Hoshi K,
Takato T. Reconstruction of a complex midface
defect from excision of a squamous cell
carcinoma, according to regional aesthetic units.
Oral Surg Oral Med Oral Pathol Oral Radiol.
2014 Feb;117(2):e97-e101.
7. Komura M, Komura H, Konishi K, Ishimaru T,
Hoshi K, Takato T, Tabata Y,Iwanaka T.
Promotion of tracheal cartilage growth by intratracheal injection of basic fibroblast growth factor(b-FGF). J Pediatr Surg. 2014 Feb;49(2):296-300.
8. Hayashida C, Ito J, Nakayachi M, Okayasu M,
Ohyama Y, Hakeda Y, Sato T.Osteocytes produce
interferon-β as a negative regulator of osteoclastogenesis. J Biol Chem. 2014 Apr 18;289(16):11545-55.
9. Kawase-Koga Y, Saijo H, Hoshi K, Takato T,
Mori Y. Surgical management of odontogenic
myxoma: a case report and review of the literature.
BMC Res Notes.2014 Apr 5;7:214.
10. Ohkubo K, Susami T, Inokuchi T, Okayasu M,
Takahashi N, Uwatoko K, Uchino N, Suenaga H,
Koga Y, Saijo H, Mori Y, Takato T. Incisor
inclination after presurgical orthodontic treatment
in patients with mandibular prognathism. Jpn J
Jaw Deform. 2014 Apr; 24(1):16-26.
11. Wang J, Suenaga H, Hoshi K, Yang L, Kobayashi
E, Sakuma I, Liao H. Augmented reality navigation with automatic marker-free image registration
using 3D image overlay for dental surgery. IEEE
Trans Biomed Eng. 2014 Apr;61(4):1295-1304.
12. Fujihara Y, Takato T, Hoshi K. Macrophageinducing fasl on chondrocytes forms immune
privilege in cartilage tissue engineering,enhancing in vivo regeneration. Stem Cells. 2014
May;32(5):1208-19.
13. Kanke K, Masaki H, Saito T, Komiyama Y, Hojo
H, Nakauchi H, Lichtler AC, Takato T, Chung UI,

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Ohba S. Stepwise differentiation of pluripotent
stem cells into osteoblasts using four small
molecules under serum-free and feeder-free
conditions. Stem Cell Reports. 2014 May 2(6):751-60.
14. Mishima K, Kitoh H, Haga N, Nakashima Y,
Kamizono J, Katagiri T, Susami T, Matsushita M,
Ishiguro N. Radiographic characteristics of thehand and cervical spine in fibrodysplasia
ossificans progressiva. Intractable Rare Dis Res.
2014 May;3(2):46-51.
15. Hikiji H, Tomizuka K, Taguchi T, Koyama H,
Chikazu D, Mori Y, Takato T. An in vivo murine
model for screening cranial bone regenerative
materials: testing of a novel synthetic collagen gel.
J Mater Sci Mater Med. 2014 Jun;25(6):1531-8.
16. Suenaga H, Unami M, Hoshi K, Mori Y, Takato T.
Ectopic complex odontoma of the nasal cavity: A
rare case. J Oral Maxillofac Surg Med Pathol.
2014 Jul;26(3):347-350.
17. Mori Y, Takato T, Hoshi K, Kanno Y, Sugiyama M,
Ohkubo K, Saijo H. Correction of upturned nasal
tip with a costal cartilage graft in bilateral cleft lip
patients. J Craniofac Surg. 2014 Sep;25(5):e443-5.
18. Susami T, Okayasu M, Inokuchi T, Ohkubo K,
Uchino N, Uwatoko K, Takahashi-Ichikawa N,
Nagahama K, Takato T. Maxillary protraction inpatients with cleft lip and palate in mixed
dentition: cephalometric evaluation after completion of growth. Cleft Palate Craniofac J. 2014
Sep;51(5):514-24.
19. Kitaura Y, Hojo H, Komiyama Y, Takato T, Chung
UI, Ohba S. Gli1 haploinsufficiency leads todecreased bone mass with an uncoupling of bonemetabolism in adult mice. PLoS One. 2014 Oct
14;9(10):e109597.
20. Kamimura W, Koyama H, Miyata T, Takato T.
Sugar-based crosslinker forms
a stableatelocollagen hydrogel that is a favorable
microenvironment for 3D cell culture. J Biomed
Mater Res A. 2014 Dec;102(12):4309-16.
21. Mikoya T, Shibukawa T, Susami T, Sato Y,
Tengan T, Katashima H, Oyama A, Matsuzawa Y,
Ito 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. 2014
May 22. (in press)
22. Inaki R, Igarashi M, Abe M, Saijo H, Hoshi K,
Takato T. A case of infective endocarditis by
Streptococcus mutans bacteremia induced byasymptomatic chronic dental caries in a wisdom
tooth. Oral Science in Japan. (in press)
23. 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. (in press)
24. Wang J, Suenaga H, Liao H, Hoshi K, Yang L,
Kobayashi E, Sakuma I. Real-time computergenerated integral imaging and 3D image
calibration for augmented reality surgicalnavigation. Comput Med Imaging Graph. (inpress)

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

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

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

Hirotaka Chikuda, M.D., Ph.D.

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

Tetsuro Yasui, M.D., Ph.D.

Associates
Shuji Taketomi, M.D.

Hiroshi Inui, M.D.

Yutaka Morizaki, M.D.

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

Takeyuki Tanaka, M.D.

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

Yasunori Omata, M.D., Ph.D.

Kentaro Hayakawa, M.D., Ph.D.

Yoshitaka Matsubayashi, M.D.

Masayaoshi Fukushima, M.D.

Ryota Yamagami, M.D.

Ken Oichi, M.D.

Kanto Mouri, M.D.

Runa Sugawara, M.D.,

Takahiro Ohki, 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
and industrial 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 minimallyinvasive surgery. We have recently been conducting
many studies related to the ossification of spinal

232

ligaments (OPLL), rheumatoid arthritis, biomechanics,
and the degenerative skeletal disorders such as
osteoporosis and osteoarthritis in response to theprogressive aging of our society.
Our department is now adept in the entire field of
medical science and medical practice related to thehuman locomotor system, the importance of which is
now clearly recognized not only in Japan, but also all
over the world. To meet the expanding needs ofsociety, we have been conducting the teaching,clinical, and research activities described below.
Faculty members of the department are one
professor, one associate professors, 4 lecturers, 15
associates, 5 medical staff members, 8 senior residents,
and 10 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 16 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 a basic 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 2014.
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.
1,299 operations were performed in 2014. These
include 254 spine surgeries (including 73 cervicalspine surgeries,126 thoracolumbar spine surgeries,
and 25 scoliosis surgeries), 65 surgeries forrheumatoid arthritis patients, 130 hip surgeries, 241knee surgeries (including 40 computer-assisted ACL

233

reconstruction, 50 computer-assisted TKA, 20 UKA),
255 hand surgeries, 75 foot and ankle surgeries, 100
surgeries for bone and soft tissue tumor, and 174
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 chemo-

therapy, 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, Sakata & Takai Laboratory of the
Graduate School of Engineering. Furthermore, we
collaborate with the Center for Disease Biology andIntegrative Medicine (CDBIM), and are developing
nonviral gene delivery vectors (polyion complex
micelles).
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.

234

Recently we have been getting achievement in the
new research topics such as “Osteoimmunology”, a
new research field studying on signaling cross-talkbetween 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. In 2014, we reported
that Notch-Hes1 signaling regulates osteoarthritis
development. We are continuously researching theroles of HIF and NF-κB signaling in chondrocytes.
We are also engaged in cartilage regenerative researchusing iPS cells with Oral-Maxillofacial Surgery andFaculty of 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
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Inui H, Taketomi S, Yamagami R, Sanada T,
Tanaka S. Twice cutting method reduces tibial
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Hayakawa K, Okazaki R, Morioka K, Nakamura
K, Tanaka S, Ogata T. Lipopolysaccharide
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Omata Y, Hagiwara F, Nishino J, Matsudaira K,
Kadono Y, Juji T, Mori T, Nakayama H, Nagase Y,
Hirose J, Yasui T, Matsumoto T, Matsui T, Tohma

S, Tanaka S. Vertebral fractures affect functional
status in postmenopausal rheumatoid arthritis
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5. Nakajima K, Taketomi S, Inui H, Nakamura K,
Sanada T, Tanaka S. Missed Medial Malleolar
Fracture Associated With Achilles Tendon
Rupture: A Case Report and Literature Review. J
Foot Ankle Surg. 2014 Nov 1; pii: S1067-2516(14)00456-6.
6. Oshima Y, Takeshita K, Inanami H, Takano Y,
Koga H, Iwahori T, Baba S, Tanaka S. Cervicalmicroendoscopic interlaminar decompression
through a midline approach in patients withcervical myelopathy: a technical note. J Neurol
Surg A Cent Eur Neurosurg. 2014 Nov; 75(6):474-478.
7. Sugita S, Chikuda H, Takeshita K, Seichi A,
Tanaka S. Progression of ossification of theposterior longitudinal ligament of the thoracic
spine following posterior decompression andstabilization. J Neurosurg Spine. 2014 Nov; 21(5):773-777.
8. Tsuda Y, Yasunaga H, Horiguchi H, Fushimi K,
Kawano H, Tanaka S. Effects of fondaparinux on
pulmonary embolism following hemiarthroplasty
for femoral neck fracture: a retrospective
observational study using the Japanese Diagnosis
Procedure Combination database. J Orthop Sci.
2014 Nov; 19(6): 991-996.
9. Muraki S, Akune T, Nagata K, Ishimoto Y,
Yoshida M, Tokimura F, Tanaka S, Oka H,
Kawaguchi H, Nakamura K, Yoshimura N.
Association of knee osteoarthritis with onset andresolution of pain and physical functional
disability: the ROAD study. Mod Rheumatol.
2014 Nov;24(6):966-973.
10. Ogura K, Yasunaga H, Horiguchi H, Fushimi K,
Tanaka S, Kawano H. Nomogram predicting
severe adverse events after musculoskeletal tumor
surgery: analysis of a national administrative
database. Ann Surg Oncol. 2014 Oct; 21(11):3564-3571.
11. Chikuda H, Ohya J, Horiguchi H, Takeshita K,
Fushimi K, Tanaka S, Yasunaga H. Ischemic
stroke after cervical spine injury: analysis of
11,005 patients using the Japanese Diagnosis

235

Procedure Combination database. Spine J. 2014
Oct 1; 14(10): 2275-2280.
12. Taketomi S, Inui H, Sanada T, Nakamura K,
Yamagami R, Masuda H, Tanaka S, Nakagawa T.
Remnant-preserving anterior cruciate ligament
reconstructionusingathree-dimensional
fluoroscopic navigation system. Knee Surg Relat
Res. 2014 Sep; 26(3): 168-76.
13. Taketomi S, Inui H, Nakamura K, Hirota J,
Sanada T, Masuda H, Takeda H, Tanaka S,
Nakagawa T. Clinical outcome of anatomic
double-bundle ACL reconstruction and 3D CT
model-based validation of femoral socket aperture
position. Knee Surg Sports Traumatol Arthrosc.
2014 Sep; 22(9): 2194-201.
14. 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. 2014 Aug;35(25):6677-86.
15. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N. Incidence of certified need of carein the long-term care insurance system and its risk
factors in the elderly of Japanese populationbased cohorts: the ROAD study. Geriatr Gerontol
Int. 2014 Jul;14(3):695-701.
16. Nakamura T, Matsumoto T, Sugimoto T, Hosoi T,
Miki T, Gorai I, Yoshikawa H, Tanaka Y, Tanaka S,
Sone T, Nakano T, Ito M, Matsui S, Yoneda T,
Takami H, Watanabe K, Osakabe T, Shiraki M,
Fukunaga M. Clinical Trials Express: fracture risk
reduction with denosumab in Japanese postmenopausal women and men with osteoporosis:
denosumab fracture intervention randomized
placebo controlled trial (DIRECT). J Clin
Endocrinol Metab. 2014 Jul; 99(7): 2599-607.
17. Muraki S, Yoshimura N, Akune T, Tanaka S,
Takahashi I, Fujiwara S. Prevalence, incidence
and progression of lumbar spondylosis by genderand age strata. Mod Rheumatol. 2014 Jul; 24(4):657-61.
18. Sugita S, Chikuda H, Kadono Y, Ohtsu H,
Takeshita K, Nishino J, Tohma S, Tanaka S.
Clinical characteristics of rheumatoid arthritis
patients undergoing cervical spine surgery: ananalysis of National Database of Rheumatic
Diseases in Japan. BMC Musculoskelet Disord.
2014 Jun 13; 15: 203.
19. Taketomi S, Inui H, Sanada T, Yamagami R,
Tanaka S, Nakagawa T. Eccentric femoral tunnel
widening in anatomic anterior cruciate ligament
reconstruction. Arthroscopy. 2014 Jun;30(6):7019.
20. 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. 2014 May 30.
[Epub ahead of print]
21. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N. Association of physical activities ofdaily living with the incidence of certified need ofcare in the long-term care insurance system ofJapan: the ROAD study. J Orthop Sci. 2014 May;
19(3):489-96.
22. Chikuda H, Yasunaga H, Takeshita K, Horiguchi
H, Kawaguchi H, Ohe K, Fushimi K, Tanaka S.
Mortality and morbidity after high-dose methylprednisolone treatment in patients with acute
cervical spinal cord injury: a propensity-matchedanalysis using a nationwide administrative
database. Emerg Med J. 2014 Mar; 31(3): 201-6.
23. 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.Grafting of poly
(2-methacryloyloxyethyl phosphorylcholine) on
polyethylene liner in artificial hip joints reduces
production of wear particles. J Mech Behav Biomed
Mater. 2014 Mar; 31: 100-106.
24. Nakamoto H, Oshima Y, Takeshita K, Chikuda H,
Ono T, Taniguchi Y, Tanaka S. Usefulness of
Quick DASH in patients with cervicallaminoplasty. J Orthop Sci. 2014 Mar;19(2):218222.
25. Kawata M, Inui H, Taketomi S, Nakamura K,
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26. Muraki S, Akune T, En-yo Y, Yoshida M, Tanaka
S, Kawaguchi H, Nakamura K, Oka H, Yoshimura
N. Association of dietary intake with joint space
narrowing and osteophytosis at the knee inJapanese men and women: the ROAD study. Mod
Rheumatol. 2014 Mar; 24(2): 236-242.
27. Hirose J, Masuda H, Tokuyama N, Omata Y,
Matsumoto T, Yasui T, Kadono Y, Hennighausen
L, Tanaka S. Bone resorption is regulated by cellautonomous negative feedback loop of Stat5-Dusp
axis in the osteoclast. J Exp Med. 2014 Jan 13;
211(1): 153-163.
28. Mori Y, Chung UI, Tanaka S, Saito T.
Determination of differential gene expression
profiles in superficial and deeper zones of mature
rat articular cartilage using RNA sequencing oflaser microdissected tissue specimens. Biomed
Res. 2014; 35(4): 263-270
29. Mori Y, Mori D, Chung UI, Tanaka S, Heierhorst
J, Buchou T, Baudier J, Kawaguchi H, Saito T.
S100A1 and S100B are dispensable for endochondral ossification during skeletal development.
Biomed Res. 2014; 35(4): 243-250.
30. Masuda H, Hirose J, Omata Y, Tokuyama N, Yasui
T, Kadono Y, Miyazaki T, Tanaka S.
Anti-apoptotic Bcl-2 family member Mcl-1
regulates cell viability and bone-resorbing activityof osteoclasts. Bone. 2014 Jan; 58: 1-10.
31. Matsumoto T, Kadono Y, Nishino J, Nakamura K,
Tanaka S, Yasui T. Midterm results of resection
arthroplasty for forefoot deformities in patientswith rheumatoid arthritis and the risk factors
associated with patient dissatisfaction. J Foot
Ankle Surg. 2014 Jan-Feb; 53(1): 41-46.
32. Okada K, Fukai A, Mori D, Hosaka Y, Yano F,
Chung UI, Kawaguchi H, Tanaka S, Ikeda T, Saito
T. Identification of SCAN domain zinc-finger
gene ZNF449 as a novel factor of chondrogenesis.
PLoS One. 2014 Dec 29; 9(12): e115169.
33. Fujiwara S, Hoshikawa S, Ueno T, Hirata M,
Saito T, Ikeda T, Kawaguchi H, Nakamura K,
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9(12):e115400.

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

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

Lecturer
Toshikatsu Kaburaki, M.D., Ph.D., Tomohiko Usui, M.D., Ph.D.,
Yasuo Yanagi, M.D., Ph.D., Chihiro Mayama,M.D.,Ph.D.

Research Associate
Yasuo Noda, M.D.,

Ryo Asaoka, M.D., Ph.D.,

Ryo Obata, 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., 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 in238practical training for medical students on
ophthalmological examinations at the outpatient clinic.
As a 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. Novel culture system of corneal limbal epitheliumand oral mucosal epithelium for ocular surface
reconstruction
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, Chen YN, Uchida S, Nakayama M,
Araie M: Hyperbaric pressure and increased

susceptibility to glutamate toxicity in retinal
ganglion cells in vitro. Mol Vis 20:606-15, 2014
2. Aizawa N, Nitta F, Kunikata H, Sugiyama T,
Ikeda T, Araie M, Nakazawa T. Laser speckle andhydrogen gas clearance measurements of optic
nerve circulation in albino and pigmented rabbitswith or without optic disc atrophy. Invest
Ophthalmol Vis Sci. 55:7991-6, 2014
3. Aoyama Y, Murata H, Tahara M, Yanagisawa M,
Hirasawa K, Mayama C, Asaoka R: A method tomeasure visual field sensitivity at the edges ofglaucomatous scotomata. Invest Ophthalmol Vis
Sci. 55:2584-91, 2014
4. Araie M, Saito H, Tomidokoro A, Murata H,
Iwase A. Relationship between macular innerretinal layer thickness and corresponding retinal
sensitivity in normal eyes. Invest Ophthalmol Vis
Sci. 55:7199-205, 2014
5. Asaoka R, Iwase A, Tsutsumi T, Saito H, Otani S,
Miyata K, Murata H, Mayama C, Araie M:
Combining multiple HRT parameters using the'Random Forests' method improves the diagnostic
accuracy of glaucoma in emmetropic and highly
myopic eyes. Invest Ophthalmol Vis Sci. 55:
2482-90, 2014
6. Asaoka R: Mapping glaucoma patients' 30-2 and10-2 visual fields reveals clusters of test points
damaged in the 10-2 grid that are not sampled in
the sparse 30-2 grid. PLoS One. 9:e98525, 2014
7. Asaoka R, Iwase A, Hirasawa K, Murata H, Araie
M: Identifying "preperimetric" glaucoma instandard automated perimetry visual fields. Invest
Ophthalmol Vis Sci. 55:7814-20, 2014
8. Arai Y, Sato Y, Yoshida A, Kawashima H,
Kaburaki T, Gomi H: Bilateral endogenous
Candida albicans subretinal abscess withsuspected mixed bacterial infection. Clin
Ophthalmol. 21:2151-4, 2014
9. Arita R, Suehiro J, Haraguchi T, Shirakawa R,
Tokoro H, Amano S. Objective image analysis of
the meibomian gland area. Br J Ophthalmol. 98:
746-55, 2014
10. Fujishiro T, Kawasaki H, Aihara M, Saeki T,
Ymagishi R, Atarashi T, Mayama C, Araie M.
Establishment of an experimental ferret ocular
hypertension model for the analysis of central
visual pathway damage. Sci Rep. 13:6501, 2014

239

11. Hiraoka T, Miyata K, Nakamura Y, Ogata M,
Okamoto F, Oshika T. Influence of cycloplegiawith topical cyclopentolate on higher-orderaberrations in myopic children. Eye (Lond). 28:
581-6, 2014.
12. Hirasawa K, Murata H, Hirasawa H, Mayama C,
Asaoka R: Clustering visual field test points basedon rates of progression to improve the predictionof future damage. Invest Ophthalmol Vis Sci. 55:
7681-5, 2014
13. Hirasawa H, Murata H, Mayama C, Asaoka R:
Validating the sumi quality of life questionnairewith rasch analysis. Invest Ophthalmol Vis Sci.
55:5776-82, 2014
14. Hirasawa H, Murata H, Mayama C, Araie M,
Asaoka R: Evaluation of various machine learning
methods to predict vision-related quality of life
from visual field data and visual acuity in patientswith glaucoma. Br J Ophthalmol. 98:1230-5, 2014
15. Ishiyama Y, Murata H, Mayama C, Asaoka R: An
objective evaluation of gaze tracking in
Humphrey perimetry and the relation with thereproducibility of visual fields: a pilot study inglaucoma. Invest Ophthalmol Vis Sci. 55:8149-52,
2014
16. Iwase A, Suzuki Y, Araie M; Tajimi Study Group.
Characteristics of undiagnosed primary openangle glaucoma: the Tajimi Study. Ophthalmic
Epidemiol. 21:39-44, 2014
17. Kaburaki T, Namba K, Sonoda KH, Kezuka T,
Keino H, Fukuhara T, Kamoi K, Nakai K, Mizuki
N, Ohguro N: Behçet's disease ocular attack score
24: evaluation of ocular disease activity before
and after initiation of infliximab. Jpn J
Ophthalmol. 58:120-30, 2014
18. Kimakura M, Usui T, Yokoo S, Nakagawa S,
Yamagami S, Amano S: Toxicity of topicalantifungal agents to stratified human cultivatedcorneal epithelial sheets. J Ocul Pharmacol Ther.
30:810-4, 2014
19. Kimoto M, Shima N, Yamaguchi M, Hiraoka Y,
Amano S, Yamagami S: Development of abioengineered corneal endothelial cell sheet to fit
the corneal curvature. Invest Ophthalmol Vis Sci.
55:2337-43, 2014
20. Mataki N, Murata H, Sawada A, Yamamoto T,
Shigeeda T, Araie M. Visual Field Progressive

Rate in Normal Tension Glaucoma Before andAfter Trabeculectomy: A Subfield-Based Analysis.
Asia Pac J Ophthalmol. 3:263-6, 2014
21. Mayama C, Tsutsumi T, Saito H, Asaoka R,
Tomidokoro A, Iwase A, Otani S, Miyata K, Araie
M: Glaucoma-induced optic disc morphometricchanges and glaucoma diagnostic ability of
Heidelberg Retina Tomograph II in highly myopic
eyes. PLoS One. 9:e86417, 2014
22. Mayama C: Calcium channels and their blockers
in intraocular pressure and glaucoma. Eur J
Pharmacol. 739:96-105, 2014
23. Minami K, Maruyama Y, Honbo M, Matsunaga J,
Miyata K. In vitro examination of surface lightscattering in hydrophobic acrylic intraocularlenses. J Cataract Refract Surg. 40:652-6, 2014
24. Mori N, Fukano Y, Arita R, Shirakawa R, Kawazu
K, Nakamura M, Amano S: Rapid identificationof fatty acids and (O-acyl)-ω-hydroxy fatty acids
in human meibum by liquid chromatography/high-resolution mass spectrometry. J Chromatogr
A. 1347:129-36, 2014
25. Mori Y, Nejima R, Masuda A, Maruyama Y,
Minami K, Miyata K, Amano S: Effect of
diquafosol tetrasodium eye drop for persistent dry
eye after laser in situ keratomileusis. Cornea.
33:659-62, 2014
26. Murata H, Araie M, Asaoka R: A new approach tomeasure visual field progression in glaucoma
patients using variational bayes linear regression.
Invest Ophthalmol Vis Sci. 55:8386-92, 2014
27. Nomura Y, Takahashi H, Tan X, Fujimura S,
Obata R, Yanagi Y: Effects of vitreomacularadhesion on ranibizumab treatment in Japanesepatients with age-related macular degeneration.
Jpn J Ophthalmol. 58:443-7, 2014
28. Obata R, Yanagi Y: Quantitative analysis of cone
photoreceptor distribution and its relationshipwith axial length, age, and early age-related
macular degeneration. PLoS One. 9:e91873, 2014
29. Ohkubo S, Higashide T, Udagawa S, Sugiyama K,
Hangai M, Yoshimura N, Mayama C, Tomidokoro
A, Araie M, Iwase A, Fujimura T: Focal
relationship between structure and function within
the central 10 degrees in glaucoma. Invest
Ophthalmol Vis Sci. 55:5269-77, 2014

240

30. Okamoto M, Sugisaki K, Murata H, Hirasawa H,
Mayama C, Asaoka R: Impact of better and worse
eye damage on quality of life in advanced
glaucoma. Sci Rep. 4:4144, 2014
31. Ohtomo K, Ueta T, Fukuda R, Usui T, Miyai T,
Shirakawa R, Amano S, Nagahara M. Tearmeniscus volume changes in dacryocystorhinostomy evaluated with quantitative measurement
using anterior segment optical coherence tomography. Invest Ophthalmol Vis Sci. 55:2057-61,
2014
32. Omodaka K, Murata T, Sato S, Takahashi M,
Tatewaki Y, Nagasaka T, Doi H, Araie M,
Takahashi S, Nakazawa T. Correlation ofmagnetic resonance imaging optic nerve
parameters to optical coherence tomography andthe visual field in glaucoma. Clin Experiment
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33. Sakata R, Shirato S, Miyata K, Aihara M:
Incidence of deepening of the upper eyelid sulcus
on treatment with a tafluprost ophthalmic solution.
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nail-patellar syndrome. J Glaucoma. 23:e122-5,
2014
35. Shiraya T, Kato S, Shigeeda T, Yamaguchi T,
Kaiya T: Comparison of burn size after retinal
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e585-6, 201436. Shoji T, Kuroda H, Suzuki M, Baba M, Hangai M,
Araie M, Yoneya S. Correlation between lamina
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38. Taketani Y, Yamagishi R, Fujishiro T, Igarashi M,
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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

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

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

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

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

Specially Appointed Lecturer
Shotaro Karino, M.D., Ph.D．

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

Research Associate
Naoya Egami, M.D.

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

Akinori Kashio, M.D.

Yuki Saito, M.D.

Chisato Fujimoto, M.D, Ph.D

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

Hironori Nisihijima, M.D.

Rumi Ueha、M.D.

Go Omura、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
club is held to introduce current research papers.

243

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
development in deaf children.
13) Physiology bone conduction innovation of bone244

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
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Usami S: High-frequency involved hearing loss
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16S ribosomal RNA gene. Otol Neurotol. 35:
1087-90, 2014
2. Amemiya K, Yumoto Y, Karino S, Ishizu T,
Yamasoba T: Distinct neural mechanisms of tonal
processing between musicians and non-musicians.
Clinical Neurophysiology125:738-747, 2014
3. Baba S, Kondo K, Kanaya K, Suzukawa K, Ushio
M, Urata S, Asakage T, Kakigi A, Suzukawa M,
Ohta K, Yamasoba T： Expression of IL-33 andits receptor ST2 in chronic rhinosinusitis withnasal polyps. Laryngoscope. 124:E115-22, 2014
4. Baba S, Kondo K, Toma-Hirano M, Kanaya K,
Suzukawa K, Ushio M, Suzukawa M, Ohta K,
Yamasoba T: Local increase of IgE and classswitch recombination to IgE in nasal polyps inchronic rhinosinusitis. Clinical and Experimental
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Saito Y, Yoshida M, Ando M, Asakage T,
Yamasoba T, Murakami Y: High Incidence of
Null-Type Mutations of the TP53 Gene inJapanese Patients with Head and Neck Squamous
Cell Carcinoma. Journal of Cancer Therapy 5:
664-671, 2014
7. Egami N, Kakigi A, Takeda T, Takeda S, Nishioka
R, Hyodo M, Yamasoba T: Type 1 AllergyInduced Endolymphatic Hydrops and theSuppressive Effect of H1-Receptor Antagonist(Olopatadine Hydrochloride). Otol Neurotol. 35:
e104-9, 2014

8. Fujimaki Y, Tsunoda K, Ishimoto SI, Okada K,
Kinoshita M, Igaki H, Terahara A, Asakage T,
Yamasoba T: Non-invasive objective evaluation ofradiotherapy-induced dry mouth. J Oral Pathol
Med 43: 97-102,2014
9. Fujimoto C, Kamogashira T, Kinoshita M, Egami
N, Sugasawa K, Demura S, Yamasoba T, Iwasaki
S. Power Spectral Analysis of Postural Sway
During Foam Posturography in Patients With
Peripheral Vestibular Dysfunction. Otology
Neurotology 35:e317-23, 2014
10. Fujimoto C, Egami N, Kinoshita M, Sugasawa K,
Yamasoba T, Iwasaki S： Postural stability investibular neuritis: Age, disease duration andresidual vestibular function. Laryngoscope. 124:974-979, 2014
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loss. Oxid Med Cell Longev. 582849 epub, 2014
12. Ge Z, Chen Q, Osada K, Liu X, Tockary TA,
Uchida S, Dirisala A, Ishii T, Nomoto T, Toh K,
Matsumoto Y, Oba M, Kano MR, Itaka K,
Kataoka K Targeted gene delivery by polyplex
micelles with crowded PEG palisade and cRGD
moiety for systemic treatment of pancreatictumors. Biomaterials 35(10): 3416-26,2014
13. Hidekane Yoshimura, Satoshi Iwasaki, Shin-ya
Nishio1, Kozo Kumakawa, Tetsuya Tono, Yumiko
Kobayashi, Hiroaki Sato, Kyoko Nagai, Kotaro
Ishikawa, Tetsuo Ikezono, Yasushi Naito,
Kunihiro Fukushima: Massively parallel DNA
sequencing facilitates diagnosis of patients with
Usher syndrome type 1PLoS ONE. 9(3) e90688
Published: March 11, 2014
14. Ichikawa K, Kashio A, Mori H, Ochi A, Karino S,
Sakamoto T, Kakigi A, Yamasoba T: A New
Computed Tomography Method to Identify
Meningitis-Related Cochlear Ossification and
FibrosisbeforeCochlear
Implantation.
Otolaryngology Head and Neck Surgery 150:
646-653,2014
15. Inoue A, Iwasaki S, Fujimoto C, Nakajima T,
Yamasoba T: Developmental changes in theprotective effect of exogenous brain-derived
neurotrophic factor and neurotrophin-3 against
ototoxic drugs in cultured rat vestibular ganglion

245

neurons. Cell and Tissue Research 356:299-308,
2014
16. Suzuki S, Enokida T, Kobayashi T, Yajima Y,
Ishiki H, Izumi K, Endo K, Tahara M. Evaluationof the impact of a flowchart-type leaflet for cancer
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18. Iwasaki S, Yamamoto Y, Togo F, Kinoshita M,
Yoshifuji Y, Fujimoto C, Yamasoba T: Noisy
vestibular stimulation improves body balance inbilateral vestibulopathy. Neurology 82:969-975,
2014
19. Iwasaki S, Yamasoba T. Dizziness and Imbalancein the Elderly: Age-related Decline in the
Vestibular System. Aging Dis. 6:38-47, 2014
20. Kanaya K, Kondo K, Suzukawa K, Sakamoto T,
Kikuta S, Okada K, Yamasoba T: Innate immune
responses and neuroepithelial degeneration andregeneration in the mouse olfactory mucosa
induced by intranasal administration of Poly(I:C).
Cell and Tissue Research 357:279-99, 2014
21. Kikkawa YS, Nakagawa T, Ying L, Tabata Y,
Tsubouchi H, Ido A, Ito J: Growth factor-eluting
cochlear implant electrode: impact on residual
auditory function, insertional trauma, and fibrosis.
J Transl Med. 12:280, 2014
22. Kikkawa YS, Nakagawa T, Taniguchi M, Ito J:
Hydrogen protects auditory hair cells from
cisplatin-induced free radicals. Neurosci Lett.
579:125-9, 2014
23. Kim HJ, Ishii T, Zheng M, Watanabe S, Toh K,
Matsumoto Y, Nishiyama N, Miyata K, Kataoka
K: Multifunctional polyion complex micellefeaturing enhanced stability, targetability, andendosome escapability for systemic siRNAdelivery to subcutaneous model of lung cancer.
Drug Delivery and Translational Research
4:50-60,2014
24. Kim HJ, Takemoto H, Yi Y, Zheng M, Maeda Y,
Chaya H, Hayashi K, Mi P, Pittella F, Christie RJ,
Toh K, Matsumoto Y, Nishiyama N, Miyata K,
Kataoka K: Precise Engineering of siRNA
Delivery Vehicles to Tumors Using Polyion

Complexes and Gold Nanoparticles,ACS Nano 8:
8979-91,2014
25. Kobayashi K, Saito Y, Omura G, Ando M,
Sakamoto T, Yamasoba T, Asakage T: ClinicalFeatures of Human Papilloma Virus-Related Headand Neck Squamous Cell Carcinoma of an
Unknown Primary Site. ORL J Otorhinolaryngol
Relat Spec. 76:137-146, 2014
26. Kohno M, Shinogami M, Yoneyama H, Nagata O,
Sora S, Sato H: Prognosis of tinnitus after
acoustic neuroma surgery--surgical managementof postoperative tinnitus. World Neurosurg. 81:
357-67,2014
27. Kondo K, Kanaya K, Baba S, Yamasoba T:
Mumps, cervical zoster, and facial paralysis:
coincidence or association?", Case Rep
Otolaryngol 289687,2014
28. Nomura T, Makizumi Y, Yoshida T, Yamasoba T:
The Relationship between the Efficacy ofTonsillectomy and Renal Pathology in the Patientswith IgA Nephropathy. Int J Otolaryngol: 45612,
2014
29. Nomoto T, Fukushima S, Kumagai M, Machitani
K, Arnida, Matsumoto Y, Oba M, Miyata K,
Osada K, Nishiyama N, Kataoka K: Three-layered
polyplex micelle as a multifunctional nanocarrier
platform for light-induced systemic gene transfer.
Nat Commun,5,3545,2014
30. Nuhn L, Gietzen S, Mohr K, Fischer K, Toh K,
Miyata K, Matsumoto Y, Kataoka K, Schmidt M,
Zentel R: Aggregation Behavior of Cationic
Nanohydrogel Particles in Human Blood Serum,
Biomacromolecules 15:1526-33,2014
31. Ohki M, Shinogami M: Allergic sensitization to
perennial allergens in adults and children
sensitized to Japanese cedar or Japanese cypress
pollen in Japan. Int J Otolaryngol 10,2014
32. Ohki M, Takeuchi N: Recovery of motor neuron
excitability after facial nerve impairment in rats.
Neuroreport 25:458-463,2014
33. Ochi A, Yamasoba T, Furukawa S. Factors that
account for inter-individual variability of lateralization performance revealed by correlations of
performance among multiple psychoacousticaltasks. Frontier in Neuroscience 8:27, 2014
34. Oe Y, Christie RJ, Naito M, Low SA, Fukushima
S, Toh K, Miura Y, Matsumoto Y, Nishiyama N,

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Miyata K, Kataoka K: Actively-targeted polyion
complex micelles stabilized by cholesterol anddisulfide cross-linking for systemic delivery ofsiRNA to solid tumors. Biomaterials 35:7887-95,
2014
35. Ogawa K, Kondoh K, Kanaya K, Ochi A,
Sakamoto T, Yamasoba T: Bilateral cervicalfistulas from heterotopic salivary gland tissues.
ORL J Otorhinolaryngol Relat Spec.76:336-41,
2014
36. Oguri G, Nakajima T, Yamamoto Y, Takano N,
Tanaka T, Kikuchi H, Morita T, Nakamura F,
Yamasoba T, Komuro I: Expression andfunctional roles of transient receptor potential
ankyrin 1 (TRPA1) in human cardiac fibroblasts.
Effects of methylglyoxal on human cardiac
fibroblast: Roles of transient receptor potential
ankyrin 1 (TRPA1) channels. AJP-Heart andCirculatory Physiology. 307:H1339-52, 201437. Omura G, Yuki Saito, Mizuo Ando, Kenya
Kobayashi, Yasuhiro Ebihara, Tatsuya Yamasoba,
Takahiro Asakage: Salvage surgery for local
residual or recurrent pharyngeal cancer afterradiotherapy or chemoradiotherapy. The Laryngscope 124. 2075-2080, 201438. Saito Y, Ebihara Y, Ushiku T, Omura G,
Kobayashi K, Ando M, Sakamoto T, Fukayama M,
Yamasoba T, Asakage T: Negative humanpapillomavirus status and excessive alcohol
consumption are significant risk factors forsecond primary malignancies in Japanese patientswith oropharyngeal carcinoma. Jpn J Clin Oncol
44:564-9,2014
39. Sakamoto T, Kikuta S, Urata S, Yasuhara K,
Kikkawa YS, Yamasoba T. Conductive Hearing
Loss with Present Acoustic Reflex: A Case Report.
Open Journal of Clinical Diagnostics 4, 177-181,
2014
40. Sasaki T, Miyata R, Hatai Y, Makita K, Tsunoda
K.: Hounsfield unit values of retropharyngeal
abscess-like lesions seen in Kawasaki disease.
Acta Otolaryngol. 134: 437-40,2014
41. Sommer DE, Tokuda IT, Peterson SD, Sakakibara
K, Imagawa H, Yamauchi A, Nito T, Yamasoba T,
Tayama N. Estimation of inferior-superior vocal
fold kinematics from high-speed stereo

endoscopic data in vivo. J Acoust Soc Am. 136:
3290, 201442. Suzuki S, Yasunaga H, Matsui H, Horiguchi H,
Fushimi K, Yamasoba T: Impact of systemic
steroids on posttonsillectomy bleeding: analysisof 61?430 patients using a national inpatient
database in Japan. JAMA Otolaryngol Head Neck
Surg 140: 906-910,2014
43. Synatschke CV, Nomoto T, Cabral H, Fortsch M,
Toh K, Matsumoto Y, Miyazaki K, Hanisch A,
Schacher FH, Kishimura A, Nishiyama N, Muller
AH, Kataoka K: Multicompartment micelles withadjustable poly(ethylene glycol) shell for efficientin vivo photodynamic therapy. ACS Nano 8:
1161-72,2014
44. Takashi Sakamoto, Yayoi S. Kikkawa, Shu Kikuta,
Makoto Kinoshita, Rumi Ueha, Keigo Suzukawa,
Akinori Kashio, Akinobu Kakigi, Ken Ito,
Mitsuya Suzuki, Tatsuya Yamasoba: Favorable
Prognostic Factors for Long-term Postoperative
Hearing Results After Canal Tympanoplasty forCongenital Aural Stenosis. Otol Neurotol 35:
966-971, 2014.
45. Takayuki Nakagawa, Kozo Kumakawa, Shin-Ichi
Usami, Naohito Hato, Keiji Tabuchi, Mariko
Takahashi, Keizo Fujiwara, Akira Sasaki, Shizuo
Komune, Tatsunori Sakamoto, Norio Yamamoto,
Shiro Tanaka, Harue Tada, Michio Yamamoto,Atsushi Yonezawa, Toshiko Ito-Ihara, Takafumi
Ikeda, Akira Shimizu, Yasuhiko Tabata, Juichi Ito:
A randomized controlled clinical trial of topicalinsulin-like growth factor-1 therapy for sudden
deafness refractory to systemic corticosteroid
treatment. BMC Medicine 11:219, 2014
46. Tsutsumi T, Ikeda T, Kikuchi S: Periodic
alternating nystagmus caused by a medullarylesion in acute disseminated encephalomyelitis.
Otol Neurotol 35:861-865,2014
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48. Tsunoda K, Morita Y, Saito M, Yabe T, Tsunoda
A: Continuous involuntary tut-tutting. Annals ofInternal Medicine 160(10):739,2014
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Y, Ishii T, Kataoka K: An injectable spheroid
system with genetic modification for cell

247

transplantation therapy. Biomaterials 35: 2499506,2014
50. Ueha R, Mukherjee S, Ueha S, Nagata D.E. A,
Sakamoto T, Kondo K, Yamasoba T, Lukacs N,
Kunkel S: Viral disruption of olfactory
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51. Urata S, Kashio A, Sakamoto T, Kakigi A,
Yamasoba T. Novel repair of stapedial footplate
defect associated with recurrent meningitis.
Otology and Neurotology. 35:1592-5, 2014
52. Urata S, Ishimoto S,Kikuta S, Ichinose H,
Takeuchi S. Preliminary Study of the Safety of
Seasonal Allergic Rhinitis Treatment in Railway
Personnel. J Otol Rhinol 3, 2014
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mediastinitis, Lancet 384: 1952,2014
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material,Acta Otorrinolaringol Esp,65,269-270,
2014
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79-80, 2014
56. Wu H, Cabral H, Toh K, Mi P, Chen YC,
Matsumoto Y, Yamada N, Liu X, Kinoh H, Miura
Y, Kano MR, Nishihara H, Nishiyama N, Kataoka
K: Polymeric micelles loaded with platinum
anticancer drugs target preangiogenic micrometastatic niches associated with inflammation,JControl Release,189,1-10,2014
57. Yamauchi A, Imagawa H, Yokonishi H, Nito T,
Yamasoba T, Sakakibara K, Tayama N:
Characteristics of Vocal Fold Vibrations in
Vocally Healthy Subjects: Analysis with
Multi-line Kymography,J Speech Lang Hear Res
57: 648-657,2014
58. Yamauchi A, Imagawa H, Yokonishi H, Ueha R,
Nito T, Yamasoba T, Sakakibara K, Tayama N:
Vocal Fold Atrophy in a Japanese Tertiary
Medical Institute: Status Quo of the Most AgedCountry. J Voice 28: 231-236,2014
59. Yamauchi A, Yokonishi H, Imagawa H,
Sakakibara K, Nito T, Tayama N, Yamasoba T:
Age- and Gender-Related Difference of Vocal
Fold Vibration and Glottal Configuration in
Normal Speakers: Analysis With Glottal Area
Waveform. J Voice 28: 525-531,2014

60. Yasuda T, Ueno T, Fukumura K, Yamato A, Ando
M, Yamaguchi H, Soda M, Kawazu M, Sai E,
Yamashita Y, Murata M, Kiyoi H, Naoe T, Mano
H.:Leukemic evolution of donor-derived cells
harboring IDH2 and DNMT3A mutations after
allogeneic stem cell transplantation. Leukemia 28:
426-428,2014
61. Yasuda T, Fukumura K, Fukuda T, Uchida Y, Iida
H, Meguro M, Sato Y, Yamasoba T, Nakajima T.
Muscle size and arterial stiffness after blood
flow-restricted low-intensity resistance training inolder adults. Scandinavian Journal of Medicene
and Science in Sports. 24:799-806, 2014
62. Yasuda T, Fukumura K, Sato Y, Yamasoba T,
Nakajima T. Effects of detraining after blood flow
restricted low-intensity training on muscle sizeand strength in older adults. Aging Clinical andExperimental Research 26:561-4, 2014
63. Yen HC, Cabral H, Mi P, Toh K, Matsumoto Y,
Liu X, Koori H, Kim A, Miyazaki K, Miura Y,
Nishiyama N, Kataoka K: Light-Induced
Cytosolic Activation of Reduction-Sensitive
Camptothecin-Loaded Polymeric Micelles for
Spatiotemporally
Controlledin
Vivo
Chemotherapy. ACS Nano 8:11591-602,2014
64. Yoshida M, Kamiya M, Yamasoba T, Urano Y: A
highlysensitive,
cell-membrane-permeable
fluorescent probe for glutathione. Bioorganic &Medical Chemistry Letters 24: 4363-4366,2014
65. Yoshihara S, Kondo K, Ochi A: Diffuse large
B-cell lymphoma in the sphenoid sinus mimicking
fibrous dysplasia in CT and MRI. BMJ Case Rep,
2014 Jul 4,2014
66. Yoshihara S, Nakaya M, Ichikawa T. T-cell
lymphoblastic lymphoma in a child presenting as
rapid thyroid enlargement. Case Rep Otolaryngol.
368590 , 2014
67. Yoshihara S, Kondo K, Kanaya K, Suzukawa K,
Baba S, Toma , Hirano M, Kikuta S, Iwasaki Y,
Fujio K, Yamasoba T: Tumour necrosis factor
inhibitor-associated sinusitis. Rhinology 52:
246-251,2014
68. Yoshihara S, Asakage T, Saito Y, Nito T, Shimizu
J, Tsuji S, Yamasoba T: Laryngeal Cancer in a
Patient with Amyotrophic Lateral Sclerosis. J Otol
Rhinol 2014, 3:3

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 twelve 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. Zhang Y, Haga N: Skeletal complications incongenital insensitivity to pain with anhidrosis: acase series of 14 patients and review of articles
published in Japanese. J Orthop Sci 19: 827-831,
2014
2. Nagata E, Kano H, Kato F, Yamaguchi R,
Nakashima S, Takayama S, Kosaki R, Tonoki H,
Mizuno S, Watanabe S, Yoshiura K, Kosho T,
Hasegawa T, Kimizuka M, Suzuki A, Shimizu K,
Ohashi H, Haga N, Numabe H, Horii E, Nagai T,
Yoshihashi H, Nishimura G, Toda T, Takada S,
Yokoyama S, Asahara H, Sano S, Fukami M,
Ikegawa S, Ogata T: Japanese founder
duplications/triplications involving BHLHA9 areassociated with split-hand/foot malformation withor without long bone deficiency and
Gollop-Wolfgang complex. Orphanet J Rare Dis
9: 125, 2014
3. Goto M, Takedani H, Haga N, Kubota M,
Ishiyama M, Ito S, Nitta O: Self-monitoring has
potential for home exercise programs in patientswith hemophilia. Haemophilia 20: e121-127, 2014
4. Inokuchi H, Yasunaga H, Nakahara Y, Horiguchi
H, Ogata N, Fujitani J, Matsuda S, Fushimi K,
Haga N: Effect of rehabilitation on mortality ofpatients with Guillain-Barre syndrome: apropensity-matched analysis using a nationwide
database. Eur J Phys Rehabil Med 50: 439-446,
2014
5. Mishima K, Kitoh H, Haga N, Nakashima Y,
Kamizono J, Katagiri T, Susami T, Matsushita M,
Ishiguro N: Radiographic characteristics of thehand and cervical spine in fibrodysplasia
ossificans progressiva. Intractable Rare Dis Res 3:46-51, 2014
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. 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, published online

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
Kenichi Kishida, M.D.,

Yoshiteru Mori, M.D.,

Yoshie Suzuki, M.D.,

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

Jun Ninagawa, M.D.,

Gaku Kawamura, M.D.,

Masaaki Asamoto, M.D.

Kanae Nagatomo, M.D.,

Yuho Tamai, M.D.,

Michiko Ushio, M.D.

Yuriko Tashiro, M.D.,

Kazuhito Mietani, M.D.,

Yuko Araki, M.D.,

Atsuko Kato, M.D.,

Takuma Hiraiwa, M.D.,

Kayo Hirose, M.D., Ph.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 25 faculty staffs, 4 part time clinical staffs, 9graduate students and 10 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 for patients suffering acute / chronic pain,
and palliative care for patients with malignancies.
Number of cases undergoing surgery is increasingin our hospital and annual number of surgery cases

exceeds 12,000. Recently, the number of high risk or
geriatric patients is increasing. Especially surgery fororgan transplant, such as heart, liver and lung requires
tight and meticulous anesthetic care. Our aim is toprovide optimal perioperative care including proper
preoperative assessment of patients, efficient plan for
intraoperative management, meticulous intraoperativeand / or postoperative care. We are a part ofperioperative management team established in our
hospital recently to play pivotal role in perioperative
patient care. Especially for patients with multiple
comorbidities, we provide preoperative assessment /consult clinic and accept 1,600 patients annually. Pain
clinic services are provided for outpatients (including
patients in the ward of the other departments) on adaily basis in all areas of diseases accompanied with
pain. From April 2014 to March 2015, the number of252

ambulatory patients was about ten thousand; four
hundred of those were newcomer patients. Currently
we have three beds in the ward. We take care 30
patients in our ward and approximately 100 in otherwards annually, with multidisciplinary approach incollaboration with neurologists, psychiatrist, andorthopedists. Our palliative care team starts to manage
varied somatic symptoms and psychological distressof inpatients and outpatients with cancer. Further, wenewly open the “cancer treatment-related chronic pain
management” outpatient clinic and also the second
opinion outpatient clinic for cancer pain patients withadvanced and terminal cancer stages.

Teaching activities
We give lectures for fourth year medical students
and provide clinical education (Clinical Clerkship) for
fifth and sixth year medical students on a man-to-man
basis with our faculty staff members. The lectures ofthe last year were the history of anesthesia, themechanisms of anesthesia, inhalational anesthesia,
intravenous anesthesia, anesthesia and respiratory/
circulatory system, the balance of body fluid, acidbase balance, muscle relaxants, management of thepatient during anesthesia, monitoring, resuscitation,
pain clinic and the physiology and the management ofpain.
The curriculum of Clinical Clerkship consists ofthree major contents: learning a practice of anesthetic
management for patients undergoing surgeries,
observing a practice of pain management for
outpatients suffering from intractable pain, andinteractive lectures on specific topics. During thepractice of anesthetic management, we teach students
how to evaluate patients in the perioperative period.
Through the practice of pain management, we teachstudents causes of intractable pain as well as treatmentof pain including nerve block, functional therapy, andcognitive-behavioral therapy. We provide 5 miniseminars that cover essential knowledge of clinicalanesthesia for medical students, each of them entitled“introduction to anesthesiology”, “airway management”, “central venous catheterization”, “spinal
anesthesia” and “pain clinic”. Moreover, students canexperience procedures of tracheal intubation, central
venous catheterization and spinal anesthesia using

simulators. Each student is required to submit a reportor a case that summarizes the procedures andmedicine applied perioperatively. We discuss thecontents of the reports and summaries with students at
the end of Clinical Clerkship, for their further
understandings.

Research activities
We have seven research groups and their fields
include respiration, circulation, pain, immune systemand shock.
These are recent major subjects of our research.
1) A role of cytokine signaling in acute lung injury2) Evaluation of optimal ventilatory strategy for
respiratory failure3) Modulation of immune system by anesthetics
4) Signal transduction pathway related to apoptosis
activated by sepsis or ischemia-reperfusion5) Pathophysiology of shock6) A role of lipid mediators in organ damage
mediated by ischemia-reperfusion injury7) A role of lipid mediators in the formation of
hyperalgesia
8) Antihyperalgesic and antipruritic effects of alpha2-adrenergic agonists
9) A role of spinal microglial cells in the development of inflammation-mediated neuropathic pain
10) Spinal contribution for analgesic pathway11) Mechanism of Pruritoceptive and Neurogenic Itch
12) Genetic analyses of pain intensity and opioid
sensitivity in clinical pain patients
13) Analysis of electroencephalography during general anesthesia
14) Clinical evaluation of neurological sequelae after
cardiac surgery15) Retrospective analysis of large administrative
database to explore rare complications related toanesthesia and / or association between anesthetic
drug and postoperative outcome16) Effect of anesthetics on glucose metabolism invivo17) Role of new plasma substitutes on hemorrhagicshock18) Mechanisms of chemotherapy-induced neuronal
dysfunction

253

Publications(1) Sumitani M, Yasunaga H, Uchida K, Horiguchi H,
Nakamura M, Ohe K, Fushima K, Matsuda S,
Yamada Y. Perioperative factors affecting theoccurrence of acute complex regional pain
syndrome following limb bone fracture surgery:
Data from the Japanese Diagnosis Procedure
Combination database. Rheumatology 2014; 53:
1186-93(2) Nakamura M, Uchida K, Akahane M, Watanabe Y,
Ohtomo K, Yamada Y. Effects on Gastric
Emptying and Carbohydrate Loading of an Oral
Nutritional Supplement and an Oral Rehydration
Solution: A Crossover Study with Magnetic
Resonance Imaging. Anesthesia and Analgesia.
2014 Jun;118(6):1268-73.
(3) Uchida K, Nakata K, Carey B, Chalk C, Suzuki T,
Sakagami T, Koch DE, Stevens C, Inoue Y,
Yamada Y, Trapnell BC. Standardized Serum
GM-CSF Autoantibody Testing for the Routine
Clinical Diagnosis of Autoimmune Pulmonary
Alveolar Proteinosis. Journal of Immunological
Methods. 2014 Jan;402(1-2):57-70(4) Uchida K, Yasunaga H, Sumitani M, Horiguchi H,
Fushimi K, Yamada Y. Effects of Remifentanil on
In-hospital Mortality and Length of Stay
Following Clipping of Intracranial Aneurysm: A
Propensity Score Matched Analysis. Journal of
Neurosurgical Anesthesiology. 2014 Oct;26(4):291-8.
(5) Sumitani M, Misaki M, Kumagaya S, Ogata T,
Yamada Y, Miyauchi S. Dissociation in accessing
space and number representation in pathologic
pain patients. Brain and Cognition 2014; 90:
151-6(6) Kusakabe Y, Uchida K, Hiruma T, Suzuki Y,
Totsu T, Suzuki T, Carey BC, Yamada Y, Trapnell
BC. A standardized blood test for the routine
clinical diagnosis of impaired GM-CSF signaling
using flow cytometry. J Immunol Methods. 2014
Nov;413:1-11.
(7) Sumitani M, Ueda H, Hozumi J, Inoue R, Kogure
T, Ogata T, Yamada Y. Minocycline does notdecrease intensity of neuropathic pain, but
improves its affective dimension. J Pain Palliat
Care Pharmacother 2014 (in press)(8) 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 2014
(in press)(9) Sumitani M, Misaki M, Kumagaya S, Yozu A,
Otake
Y,
Osumi
M,
MiyauchiS.
Internally-represented
space
and
its
mirror-reveresed image of the visuospatial
representation: a possible association. Medical
Hypotheses 2014 (in press)(10) Suka M, Odajima T, Okamoto M, Sumitani M,
Nakayama
T,
Sugimori
H.
Readingcomprehension of health checkup reports andhealth literacy in Japanese people. Environmental
Health and Preventive Medicine 2014; 19:295-306(11) Nakamura M, Nishiwaki Y, Sumitani M, Ushida T,
Yamashita T, Konno S, Taguchi T, Toyama Y.
Investigation of chronic musculoskeletal pain
(third report): with special reference to theimportance of neuropathic pain and psychogenic
pain. J Orthop Sci 2014; 19: 667-75(12) Kogure T, Sumitani M, Suka M, Ishikawa H,
Odajima T, Igarashi A, Kusama M, Okamoto M,
Sugimori H, Kawahara K. Validity and Reliabilityof the Japanese version of the Newest Vital Sign:
a preliminary study. Plos One 2014; 9: e94582(13) Nakagaki K, Nunomura Y, Uchida K, Nakata K,
Tazawa R. Up-Regulation of Cluster ofDifferentiation (CD) 11b Expression on the
Surface of Canine Granulocytes with Human
Granulocyte-Macrophage
Colony-Stimulating
Factor (GM-CSF). Journal of Veterinary Medical
Science. 2014 Aug;76(8):1173-6.

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.
Kent Doi, M.D.

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

Takehiro Matsubara, M.D.

Associate
Shinji Matsuse, M.D. Hideaki Miyamoto, M.D. Rei Ito, M.D. Kanae Nagatomo, M.D.
Hattori Motoko, M.D. Shota Den, M.D. Toshifumi Asada, M.D. Tomohiro Sonoo, M.D.
Hiromi Matsuda, M.D. Satoki Deguchi, M.D. Taro Kasai, M.D. Shuichiro Oya, M.D.
Koichiro Kawasaki, M.D. Ichiro Hirayama, M.D. Kazuya Higashizono,M.D.

Staff
Yusuke Komiyama, D.D.S. Hiroaki Kobayashi, M.D.
Akinori Maeda, M.D.
Keiichi Tomita, M.D. Satoshi Iwai, M.D. Keiichiro Nakagomi, M.D. Yohei Komaru, M.D.
Kaori Jones Horikawa, M.D. Naoyuki Fukuda, M.D. Atsumi Yamaguchi, 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 anotheropportunity for exposure to critically ill patients.

255

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 2006,
we had about 6,000 ambulance patients out of total
20,300 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 2,700 ICU/CCU patients in the 2007. 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 clinical clerkship and 1 week of
bed-side training for the 3rd year. ACLS Basiccourse (ICLS) is held for the participants in theclinical clerkship program, and successful
completion of this course will enable students to be
ICLS certified.
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. After learning a
ACLS course, students experience the real practiceof emergency medicine as fellow passengers in theambulance and as 2.5-day trainees in affiliatedhospitals’ 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.
Junior residents are also assigned to ICU services
to gain the knowledge of intensive care from

256

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. Doi K, Noiri E, Nangaku M, Yahagi N,
Jayakumar C, Ramesh G: Repulsive guidance cue
semaphorin 3A in urine predicts the progressionof acute kidney injury in adult patients from amixed intensive care unit. Nephrol Dial
Transplant 29 (1):73-80, 2014
2. Iwagami M, Yasunaga H, Doi K, Horiguchi H,
Fushimi K, Matsubara T, Yahagi N, Noiri E:
Postoperative Polymyxin B Hemoperfusion andMortality in Patients with Abdominal Septic
Shock: A Propensity-Matched Analysis.
Crit Care Med Dec20, 2013. [Epub ahead ofprint], 2014; 42 (5): 1187-1193.
3. Inokuchi R, Ishida T, Maeda J, Nakajima S,
Yahagi N, Matsumoto A: Anaerobiospirillum
succiniciproducens- induced bacteremia in ahealthy man. Am J Emer Med 2014 Jul;32(7):812.

e1-3. doi: 10.1016/j.ajem. 2013.12.028. Epub
2013 Dec 18.
4. Qian K, Ando T, Nakamura K, Liao H, Kobayashi
E, Yahagi N, Sakuma I:Ultrasound imaging
method for internal jugular vein measurement andestimation of circulating blood volume. Int J
Comput Assist Radiol Surg Mar;9 (2):231-9,2014.
doi:10.1007/s11548-013-0921-8. Epub2013 Jul 18.
5. Nakamura K, Inokuchi R, Doi K, Fukuda T,
Tokunaga K, Nakajima S, Noiri E, Yahagi N:
Septic ketoacidosis. Int Med 53 (10):1071-3, 2014
6. Fukuda T, Ohashi N, Nishida M, Gunshin M, Doi
K, Matsubara T, Nakajima S, Yahagi N:
Application of cerebral oxygen saturation toprediction of the futility of resuscitation forout-of- hospital cardiopulmonary arrest patients: asingle-center, observational study. Can cerebral
regional oxygen saturation predict the futility of
CPR? Am J Emer Med 2014 Mar 5. pii: S07356757(14)00131-4. doi: 10.1016/j.ajem.2014.02.
039. [Epub ahead of print]
7. Fukuda T, Ohashi N, Matsubara T, Doi K,
Gunshin M, Ishii T, Kitsuta Y, Nakajima S,
Yahagi N: Applicability of the prehospitaltermination of resuscitation rule in an area densewith hospitals I Tokyo: a single-center, retrospective, observational study. Is the pre hospital
TOR rule applicable in Tokyo?
Am J Emer Med 32:144-9, 2014
8. Inokuchi R, Nakajima S, Yahagi N, Sato H:
Current policies on informed consent in Japan
constitute a formidable barrier to emergency
research. Resuscitation 85(2): e27, 2014
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 group protein B1–Toll-likereceptor 4 pathway contributes to the acute lunginjury induced by bilateral nephrectomy.
Kidney Int 2014 Aug; 86 (2):316-26. doi: 10.
1038/ki.2014.62. Epub 2014 Mar 19.
10. Inokuchi R, Wada T, Ohta F, Sonoo T, Aoki Y,
Asada T, Hiruma T, Shinohara K, Nakajima S,
Yahagi N: Retropharyngeal tendonitis. Ann
Emerg Med 63: 86, 2014
11. Tsukamoto-Sumida M, Doi K, Kinoshita O,
Kimura M, Ono M, Hamasaki Y, Matsubara T,

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Ishii T, Yahagi N, Nangaku M, Noiri E:
Perioperative plasma neutrophil gelatinaseassociated lipocalin measurement in left ventricular assist device implantation surgery. Circ J 78(8): 1891-1899, 2014. Epub 2014 Jun 13.
12. Wada T, Yasunaga H, Inokuchi R, Matsubara T,
Nakajima S, Horiguchi H, Fushimi K, 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.
13. Inokuchi R, Sato H, Nakamura K, Aoki Y,
Shinohara K, Gunshin M, Matsubara T, Kitsuta Y,
Yahagi N, Nakajima S: Motivations and barriers
to implementing electronic health records and ED
information systems in Japan.
Am J Emer Med 2014 Jul;32(7):725-30. doi: 10.
1016/j.ajem.2014. 03.035. Epub 2014 Mar 28.
14. Inokuchi R, Manabe H, Ohta F, Nakamura K,
Nakajima S, Yahagi N: Granulocyte colonystimulating factor- producing lung cancer andacute respiratory distress syndrome. Clin Resp J
2014 Jan 24. doi: 10.1111/crj.12111. [Epub aheadof print].
15. Kawakami Y, Inokuchi R, Tanji M, Ito F,
Kumada Y, Matsuse S, Yahagi N,Shinohara K:
Coronary artery dissection after blunt trauma
without abnormal ECG findings.Am J Emer Med
2014 Sep; 32(9): 1157. e5-6. doi: 10.1016/j.ajem.
2014. 02.046. Epub 2014 Mar 5.
16. Yamamoto M, Inokuchi R, Doi K, Yahagi N:
An anterior chest wall abscess penetrating thepleural cavity.
Intensive Care Med 2014 May;40(5): 736-7. doi:
10.1007/s00134-014-3249-0. Epub 2014 Feb 25.
17. Sonoo T, Ohshima K, Kobayashi H, Asada T,
Hiruma T, Doi K, Gunshin M, Murakawa T,
Anraku M, Nakajima S, Nakajima J, Yahagi N:
Acute respiratory distress syndrome (ARDS)
treated successfully by veno-venous extracorporeal membrane oxygenation (ECMO) in anearly drowned patient.
J Artif Organs 2014 Sep; 17 (3): 281-284. doi: 10.
1007/s10047-014-0776-y. Epub 2014 Jun 12.
18. Fukuda T, Ohashi N, Doi K, Matsubara T, Kitsuta
Y, Nakajima S, Yahagi N: Impact of seasonaltemperature environment on the neurologicalprognosis of out-of- hospital cardiac arrest: anationwide, population-based cohort study.
J Crit Care 2014; 29: 840-847.
19. Inokuchi R, Fukuda T, Yahagi N, Nakamura K:
Severe hepatic portal venous gas that was
spontaneously resolved within a day. Intensive
Care Med 2014 Sep; 40(9):1369. doi: 10.1007/
s00134-014-3390-9. Epub 2014 Jul 15.
20. Wada T, Yasunaga H, Inokuchi R, Horiguchi H,
Fushimi K, Matsubara T, Nakajima S, Yahagi
N: Effects of Edaravone on Early Outcomes in
Acute Ischemic Stroke Patients Treated with
Recombinant Tissue Plasminogen Activator. J
Neurol Sci 2014 Oct 15; 345 (1-2): 106-111. doi:
10.1016/j.jns.2014.07.018. Epub 2014 Jul 16.
21. Nagai H, Maeda H, Kuroda R, Komori M,
Nakajima M, Nara A, Ito-Tsujimura T, ShintaniIshida K, Yahagi N, Yoshida K. Lethal pulmonary
air embolism caused by the removal of a doublelumen hemodialysis catheter. Am J Forensic
Med Pathol. 2014 Dec;35(4):237-8. doi: 10.1097/
PAF.0b013e318288b1ee.
22. 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: a prospective
observational study. Crit Care 18:716, 2014.
23. Fukuda T, Matsubara T, Doi K, Fukuda-Ohashi N,
Yahagi N: Predictors of favorable and poor
prognosis in unwitnessed out-of-hospital cardiac
arrest with a non-shockable initial rhythm.
Int J Cardiol 2014 Oct 20;176(3):910-5. doi: 10.
1016/j.ijcard.2014.08.057. Epub 2014 Aug 17.
24. Inokuchi R, Aoki A, Aoki Y, Yahagi N: Inhaledfurosemide effectiveness for acute asthma exacerbations: A meta- analysis. Crit Care 2014 Nov
24;18(6):621.doi:10.1186/s13054-014-0621-y.
25. Hiruma T, Asada T, Yamamoto M, Inokuchi R,
Matsubara T, Ishii T, Tsukamoto M, Isshiki R,
Mayumi K, Noiri E, Nangaku M, Yahagi N, Doi
K: Mortality prediction by acute kidney injury
biomarkers in comparison with serum creatinine.
Biomarkers 2014 Dec; 19(8):646-51.doi:10.3109/
1354750X.2014.968209. Epub 2014 Oct 1.

Health Sciences and Nursing
1. Health Sciences

259

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, a project associate professor, aproject researcher, part-time lecturers, a technicalspecialist, visiting research fellows, 7 doctoral course
students, 5 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.

260

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., 2014)
1. Bakker AB, Shimazu A, Demerouti E, Shimada K,
Kawakami N. Work engagement versus
workaholism: a test of the spillover-crossovermodel. J Business Psychology 2014; 29: 63-80.
2. Chiba R, Miyamoto Y, Kawakami N, Harada N.
Effectiveness of a program to facilitate recovery
for people with long-term mental illness in Japan.
Nursing Health Sciences, 2014; 16(3), 277-283.
3. Curhan KB, Sims T, Markus HR, Kitayama S,
Karasawa M, Kawakami N, Love GD, Coe CL,
Miyamoto Y, Ryff CD. Just how bad negative
affect is for your health depends on culture.
Psychol Sci. 2014; 25(12): 2277-80.
4. Imamura K, Kawakami N, Furukawa TA,
Matsuyama Y, Shimazu A, Umanodan R,
Kawakami S & Kasai K. Effects on an internetbased cognitive behavioral therapy (iCBT)
program in Manga format on improving
subthreshold depressive symptoms among healthy
workers: A randomized controlled trial. PLoS
ONE. 2014; 9(5): e97167.
5. Inoue A, Kawakami N, Shimomitsu T, Tsutsumi A,
Haratani T, Yoshikawa T, Shimazu A, Odagiri Y.
Development of a short questionnaire to measure
an extended set of job demands, job resources,
and positive health outcomes: the New Brief Job
Stress Questionnaire. Ind Health 2014; 52(3):175-89.
6. Inoue A, Kawakami N, Tsutsumi A, Shimazu A,
Miyaki K, Takahashi M, Kurioka S, Eguchi H,
Tsuchiya M, Enta K, Kosugi Y, Sakata T,
Totsuzaki T. Association of jobdemands withwork engagement of Japanese employees:
comparison of challenges with hindrances(J-HOPE). PLoS ONE 2014; 9(3): e91583.
7. Kan C, Kawakami N, Karasawa M, Love GD,
Coe CL, Miyamoto Y, et al. Psychologicalresources as mediators of the association betweensocial class and health: comparative findings fromJapan and the USA. Int J Behav Med 2014; 21(1):53-65.
8. Kawakami N, Tsuchiya M, Umeda M, Koenen KC,
Kessler RC; World Mental Health Survey Japan.
Trauma and posttraumatic stress disorder inJapan: Results from the World Mental HealthJapan Survey. J Psychiatr Res. 2014; 53:157-65.
9. Kayama, M., Akiyama, T., Ohashi, A., Horikoshi,N., Kido, Y., Murakata, T., & Kawakami, N.
Experiences of municipal public health nurses
following Japan's earthquake, tsunami, andnuclear disaster. Public Health Nursing. 2014; 31:
517-25.
10. Kessler RC, Rose S, Koenen KC, Karam EG,
Stang PE, Stein DJ, Heeringa SG, Hill ED,
Liberzon I, McLaughlin KA, McLean SA, Pennell
BE, Petukhova M, Rosellini AJ, Ruscio AM,
Shahly V, Shalev AY, Silove D, Zaslavsky AM,
Angermeyer MC, Bromet EJ, de Almeida JM, deGirolamo G, de Jonge P, Demyttenaere K,
Florescu SE, Gureje O, Haro JM, Hinkov H,
Kawakami N, Kovess-Masfety V, Lee S,
Medina-Mora ME, Murphy SD, Navarro-Mateu F,
Piazza M, Posada-Villa J, Scott K, Torres Y,
Carmen Viana M. How well can post-traumaticstress disorder be predicted from pre-trauma risk
factors? An exploratory study in the WHO World
Mental Health Surveys. World Psychiatry. 2014;13(3):265-74.
11. Kodaka M, Matsumoto T, Katsumata Y, Akazawa
M, Tachimori H, Kawakami N, Eguchi N,
Shirakawa N, Takeshima T. Suicide risk amongindividuals with sleep disturbances in Japan: acase-control psychological autopsy study. Sleep
Med. 2014; 15(4):430-5.
12. Kubota K, Shimazu A, Kawakami N, Takahashi
M. Workaholism and sleep quality among
Japanese employees: a prospective cohort study,
Int J Behav Med 2014; 21(1), 66-76.

261

13. Kurioka S, Horie S, Inoue A, Mafune K, Tsuda Y,
Otsuji Y. Risk of progression to hypertension in
non-hypertensive Japanese workers aged 20-64
years. J Hypertens 2014; 32(2): 236-44.
14. Niitsu T, Takaoka K, Uemura S, Kono A, Saito A,
Kawakami N, Nakazato M, Shimizu E. The
psychological impact of a dual-disaster caused byearthquakes and radioactive contamination in
Ichinoseki after the Great East Japan Earthquake.
BMC Res Notes. 2014; 7(1):307.
15. Ochi M, Fujiwara T, Mizuki R, Kawakami N.
Association of socioeconomic status in childhood
with major depression and generalized anxiety
disorder: results from the World Mental HealthJapan survey 2002-2006. BMC Public Health.
2014; 14(1): 359.
16. Panthee B, Shimazu A, Kawakami N. Validationof Nepalese version of Utrecht Work Engagement
Scale. J Occup Health. 2014; 56, 421-429.
17. Qiao H, Schaufeli WB, Taris TW, Hessen D,
Hakanen J, Salanova M, Shimazu A. “East is Eastand West is West and never the twain shall meet”
work engagement and workaholism across eastern
and western cultures. J Behav Social Sci.2014; 1,
6-24.
18. Scott KM, Al-Hamzawi AO, Andrade LH, Borges
G, Caldas-de-Almeida JM, Fiestas F, Gureje O,
Hu C, Karam EG, Kawakami N, Lee S, Levinson
D, Lim CC, Navarro-Mateu F, Okoliyski M,
Posada-Villa J, Torres Y, Williams DR, Zakhozha
V, Kessler RC. Associations between subjective
social status and DSM-IV mental disorders:
results from the World Mental Health Surveys.
JAMA Psychiatry. 2014; 71(12):1400-8.
19. Shimazu A, de Jonge J, Kubota K, Kawakami N.
Psychological detachment from work during
off-job time: Predictive role of work and nonwork factors in Japanese employees. Ind Health2014; 52(2):141-6.
20. Song Y, Miyaki K, Suzuki T, Sasaki Y, Tsutsumi A,
Kawakami N, Shimazu A, Takahashi M, Inoue A,
Kan C, Kurioka S, Shimbo T. Altered DNA
methylation status of human brain derived
neurotrophis factor gene could be useful asbiomarker of depression. Am J Med Genet B
Neuropsychiatr Genet. 2014; 165B(4): 357-64.

21. Stein DJ, McLaughlin KA, Koenen KC, Atwoli L,
Friedman MJ, Hill ED, Maercker A, Petukhova M,
Shahly V, van Ommeren M, Alonso J, Borges G,
de Girolamo G, de Jonge P, Demyttenaere K,
Florescu S, Karam EG, Kawakami N, Matschinger
H, Okoliyski M, Posada-Villa J, Scott KM, Viana
MC, Kessler RC. DSM-5 and ICD-11 definitionsof posttraumatic stress disorder: investigating"narrow" and "broad" approaches. Depress
Anxiety. 2014; 31(6):494-505.
22. Suzuki T, Miyaki K, Sasaki Y, Song Y, Tsutsumi A,
Kawakami N, Shimazu A, Takahashi M, Inoue A,
Kurioka S, Shimbo T. Optimal cutoff values of
WHO-HPQ presenteeism scores by ROC analysis
for preventing mental sickness absence inJapanese prospective cohort. PLoS One. 2014;
9(10): e111191.
23. Takagaki K, Okamoto Y, Jinnin R, Mori A,
Nishiyama Y, Yamamura T, Takebayashi Y, Ogata
A, Okamoto Y, Miyake Y, Shimoda H, Kawakami
N, Yamawaki S. Behavioral characteristics ofsubthreshold depression. J Affect Disord. 2014;
168: 472-5.
24. Takahashi M, Tsutsumi A, Kurioka S, Inoue A,
Shimazu A, Kosugi Y, Kawakami N. Occupationaland socioeconomic differences in actigraphicallymeasured sleep. J Sleep Res 2014; 23(4): 458-62.
25. Umanodan R, Shimazu A, Minami M, Kawakami
N. Evaluation of a computer-based stress management training program for workers’ psychologicalwell-being and work performance: a cluster
randomized controlled trial. Ind Health 2014;
52(6):480-91.
26. Umeda M, Kawakami N. Cross-cultural
measurement equivalence of the Japanese version
of Revised Conflict Tactics Scales Short Form
(J-CTS2SF) among Japanese men and women.
Psychiatry Clin Neurosci. 2014; 68(11): 804-11.
27. Yokoyama Y, Otsuka K, Kawakami N, Kobayashi
S, Ogawa A, Tannno K, Onoda T, Yaegashi Y,
Sakata K. Mental health and related factors after
the Great East Japan earthquake and tsunami.
PLoS One. 2014; 9(7): e102497.

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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

2631) 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. Kitai S, Kudo M, Izumi N, Kaneko S, Ku Y,
Kokudo N, Sakamoto M, Takayama T, Nakashima
O, Kadoya M, Matsuyama Y, Matsunaga T.
Validation of three staging systems forhepatocellular carcinoma (JIS score, biomarkercombined JIS score and BCLC system) in 4,649
cases from a Japanese nationwide survey.
Digestive diseases. 2014; 32(6):717-724.
2. Otsuka M, Yokoi H, Matsuyama Y, Hayashi Y,
Shiode N, Masaoka Y, Okimoto T, Tamekiyo H,
Kawase T, Yamane K, Kagawa Y, Nakamura M,
Muramatsu T, Nanto S; J-DESsERT investigators.
Comparison of sirolimus- and paclitaxel-eluting
stents in patients with moderate renal insufficiency: results from the J-DESsERT trial.
Cardiovascular Revascularization Medicine 2014;
15: 323-328.
3. Taguri M, Matsuyama Y, Ohashi Y. Modelselection criterion for causal parameters instructural mean models based on a quasilikelihood. Biometrics 2014; 70(3): 721–730.
4. Isotani S, Shimoyama H, Yokota I, China T,
Hisasue SI, Ide H, Muto S, Yamaguchi R,
Ukimura O, Horie S. Feasibility and accuracy ofcomputational robot-assisted partial nephrectomy
planning by virtual partial nephrectomy analysis.
Int J Urol. 2015: [Epub ahead of print]
5. Isotani S, Shimoyama H, Yokota I, Noma Y,
Kitamura K, China T, Saito K, Hisasue SI, Ide H,
Muto S, Yamaguchi R, Ukimura O, Gill IS, Horie
S. Novel prediction model of renal function after
nephrectomy from automated renal volumetry
with preoperative multidetector computed tomography (MDCT). Clin Exp Nephrol [epub a headof print]
6. Kitamura K, Muto S, Yokota I, Hoshimoto K,
Kaminaga T, Noguchi T, Sugiura S, Ide H,
Yamaguchi R, Furui S, Horie S. Feasibility ofmultiparametric prostate magnetic resonanceimaging in the detection of cancer distribution:
histopathological correlation with prostatectomy
specimens. Prostate Int 2014; 2:188-95.
7. Kuramitsu S, Hiromasa T, Enomoto S, Shinozaki

264

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. (in press).
8. Arai Y, Aoyama T, Inaba Y, Okabe H, Ihaya T,
Kichikawa K, Ohashi Y, Sakamoto J, Oba K, Saji
S. Phase II study on hepatic arterial infusion
chemotherapy using percutaneous catheter
placement techniques for liver metastases fromcolorectal cancer (JFMC28 study). Asia Pac J Clin
Oncol 2015;11:41-8.
9. Inokuchi K, Kumagai T, Matsuki E, Ohashi K,
Shinagawa A, Hatta Y, Takeuchi J, Yoshida C,
Wakita H, Kozai Y, Shirasugi Y, Fujisawa S,
Iwase O, Yano S, Okamoto S, Oba K, Sakamoto J,
Sakamaki H. Efficacy of Molecular Response at 1
or 3 Months after the Initiation of Dasatinib
Treatment Can Predict an Improved Response to
Dasatinib in Imatinib-Resistant or ImatinibIntolerant Japanese Patients with Chronic
Myelogenous Leukemia during the Chronic Phase.
J Clin Exp Hematop 2014;54:197-204.
10. Fujita H, Hatanaka Y, Sutoh Y, Suzuki Y, Oba K,
Hatanaka KC, Mitsuhashi T, Otsuka N, Fugo K,
Kasahara M, Matsuno Y. Immunohistochemical
Validation and Expression Profiling of NKG2D
Ligands in a Wide Spectrum of Human Epithelial
Neoplasms. J Histochem Cytochem 2014 Dec 3.
11. Eguchi K, Honda M, Kataoka T, Mukouyama T,
Tsuneto S, Sakamoto J, Oba K, Saji S. Efficacy ofcorticosteroids for cancer-related fatigue: A pilot
randomized placebo-controlled trial of advanced
cancer patients. Palliat Support Care 2014; 2014
Nov 5:1-8.
12. Sakashita T, Homma A, Hatakeyama H,
Mizumachi T, Kano S, Furusawa J, Iizuka S,
Hoshino K, Hatanaka K, Oba K, Fukuda S. The
potential diagnostic role of the number ofultrasonographic characteristics for patients withthyroid nodules evaluated as Bethesda I-V. Front
Oncol 2014; 4:261.
13. Kuwatani M, Kawakami H, Hayashi T, Eto K,
Yamato H, Onodera M, Naruse H, Oba K. Effectof antispasmodic drugs on endoscopic ultrasound/endoscopic ultrasound-guided fine-needle aspira-tion: A multicenter randomized controlled trial.
Endoscopic Ultrasound 2014; 3: 167-73.
14. Tsunedomi R, Hazama S, Fujita Y, Okayama N,
Kanekiyo S, Inoue Y, Yoshino S, Yamasaki T,
Suehiro Y, Oba K, Mishima H, Sakamoto J,
Hamamoto Y, Oka M. A novel system forpredicting the toxicity of irinotecan based on
statistical pattern recognition with UGT1A
genotypes. Int J Clin Oncol 2014; 45: 1381-90.
15. Kamiya K, Sakakibara M, Asakawa N, Yamada S,
Yoshitani T, Iwano H, Komatsu H, Naya M, Chiba
S, Yamada S, Manabe O, Kikuchi Y, OyamaManabe N, Oba K, Tsutsui H. Cardiac Magnetic
Resonance Performs Better in the Detection of
Functionally Significant Coronary Artery Stenosis
Compared to Single-Photon Emission Computed
Tomography and Dobutamine Stress Echocardiography. Circ J 2014; 78:2468-76.
16. Aihara T, Yokota I, Hozumi Y, Aogi K, Iwata H,
Tamura M, Fukuuchi A, Makino H, Kim R,
Andoh M, Tsugawa K, Ohno S, Yamaguchi T,
Ohashi Y, Watanabe T, Takatsuka Y, Mukai H.
Anastrozole versus tamoxifen as adjuvant therapy
for Japanese postmenopausal patients withhormone-responsive breast cancer: efficacy
results of long-term follow-up data from the
N-SAS BC 03 trial. Breast Cancer Res Treat.
2014; 148: 337-43.
17. Igarashi A, Ishibashi T, Shinozaki T, YamamotoMitani N. Combinations of long-term care insurance services and associated factors in Japan: aclassification tree model. BMC Health Serv Res.
2014; 14: 382.
18. Sugimoto T, Shinozaki T, Naruse T, Miyamoto Y.
Who was concerned about radiation, food safety,
and natural disasters after the great East Japan
earthquake and Fukushima catastrophe? A nationwide cross-sectional survey in 2012. PLoS ONE.
2014; 9: e106377.
19. Kuramitsu S, Sonoda S, Yokoi H, Nishizaki Y,
Shinozaki T, Iwabuchi M, Domei T, Inoue K,
Hyodo M, Shirai S, Ando K, Nobuyoshi M.
Long-term coronary arterial response tobiodegradable polymer biolimus-eluting stents incomparison with durable polymer sirolimuseluting stents and bare-metal stents: Five-year
follow-up optical coherence tomography study.

265

Atherosclerosis. 2014; 237(1): 23-29.
20. 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. Publish online.
21. Takao T, Matsuyama Y, Suka M, Yanagisawa H,
Kikuchi M, Kawazu S. Time-to-effect relationships between systolic blood pressure and therisks of nephropathy and retinopathy in patientswith type 2 diabetes. Journal of Diabetes and its
Complications 2014; 28(5): 674-678.
22. Takao T, Matsuyama Y, Yanagisawa H, Kikuchi
M, Kawazu S. Association between HbA1cvariability and mortality in patients with type 2
diabetes. Journal of Diabetes and Its Complications 2014; 28(4): 494-499.
23. Kashiwabara K, Matsuyama Y, Ohashi Y. A
Bayesian stopping rule for sequential monitoringof serious adverse events. Therapeutic Innovation
and Regulatory Science 2014; 48: 444-452.
24. Imamura K, Kawakami N, Furukawa TA,
Matsuyama Y, Shimazu A, Umanodan R,
Kawakami S, Kasai K. Effects of an Internetbased cognitive behavioral therapy (iCBT)
program in Manga format on improving
subthreshold depressive symptoms among healthy
workers: a randomized controlled trial. PLoS One
2014; 9(5): e97167.
25. Nitta T, Mitsuhashi T, Hatanaka Y, Miyamoto M,
Oba K, Tsuchikawa T, Suzuki Y, Hatanaka KC,
Hirano S, Matsuno Y. Prognostic significance ofepithelial-mesenchymal transition-related markers
in extrahepatic cholangiocarcinoma: comprehensive immunohistochemical study using a tissue
microarray. Br J Cancer 2014;111:1363-72.
26. Hirano D, Fujinaga S, Shinozaki T, Endo A,
Watanabe T, Murakami H, Ida H. Optimal urinary
protein-to-creatinine ratio as a renal biopsy
criterion in children with asymptomatic
proteinuria. Clin Nephrol. 2014;82(2):115-21.
27. Shinozaki T, Matsuyama Y, Ohashi Y. Estimationof controlled direct effects in time-varying
treatments using structural nested mean models:application to a primary prevention trial forcoronary events with pravastatin. Stat Med.

2014;33(18):3214-28.
28. Takao T, Matsuyama Y, Yanagisawa H, Kikuchi
M, Kawazu S. Visit-to-visit variability in systolicblood pressure predicts development andprogression of diabetic nephropathy, but not
retinopathy, in patients with type 2 diabetes.
Journal of Diabetes and its Complications 2014;28(2): 185-190
29. Aramaki O, Takayama T, Higaki T, Nakayama H,
Ohkubo T, Midorikawa Y, Moriguchi M,
Matsuyama Y. Decreased blood loss reduces
postoperative complications in resection forhepatocellular carcinoma. Journal of Hepatobiliary Pancreatic Sciences 2014; 21(8): 585-591.
30. Oba M, Hasegawa K, Matsuyama Y, Shindoh J,
Mise Y, Aoki T, Sakamoto Y, Sugawara Y,
Makuuchi M, Kokudo N. Discrepancy between
recurrence-free survival and overall survival inpatients with resectable colorectal liver
metastases: a potential surrogate endpoint for time
to surgical failure. Annals of Surgical Oncology
2014; 21(6): 1817-1824.
31. Naito S, Imamura H, Tukada A, Matsuyama Y,
Yoshimoto J, Sugo H, Ishizaki Y, Kawasaki S.
Postoperative recurrence pattern and prognosis ofpatients with hepatocellular carcinoma, withparticular reference to the hepatitis viral infection
status. Liver International 2014; 34(5): 802-813.
32. Aoki T, Kokudo N, Matsuyama Y, Izumi N,
Ichida T, Kudo M, Ku Y, Sakamoto M, Nakashima
O, Matsui O, Makuuchi M; for the Liver Cancer
Study Group of Japan. Prognostic impact ofspontaneous tumor rupture in patients with
hepatocellular carcinoma: An analysis of 1160
cases from a nationwide survey. Annals ofSurgery 2014; 259(3): 532-542.
33. Utsunomiya T, Shimada M, Kudo M, Ichida T,
Matsui O, Izumi N, Matsuyama Y, Sakamoto M,
Nakashima O, Ku Y, Kokudo N, Makuuchi M;
Liver Cancer Study Group of Japan. Nationwide
study of 4741 patients with non-B non-C
hepatocellular carcinoma with special reference tothe therapeutic impact. Annals of Surgery 2014;
259(2): 336-345.
34. Hasegawa K, Makuuchi M, Kokudo N, Izumi N,
Ichida T, Kudo M, Ku Y, Sakamoto M, Nakashima
O, Matsui O, Matsuyama Y. Impact of266

histologically confirmed lymph node metastases
on patient survival after surgical resection forhepatocellular carcinoma: Report of a Japanesenationwide survey. Annals of Surgery 2014;
259(1): 166-170.
35. Tsuburaya A, Yoshida K, Kobayashi M, Yoshino S,
Takahashi M, Takiguchi N, Tanabe K, Takahashi
N, Imamura H, Tatsumoto N, Hara A, Nishikawa
K, Fukushima R, Nozaki I, Kojima H, Miyashita
Y, Oba K, Buyse M, Morita S, Sakamoto J.
Sequential paclitaxel followed by tegafur anduracil (UFT) or S-1 versus UFT or S-1
monotherapy as adjuvant chemotherapy for T4a/b
gastric cancer (SAMIT): a phase 3 factorial
randomised controlled trial. Lancet Oncol 2014;
15:886-93
36. Kono M, Yasuda S, Kato M, Kanetsuka Y, Kurita
T, Fujieda Y, Otomo K, Horita T, Oba K, Kondo
M, Mukai M, Yanai M, Fukasawa Y, Atsumi T.
Long-term outcome in Japanese patients withlupus nephritis. Lupus 2014; 23:1124-32.
37. Fujimoto S, Kondo T, Yamamoto H, Yokoyama N,
Tarutani Y, Takamura K, Urabe Y, Konno K,
Nishizaki Y, Shinozaki T, Kihara Y, Daida H,
Isshiki T, Takase S. Development of new risk
score for pre-test probability of obstructive
coronary artery disease based on coronary CT
angiography. Heart Vessels. 2014, published
online ahead of print.
38. Kurita T, Yasuda S, Oba K, Odani T, Kono M,
Otomo K, Fujieda Y, Oku K, Bohgaki T,
Amengual O, Horita T, Atsumi T. The efficacy oftacrolimus in patients with interstitial lungdiseases complicated with polymyositis ordermatomyositis. Rheumatology (Oxford). 2014
Apr 24.
39. Katakami N, Kunikane H, Takeda K, Takayama K,
Sawa T, Saito H, Harada M, Yokota S, Ando K,
Saito Y, Yokota I, Ohashi Y, Eguchi K.
Prospective study on the incidence of bonemetastasis (BM) and skeletal-related events(SREs) in patients (pts) with stage IIIB and IVlung cancer - CSP-HOR 13. J Thorac Oncol.
2014; 9:231-8.
40. Nishizaki Y, Shimada K, Tani S, Ogawa T, Ando J,
Takahashi M, Yamamoto M, Shinozaki T,
Miyauchi K, Nagao K, Hirayama A, Yoshimura M,

Komuro I, Nagai R, Daida H. Significance ofimbalance in the ratio of serum n-3 to n-6
polyunsaturated fatty acids in patients with acutecoronary syndrome. Am J Cardiol. 2014;113(3):441-5.
41. Nakai Y, Inoue T, Toda H, Toyomaki A, Nakato Y,
Nakagawa S, Kitaichi Y, Kameyama R,
Hayashishita Y, Wakatsuki Y, Oba K, Tanabe H,
Kusumi I. The influence of childhood abuse, adultstressful life events and temperaments on
depressive symptoms in the nonclinical generaladult population. J Affect Disord 2014; 158:
101-7.
42. Maeda H, Hazama S, Shavkat A, Okamoto K, Oba
K, Sakamoto J, Takahashi K, Oka M, Nakamura D,
Tsunedomi R, Okayama N, Mishima H,
Kobayashi M. Differences in UGT1A1, UGT1A7,
and UGT1A9 Polymorphisms between Uzbek andJapanese Populations. Mol Diagn Ther 2014; 18:
333-42.
43. Iwamoto S, Hazama S, Kato T, Miyake Y,
Fukunaga M, Matsuda C, Bando H, Sakamoto J,
Oba K, Mishima H. Multicenter phase II study ofsecond-line cetuximab plus folinic acid/
5-fluorouracil/irinotecan (FOLFIRI) in KRAS
wild-type metastatic colorectal cancer: the FLIER
study. Anticancer Res 2014; 34: 1967-73.
44. Cho H, Yoshikawa T, Oba MS, Hirabayashi N,
Shirai J, Aoyama T, Hayashi T, Yamada T, Oba K,
Morita S, Sakamoto J, Tsuburaya A. Matched pairanalysis to examine the effects of a planned
preoperative exercise program in early gastriccancer patients with metabolic syndrome to
reduce operative risk: The adjuvant exercise forgeneral elective surgery (AEGES) study group.
Ann Surg Oncol 2014; 21: 2044-50.
45. Kumagai T, Matsuki E, Inokuchi K, Ohashi K,
Shinagawa A, Takeuchi J, Yoshida C, Okamoto S,
Wakita H, Kozai Y, Shirasugi Y, Fujisawa S,
Iwase O, Yano S, Nishiwaki K, Oba K, Sakamoto
J, Sakamaki H. Relative increase in lymphocytes
from as early as one month predicts improved
response to dasatinib in chronic-phase chronic
myelogenous leukemia. Int J Hematol 2014; 99:
41-52.
46. Fukudome I, Kobayashi M, Dabanaka K, Maeda
H, Okamoto K, Okabayashi T, Baba R, Kumagai

267

N, Oba K, Fujita M, Hanazaki K. Diamineoxidase as a marker of intestinal mucosal injury
and the effect of soluble dietary fiber on
gastrointestinal tract toxicity after intravenous
5-fluorouracil treatment in rats. Med Mol
Morphol 2014;47:100-7.
47. Koseki N, Kaiho M, Kikuta H, Oba K, Togashi T,
Ariga T, Ishiguro N. Comparison of the clinicaleffectiveness of zanamivir and laninamivir
octanoate for children with influenza A(H3N2)
and B in the 2011-2012 season. Influenza andOther Respiratory Viruses 2014;8:151-8.
48. Shimada H, Noie T, Ohashi M, Oba K, Takahashi
Y. Clinical significance of serum tumor markers
for gastric cancer: a systematic review ofliterature by the Task Force of the Japanese
Gastric Cancer Association. Gastric Cancer 2014;
17:26-33.

268

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 eight graduate lecturers
from other organizations, and seven visiting
researchers contribute to department teaching andresearch activities.
We have nine department graduate students. All269

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

Teaching activities
Our departments highly prioritize the teaching andguidance of graduate students and their research
activities. Sixteen bachelor theses, twenty mastertheses, and nine doctoral dissertations were completed
between April 2004 and March 2015. Our
departments’ staff members are also responsible forthe following undergraduate and graduate courses.
Undergraduate Courses
Required courses
1) Health Administration (2 credits, lecture)2) Biomedical Ethics (2 credits, lecture)3) Occupational Health and Law (1 credit, lecture)
Elective courses
4) Health & Education (2 credits, lecture)5) Health Care & Welfare I & II (2 credits, lecture)6) Field Work for Health Administration (2 credits,
practicum)7) Health Promotion Sciences (1 credit, lecture)8) Health Policy & Administration (2 credits,
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,
implementation, and evaluation of health promotion
programs for the prevention of lifestyle-relateddisease in the community and workplace.

Research activities
Department of Biomedical Ethics
The Department of Biomedical Ethics is interested in
the current topics of health care ethics. We are
currently conducting studies in the fields ofbiomedical ethics, research ethics and clinical ethics.
Methodology is two-folded―theoretical and empirical.
While conducting theoretical research on ethics andphilosophy of health care, we also have adopted a
descriptive approach.
We have recently established The University ofTokyo Center for Biomedical Ethics and Law (CBEL)―a new interdisciplinary and international education
research center aimed to address bioethical issues
relevant to Japan and the international community.
Our center will form an international network by
establishing partnerships with research centersoverseas (GABEX: Global Alliance of Biomedical
Ethics Centers Project). Through these efforts, we will
foster the next generation of bioethics experts inpolicy-making, research, and clinical medicine whoare capable of providing international leadership in the
future (http://www.cbel.jp/).
Specific research topics include:
1) Study of methods for promoting social consensus
on topics related to advanced medical technology
2) Study of the function and responsibilities of
ethics committees in Japan
3) Acceptability of advance directives in Japanesesociety4) Development of evaluative methods forbio-medical ethics education
5) Ethical and psychosocial aspects of living relatedorgan transplantation
6) Publication of a medical ethics case book forJapan7) Comparative study of clinical ethics in the Asian
region8) Historical analyses for the term “bioethics” in theJapanese context
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 the270

community 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. A 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 (in press)
2. Fujita M, Hayashi Y, Tashiro S, Takashima K,
Nakazawa E, Akabayashi A. Handling incidental
findings in neuroimaging research in Japan:
current state of research facilities and attitudes ofinvestigators and the general population. HealthResearch Policy and Systems 12(1): 58. 2014.
3. 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(in press)
4. Mori K, Tamate S. Pasinetti after Sen: Toward a
Capability Approach to Structural Dynamics ofConsumption. Metroeconomica. 65(4): 690-716.
2014.
5. Tajima M, Lee JS, Watanabe E, Park JS, Tsuchiya
R, Fukahori A, Mori K, Kawakubo K. Association
between the changes of twelve lifestyle behaviors
and the development of metabolic syndromeduring one year among workers in the Tokyo
metropolitan area. Cir J 78(5):1152-1159. 2014.
6. Takimoto Y, Yoshiuchi K, Ishizawa T, Yamamoto
Y, Akabayashi A. Autonomic dysfunction
responses to head-up tilt in anorexia nervosa. Clin
Auton Res 24(4):175-81 2014.
7. Tamate S. External Norms and SystematicallyObserved Norms. Japanese Economic Review (inpress)
8. Yasui T, Hayashi K, Mizunuma H, Kubota T, Lee
JS, Suzuki S. Risk profiles for endometriosis inJapanese women- Results from a repeated surveyof self reports. Journal of Epidemiology (in press)
9. Tamte S. Critical natural capital and basic needs.
Syakai to Rinri [Society and Ethics] 29:21-35 [inJapanese].
10. Tamte S. The potential of the Marxian concept ofalienation as a radical critique of normative
theories.
Political
EconomyQuarterly
51(3):65-70.
11. Nakazawa E, Takimoto Y. How do cancer
notification to patients and their families? Fromthe point of view of medical ethics. Clinics in
Gastroenterology 17(3):210–213 [in Japanese].
12. Yamamoto K, Tashiro S. Clinical research andethics of regenerative medicine: Medical
innovation is whether research or treatment?
Medicine and Drug Journal 50(8):87-90 [inJapanese].
13. Ozeki R. CPR and Slow Code among acute
deterioration situations in advanced cancer

271

patients. New Medical World Weekly 3104:3 [inJapanese].
14. Takimoto Y. Basis of clinical ethics and practicefor psychosomatic medicine specialist vol. 2: Fourprinciples of biomedical ethics. Japanese Journalof Psychosomatic Medicine 54(4):371-372 [inJapanese].
15. Takimoto Y. Basis of clinical ethics and practicefor psychosomatic medicine specialist vol. 3:
Procedural justice. Japanese Journal of
Psychosomatic Medicine 54(7):703-704 [inJapanese].
16. Takimoto Y. Basis of clinical ethics and practicefor psychosomatic medicine specialist vol. 4:
Considering cases. Japanese Journal of
Psychosomatic Medicine 54(10):945-947 [inJapanese].
17. Takimoto Y. Basis of clinical ethics and practicefor psychosomatic medicine specialist vol. 5: How
to analyze ethical dilemma in ethical theory.
Japanese Journal of Psychosomatic Medicine
54(12): 1124-1126 [in Japanese].
18. Takimoto Y. Clinical Ethics and Compliance, andPatient First: What is needed is to introduce
bioethics to clinical practice? What is the
problem? Clinics in Gastroenterology 17(3):201204 [in Japanese].
19. Takimoto Y, Kanai Y, Kaitsu M. Answers of
Ethics vol.1: I wonder if the patient's intention,
May I've received truly? The Japanese Journal of
Hospice and Palliative Care 24(6):482-485 [inJapanese].
20. Narita K, Yamamoto K, Obata S. Report of the
13th Conference of the International Society for
Utilitarian Studies. Studies in British Philosophy
38: 95-100 [in Japanese].

Health Sciences and Nursing
2. Preventive and Administrative Nursing

273

Department of
Nursing Administration /Advanced Clinical Nursing
Professor
Hiromi Sanada, Ph.D., R.N.

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

Homepage

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

Introduction and Organization
The Department of Nursing Administration/
Advanced Clinical Nursing has 60 years of history andtradition. It was first established as 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. Hiromi Sanada, the department chair in the

Department of Gerontologicalresponsibility concurrently.

Nursing,

held

Teaching activities
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 are successful in various
places to learn clinical application of these knowledge
and discuss 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 in274

communication, 2) physicalessential to health assessment

examination

skillsFundamental 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 Fundamental Nursing.
Nursing Administration (2 credits)
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 (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
with the Department of Gerontological Nursing every
week, where members provide the actual plans fortheir own research and discuss the topic.

Research activities
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 conducted cross-cultural comparison of nursing
practice and nursing education to clarify the current
status and issues in order to better understand the stateof individual patient.

References
1. Otsuka-Ono H, Sato I, Ikeda M, ,Kamibeppu K.
Premenstrual Distress among Japanese HighSchool Students: Self-Care Strategies andAssociated Physical and Psychosocial Factors.
Women and Health. 2014 (in press)
2. Ikeda M, Nishigaki K, Kida M, Setoyama A,
Kobayashi K, Kamibeppu K. The development
and feasibility study of Maternal Mental Health
Promotion Program (MMHPP) for women during
their pregnancy. Open Journal of Nursing, 2014
(in press)
3. Ikeda M, Hayashi M, Kamibeppu K. The
relationship between attachment style andpostpartum depression. Attachment and Human

275

Development. 2014. DOI:10.1080/14616734.2014.
941884 (Epub ahead)
4. Sanada H, Nakagami G, Takehara K, Goto T, Ishii
N, Yoshida S, Ryu M, Tsunemi Y. Antifungal
Effect of Non-Woven Textiles Containing
Polyhexamethylene Biguanide with Sophorolipid:
A Potential Method for Tinea Pedis Prevention.
Healthcare. 2014;2:183-191.
5. Miura Y, Takehara K, Nakagami G, Amemiya A,
Kanazawa T, Kimura N, Kishi C, Koyano Y,
Tamai N, Nakamura T, Kawashima M, Tsunemi
Y, Sanada H. Screening for tinea unguium bythermography in older adults with subungual
hyperkeratosis. Geriatr Gerontol Int. 2014. DOI:
10.1111/ggi.12380. (Epub ahead)
6. Tsunemi Y, Takehara K, Miura Y, Nakagami G,
Sanada H, Kawashima M. Screening for tinea
unguium by dermatophyte test strip. Br J
Dermatol. 2014;170(2):328-331.

276

Department of Family Nursing
Professor
Kiyoko Kamibeppu, Ph.D., R.N., P.H.N.

Assistant Professors
Iori Sato, Ph.D., R.N., P.H.N.
Rieko Fukuzawa, Ph.D., R.N., M.W., P.H.N.
Rachel Marie Amiya, Ph.D.

Homepage

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

Introduction and Organization

Research

This department was established in 1992. In 1994,
we founded the Japanese Association for Research in
Family Nursing. Four faculty members currently serve
the department: a professor and three assistantprofessors. Enrolled at present are 9 doctoral students,
15 master’s students, 2 research students, and 22
visiting researchers.

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 and posttraumatic stressdisorder in children with cancer;
4. Support for mothers with mental illness and theiroffspring;
5. Roles and competencies of nursing staff in childday-care centers;
6. Caregiving burden and utilization of respite careservices in families of severely disabled children;
7. Support for dying patients and their families(QOL and family functioning);
8. Nurses’ attitudes toward family nursing.

Education
1. Graduate Courses, School of Health Sciences andNursing (credit hours)
Advanced Family Nursing I (2)Advanced Family Nursing II (2)Laboratory and/or Field Work on Family Nursing(16)
Practicum in Translational Research Nursing (2)2. Undergraduate Courses for Students in the Schoolof Integrated Health Sciences (credit hours)
Family 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)In particular, through our research project titled,“Establishment of family nursing skills anddevelopment of a medical collaboration system model
for child abuse prevention from the perinatal period”,
we are developing a perinatal mental health and childcare support system, in collaboration with the277

University of Tokyo Hospital and community-based
networks.
Since 2013, under the Health Labour Sciences
Research Grant and as part of a new research project
titled, “Situation analysis and quality improvement
study on sick and convalescent child day-careservices”, we have also been investigating the
distribution and role of day-care nursing staff inserving sick and convalescing children. Particularly, in
2014, we investigated a day-care and nursing forchildren with chronic illness and formulated
guidelines.
Further 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 offamily support organizations across the country.
Funding for these research projects was granted
through a 2004-2006 Ministry of Education, Culture,
Sports, Science and Technology Grant-in-Aid for
Scientific Research and currently through a Cancer
Research-specific Health Labour Sciences Research
Grant.
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 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. Ozono S, Ishida Y, Honda M, Okamura J, Asami
K, Maeda N, Sakamoto N, Inada H, Iwai T,
Kamibeppu K, Kakee N, Horibe K. General healthstatus and late effects among adolescent andyoung adult survivors of childhood cancer inJapan. Japanese Journal of Clinical Oncology.
2014; 44(10): 932-940.
2. Taguchi R, Sakamoto N, Sato I, Kamibeppu K. A
study of posttraumatic stress symptoms among
young adults in Japan: correlates and effects on
mental health and quality of life. Journal of
Health and Human Ecology. 2014; 80(6): 245259.
3. Ikeda M, Hayashi M, Kamibeppu K. The
relationship between attachment style andpostpartum depression. Attachment & Human
Development. 2014; 16(6): 557-572.
4. Ikeda M, Nishigaki K, Kida M, Setoyama A,
Kobayashi K, Kamibeppu K. The development
and implementation of the maternal mental healthpromotion program for expectant mothers. Open
Journal of Nursing. 2014; 13(4): 971-979.
5. Kaneko M*, Sato I*, Soejima T, Kamibeppu K.
Health-related quality of life in young adults in
education, employment, or training: developmentof the Japanese version of Pediatric Quality ofLife Inventory (PedsQL) Generic Core Scales
Young Adult Version. Quality of Life Research.
2014; 23(7): 2121-2131. (*The first two authors
contributed equally to this work.)
6. Sato I, Higuchi A, Yanagisawa T, Mukasa A, Ida
K, Sawamura Y, Sugiyama K, Saito N, Kumabe T,
Terasaki M, Nishikawa R, Ishida Y, Kamibeppu K.
Cancer-specific health-related quality of life inchildren with brain tumors. Quality of Life
Research. 2014; 23(4): 1059-1068.
7. Sato I, Higuchi A, Yanagisawa T, Murayama S,
Kumabe T, Sugiyama K, Mukasa A, Saito N,
Sawamura Y, Terasaki M, Shibui S, Takahashi J,
Nishikawa R, Ishida Y, Kamibeppu K. Impact oflate effects on health-related quality of life insurvivors from pediatric brain tumors: motility
disturbance of limb(s), seizure, ocular/visual
impairment, endocrine abnormality, and higher
brain dysfunction. Cancer NursingTM: An278

International Journal for Cancer Care. 2014;37(6): E1-E14.
8. Fukuzawa RK*, Kodate N*. Maternity services inJapan: a comparative perspective. University ofTokyo Journal of Law and Politics. 2014; 11:129-158. (*The first two authors contributed
equally to this work.)
9. Morishita M, Kamibeppu K. Quality of life andsatisfaction with care among family caregivers ofpatients with recurrent or metastasized digestivecancer requiring palliative care. Supportive Carein Cancer. 2014; 22(10): 2687-2696.
10. Soejima T, Murayama S, Toju K, Sato I, Hiraga K,
Takeda T, Kamibeppu K. Recognition ofchildhood cancer and support for chilhood cancer
survivors in elementary and junior high school
teacher. The Journal of Child Health. 2014; 73(5):697-705.11.
11. Matsubara Y, Murayama S, Namiki Y, Kamibeppu
K. The expertise of nurses and the problems thenurses identify about infection control at nurseryschools. The Journal of Child Health. 2014; 73(6):826-835.
12. Kibi S, Ikeda M, Kamibeppu K. Study on life
education for children in Japan: focus on
education conducted by medical or health care
professionals. Journal of Japanese Society ofChild Health Nursing. 2014; 23(3): 70-76.
13. Ando A, Kurihara K, Kawai N, Hiraoka Y, Sato
N, Ishii N, Yamaguchi K. A research on the very
low birth weight children's development (10):The relationships between the intellectualdevelopment of 9 years-old and the backgroundfactors. Reports of Studies of Japan Child andFamily Research Institute. 2014; 50: 247-252.
14. Nishigaki K, Kuroki H, Fujioka H, Kamibeppu K.
Relevant factors of primary caregiver’s demandsof respite care for severely disabled children at
home. The Journal of Child Health. 2014; 73(3):475-483.

279

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. At present,
there are five faculty members introduced above and
15 graduate course students (7 in master course, 8 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) Health Guidance (2 credits, lectures)This class is to study the methodology andpractice of health guidance, which is the
supporting technique to promote health of thepeople living in the 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
multilaterally how characteristics of the residents,
health resources and environment of the280

community 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 homecareresearchandqualitative
researchmethodology 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 in public health nursing)*
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,
and leadership. 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 inprograms, meetings, and other daily activities heldby public health nurses. Throughout theirassessment, students are expected to foster theirability to manage and research public healthnursing practice.
We hold departmental meetings (journal reading
and introduction of research) every Tuesday andmonthly research seminars every third Friday toenhance research capacity.

Research
Our research focuses on the development andevaluation of health care programs, establishment ofcommunity health care systems, and standardizationof skills among public health nurses in response to the281

health 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) the developmentof preventive care programs (e.g., preventive care exercises, programs for (pre-) house-bound prevention,(2) identification of service needs among frail elderly
persons in community dwellings, (3) evaluation ofcommunity care services’ impact on the elderly andtheir family caregivers, and (4) the development of an
approach aimed at providing 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 child-rearing, supporting
untreated residents in the community, and groupdynamics.

Publications(1) Satoko Nagata, Chie Teramoto, Reiko Okamoto,
Keiko Koide, Masumi Nishida, Ruriko Suzuki,
Michie Nomura, Toshiko Tada, Emiko Kishi,
Yoko Sakai, Noriko Jojima, Emiko Kusano, Saori
Iwamoto, Miki Saito, Sachiyo Murashima. The
tsunami's impact on mortality in a town severely
damaged by the 2011 Great East Japan Earthquake. Disasters, 38(2), 111-122, 2014.
(2) Mahiro Sakai, Takashi Naruse, Satoko Nagata.
Work Engagement and Attitudes toward Caring
for Dying Patients and the Families among Home
Visiting Nurses.International Journal of Palliative
Nursing, 20(7), 343-348, 2014.

282(3) Mahiro Sakai, Midori Mizui, Takashi Naruse,
Satoko Nagata. Attendance at End-of-Life Care
Seminars and Related Factors among Home
Visiting Nurses. Clinical Nurisng Studies, 2(3),116-126, 2014.
(4) 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.
(5) 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,(DOI: 10.1007/s00520-015-2638-4), 2015 Feb. 8.
(Epub ahead of print).
(6) 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), 2015(inpress).
(7) 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, (DOI: 10.1111/jjns.12071),
2015 Mar 4. (Epub ahead of print).
(8) 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 Health Nursing, (DOI: 10.1111/phn.
122012015), 2015 MAY 28. (Epub ahead ofprint).
(9) Hiroshige Matsumoto, Takashi Naruse, Mahiro
Sakai, Satoko Nagata. Who prefers to age inplace? Cross-sectional survey of middle-aged
people in Japan. Geriatrics & Gerontology
International, (DOI: 10.1111/ggi.125032015),
2015 May 15. (Epub ahead of print).

(10) Masako Kageyama, Keiko Yokoyama, Yukako
Nakamura, Iwao Oshima. Diffusion anddissemination of a family peer-education program
on mental disorders
A case study of the
Omotenashi - Family Experiences Learning
Program. Japanese Journal of Public Health,61(5), 221-232, 2014.
(11) Masako Kageyama, Keiko Yokoyama, Yukako
Nakamura, Sayaka Kobayashi, Yusuke Nishina,
Iwao Oshima. Factors related to adoption of afamily peer-education program on mental disorders Dissemination research of the OmotenashiFamily Experiences Learning Program. Japanese
Journal of Public Health, 61(10), 625-636, 2014.
(12) Masako Kageyama. Relationships between
organizational development of family groups withmental disorders and a family Peer-education
program: The Omotenashi – Family experiences
learning program. Japanese Journal of Public
Health Nursing, 3(1), 31-39, 2014.
(13) Masako Kageyama, Keiko Yokoyama, Yukako
Nakamura, Sayaka Kobayashi．Factors Related to
Family Groups’ Intention Regarding Continuation
in a Family Peer-education Program on Mental
Disorders. Japan Academy of Community HealthNursing. 17(2), 36-44, 2014.
(14) Takashi Naruse, Mahiro Sakai, Satoko Nagata.
Reliability and validity of the Japanese version of
the Relational Coordination Scale. Japanese
Journal of Public Health, 61(9), 565-573, 2014.
(15) 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．
(16) Masako Kageyama, Keiko Yokoyama, Sayaka
Kobayashi, Yukako Nakamura. Qualitative Evaluation of a Family Peer-Education Program on
Mental Disorders: An Analysis of Free-Response
Descriptions at Post-Test of the Program. Journalof Japan Academy of Nursing Science, 35, 43-52,
2015．

Health Sciences and Nursing
3. Clinical Nursing

284

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)
Miho Suzuki, Ph.D., ANP-BC, R.N.
Ayumi Igarashi, 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

285

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 2014. Details of our publications andfunding are shown in our department website andannual report.

A) Developing an educational program for quality
improvement in care of chronic pain at long-termcare 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 interviewed various
professionals working at long-term care facilities forolder people. We have explored the way for improving
quality of care, problems each professional faced,barriers to solve the problems, and effective supports
from other organizations. We presented some findingsof the study at Annual Scientific Meeting of Japan
Academy of Gerontological nursing, and other results
will be presented at some other conferences. The
papers were currently under review/ in preparation.
B) Development of nursing care standards for older
people with chronic pain
We have developed a guideline for nursing care ofchronic pain and uploaded the guideline to a website.
We have also explored experience and self-care

286

among older people with chronic pain using groundedtheory approach.
C) 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 have started
descriptive studies to explore the convenience stores’
support for the elderly persons as the first step.

Publications
1. Kawakami A, Tanaka M, Nishigaki M,
Yoshimura N, Suzuki R, Maeda S, Kunisaki R,
Yamamoto-Mitani N. A screening instrument to
identify ulcerative colitis patients with the highpossibility of current non-adherence to aminosalicylate medication based on the Health Belief
Model: a cross-sectional study. BMC Gastroenterol. 2014 Dec 19;14:220. doi:10.1186/s12876014-0220-z.
2. Fukui S, Yamamoto-Mitani N,Fujita J. Five types
of home-visit nursing agencies in Japan based on
characteristics of service delivery: cluster analysisof three nationwide surveys. BMC Health Serv
Res. 2014 Dec 20;14:644. doi: 10.1186/s12913014-0644-8.
3. Igarashi A, Ishibashi T, Shinozaki T, YamamotoMitani N. Combinations of long-term careinsurance services and associated factors in Japan:
a classification tree model. BMC Health Serv Res.
2014 Sep 10;14:382. doi: 10.1186/1472-6963-14382.

4. Yamamoto-Mitani N, Igarashi A, Watanabe M,
Suzuki M. Factors of “good collaboration” inhome-based end-of-life care: a questionnaire
survey of Japanese homecare nurses, homehelpers, and care managers. Care Manag J. 2014
Sep 10;14:382. doi: 10.1186/1472-6963-14-382.
5. Sato K, Inoue Y, Umeda M, Ishigamori I, Igarashi
A, Togashi S, Harada K, Miyashita M, Sakuma Y,
Oki J, Yoshihara R, Eguchi K. A Japanese
Region-wide Survey of the Knowledge,
Difficulties and Self-reported Palliative Care
Practices Among Nurses. Jpn J Clin Oncol. 2014
Aug;44(8):718-28. doi: 10.1093/jjco/hyu 075.
6. Takai, Y., Abe, A., Torimoto-Sasai, Y.,
Okamoto, Y., Kamiyama, M. & YamamotoMitani, N. Compliance of urinary continence care
for Japanese residents on short-stay respite
services, Int J Urol Nurs, 2014 Jul; 8 (2): 90-6.
(journal article - research, tables/charts) ISSN:
1749-7701
7. Fujimori M, Shirai Y, Asai M, Kubota K,
Katsumata N, Uchitomi Y. Effect of communication skills training program for oncologists basedon patient preferences for communication when
receiving bad news: a randomized control trial. J
Clin Oncol. 2014 Jul 10;32(20):2166-72. doi:10.
1200/JCO. 2013.51.2756.
8. Fujimori M, Shirai Y, Asai M, Kubota K,
Katsumata N, Uchitomi Y. Development andpreliminary evaluation of communication skills
training program for oncologists based on patient
preferences for communicating bad news. Palliat
Support Care. 2014 Oct;12(5):379-86. doi: 10.
1017/S147895151300031X.
9. Takai Y, Yamamoto-Mitani N, & Ko A.
Prevalence of and factors related to pain among
elderly Japanese residents in long-term healthcare
facilities. Geriatr Gerontol Int, 2014 Apr;14(2):481-9. doi: 10.1111/ggi.12094.
10. Takai, Y., Yamamoto-Mitani, N., Abe Y. &Suzuki, M. Literature review of pain management
for people with chronic pain, Jpn J Nurs Sci. 2014
Nov 19. doi:10.1111/jjns. 12065.
11. Takai, Y., Yamamoto-Mitani, N., Ko, A., &Heilemann, M.V. Differences in pain measures by
Mini-Mental State Examination scores ofresidents in aged care facilities: Examining the287

usability of the Abbey Pain Scale- Japaneseversion, Pain Manag Nurs. 2014 Mar;15(1):236-45. doi: 10.1016/j.pmn.2012.09.004.
12. Takai, Y., Yamamoto-Mitani, N., Chiba, Y., &Kato, A. Feasibility and clinical utility of theJapanese Version of the Abbey Pain Scale inJapanese aged care, Pain Manag Nurs. 2014 Jun;
15(2):439-48. doi: 10.1016/j.pmn.2012.02.003.
13. Igarashi A, Miyashita M, Morita T, Akizuki N,
Akiyama M, Shirahige Y, Eguchi K. A populationbased survey on perceptions of opioid treatment
and palliative care units: OPTIM Study. Am J
Hosp Palliat Med. 2014 Mar;31(2):155-60. doi:10.
1177/1049909113481260.
14. Takai Y, Yamamoto-Mitani N, Ko A. Prevalenceof and factors related to pain among elderly
Japanese residents in long-term healthcare
facilities. Geriat Gerontol Int. 2014 Apr;14(2):481-9. doi: 10.1111/ ggi.12094.
15. Takai Y, Yamamoto-Mitani N, Ko A, Heilemann
MV. Differences in pain measures by Mini-Mental
State Examination scores of residents in aged carefacilities: examining the usability of the Abbey
Pain Scale- Japanese version. Pain Manag Nurs.
2014 Mar;15(1):236-45. doi: 10.1016/j.pmn.2012.
09.004.

288

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
Mie Shiraishi, Ph.D., R.N.M., P.H.N.

Homepage http://midwifery.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002. The midwifery course was
upgraded from undergraduate to master course in2014.
Currently, it has 3 faculty members introduced above
and 15 graduate students (8 in master course, 7 indoctoral course) and a visiting researcher.

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,

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lipid metabolic biomarkers and nutritional intake
to optimize weight management and a healthy
lifestyle during pregnancy to prevent low birthweight. 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. Haruna, M., Matsuzaki, M., Ota, E., Shiraishi, M.,
Hanada, N., & Mori, R. (2014). Guided Imagery for
Treating Hypertension in Pregnancy. CochranePregnancy and Childbirth Group, doi: 10.1002/
14651858.CD011337.
2. Matsuzaki, M., Haruna, M., Nakayama, K.,
Shiraishi, M., Ota, E., Murayama, R., MurashimaS., Yeo, S. (2014). Adapting the Pregnancy
Physical Activity Questionnaire for JapanesePregnant Women. Journal of Obstetric,
Gynecologic, & Neonatal Nursing, 1, 107-16.
3. Matsuzaki, M., Haruna, M., Ota, E., Murayama, R.,
Yamaguchi, T., Shioji, I., Sasaki, S., Yamaguchi, T.,
Murashima, S. (2014). Effects of lifestyle factors on
urinary oxidative stress and serum antioxidant
markers in pregnant Japanese women: A cohort
study. Bioscience trends, 8(3), 176-84. ·4. 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. Nurs
Health Sci, 17(2), 257-62.
5. 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.
6. Shiraishi, M., Haruna, M., Matsuzaki, M., &Murayama, R. (2014). Demographic and lifestyle290

factors associated with vitamin D status in pregnant
Japanese women. Journal of Nutritional Science andVitaminology, 60(6), 420-8.
7. Shiraishi, M., Haruna, M., Matsuzaki, M., Ota E,
Murayama R, Sasaki S, Yeo S, & Murashima S.
(2014). Relationship between plasma total
homocysteine level and dietary caffeine and vitamin
B6 intakes in pregnant women. Nurs Health Sci,
16(2), 164-70.
8. Kita, S., Minatani, M., Hikita, N., Matsuzaki, M.,
Shiraishi, M., & Haruna, M. (2015). A Systematic
Review of the Physical, Mental, Social, andEconomic Problems of Immigrant Women in the
Perinatal Period in Japan. Journal of Immigrant andMonirty Health (in press).
9. Takegata, M., Haruna, M., Matsuzaki, M., Shiraishi,
M., Okano, Y., & Severinsson, E. (2014). Antenatal
fear of childbirth and sense of coherence among
healthy pregnant women in Japan: A cross-sectional
study. Archieves of Women’s Mental Health, 17(5),403-409.
10. Takegata, M., Kitamura, T., Haruna, M., Sakanashi,K., & Tanaka, T. (2014). Childbirth as a trauma:
Psychometric properties of the Impact of Event
Scale in Japanese mothers of neonates. Psychology
and Behavioral Sciences, 3(2), 46-50.
11. Yonezawa, K., Haruna, M., Shiraishi, M., Matsuzaki,
M., & Sanada, H. (2014). Relationship Between
Skin Barrier Function in Early Neonates and Diaper
Dermatitis During the First Month of Life: A
Prospective Observational Study. Pediatric Dermatology, 31(6), 692-97.
12. Ohashi, Y., Kitamura, T., Kita, S., Haruna, M.,
Sakanashi, K., & Tanaka, T. (2014). Mothers’
Bonding Attitudes towards Infants: Impact of
Demographics, Psychological Attributes, andSatisfaction with Usual Clinicalcare during
Pregnancy. International Journal of Nursing and
Health Science, 1(3), 16-21.
13. Kitamura, T., Ohashi, Y., Minatani, M., Haruna,M., Murakami, M., & Goto, Y. (2014).
Emotionality Activity Sociability and Impulsivity(EASI) Survey: Psychometric properties andassessment biases of the Japanese version,
Psychology and Behavioral Sciences, 3(4), 11320.

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Department of Psychiatric Nursing
Professor
Norito Kawakami, M.D., Ph.D.

Lecturer
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, part-time lecturers,
visiting research fellows, 5 doctoral course students, 6
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292

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

Publications
1. Bakker AB, Shimazu A, Demerouti E, Shimada K,
Kawakami N. Work engagement versus
workaholism: A test of the spillover-crossovermodel. Journal of Business Psychology 2014; 29:
63-80.
2. Chiba R, Miyamoto Y, Funakoshi A. The conceptof "benefit finding" for people at different stagesof recovery from mental illness; a Japanese study.
J Ment Health, 23(1), 20-24, 2014.
3. Chiba R, Miyamoto Y, Kawakami N, Harada N.
Effectiveness of a program to facilitate recovery
for people with long-term mental illness in Japan.
Nursing Health Sciences, 2014; 16(3), 277-283.
4. Curhan KB, Sims T, Markus HR, Kitayama S,
Karasawa M, Kawakami N, Love GD, Coe CL,
Miyamoto Y, Ryff CD. Just How Bad Negative
Affect Is for Your Health Depends on Culture.
Psychol Sci. 2014; 25(12): 2277-80.
5. Funakoshi A, Miyamoto Y. Significant factors infamily difficulties for fathers and mothers who
use support services for children with hikikomori.
Psychiatry Clin Neurosci. 2014; 69(4): 210-9.
6. Imamura K, Kawakami N, Furukawa TA,
Matsuyama Y, Shimazu A, Umanodan R,
Kawakami S & Kasai K. Effects on an internetbased cognitive behavioral therapy (iCBT)
program in Manga format on improving
subthreshold depressive symptoms among healthy
workers: A randomized controlled trial. PLoS
ONE. 2014; 9(5): e97167.
7. Inoue A, Kawakami N, Shimomitsu T, Tsutsumi A,
Haratani T, Yoshikawa T, Shimazu A, Odagiri Y.
Development of a short questionnaire to measure
an extended set of job demands, job resources,
and positive health outcomes: the New Brief Job
Stress Questionnaire. Ind Health 2014; 52(3):175-89.
8. Inoue A, Kawakami N, Tsutsumi A, Shimazu A,
Miyaki K, Takahashi M, Kurioka S,Eguchi H,
Tsuchiya M, Enta K, Kosugi Y, Sakata T,

Totsuzaki T. Association of jobdemands withwork engagement of Japanese employees:
comparison of challenges with hindrances(J-HOPE). PLoS ONE 2014; 9(3): e91583.
9. Kan C, Kawakami N, Karasawa M, Love GD,
Coe CL, Miyamoto Y, et al. Psychologicalresources as mediators of the association betweensocial class and health: comparative findings fromJapan and the USA. Int J Behav Med. 2014;21(1):53-65.
10. Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS,
et al. Global, regional, and national levels andcauses of maternal mortality during 1990-2013: asystematic analysis for the Global Burden of
Disease Study 2013. Lancet. 2014; 13;384(9947):
980-1004.
11. Kayama, M., Akiyama, T., Ohashi, A., Horikoshi,N., Kido, Y., Murakata, T., & Kawakami, N.
Experiences of municipal public health nurses
following Japan's earthquake, tsunami, andnuclear disaster. Public Health Nursing. 2014;31(6):517-25.
12. Kayama M, Kido Y, Setoya N, Tsunoda A,
Matsunaga A, Kikkawa T, Fukuda T, Noguchi M,
Mishina K, Nishio M, Ito J. Community outreachfor patients who have difficulties in maintaining
contact with mental health services: longitudinal
retrospective study of the Japanese outreachmodel project. BMC psychiatry. 2014; 14(1), 311.
13. Kawakami N, Tsuchiya M, Umeda M, Koenen KC,
Kessler RC; World Mental Health Survey Japan.
Trauma and posttraumatic stress disorder inJapan: Results from the World Mental HealthJapan Survey. J Psychiatr Res. 2014;53:157-65.
14. Kessler RC, Rose S, Koenen KC, Karam EG,
Stang PE, Stein DJ, Heeringa SG, Hill ED,
Liberzon I, McLaughlin KA, McLean SA, Pennell
BE, Petukhova M, Rosellini AJ, Ruscio AM,
Shahly V, Shalev AY, Silove D, Zaslavsky AM,
Angermeyer MC, Bromet EJ, de Almeida JM, deGirolamo G, de Jonge P, Demyttenaere K,
Florescu SE, Gureje O, Haro JM, Hinkov H,
Kawakami N, Kovess-Masfety V, Lee S,
Medina-Mora ME, Murphy SD, Navarro-Mateu F,
Piazza M, Posada-Villa J, Scott K, Torres Y,
Carmen Viana M. How well can post-traumaticstress disorder be predicted from pre-trauma risk

293factors? An exploratory study in the WHO World
Mental Health Surveys. World Psychiatry. 2014;13(3):265-74.
15. Kodaka M, Matsumoto T, Katsumata Y, Akazawa
M, Tachimori H, Kawakami N, Eguchi N,
Shirakawa N, Takeshima T. Suicide risk amongindividuals with sleep disturbances in Japan: acase-control psychological autopsy study. Sleep
Med. 2014; 15(4):430-5.
16. Kubota K, Shimazu A, Kawakami N, Takahashi
M. Workaholism and sleep quality among
Japanese employees: A prospective cohort study,
Int J Behav Med 2014; 21(1), 66-76.
17. Matsumoto T, Tachimori H, Tanibuchi Y, Takano
A, Wada K. Clinical features of patients withdesigner-drug-related disorder in Japan: acomparison with patients with methamphetamineand
hypnotic/anxiolytic-relateddisorders.
Psychiatry Clin Neurosci. 2014;68(5):374-82.
18. Miyamoto Y, Koichi R, Akiyama M, Takamura S.
Social support and health-related quality of life
among mental health service users in Japan. SOJ
Psychol. 2014; 1(4): 1-8.
19. Murray CJ, Ortblad KF, Guinovart C, et al. Global,
regional, and national incidence and mortality forHIV, tuberculosis, and malaria during 1990-2013:a systematic analysis for the Global Burden of
Disease Study 2013. Lancet. 2014 13;384(9947):
1005-70.
20. Niitsu T, Takaoka K, Uemura S, Kono A, Saito A,
Kawakami N, Nakazato M, Shimizu E. The
psychological impact of a dual-disaster caused byearthquakes and radioactive contamination in
Ichinoseki after the Great East Japan Earthquake.
BMC Res Notes. 2014; 7(1):307.
21. Ochi M, Fujiwara T, Mizuki R, Kawakami N.
Association of socioeconomic status in childhood
with major depression and generalized anxiety
disorder: results from the World Mental HealthJapan survey 2002-2006. BMC Public Health.
2014;14(1):359.
22. Panthee B, Shimazu A, Kawakami N. Validationof Nepalese Version of Utrecht Work Engagement
Scale. J Occup Health. 2014 Sep 11. 56, 421-429.
23. Scott KM, Al-Hamzawi AO, Andrade LH, Borges
G, Caldas-de-Almeida JM, Fiestas F, Gureje O,
Hu C, Karam EG, Kawakami N, Lee S, Levinson

D, Lim CC, Navarro-Mateu F, Okoliyski M,
Posada-Villa J, Torres Y, Williams DR, Zakhozha
V, Kessler RC. Associations between subjective
social status and DSM-IV mental disorders:
results from the World Mental Health Surveys.
JAMA Psychiatry. 2014; 71(12):1400-8.
24. Shimazu A, de Jonge J, Kubota K, Kawakami N.
Psychological detachment from work during
off-job time: Predictive role of work andnon-work factors in Japanese employees. Ind
Health. 2014; 52:141-146.
25. Song Y, Miyaki K, Suzuki T, Sasaki Y, Tsutsumi A,
Kawakami N, Shimazu A, Takahashi M, Inoue A,
Kan C, Kurioka S, Shimbo T. Altered DNA
methylation status of human brain derived
neurotrophis factor gene could be useful asbiomarker of depression. Am J Med Genet B
Neuropsychiatr Genet. 2014; 165B(4): 357-64.
26. Stein DJ, McLaughlin KA, Koenen KC, Atwoli L,
Friedman MJ, Hill ED, Maercker A, Petukhova M,
Shahly V, van Ommeren M, Alonso J, Borges G,
de Girolamo G, de Jonge P, Demyttenaere K,
Florescu S, Karam EG, Kawakami N, Matschinger
H, Okoliyski M, Posada-Villa J, Scott KM, Viana
MC, Kessler RC. DSM-5 and ICD-11 definitionsof posttraumatic stress disorder: investigating"narrow" and "broad" approaches. Depress
Anxiety. 2014;31(6):494-505.
27. Suzuki T, Miyaki K, Sasaki Y, Song Y, Tsutsumi A,
Kawakami N, Shimazu A, Takahashi M, Inoue A,
Kurioka S, Shimbo T. Optimal cutoff values of
WHO-HPQ presenteeism scores by ROC analysis
for preventing mental sickness absence inJapanese prospective cohort. PLoS One. 2014;
9(10): e111191.
28. Sugimoto T, Shinozaki T, Naruse T, Miyamoto Y.
Who Was Concerned about Radiation, Food
Safety, and Natural Disasters after the Great East
Japan Earthquake and Fukushima Catastrophe? A
Nationwide Cross-Sectional Survey in 2012.
PLoS One. 2014;9(9):e106377.
29. Takagaki K, Okamoto Y, Jinnin R, Mori A,
Nishiyama Y, Yamamura T, Takebayashi Y, Ogata
A, Okamoto Y, Miyake Y, Shimoda H, Kawakami
N, Yamawaki S. Behavioral characteristics ofsubthreshold depression. J Affect Disord. 2014;
168: 472-5.

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30. Takahashi M, Tsutsumi A, Kurioka S, Inoue A,
Shimazu A, Kosugi Y, Kawakami N. Occupationaland socioeconomic differences in actigraphicallymeasured sleep. J Sleep Res 2014; 23(4): 458-62.
31. Umanodan R, Shimazu A, Minami M, Kawakami
N. Evaluation of a computer-based stressmanagement training program for workers’
psychological well-being and work performance:
A cluster randomized controlled trial. Ind Health2014;52(6):480-91..
32. Umeda M, Kawakami N. Cross-cultural
measurement equivalence of the Japanese version
of Revised Conflict Tactics Scales Short Form
(J-CTS2SF) among Japanese men and women.
Psychiatry Clin Neurosci. 2 2014; 68(11): 804-11.
33. Yokoyama Y, Otsuka K, Kawakami N, Kobayashi
S, Ogawa A, Tannno K, Onoda T, Yaegashi Y,
Sakata K. Mental health and related factors after
the Great East Japan earthquake and tsunami.
PLoS One. 2014; 9(7): e102497.

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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/english/index-e.html

Introduction and Organization
The Department of Gerontological Nursing wasestablished in June 2003, followed by theestablishment of the Department of Wound CareManagement in April 2006. 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 forundergraduate course, and 7 part-time lecturers forgraduate course. The student consists of 10 doctoral
course students and 7 master course students. The goalof 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 2014 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, in
continence malnutrition, infection, dementia andpressure ulcer)e) Future perspectives of gerontological nursing,such as biological nursing, Mimamori engineering,and nursing engineering.
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 2014 contents were as follows;a) Age-related changes in the physiologic system

296

b)
c)
d)
e)

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 developed under thecooperation from the Department of GeriatricMedicine and other departments at The University ofTokyo 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 2014 was
supported by the long-term care facility owned by
Medical Corporation Tatsuoka.
3) Bachelor’s thesis
The following was research theme in 2014;“Relationship between in-home activity monitoringdata by pyroelectric sensors and health status among
elderly people living alone (in Japanese)”
2. Graduate course
1) Gerontological Nursing I(Summer course/ 2 credits)
The main theme of Gerontological Nursing I in 2014
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 clinicalnursing research. Recent research papers wereselected from these three fields and criticallyevaluated.
2) Gerontological Nursing II(Winter course/ 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 thepart-time 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 2014 were as follows;a) Management of sarcopeniab) Nutritional management for pressure ulcersc) Metabolic change by agingd) Next generation predictive medicine bybiomechanical simulatione) Care for the individuals with early-onset dementia
and their caregiversf) Innovation of food for medicineg) Life engineeringh) Skin tear3) Wound Care Management I(Summer course/ 2 credits)
The main topic of Wound Care Management I in 2014
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(Winter course/ 2 credits)
The main theme of Wound Care Management II in2014 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) Advanced wound care provided by wound,ostomy, and continence nursesb) Basic and advanced wound healing fromdermatological aspectc) Basic and advanced knowledge for support
surfaced) Prevention and management of foot ulcerse) Basic knowledge and clinical application of

297

ultrasonographyf) Theory and practice of nursing pharmacology forsking) Nutritional assessment of elderly people
5) Master’s thesis
The followings were research themes in 2014;
Nerve growth factor and S100A8/A9 in exudate
from venous leg ulcers are associated with wound
pain status”
Is thrombus with subcutaneous edema detected byultrasonography related to peripheral intravenous
catheter failure?”
Telogen elongation in the hair cycle of ob/ob mice”
Microclimate is an independent risk factor for
development of intraoperatively acquired pressure
ulcers in the park-bench position: a prospective
observational study”
5) Doctor’s thesis
The followings were research themes in 2014;“Microsatellite polymorphism in the Heme
oxygenase-1 gene promoter is associated with dermal
collagen density in Japanese obese male subjects”

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 2014, 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. We
organized introductory seminar for bioengineering
nursing research supported by JSPS Grant-in-Aid for
Scientific Research (A). We had many nursing
researchers and clinical nurses from intra- andextramural ways. We furthermore organized advanced
hands-on seminar of bioengineering nursing researchmethodologies for those who attended the introductory
seminar and are interested in this research framework.
Furthermore, we have published Bioengineering
Nursing: New Horizons of Nursing Research in April,2014. The textbook for bioengineering nursing inJapanese was edited and will be published in 2015.
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
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.
2. Research fields and themes in 2014
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

298

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 andpre-injury status using 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.
・ Ohura Award from Japanese Society of Pressure
UlcersAssessment of atypical pressure ulcers suspected to be
malignant wounds by wound blotting method. J Jpn
PU. 2014;16(2):154-158
Predictive validity of granulation tissue color
measured by digital image analysis for deep pressure
ulcer healing: a multicenter prospective cohort study.
Wound Repair Regen. 2013;21(1):25-34.
・ Research Award from 22nd Conference ofJapanese Society of Wound, Ostomy, andContinence Management
Development and evaluation of a new pouch product,
for male urinary incontinence care. J Jpn Soc WOC
Manage. 2013;17(1):11-22.
・ SICE System Integration (SI2014) Presentation
award
Relationship between in-home activity monitoringdata by pyroelectric sensors and cognitive function/
locomotion among elderly people living alone
・ Research Award from 2nd Conference of Nursing
Science and Engineering
Ultrasonographic evaluation for muscle strength
responsible for jaw opening
Ultrasonographic observation of intra-vessel changes
during peripheral intravenous catheterization
・ EPUAP2014- 17th Annual Meeting of theEuropean Pressure Ulcer Advisory Panel Best
Student Presentation Award“Development of biomarkers for the Wound Fluid
RT-PCR method to detect critically colonized andinfected wounds”
・ Prize for research article 23rd Conference ofJapanese Society of Wound, Ostomy, andContinence Management
Reliability and validity of Japanese version Intermittent Self-catheterization Questionnaire (J-ISC-Q)
Microsatellite polymorphism in the Heme oxygenase-1
gene promoter is associated with dermal collagendensity in Japanese obese male subjects“
Objective evaluation of pain related to venous leg
ulcers by infrared thermography
・ The 20th Conference of Australian Wound
Management Association New InvestigatorAward: Science & Technology 2014, May.
“Wound blotting: a two-dimensional tool for assessing
exudate proteins on the wound bed”
“Skin blotting: a novel technique for assessing
physiological skin conditions”
・ The 20th Conference of Australian Wound
Management Association Best Poster Award:
Science & Technology 2014, May.
“Variations in the healing course of diabetic footulcers based on the Kobe classification”
・ Symbols of Tomorrow
Dr. Gojiro Nakagami (Lecturer)

299

References
1. Sanada H, Mori T (Edit). Bioengineering Nursing:
New Horizons of Nursing Research. Nova Science
Pub Inc. 2014 Apr.
2. Sanada H. Expert commentary: pressure ulcers inthe surgical patient. Wounds Int. 2014;5(4):19.
3. Yonezawa K, Haruna M, Shiraishi M, Matsuzaki
M, Sanada H. Relationship between skin barrier
function in early neonates and diaper dermatitis
during the first month of life: A prospective
observational study. Pediatric Dermatology. 2014;31(6):692-697.
4. Yabunaka K, Konishi H, Nakagami G, Matsuo J,
Noguchi A, Sanada H. Videofluoroscopy-guided
balloon dilatation for treatment of severe
pharyngeal dysphagia. Diagn Interv Radiol. 2014.
doi:10.5152/dir.2014.14146
5. Arias S, Rogeli P, Cardiel E, Sanada H, Mori T,
Noguchi H, Nakagami G. Assessment of threealternating pressure sequences applied to a
dynamic cushion to relieve pressure on seatingareas. Revista mexicana de ingenieria biomedica.
2014;35(3):253-262.
6. Sanada H, Nakagami G, Koyano Y, Iizaka S,
Sugama J. Incidence of skin tears in theextremities among elderly patients at a long-term
medical facility in Japan: A prospective cohort
study. Geriatr Gerontol Int. 2014. doi: 10.1111/ggi.
12405.
7. Ichikawa-Shigeta Y, Sanada H, Konya C, Yusuf S,
Supriadi, Sugama J. Risk Assessment tool forincontinence-associated dermatitis in elderly
patients combining tissue tolerance and perineal
environment predictors: a prospective clinicalstudy. Chronic Wound Care Management andResearch. 2014;1:41-47.
8. Tokunaga-Nakawatase Y, Nishigaki M, Taru C,
Miyawaki I, Nishida J, Kosaka S, Sanada H,
Kazuma K. Computer-supported indirect-form
lifestyle-modification support program using
Lifestyle Intervention Support Software for
Diabetes Prevention (LISS-DP) for people with afamily history of type 2 diabetes in a medical
checkup setting: a randomized controlled trial.
Prim Care Diabetes. 2014;8(3):207-214.

9. Miura Y, Takehara K, Nakagami G, Amemiya A,
Kanazawa T, Kimura N, Kishi C, Koyano Y,
Tamai N, Nakamura T, Kawashima M, Tsunemi Y,
Sanada H. Screening for tinea unguium bythermography in older adults with subungual
hyperkeratosis. Geriatr Gerontol Int. 2014;14. doi:
10.1111/ggi.12380.
10. Matsumoto M, Ibuki A, Minematsu T, Sugama J,
Horii M, Ogai K, Nishizawa T, Dai M, Sato A,
Fujimoto Y, Okuwa M, Nakagami G, Nakatani T,
Sanada H. Structural changes in dermal collagenand oxidative stress levels in the skin of Japanese
overweight males. Int J Cosmet Sci. 2014;36(5):477-484.
11. Goto T, Naito A, Tamai N, Nakagami G, Mo M,
Sanada H. Objective evaluation for venous leg
ulcer-related nociceptive pain using thermography.
Chronic Wound Care Management and Research.
2014;1:23-30.
12. Takano M, Noguchi H, Oe M, Sanada H, Mori T.
Development and evaluation of a system to assess
the effect of footwear on the in shoe plantarpressure and shear during gait. ROBOMECH
Journal. 2014; 1:4. doi:10.1186/s40648-014-00049.
13. Kanazawa T, Nakagami G, Minematsu T, Yamane
T, Huang L, Mugita Y, Noguchi H, Mori T,
Sanada H. Biological responses of threedimensional cultured fibroblasts by sustained
compressive loading include apoptosis andsurvival activity. PLoS One. 2014;9(8):e104676.
14. Iuchi T, Nakajima Y, Fukuda M, Matsuo J,
Okamoto H, Sanada H, Sugama J. Using an
extreme bony prominence anatomical model toexamine the influence of bed sheet materials andbed making methods on the distribution ofpressure on the support surface. J Tissue Viability.
2014;23(2):60-68.
15. Amemiya A, Noguchi H, Oe M, Ohashi Y, Ueki K,
Kadowaki T, Mori T, Sanada H. Elevated plantarpressure in diabetic patients and its relationshipwith their gait features. Gait Posture. 2014:40(3);408-414.
16. Yotsu RR, Pham NM, Oe M, Nagase T, Sanada H,
Hara H, Fukuda S, Fujitani J, Yamamoto-Honda R,
Kajio H, Noda M, Tamaki T. Comparison ofcharacteristics and healing course of diabetic foot300

ulcers by etiological classification: Neuropathic,ischemic, and neuro-ischemic type. J Diabetes
Complications. 2014. doi: 10.1016/j.jdiacomp.
2014.03.013.
17. Minematsu T, Horii M, Oe M, Sugama J, Mugita
Y, Huang L, Nakagami G, Sanada H. Skinblotting: a noninvasive technique for evaluating
physiological skin status. Adv Skin Wound Care.
2014 Jun;27(6):272-9.
18. Kato A, Fukazawa Y, Sanada H, Mori T.
Extraction of food-related onomatopoeia fromfood reviews and its application to restaurant
search. JACIII. 2014;18(3):418-428.
19. Miura Y, Nakagami G, Yabunaka K, Tohara H,
Murayama R, Noguchi H, Mori T, Sanada H.
Method for detecting aspiration based on image
prosessing-assisted B-mode video ultranonography. Journal of Nursing Science Engineering.
2014;1(1):12-20.
20. Iizaka S, Koyanagi H, Sasaki S, Sekine R, Konya
C, Sugama J, Sanada H. Nutrition-related status
and granulation tissue colour of pressure ulcers
evaluated by digital image analysis in older
patients. J Wound Care. 2014;23(4):198-206.
21. Miura Y, Nakagami G, Yabunaka K, Tohara H,
Murayama R, Noguchi H, Mori T, Sanada H.
Method for detection of aspiration based on
B-mode video ultrasonography. Radiol Phys
Technol. 2014. doi: 10.1007/s12194-014-0264-3.
22. Sanada H, Nakagami G, Takehara K, Goto T, Ishii
N, Yoshida S, Ryu M, Tsunemi Y. Antifungal
effect of non-woven textiles containing
polyhexamethylene biguanide with sophorolipid:
A potential method for tinea pedis prevention.
Healthcare. 2014;2:183-91.
23. Koyano Y, Nakagami G, Iizaka S, Minematsu T,
Noguchi H, Tamai N, Mugita Y, Kitamura A,
Tabata K, Abe M, Murayama R, Sugama J,
Sanada H. Exploring the prevalence of skin tears
and skin properties related to skin tears in elderly
patients at a long-term medical facility in Japan.
Int Wound J. 2014. doi: 10.1111/iwj.12251.
24. Iizaka S, Asada M, Koyanagi H, Sasaki S, Naito A,
Konya C, Sanada H. The reliability and validity ofcolor indicators using digital image analysis ofperistomal skin photographs: Results of apreliminary prospective clinical study, Ostomy
Wound Manage. 2014;60(3):12-29.
25. Matsumoto M, Matsuo J, Dai M, Nishizawa T,
Matsui K, Ichikawa Y, Okuwa M, Sugama J,
Sanada H. Influence of differences in washingmethods on skin texture. Int J Cosmet Sci. 2014.
doi: 10.1111/ics.12114.
26. Noguchi H, Handa M, Fukui R, Shimosaka M,
Mori T, Sato T, Sanada H. Measurement of dense
static point cloud and online behavior recognition
using horizontal LIDAR and pan rotation ofvertical LIDAR with mirrors, SICE JCMSI. 2014;
7(1):12-20.
27. Ichikawa-Shigeta Y, Sugama J, Sanada H,
Nakatani T, Konya C, Nakagami G, Minematsu T,
Yusuf S, Mugita Y. Physiological and appearance
characteristics of skin maceration in elderly
women with incontinence. J Wound Care. 2014;23(1):18-30.
28. Miura Y, Nakagami G, Tohara H, Murayama R,
Noguchi H, Mori T, Sanada H. B-mode video
ultrasonography for detecting aspiration: two casestudies. Journal of Society of Nursing Practice.
2014;27(1):42-49.
29. Kitamura A, Nakagami G, Yoshida M, Noguchi H,
Nishijima Y, Minematsu T, Naito A, Sugawara J,
Shibayama H, Takahashi K, Hakuta A, Umemoto
J, Terada N, Segawa R, Mori T, Sanada H.
Visualization of tumor necrosis factor-α distributions within pressure ulcer tissue using the woundblotting method: a case report and discussion.
WOUNDS. 2014;26(11):323-329.

International Health
1. International Social Medicine

302

Department of
Global Health Policy
Professor
Kenji Shibuya, MD, DrPH

Faculty members
Manami Inoue, MD, PhD
Hiroshi Nishiura, MD, PhD
Stuart Gilmour, MPH, MStat, PhD
Shinji Nakaoka, MEng, PhD
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); one post-doctoral fellow; 10 adjunct lecturers;
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).
Finally, the fundamental role of the department is to
produce the next generations of leaders in global
health.

Education
All lectures in the department are conducted in
English, in order to ensure that student writing and303

presentation 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.

-

Health system performance assessment
Health service quality
Monitoring and evaluation
Financing health systems

GHP Monday seminar
Master's program
The Master's program is a demanding, interdisciplinary program emphasizing student-directed
learning, problem-solving, and the acquisition of
fundamental public health skills required for global
health practices (health policy, statistics, epidemiology,
and social sciences). Students are required to completea minimum of 30 course credits and a master’s thesis.
Beyond the program and concentration requirements,
students are encouraged to consult with faculty
advisers to choose elective courses best suited to theirneeds.
PhD program
The PhD program is designed to train the next
generation of leaders in global health. PhD students
are required to complete a minimum of 24 course
credits and a doctoral thesis with which needs to be
published in a peer-reviewed journal. PhD students
without MPH degree should take the lectures toacquire fundamental public health skills such as healthpolicy, biostatistics and epidemiology.
Global Health Policy I and IIThis course introduces the principles and theories ofglobal health problems, as well as practical applications of quantitative methods (demography, statistics,
epidemiology and econometrics) to analyze andinterpret issues and challenges for policy.
The followings are the topics covered in the academic
year 2014:- Innovations in global health- Global health policy- Global health governance- Social determinants of health- Universal health coverage- Global health diplomacy- Quantifying health outcomes- Using GBD to inform policies- Old and new challenges in global health- Comparative risk assessment

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 Shibuya
An evidence-based assessment of the Japanese healthsystem. Ministry of Health, Labour, and Welfare Healthand 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, andWelfare 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

304

Mellitus: Projection of disease burden and economic
burden allowing for change in population structure,socioeconomic status, and lifestyles in Japan. Ministry of
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, Scienceand 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
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, Institute for Health
Economics and Policy Research Grant program. PI:
Hiroshi Nishiura
Donation for Scientific Research, Daiwa HealthFoundation research grant support.PI:Hiroshi Nishiura
Detecting premonitory signs, real time forecasting anddesigning interventions against a pandemic using large
scale biological datasets. Japan Science andTechnology Agency CREST project on the applicationof 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
Donation for Scientific Research, Kurozumi Medical
Foundation. PI: Hiroshi Nishiura.
Donation for Scientific Research, Public HealthResearch Center. 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
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 foryoung 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
anti-virus therapies development. Ministry of
Education, Culture, Sports, Science and Technology,
Grants-in-aid for Scientific Research (C). CI: Shinji
Nakaoka.

305

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
non-response to psychosocial questions andsuicide: 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 theDevelopment and Evaluation of Cancer
Prevention Strategies in Japan. Diabetes mellitus
and liver cancer risk: an evaluation based on asystematic review of epidemiologic evidence
among the Japanese population. Japanese Journalof Clinical Oncology. 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:
CD003363.
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.

306

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 ClinicalOncology. 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 andsubnational 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.

307

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.

308

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(1999-2005), 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:

bottom-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, 19 doctoral course
students, 15 Master’s course students, 1 research
student, and 34 visiting researchers. About 51% of thestudents are international students.

International Cooperation
Activities

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 anddevelopment.
Our research focuses on how to activate
community-based activities and how to link a

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.
In addition, we contributed to developing a WHO’s
guideline on human resource for health as well as the
Asia Pacific Action Alliance on Human Resources for
Health.
Furthermore, we carried out a research project onmaternal and child health in Ghana in collaboration
with JICA and the Ministry of Health, Ghana.

309

Teaching Activities
The main objectives of our teaching activities are
the following two:1) To train researchers who understand andcomplement the wise activities of practitioners in
the field.
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 based oncommunity-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) Shrestha S, Poudel KC, Poudel-Tandukar K,
Kobayashi J, Pandey BD, Yasuoka J, Otsuka K,
Jimba M. Perceived family support anddepression among people living with HIV/AIDS
in the Kathmandu Valley, Nepal. J Int Assoc
Provid AIDS Care. 2014 May-Jun;13(3):214-22.
2) Kikuchi K, Poudel KC, Muganda J, Sato T,
Mutabazi V, Muhayimpundu R, Majyambere A,
Nyonsenga SP, Sase E, Jimba M. What makes
orphans in Kigali, Rwanda, non-adherent toantiretroviral therapy? Perspectives of theircaregivers. J Int AIDS Soc. 2014 Dec 3;17(1):19310.
3) Miyaguchi M, Yasuoka J, Poudyal AK, Silwal RC,
Jimba M. Female community health volunteers
service utilization for childhood illness- improving quality of health services only is not enough: across-sectional study in mid-western region,
Nepal. BMC Health Serv Res. 2014 Sep 11;14:383.
4) Matsumoto-Takahashi EL, Tongol-Rivera P,
Villacorte EA, Angluben RU, Yasuoka J, Kano S,
Jimba M. Determining the impact of community
awareness-raising activities on the prevention ofmalaria transmission in Palawan, the Philippines.
Parasitol Int. 2014 Jun;63(3):519-26.
5) Sunguya BF, Ong KI, Dhakal S, Mlunde LB,
Shibanuma A, Yasuoka J, Jimba M. Strong

310

nutrition governance is a key to addressing
nutrition transition in low and middle-income
countries: review of countries' nutrition policies.
Nutr J. 2014 Jun 27;13:65.
6) Poudel KC, Palmer PH, Jimba M, Mizoue T,
Kobayashi J, Poudel-Tandukar K. Coinfection
with hepatitis C virus among HIV-positive people
in the Kathmandu Valley, Nepal. J Int Assoc
Provid AIDS Care. 2014 May-Jun;13(3):277-83.
7) Sunguya BF, Poudel KC, Mlunde LB, Urassa DP,
Yasuoka J, Jimba M. Poor nutrition status andassociated feeding practices among HIV-positive
children in a food secure region in Tanzania: a callfor tailored nutrition training. PLoS One. 2014
May 20;9(5):e98308.
8) Nanishi K, Jimba M. Reliability and Validity of
the Japanese Version of the Iowa Infant Feeding
Attitude Scale: A Longitudinal Study. J Hum Lact.
2014 May 13;30(3):346-352.
9) Sunguya BF, Hinthong W, Jimba M, Yasuoka J.
Interprofessional
educationforwhom?
--challenges and lessons learned from its
implementation in developed countries and theirapplication to developing countries: a systematic
review. PLoS One. 2014 May 8;9(5):e96724.
10) Yoshikawa K, Shakya TM, Poudel KC, Jimba M.
Acceptance of wife beating and its association
with physical violence towards women in Nepal: across-sectional study using couple's data. PLoS
One. 2014 Apr 21;9(4):e95829.
11) Yasuoka J, Jimba M, Levins R. Application ofloop analysis for evaluation of malaria control
interventions. Malar J. 2014 Apr 9;13:140.
12) 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. 2014 Apr 2.
13) Amiya RM, Poudel KC, Poudel-Tandukar K,
Pandey BD, Jimba M. Perceived family support,
depression, and suicidal ideation among people
living with HIV/AIDS: a cross-sectional study in
the Kathmandu Valley, Nepal. PLoS One. 2014
Mar 6;9(3):e90959.
14) Jimba M. Power of community health in
implementing the universal health insurance

system in Japan. Japan Med Assoc J. 2014 Feb
1;57(1):10-4.
15) Tashiro M, Yasuoka J, Poudel KC, Noto H, Masuo
M, Jimba M. Acculturation factors and metabolic
syndrome among Japanese-Brazilian men in
Japan: a cross-sectional descriptive study. J
Immigr Minor Health. 2014 Feb;16(1):68-76.
16) Otsuka K, Taguri M, Dennis CL, Wakutani K,
Awano M, Yamaguchi T, Jimba M. Effectivenessof a breastfeeding self-efficacy intervention: do
hospital practices make a difference? Matern
Child Health J. 2014 Jan;18(1):296-306.
17) Phoutthakeo
P,
OtsukaK,
ItoC,
Sayamoungkhoun P, Kounnavong S, Jimba M.
Cross-border promotion of formula milk in Lao
People's Democratic Republic. J Paediatr Child
Health. 2014 Jan;50(1):51-6.

International Health
2. International Biomedical Sciences

312

Department of Human Genetics
Professor
Katsushi Tokunaga, Ph.D.

Associate Professor
Akihiko Mabuchi, M.D., Ph.D.

Research Associate
Taku Miyagawa, Ph.D.,

Yuki Hitomi, Ph.D.

Project Research Associate
Hiromi Sawai, 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 research associates,
8 graduate students, 2 research fellows, and 8 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.

313

References
1. 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,
Ishii-Takahashi A, Kawakubo Y, and Kasai K:
Genetic influences on prefrontal activation during
a verbal fluency task in adults: A twin study basedon multichannel near-infrared spectroscopy.
Neurolimage. 85 Pt1: 508-517, 2014.
2. Nishida N, Sawai H, Kashiwase K, Minami M,
Sugiyama M, Seto WK, Yuen MF, Posuwan N,
Poovorawan Y, Ahn SH, Han KH, Matsuura K,
Tanaka Y, Kurosaki M, Asahina Y, Izumi N, Kang
JK, Hige S, Ide T, Yamamoto K, Sakaida I,
Murawaki Y, Itoh Y, Tamori A, Orito E, Hiasa Y,
Honda M, Kaneko S, Mita E, Suzuki K, Hino K,
Tanaka E, Mochida S, Watanabe M, Eguchi Y,
Masaki N, Murata K, Korenaga M, Mawatari Y,
Ohashi J, Kawashima M, Tokunaga K, andMizokami M: New susceptibility and resistance
HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia.
PLoS ONE 9(2): e86449, 2014.
3. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari
K, Kochi Y, Ohmura K, Suzuki A, Yoshida S,
Graham RR, Manoharan A, Ortmann W, Bhangale
T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD,
Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su
DF, Yang J, Xie G, Keystone E, Westra HJ, Esko T,
Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA,
Diogo D, Cui J, Liao K, Guo MH, Myouzen K,
Kawaguchi T, Coenen MJ, van Riel PL, van deLaar MA, Guchelaar HJ, Huizinga TW, Dieudé P,
Mariette X, Bridges SL Jr, Zhernakova A, Toes
RE, Tak PP, Miceli-Richard C, Bang SY, Lee HS,
MartinJ,
Gonzalez-Gay
MA,
Rodriguez-Rodriguez L, Rantapää-Dahlqvist S,
Arlestig L, Choi HK, Kamatani Y, Galan P,
Lathrop M; RACI consortium; GARNET
consortium, Eyre S, Bowes J, Barton A, de Vries
N, Moreland LW, Criswell LA, Karlson EW,
Taniguchi A, Yamada R, Kubo M, Liu JS, Bae SC,

4.

5.

6.

7.

8.

9.

Worthington J, Padyukov L, Klareskog L,
Gregersen PK, Raychaudhuri S, Stranger BE, De
Jager PL, Franke L, Visscher PM, Brown MA,
Yamanaka H, Mimori T, Takahashi A, Xu H,
Behrens TW, Siminovitch KA, Momohara S,
Matsuda F, Yamamoto K, Plenge RM. Genetics ofrheumatoid arthritis contributes to biology anddrug discovery. Nature 506(7488): 376-381, 2014.
Yang JO, Hwang S, Kim WY, Park SJ, Kim SC,
Park K, Lee B; HUGO Pan-Asian SNP
Consortium: Identification of ethnically specificgenetic variations in Pan-Asian ethnos. Genomics
Inform. 12(1) 42-47, 2014.
Nishino J, Sugiyama M, Nishida N, Tokunaga K,
Mizokami M, and Mano S. The interaction of asingle nucleotide polymorphism with age on
response to interferon-α and ribavirin therapy infemale patients with hepatitis C infection. J. Med.
Virol. 86(7): 1130-1133, 2014.
Miura K, Mishima H, Kinoshita A, Hayashida C,
Abe S, Tokunaga K, Masuzaki H, and Yoshiura KI.
Genome-wide association study of HPVassociated cervical cancer in Japanese women. J.
Med. Virol. 86(7): 1153-1158, 2014.
Aiba Y, Harada K, Komori A, Ito M, Shimoda S,
Nakamura H, Nagaoka S, Abiru S, Migita K,
Ishibashi H, Nakanuma Y, Nishida N, Kawashima
M, Tokunaga K, Yatsuhashi H, and Nakamura M.
Systemic and local expression levels of TNF-like
ligand 1A and its decoy receptor 3 are increased inprimary biliary cirrhosis. Liver Int. 34(5): 679688, 2014.
Takezawa Y, Kato K, Oota H, Caulfied T,
Fujimoto A, Honda S, Kamatani N, Kawamura S,
Kimura R, Matsumae H, Saito A, Savage P,
SeguchiN,
ShimizuK,
Terao
S,
Yamaguchi-Kabata Y, Yasukouchi A, Yoneda M,
and Tokunaga K. Human genetic research, race,
ethnicity and the labeling of populations:recommendations based on an interdisciplinary
workshop in Japan. BMC Medical Ethics 15(1):e33, 2014.
Ueta M, Kaniwa N, Sotozono C, Tokunaga K,
Saito Y, Sawai H, Miyadera H, Sugiyama E,
Maekawa K, Nakamura R, Nagato M, Aihara M,
Matsunaga K, Takahashi Y, Furuya H, Muramatsu
M, Ikezawa Z, and Kinoshita S. Independent314

strong association of HLA-A*02:06 and HLA-B*
44:03 with cold medicine-related Stevens-Johnson
syndrome with severe mucosal involvement. Sci.
Rep. 4: e4862, 2014.
10. Yamasaki M, Miyagawa T, Toyoda H, Khor SS,
Koike A, Nitta A, Akiyama K, Sasaki T, Honda M,
and Tokunaga K. Genome-wide analysis of CNV(copy number variation) and their associations
with narcolepsy in a Japanese population. J. Hum.
Genet. 59(5): 235-240, 2014.
11. Srilohasin P, Chaiprasert A, Tokunaga K, NishidaN, and Prammananan T. A novel DNA chip basedon modified DigiTag2 assay for high throughput
species identification and genotyping of
Mycobacterium tuberculosis complex. J. Clin.
Microbiol. 52(6): 1962-1968, 2014.
12. Ueta M, Kannabiran C, Wakamatsu TH, Kim MK,
Yoon K-C, Seo KY, Joo C-K, Sangwan V, Rathi V,
Basu S, Shamaila A, Lee HS, Yoon S, Sotozono C,
Gomes JAP, Tokunaga K, and Kinoshita S. Transethnic study confirmed independent associationsof HLA-A*02:06 and HLA-B*44:03 with cold
medicine-related Stevens-Johnson syndrome withsevere ocular surface complications. Sci. Rep. 4:
e5981, 2014.
13. Oda K, Uto H, Kumagai K, Ido A, Kusumoto K,
Shimoda K, Hayashi K, Stuver SO, Tanaka Y,
Nishida N, Tokunaga K, and Tsubouchi H. Impactof a single nucleotide polymorphism upstream of
the IL28B gene in patients positive for anti-HCV
antibody in an HCV hyperendemic area in Japan.
J. Med. Virol. 86(11): 1877-1885, 2014.
14. Kawasaki A, Furukawa H, Nishida N, Warabi E,
Kondo Y, Ito S, Matsumoto I, Kusaoi M, Amano
H, Suda A, Nagaoka S, Setoguchi K, Nagai T,
Hirohata S, Shimada K, Sugii S, Okamoto A,
Chiba N, Suematsu E, Ohno S, Katayama M,
Okamoto A, Kono H, Tokunaga K, Takasaki Y,
Hashimoto H, Sumida T, Tohma S, and Tsuchiya
N. Association of functional polymorphisms ininterferon regulatory factor 2 (IRF2) withsusceptibility to systemic lupus erythematosus: acase-control association study. PLoS ONE 9(10):e109764, 2014.
15. Awata T, Yamashita H, Kurihara S, MoritaOhkubo T, Miyashita Y, Katayama S, Mori K,
Yoneya S, Kohda M, Okazaki Y, Maruyama T,

Shimada A, Yasuda K, Nishida N, Tokunaga K,
and Koike A. A genome-wide association study
for diabetic retinopathy in a Japanese population:
potential association with a long intergenic noncoding RNA. PLoS ONE 9(11): e111715, 2014.
16. Srilohasin P, Chaiprasert A, Tokunaga K,
Nishida N, Prammananan T, Smittipat N,
Mahasirimongkol S, Chaiyasirinroje B, Yanai H,
and Palittapongarnpimh P. Genetic Diversity andDynamic Distribution of Mycobacterium tuberculosis Isolates Causing Pulmonary and Extrapulmonary Tuberculosis in Thailand. J. Clin.
Microbiol. 52(12): 4267- 4274, 2014.

315

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 1992
as the Department of Developmental Medical
Sciences. Up to now, it has been engaged inexperimental 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,
eleven 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

316

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
geneticallyengineered animals.
(3) Medical genetic studies on congenital anomalies
caused by abnormal intracellular signaltransduction, 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 onmolecules regulating neuronal migration, such as
Doublecortin and Cdk5.
(6) Molecular genetics and biochemistry of inheritedmetabolic disorders, such as peroxisomal
disorders, and of neurodegenerative diseases,
such as 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. Akamatsu T, Dai H, Mizuguchi M, Goto Y, Oka A,
Itoh M. LOX-1 is a novel therapeutic target inneonatal
hypoxic-ischemic
encephalopathy.
American Journal of Pathology 2014; 184(6):1843-1852.

2. Araki M, Matsuoka T, Miyamoto K, Kusunoki S,
Okamoto T, Murata M, Aranami T, Yamamura T.
Efficacy of the anti-IL-6 receptor antibody
tocilizumab in neuromyelitis optica. Neurology
2014; 82(15): 1302-1306.
3. Chaimongkol N, Khamrin P, Malasao R,
Thongprachum A, Kongsricharoern T, Ukarapol
N, Ushijima H, Maneekarn N. Molecularcharacterization of norovirus variants and genetic
diversity of noroviruses and sapoviruses inThailand. Journal of Medical Virology 2014;
86(7): 1210-1218.
4. Chan-It W, Thongprachum A, Okitsu S,
Mizuguchi M, Ushijima H. Genetic analysis andhomology modeling of capsid protein of norovirus
GII.14. Journal of Medical Virology 2014; 86(2):329-324.
5. Igarashi T, Ito S, Sako M, Saitoh A, Hataya H,
Mizuguchi M, Morishima T, Ohnishi K,
Kawamura N, Kitayama H, Ashida A, Kaname S,
Taneichi H, Tang J, Ohnishi M; Study group forestablishing guidelines for the diagnosis andtherapy of hemolytic uremic syndrome.
Guidelines for the management and investigationof hemolytic uremic syndrome. Clinical andExperimental Nephrology 2014; 18(8): 525-557.
6. Khamrin P,
Thongprachum
A, Okitsu S,
Maneekarn N, Hayakawa S, Ushijima H.
Comparison of three rapid tests for detection of
norovirus in stool samples of acute gastroenteritis
pediatric patients. Journal of Tropical
Pediatrics 2014; 60(6): 481-483.
7. Nakamura M, Matsuoka T, Chihara N, Miyake S,
Sato W, Araki M, Okamoto T, Lin Y, Ogawa M,
Murata M, Aranami T, Yamamura T. Differential
effects of fingolimod on B-cell populations in
multiple sclerosis. Multiple Sclerosis 2014;20(10): 1371-1380.
8. Okitsu S, Khamrin P, Thongprachum A, Kalesaran
AF, Takanashi S, Shimizu H, Maneekarn N,
Mizuguchi M, Hayakawa S, Ushijima H.
Molecular characterization and sequence analysisof the 2B region of Aichivirus C strains in Japanand Thailand. Infection, Genetics and Evolution
2014; 26C: 89-94.
9. Takanashi JI, Taneichi H, Misaki T, Yahata Y,
Okumura A, Ishida YI, Miyawaki T, Okabe N,

317

Sata T, Mizuguchi M. Clinical and radiologic
features of encephalopathy during 2011 E coli
O111 outbreak in Japan. Neurology 2014; 82(7):564-572.
10. Takanashi S, Saif LJ, Hughes JH, Meulia T, Jung
K, Scheuer KA, Wang Q. Failure of propagationof human norovirus in intestinal epithelial cellswith microvilli grown in three-dimensional
cultures. Archives of Virology 159(2): 257-266,
2014.
11. Takayama-Ito M, Nakamichi K, Kinoshita H,
Kakiuchi S, Kurane I, Saijo M, Lim CK: A
sensitive in vitro assay for the detection ofresidual viable rabies virus in inactivated rabies
vaccines. Biologicals. 2014; 42(1): 42-47.
12. Thongprachum A, Chan-It W, Khamrin P,
Saparpakorn P, Okitsu S, Takanashi S, Mizuguchi
M, Hayakawa S, Maneekarn N, Ushijima H.
Molecular epidemiology of norovirus associatedwith gastroenteritis and emergence of norovirus
GII.4 variant 2012 in Japanese pediatric patients.
Infection, Genetics and Evolution 2014; 23:
65-73.
13. Tran DN, Nguyen TQ, Nguyen TA, Hayakawa S,
Mizuguchi M, Ushijima H. Human bocavirus inchildren with acute respiratory infections in
Vietnam. Journal of Medical Virology 2014;
86(6): 988-994.
14. Tran DN, Nguyen TQN, Okitsu S, Hayakawa S,
Mizuguchi M, Ushijima H. Epidemiology ofrubella epidemic in Vietnam. Clinical Virology
2014; 42(1): 35-46.
15. Ushijima H, Nishimura S, Thongprachum A,
Shimizu-Onda Y, Tran DN, Pham NT, Takanashi
S, Dey SK, Okitsu S, Yamazaki W, Mizuguchi M,
Hayakawa S. Sensitive and rapid detection of
campylobacter species from stools of children
with diarrhea in Japan by the loop-mediated isothermal amplification method. Japanese Journal of
Infectious Diseases 2014; 67(5): 374-378.
16. Okitsu S, Khamrin P, Thongprachum A,
Nishimura S, Kalesaran AF, Takanashi S, Shimizu
H, Hayakawa S, Mizuguchi M, Ushijima H.
Detection and molecular characterization ofhuman cosavirus in a pediatric patient with acutegastroenteritis, Japan. Infection, Genetics andEvolution 2014; 28C: 125-129.

17. Yazawa S, Yokobori T, Ueta G, Ide M, Altan B,
Thongprachum A, Nishimura T, Nakajima T,
Kominato Y, Asao T, Saniabadi AR, Furukawa K,
Kuwano H, Le Pendu J, Ushijima H. Blood group
substances as potential therapeutic agents for theprevention and treatment of infection withnoroviruses proving novel binding patterns inhuman tissues. PLoS One 2014; 9(2): e89071.

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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 FY2014,
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

319

been adopted as one of the MEXT-funding“Re-inventing 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
charge of coordinating the program from SIH side.

Research activities
Human ecology is literally the understanding of
human population in the context of their respective
ecology as well as in the global context. Most of 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“earth-observation data” will be used to solve
health-related issues. Almost all the studies require“transdisciplinary” approach, hence, we arecollaborating with 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 andhealth-related information in the framework of“human” ecology and tried to identify newly emerging
health risks due to climate change and sociodemographical change. In this project, we have beencollaborating with other Schools in U Tokyo, a coupleof Japanese universities and institutions, as well as
many overseas universities, governmental agencies,
etc. Namely, we are trying to address the issue of heat
and air pollution, urban water issues, and tropicalinfectious diseases associated with human land use.
Combining the physicochemical (secondary) data and(primary) health event data, (1) short-term effects ofheat/cold on 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.
7. Health impacts of heat and air pollution:
Concerns are growing over the potential healtheffects of climate change, especially global warming,
as well as of air pollution, especially long-range
pollution that could occur beyond national borders.
This program was conducted under “Seamless
Chemical Assimilation System and its Application for
Atmospheric Environmental Materials (SALSA: PI
Prof. Nakajima, AORI at UTokyo), which in turn run
under the MEXT-funded “Research Program on
Climate Change Adaptation” (RECCA). In collaboration with National Institute for Environmental Studies(NIES), it has been suggested that the relationshipbetween airborne pollen concentrations and number ofpollinosis consultation was modified by the level ofthe PM2.5. In another study, effects of daily ambient
temperature on cause-specific mortality in Japan wereanalyzed and its geographical variation was examined.

References
1. Inoue Y., Umezaki M., Jiang H., Li D., Du J., Jin
Y., Yang B., Li B., Li Y., Watanabe C. (2014)
Urinary Concentrations of Toxic and Essential
Trace Elements among Rural Residents in Hainan
Island, China. International Journal of Environmental Research and Public Health. 11(12):13047-13064
2. Parajuli RP., Fujiwara T., Umezaki M., Furusawa
H., Watanabe C. (2014) Home environment andprenatal exposure to lead, arsenic and zinc on theneurodevelopment of six-month-old infants living
in Chitwan Valley, Nepal. Neurotoxicology andTeratology. 41: 89-95.
3. Konishi S., Ng CFS., Stickley A., Nishihata S.,
Shinsugi C., Ueda K., Takami A., Watanabe C.
(2014) Particulate matter modifies the association
between airborne pollen and daily medical
consultations for pollinosis in Tokyo. Science of
the Total Environment. 499: 125-132.
4. Konishi S., Nishihama Y., Iida A., Yoshinaga J.,
Imai H. (2014) The association of antimüllerian
hormone levels with menstrual cycle type anddysmenorrhea in young asymptomatic women.
Fertility and Sterility. 102: 1439-1443.
5. Yoshida M., Honda A., Watanabe C., Satoh M.,
Yasutake A. (2014) Neurobehavioral changes in
response to alterations in gene expression profiles
in the brains of mice exposed to low and highlevels of mercury vapor during postnatal development . Journal of Toxicological Sciences. 39: 561570.
6. Stickley A., Koyanagi A., Koposov R., SchwabStone M., Ruchkin V. (2014) Loneliness andhealth risk behaviours among Russian and U.S.
adolescents: a cross-sectional study. BMC Public
Health. 14:366.
7. Nakamura M., Hachiya N., Murata K., NakanishiI., Kondo T., Yasutake A., Miyamoto K., Ser PH.,
Omi S., Furusawa H., Watanabe C., Usuki F.,
Sakamoto M. (2014) Methylmercury exposure

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and neurological outcomes in Taiji residents
accustomed to consuming whale meat. Environment International. 68: 25–32.
8. Hoshikawa K., Umezaki M. (2014) Effect ofterrain-induced shade removal using global DEM
datasets on land-cover classification. International
Journal of Remote Sensing. 35: 1331-1355.
9. Yasumoto S., Jones A., and Shimizu C. (2014)
Longitudinal trends in equity of park accessibility
in Yokohama, Japan: An investigation of the roleof causal mechanisms. Environment and Planning
A. 6(3): 682-699.
10. Murphy A., Roberts B., Ploubidis GB., StickleyA., McKee M. (2014) Using multi-level data toestimate the effect of an ‘alcogenic’ environmenton hazardous alcohol consumption in the former
Soviet Union. Health & Place. 27: 205-211.
11. Parajuli RP., Fujiwara T., Umezaki M., Watanabe
C. (2014) Impact of caste on the neurodevelopment of young children from birth to 36
months of age: A birth cohort study in Chitwan
Valley, Nepal. BMC Pediatrics. 14: 56.
12. Hamamatsu Y., Inoue Y., Watanabe C., Umezaki,
M. (2014) Impact of the 2011 earthquake on
marriage, births and the secondary sex ratio inJapan. Journal of Biosocial Science. 46: 830-841.
13. Kosaka S., Umezaki M., Ishikawa M., Watanabe
C. (2014) Physical activity and the neighborhood
environment in a heavy snowfall area in Japan:
The role of “Gangi-dori”. Landscape and Urban
Planning 123: 124-133.
14. Konishi S. (2014) High fertility and highout-migration rates in the Kingdom of Tonga:
features of demographic transition in a MIRAB
society. Japanese Journal of Health and Human
Ecology (in press, in Japanese)
15. Parajuli RP., Fujiwara T., Umezaki M., Konishi S.,
Takane E., Maharjan M., Tachibana K., Jiang HW.,
Pahari K., Watanabe C. (2014) Prevalence andrisk factors of Soil-transmitted helminth (STH)
infection in Nepal. Transactions of the Royal
Society of Tropical Medicine and Hygiene. 108:228-236
16. Konishi S., Parajuli RP., Takane E., Maharjan M.,
Tachibana K., Jiang HW., Pahari K., Inoue Y.,
Umezaki M., Watanabe C. (2014) Significant sex
difference in the association between C-reactive

protein concentration and anthropometry among
13- to 19-year olds, but not 6- to 12-year olds in
Nepal. American Journal of Physical Anthropology. 154: 42-51.
17. Parajuli RP., Fujiwara T., Umezaki M., Furusawa
H., Watanabe C. (2014) Home environment andprenatal exposure to lead, arsenic and zinc on theneurodevelopment of six-month-old infants living
in Chitwan Valley, Nepal. Neurotoxicology andTeratology (2014)
18. Ng CFS., Ueda K., Takeuchi A., Nitta H., KonishiS., Bagrowicz R., Watanabe C. (2014) Sociogeographic variation in the effects of heat andcold temperature on daily mortality in Japan.
Journal of Epidemiology 24(1): 15-24.
19. Inoue Y., Yazawa A., Li D., Du J., Jin Y., Chen Y.,
Watanabe C., Umezaki M. (2014) Epstein-Barrvirus titer and its association with the domainscores from the World Health Organization’s
Quality of Life Questionnaire: Findings from rural
Hainan province, China. American Journal of
Human Biology 26(1): 51-55.
20. Yazawa A., Inoue Y., Li D., Du J., JIN Y., Chen Y.,
Nishitani M., Watanabe C., Umezaki M. (2014)
Impact of Lifestyle Changes on Stress in aModernizing Rural Population in Hainan Island,
China. American Journal of Human Biology
26(1): 36-42.

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Department of
Biomedical Chemistry
Professor
Kiyoshi Kita, Ph.D.

Associate Professor
Yoh-ichi Watanabe, Ph.D.

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 activity 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: Biochemistry and Nutrition I, IIThis course is comprised of lectures and seminars toprovide basic concepts and newer vistas forunderstanding nutrition with special reference tobiochemistry and molecular biology. These include thestructure 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 livingorganisms. From the standpoint of biological
adaptation, we have been studying on the molecularmechanism of energy transducing systems such as
mitochondrial and bacterial respiratory chain. In
addition, we are interested in the basic biologicalreactions such as protein synthesis. Our research havebeen 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)

3233) C. elegans as a model system of parasitic
nematode (expression of foreign genes or
cDNAs, gene knockout)

5.

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

6.

References
1. Anemia amelioration by lactose infusion during
trypanosomosis could be associated with erythrocytes membrane de-galactosylation. Baloguna,E. O., Balogund, J. A. B., Yusufe, S., Inuwaa, H.
M., Ndamsf, I. S., Sheridang, P., Inaoka, D. K.,
Shiba, T., Harada, S., Kita, K., Esievoh, K. A. N.
and Nok. A. J. (2014) Vet. Parasitol. 199, 259-263
2. Prevalencia de la infección por Trypanosoma
cruzi en niños de 5 a 15 años de edad en
localidades rurales de El Salvador, 2008-2009.
(Prevalence of Trypanosoma cruzi infection
among children aged 5-15 years old in rural area,
El Salvador 2008-2009). Sasagawa E, Romero JE,
Gavidia ME, Hernández MA, Corado EY, Cuyuch
BL, Nakagawa J, Misago C, Kita K, Cedillos RA.
(2014) Minerva Revista en línea CIC-UES. 4,
24-32
3. Probing the ubiquinol-binding site of recombinant
Sauromatum guttatum alternative oxidase
expressed in E. coli membranes through sitedirected mutagenesis. Young, L., May, B.,
Pendlebury-Watt,A., Shearman, J., Elliott, C.
Albury, M. S., Shiba, T., Inaoka, D. K., Harada, S.,
Kita, K. and. Moore, A. L. (2014) Biochim
Biophys. Acta (Bioenergetics), 1837, 1219-1225
4. Prevalence of Trypanosoma cruzi infection inblood donors in El Salvador between 2001 and2011. Sasagawa E, Guevara de Aguilar AV,
Hernández de Ramírez MA, Romero Chévez JE,

7.

8.

9.

Nakagawa J, Cedillos RA, Misago C, Kita K.
(2014) J Infect Dev Ctries. 13, 1029-1036
New members of the Plasmodium 6-Cys family
have distinct and critical roles in liver stage
development. Annoura, T., van Schaijk, B.C.L.,
Ploemen, I.H.J., Sajid, M., Lin, J., Vos, M.W.,
Dinmohamed, A.G., Inaoka, D.K., van Gemert, G.,
Chevalley-Maurel, S., Kiełbasa, S.M., Scheltinga,
F., Franke-Fayard, B.M.D., Klop, O., Herman,
C.C., Kita, K., Gego, A., Franetich, J., Mazier, D.,
Hoffman, S.L., Janse, C.J., Sauerwein R.W. andKhan, S.M. (2014) FASEB J. 28, 2158-2170
Acute Chagas disease in El Salvador 2000-2012-need for survailance and control. Sasagawa E, deAguilar AV, de Ramírez MA, Chévez JE,
Nakagawa J, Cedillos RA, Kita K. (2014) Mem
Inst Oswaldo Cruz. 109, 256-258
Molecular basis for the reverse reaction of African
human trypanosomes glycerol kinase. Balogun,
E. O., Inaoka, D. K., Shiba, T., Kido, Y., Tsuge, C.,
Nara, T., Aoki, T., Honma, T., Tanaka, A., Inoue,M., Matsuoka, S., Michels, P. A.M., Kita, K. andHarada, S. (2014) Molecular Microbiol., 94,
1315-1329
Arabidopsis thaliana mitochondrial EF-G1
functions in two different translation steps.
Suematsu T, Watanabe O, Kita K, Yokobori S,
Watanabe Y. (2014) J. Biochem. 155,107-114
Losing the stem-loop structure from metazoan
mitochondrial tRNAs and co-evolution ofinteracting factors. (2014) Watanabe Y, Suematsu
T, Ohtsuki T. Front. Genet. 5, 109

School of Public Health
1. Epidemiology and Health Sciences

325

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 thesame time of the establishment of the School of Public
Health, the University of Tokyo (April 2007).
Epidemiology is a study of quantitatively assessing
health status and disease development in populations
and statistically analyzing the relationship of risk
factors with the development of certain disease. In
addition to traditional risk factors including alcohol
drinking, smoking, nutrition, and physical activity,
gene and factors controlling gene and socioeconomic
factors are also important topics in epidemiologic
research. Epidemiologic data are needed for
conducting the assessment of certain treatment
including medicine and estimating situation of diseasedevelopment.
Epidemiology not only provides research methodology in the field of public health but also is considereda practical study for public health and thus a central
field of health science. However, both education andresearch systems have long been insufficient in Japan.
Social and preventive epidemiology is a study of
epidemiologically clarifying the relationship between
various phenomena in human society (including
individual lifestyle) and certain disease.
The Department of Social and Preventive Epidemiology particularly focuses on nutrition, which isessential for individual and population health, as 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
with various kinds of disease.

326

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. Fukumoto A, Asakura K, Murakami K, Sasaki S,
Okubo H, Hirota N, Notsu A, Todoriki H, Miura A,
Fukui M, Date C. Within-and between-individual
variation in energy and nutrient intake in Japanese
adults: effect of age and sex difference on groupsize and number of records required for adequate
dietary assessment. J Epidemiol 2013; 23(3): 17886.
2. Goto M, Morita A, Goto A, Deura K, Sasaki S,
Aiba N,Shimbo T, Terauchi Y, Miyachi M, Noda
M, Watanabe S, for the SCOP Study Group.
Reduction in adiposity, β-cell function, insulin
sensitivity, and cardiovascular risk factors: aprospective study among Japanese with obesity.
PLoS One 2013; 8(3): e57964.
3. Tanaka E, Yatsuya H, Uemura M, Murata C,
Otsuka R, Toyoshima H, Tamakoshi K, Sasaki S,
Kawaguchi L, Aoyama A. Associations of protein,fat, and carbohydrate intakes with insomnia
symptoms among middle-aged Japanese workers.
J Epidemiol 2013; 23(2): 132-8.
4. Takezawa J, Yamada K, Miyachi M, Morita A,
Aiba N, Sasaki S, Watanabe S. Preproghrelin gene
polymorphisms in obese Japanese women. Minorhomozygotes are light eaters, do not prefer protein
or fat, and apparently have a poor appetite.
Appetite 2013; 63: 105-11.
5. Miyake Y, Tanaka K, Okubo H, Sasaki S,
Arakawa M. Fish and fat intake and prevalence ofdepressive symptoms during pregnancy in Japan:
Baseline data from the Kyushu Okinawa Maternaland Child Health Study. J Psychiatr Res 2013;
47(5): 572-8.
6. Miyajima I, Kawaguchi T, Fukami A, Nagao Y,
Adachi H, Sasaki S, Imaizumi T, Sata M. Chronic
HCV infection was associated with severe insulin
resistance and mild atherosclerosis: a populationbased study in an HCV hyperendemic area. J

Gastroenterol 2013; 48(1): 93-100.
7. Goto A, Morita A,Goto M, Sasaki S, Miyachi M,
Aiba N, Kato M, Terauchi Y, Noda M, Watanabe S,
for the Saku cohort Study Group. Validity of
diabetes self-reports in the Saku Diabetes Study. J
Epidemiol 2013; 23(4): 295-300.
8. Sasaki S. Dietary reference intakes for Japanese
2010: Basic theories for the development. J Nutr
Sci Vitaminol 2013; 59: S9-S17.
9. Sasaki S. Dietary reference intakes for Japanese
2010: Basic concepts for application J Nutr Sci
Vitaminol 2013; 59: S18-S25.
10. Horiguchi H, Oguma E, Sasaki S, Okubo H,
Murakami K, Miyamoto K, Hosoi Y, Murata K,
Kayama F. Age-relevant renal effects of cadmium
exposure through consumption of home-harvested
rice in female Japanese farmers. Environ Int 2013;
56: 1-9.
11. Murakami K, Sasaki S, Uenishi K,Japan Dietetic
Students Study for Nutrition and Biomarkers
Group. Serum adiponectin concentration in
relation to macronutrient and food intake in young
Japanese women. Nutrition 2013; 29(11-12):1315-20.
12. Hiratsuka C, Fukuwatari T, Sano M, Saito K,
Sasaki S, Shibata K. Supplementing healthy
women with up to 5.0 g/d of L-Tryptophan has noadverse effects. J Nutr 2013; 143(6): 859-66.
13. Suga H, Murakami K, Sasaki S. Development ofan amino acid composition database andestimation of amino acid intake in Japanese adults.
Asia Pac J Clin Nutr 2013; 22: 188-99.
14. Kato M, Goto A, Tanaka T, Sasaki S, Igata A,
Noda M. Effects of walking on medical cost: A
quantitative evaluation by simulation focusing on
diabetes. J Diabetes Investig 2013; 4(6): 667-72.
15. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Validity of a diet history questionnaire estimating beta-carotene, vitamin C andalpha-tocopherol intakes in Japanese pregnant
women. Int J Food Sci Nutr 2013; 64(6): 694-9.
16. Tanaka K, Miyake Y, Sasaki S, Hirota Y. Infant
feeding practices and risk of dental caries inJapan: The Osaka Maternal and Child HealthStudy. Pediatric Dentistry 2013; 35: 267-71.
17. Murakami K, Sasaki S, Uenishi K; Japan Dietetic
Students’ Study for Nutrition and Biomarkers

327Group. Higher intake of vitamin B-6 and dairy
products and lower intake of green and oolong tea
are independently associated with lower serum
homocysteine concentration in young Japanesewomen. Nutr Res 2013; 33(8): 653-60.
18. Kiyohara C, Miyake Y, Koyanagi M, Fujimoto T,
Shirasawa S, Tanaka K, Fukushima W, Sasaki S,
Tsuboi Y, Yamada T, Oeda T, Shimada H,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M; Fukuoka Kinki Parkinson's Disease
Study Group. MDR1 C3435T polymorphism andinteraction with environmental factors in risk of
Parkinson's disease: a case-control study in Japan.
Drug Metab Pharmacokinet. 2013; 28: 138-43.
19. Kaino W, Daimon M, Sasaki S, Karasawa S,
Takase K, Tada K, Wada K, Kameda W, Susa S,
Oizumi T, Fukao A, Kubota I, Kayama T, Kato T.
Lower physical activity is a risk factor for aclustering of metabolic risk factors in non-obese
and obese Japanese subjects: The Takahata study.
Endocr J 2013; 60: 617-28.
20. Sakurai M, Nakamura K, Miura K, Takamura T,
Yoshita K, Sasaki S, Nagasawa S, Morikawa Y,
Ishizaki M, Kido T, Naruse Y, Suwazono Y and
Nakagawa H. Family history of diabetes, lifestylefactors, and the 7-year incident risk of type 2
diabetes mellitus in middle-aged Japanese men
and women. Journal of Diabetes Investigation
2013; 4: 261-8.
21. Shibata K, Fukuwatari T, Sasaki S, Sano M,
Suzuki K, Hiratsuka C, Aoki A, Nagai C. Urinary
excretion levels of water-soluble vitamins in
pregnant and lactating women in Japan. J Nutr Sci
Vitaminol 2013; 59: 178-86.
22. Yaguchi-Tanaka Y, Kawagoshi Y, Sasaki S, Fukao
A. Cross-Sectional Study of Possible Association
between Rapid Eating and High Body Fat Rates
among Female Japanese College Students. J Nutr
Sci Vitaminol (Tokyo) 2013; 59: 243-9.
23. Hara M, Yakushiji Y, Nannri H, Sasaki S, Noguchi
T, Nishiyama M, Hirotsu T, Nakajima J, Hara H.
Joint effect of hypertension and lifestyle-related
risk factors on the risk of brain microbleeds inhealthy individuals. Hypertens Res 2013; 36:
789-94.
24. Shibata K, Fukuwatari T, Sasaki S. Nutritional
Status of Water-soluble Vitamins Did not Differ

According to Intake Levels of Wheat and Wheat
Alternatives and Rice and Rice Alternatives as aStaple Food in Pregnant Japanese Women.
Nutrition and Metabolic Insights 2013; 6: 51-7.
25. Shibata K, Tachiki A, Mukaeda K, Fukuwatari T,
Sasaki S, Jinno Y. Changes in Plasma Pyridoxal
5'-Phosphate Concentration during Pregnancy
Stages in Japanese Women. J Nutr Sci Vitaminol
2013; 59: 343-6.
26. Shin MN, Lee KH, Lee HS, Sasaki S, Oh HY, Lyu
ES, Kim MK. Maternal and grandmaternal obesityand environmental factors as determinants ofdaughter's obesity. Nutr Res Pract 2013; 7: 400-8.
27. Kobayashi S, Asakura K, Suga H, Sasaki S. Highprotein intake is associated with low prevalence offrailty among old Japanese women: a multicentercross-sectional study Nutr J 2013; 12: 164-73.
28. Fujii H, Iwase M, Ohkuma T, Ogata-Kaizu S, Ide
H, Kikuchi Y, Idewaki Y, Joudai T, Hirakawa Y,
Uchida K, Sasaki S, Nakamura U, Kitazono T.
Impact of dietary fiber intake on glycemic control,
cardiovascular risk factors and chronic kidneydisease in Japanese patients with type 2 diabetes
mellitus: the Fukuoka Diabetes Registry. Nutr J
2013; 12: 159.
29. Miyake Y, Tanaka K, Okubo H, Sasaki S,
Arakawa M. Maternal fat intake during pregnancy
and wheeze and eczema in Japanese infants: theKyushu Okinawa Maternal and Child HealthStudy. Ann Epidemiol 2013; 23(11): 674-80.
30. Ilmiawati C, Ogawa M, Sasaki S, Watanabe T,
Kayama F. Urinary arsenic excretion profiles andassociated dietary in Japanese women from acoastal area in Chiba Prefecture. Jichi Medical
University Journal 2013; 36: 1-11.

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Department of Clinical
Epidemiology and Health
Economics
Professor
Hideo Yasunaga, MD, PhD.

Assistant Professor
Hiroki Matsui, MPH.

Homepage

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

Introduction and Organization
The Department of Clinical Epidemiology and Health
Economics was established in April 2007, as a part ofMaster of Public Health (MPH) program under the
new School of Public Health (SPH). The Department
is also affiliated with the Division of Social Medicine
for doctoral education.
The mission of the Department is two folds; to help
health professionals obtain scientifically sound basis
and skills for evidence-based practice, and toempirically evaluate the clinical practice, health caresystem/policy for further improvement of the qualityof health care. For this purpose, the Department puts aunique emphasis on quantitative analytic methods andinter-disciplinary theories across clinical epidemiology, health service research, health economics andhealth policy.

Teaching activities
Under the MPH program, the Department is
responsible for 6 courses, one on introduction toclinical medicine for non-MD students, two on
clinical epidemiology, two on health economics, andone 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, andmanagement 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 2014.

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.

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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. Chikuda H Yasunaga H, Takeshita K, Horiguchi
H, Kawaguchi H, Ohe K, Fushimi K, Tanaka S.
Mortality and morbidity after high-dose
methylprednisolone treatment in patients withacute cervical spinal cord injury: A propensity
matched analysis using a nationwide administrative database. Emergency Medicine Journal 2014;31(3):201-6
2. Chikuda H Yasunaga H, Takeshita K, Horiguchi
H, Kawaguchi H, Fushimi K, Tanaka S. Ischemic
Stroke after Cervical Spine Injury: Analysis of
11,005 Patients Using the Japanese Diagnosis
Procedure Combination Database. Spine Journal
2014 14(10):2275-80.
3. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Fushimi K, Koike K. Impact of
hospital volume on outcomes in acute pancreatitis: a study using a nationwide administrative
database. J Gastroenterol 2014;49:148-55.
4. Hamada T, Nakai Y, Yasunaga H, Isayama H,
Matsui H, Takahara N, Sasaki T, Takagi K,
Watanabe T, Yagioka H, Kogure H, Arizumi T,
Yamamoto N, Ito Y, Hirano K, Tsujino T, Tada M,
Koike K. Prognostic nomogram for nonresectablepancreatic cancer treated with gemcitabine-based
chemotherapy. British Journal of Cancer 2014;
110(8):1943-9.
5. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Matsuda S, Fushimi K, Koike K.
Severe bleeding and perforation are rare complications of endoscopic ultrasound-guided fineneedle aspiration for pancreatic masses: An
analysis of 3,090 patients from 212 hospitals. Gut
and Liver 2014;8(2):215-8.

6. Hasegawa W, Yamauchi Y, Yasunaga H,
Sunohara M, Jo T, Matsui H, Fushimi K,
Takami K, Nagase T. Factors affecting mortality
following emergency admission for chronic
obstructive pulmonary disease. BMC Pulmonary
Medicine 2014;14:151.
7. Inokuchi H, Yasunaga H, Nakahara Y, Horiguchi
H, Ogata N, Fujitani J, Matsuda S, Fushimi K,
Haga N. Effect of Rehabilitation on Mortality ofPatients with Guillain-Barre Syndrome: A
Propensity-matched Analysis Using a Nationwide
Database. Eur J Phys Rehabil Med 2014;50(4):439-46
8. Isogai T, Yasunaga H, Matsui H, Tanaka H, Ueda
T, Horiguchi H, Fushimi K. Out-of-hospitalversus in-hospital Takotsubo cardiomyopathy:
analysis of 3719 patients in the Diagnosis
Procedure Combination database in Japan.
International Journal of Cardiology 2014;176(2):413-7.
9. Iwagami M, Yasunaga H, Doi K, Horiguchi H,
Fushimi K, Matsubara T, Yahagi N, Noiri E.
Postoperative Polymyxin B Hemoperfusion andMortality in Patients with Abdominal Septic
Shock: A Propensity-Matched Analysis. Crit Care
Med 2014;42(5):1187-93
10. Kumamaru H, Tsugawa Y, Horiguchi H,
Kumamaru KK, Hashimoto H, Yasunaga H.
Association between Hospital Case Volume andMortality in Non-elderly Pneumonia Patients
Stratified by Severity: a Retrospective Cohort
Study. BMC Health Services Research 2014;14:302
11. Lee SL, Hashimoto H, Kohro T, 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 underJapan’s Universal Health-Care Coverage. PlosOne 2014;9(10):e111071
12. Michihata N, Matsui H, Fushimi K, Yasunaga H.
Comparison between Enteral Nutrition andIntravenous Hyperalimentation in Patients with
Eating Disorders: Results from the Japanese Diagnosis Procedure Combination Database. Eating
and Weight Disorders - Studies on Anorexia,
Bulimia and Obesity 2014 ;19(4):473-8

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13. Ogura K, Yasunaga H, Horiguchi H, Fushimi K,
Tanaka S, Kawano H. Nomogram Predicting
Severe Adverse Events after Musculoskeletal
Tumor Surgery: Analysis of a National Administrative Database. Annals of Surgical Oncology
2014;21(11):3564-71
14. Ogura K, Yasunaga H, Horiguchi H, Fushimi K,
Kawano H. What Is the Effect of Advanced Age
and Comorbidity on Postoperative Morbidity andMortality After Musculoskeletal Tumor Surgery?
Clinical Orthopaedics and Related Research2014 ;472(12):3971-8
15. Sako A, Yasunaga H, Horiguchi H, Fushimi K,
Yanai H, Uemura N. Prevalence and In-hospital
Mortality of Gastrostomy and Jejunostomy inJapan: A Retrospective Study Using a National
Administrative Database. Gastrointestinal Endoscopy 2014;80:88-96.
16. Sato M, Tateishi R, Yasunaga H, Horiguchi H,
Yoshida H, Matsuda S, Fushimi K, Koike K.
Acute liver disease in Japan – a nationwide
analysis of the Japanese Diagnosis Procedure
Combination database. J Gastroenterol 2014;49(3):547-54
17. Sugihara T, Yasunaga H, Horiguchi H, Matsuda S,
Fushimi K, Kattan M, Homma Y. Does
mechanical bowel preparation ameliorate damage
from rectal injury in radical prostatectomy?
Analysis of 151 rectal injury cases. Int J Urol
2014;21(6):566-70
18. Sugihara T, Yasunaga H, Horiguchi H, Fushimi K,
Dalton J, Schold J, Kattan M, Homma Y.
Performance comparisons in major urooncological surgeries between the United States
and Japan. Int J Urol 2014 ;21(11):1145-50
19. Sugihara T, Yasunaga H, Horiguchi H, Matsui H,
Nishimatsu H, Nakagawa T, Fushimi K, Kattan
MW, Homma Y. Comparison of Perioperative
Outcomes Including Severe Bladder Injury
Between Monopolar and Bipolar Transurethral
Resection of Bladder Tumors: A Population-BasedComparison. Journal of Urology 2014;192(5):1355-9.
20. Sugihara T, Yasunaga H, Horiguchi H, Matsui H,
Fujimura T, Nishimatsu H, Fukuhara H, Kume H,
Changhong Y, Kattan MW, Fushimi K, Homma Y.
Robot-assisted versus other types of radical

prostatectomy: population-based safety and costcomparison in Japan, 2012–2013. Cancer Science
2014;105(11):1421-6
21. Sugihara T, Yu C, Kattan MW, Yasunaga H, Ihara
H, Onozawa M, Hinotsu S, Akaza H. Long-Term
Survival in Extremely Advanced Prostate Cancer
Patients Diagnosed with Prostate Specific Antigen
over 500 ng/mL. Japanese Journal of ClinicalOncology 2014;44(12):1227-32.
22. Sugihara T, Yasunaga H, Horiguchi H, Fujimura
T, Fushimi K, Yu C, Kattan M, Homma Y. Factors
Affecting the Choice of Ureterostomy, Ileal
Conduit and Continent Reservoir after Radical
Cystectomy: Japanese Series. Int J Clin Oncol
2014;19(6):1098-104
23. Sumitani M, Yasunaga H, Uchida K, Horiguchi H,
Nakamura M, Ohe K, Fushimi K, Matsuda S,
Yamada Y. Perioperative factors affecting theoccurrence of acute complex regional pain
syndrome following limb bone fracture surgery:
Data from the Japanese Diagnosis Procedure
Combination database. Rheumatology 2014;53(7):1186-93
24. Suzuki S, Yasunaga H, Matsui H, Horiguchi H,
Fushimi K, Yamasoba T. Impact of Systemic
Steroids on Posttonsillectomy Bleeding: Analysisof 61430 Patients using a National Inpatient
Database in Japan. JAMA Otolaryngology-Head& Neck Surgery 2014;140(10):906-10.
25. Tagami T, Matsui H, Horiguchi H, Fushimi K,
Yasunaga H. Antithrombin and mortality insevere pneumonia patients with sepsis-associateddisseminated intravascular coagulation: an observational nationwide study. J Thrombosis Haemost
2014;12(9):1470-9
26. Taguchi M, Kubo T, Yamamoto M, Muramatsu K,
Yasunaga H, Horiguchi H, Fujimori K, Matsuda
S, Fushimi K, Harada M. Body Mass Index
Influences the Outcome of Acute Pancreatitis: An
Analysis Based on the Japanese Administrative
Database. Pancreas 2014 ;43(6):863-6.
27. Takagi T, Sugihara T, Yasunaga H, Horiguchi H,
Fushimi K, Kattan MW, Homma Y, Tanabe K.
Cytoreductive nephrectomy for metastatic renal
cell carcinoma: a population-based analysis ofperioperative outcomes according to clinical stage.
Int J Urol 2014 ;21(8):770-5.

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28. Tsuda Y, Yasunaga H, Horiguchi H, Fushimi K,
Kawano H, Tanaka S. Effects of Fondaparinux on
Pulmonary Embolism following Hemiarthroplasty
for Femoral Neck Fracture: a Retrospective
Observational Study Using the Japanese Diagnosis Procedure Combination Database. J Orthop
Sci 2014 ;19(6):991-6.
29. Uchida K, Yasunaga H, Sumitani M, Horiguchi H,
Fushimi K, Yamada Y. Effects of Remifentanil on
In-hospital Mortality and Length of Stay
Following Clipping of Intracranial Aneurysm: A
Propensity Score Matched Analysis. J Neurosurg
Anesth 2014 ;26(4):291-8.
30. Uehara K, Yasunaga H, Morizaki Y, Horiguchi H,
Fushimi K, Tanaka S. Necrotising soft-tissue
infections of the upper limb: risk factors for
amputation and death. Bone Joint J 2014;96-B(11):1530-4.
31. Uematsu H, Hashimoto H, Iwamoto T, Horiguchi
H, Yasunaga H. Impact of guideline-concordant
microbiological testing on outcomes of pneumonia. Int J Quality Health Care 2014;26(1):100-7.
32. Wada T, Yasunaga H, Inokuchi R, Horiguchi H,
Fushimi K, Matsubara T, Nakajima S, Yahagi N.
Effects of Edaravone on Early Outcomes in Acute
Ischemic Stroke Patients Treated with Recombinant Tissue Plasminogen Activator. Journal of the
Neurological Sciences 2014 ;345(1-2):106-11.
33. Yamamoto H, Hashimoto H, Nakamura Horiguchi
H, Yasunaga H. Relationship between hospital
volume and hemorrhagic complication after percutaneous renal biopsy: results from the JapaneseDiagnosis Procedure Combination Database.
Clinical and Experimental Nephrology 2014 epub
34. Yamauchi Y, Hasegawa W, Yasunaga H,
Sunohara M, Jo T, Takami K, Matsui H, Fushimi
K, Nagase T. Paradoxical association between
body mass index and in-hospital mortality inelderly patients with chronic obstructive
pulmonary disease in Japan. International Journalof Chronic Obstructive Pulmonary Disease 2014
Dec 9;9:1337-46.
35. Yoshioka R, Yasunaga H, Hasegawa K,
Horiguchi H, Fushimi K, Aoki T, Sakamoto Y,
Sugawara Y, Kokudo N. Hospital volume affects
in-hospital mortality, length of stay, and total

costs after pancreaticoduodenectomy: Analysis ofdata from 10,652 patients from the JapaneseDiagnosis Procedure Combination database. Brit J
Surg 2014;101(5):523-9.

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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 healthprofessionals as well as researchers. We strive to
make the most of our professional activities andexperience at UMIN Center. We provide lectures andpractical instruction in the program. The following is
the current 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. Social marketing
8. Evaluation and research in health communication
9. Media and communication(1): Television
10. Media and communication(2): News paper
11. Media and communication(3): Internet
12. Entertainment education
13. Health communication campaign[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 undergraduate program, Professor Kiuchi presents a lecture
entitled “Medical Literature Informatics.”

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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. Okuhara T., Ishikawa H., Okada H., Kiuchi T.
Identification of gain- and loss-framed cancer
screening messages that appeared in municipal
newsletters in Japan. BMC Research Notes. 2014;
7(1): 896.
2. Ishikawa H., Eto M., Kitamura K., Kiuchi T.
Resident physicians' attitudes and confidence incommunicating with patients: a pilot study at aJapanese university hospital. Patient Education &Counseling. 2014; 96(3): 361-6.
3. Kogure T., Sumitani M., Suka M., Ishikawa H.,
Odajima T., Igarashi A., Kusama M., Okamoto M.,
Sugimori H., Kawahara K. Validity and reliabilityof the Japanese version of the newest vital sign: apreliminary study. PLoS One. 2014; 9(4): e94582.
4. Sakakibara K., Ishikawa H., Yamazaki Y.
Participative climate as a key for creating healthworkplaces. 183-202. In: Biron C. Burke RJ.,
Cooper CL. Creating healthy workplaces: Stress
reduction, improved well-being, and organizational effectiveness. Gower Publishing, London,
2014.

School of Public Health
2. Behavioral Health Sciences

336

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, MD, PhD.

Lecturer
Currently vacancy

Associates
Misato Takada, Ph.D.

Homepage

Daisuke Takagi, Ph.D.

Under construction

Introduction and Organization
The department originated as one of the firstdepartments dedicated to health education andbehavioral science in Japan, led by former Prof.
Emeritus Tadao Miyasaka, who had double degrees of
M.D. from the University of Tokyo and MPH in healtheducation from Harvard School of Public Health in1950s. He was succeeded by a sociologist, former Prof.
Kyoichi Sonoda who founded the first healthsociology department affiliated with the medical
school in Japan. Since then, the program has beenleading research focusing on socio-behavioral aspectsof health in this country. The legend was extended by
Prof. Chieko Kawada who raised academic andpractical attention on the concept of empowerment
and adult pedagogy in health education. Since 1997,
the department was further evolved by Prof. Ichiro
Kai who integrated diverse health and social science
disciplines into social gerontology program, and by
Associate Prof. Yoshihiko Yamazaki who ledsociological research projects on salutogenesis, social
stigma, power, and agency in health settings. The
departments were reorganized under the newly
established School of Public Health since 2007. In
2012, the Department of Social Gerontology has beenrenamed the Department of Health and Social
Behavior to apply a life-course perspective to a wider
range of social conditions and human wellbeing.
The new department intends to further integrate
health science (medicine and public health) and social
science (economics, sociology, and psychology) toreveal a causal mechanism linking social structure andindividual health for realizing health equity as afundamental goal to human security.

Teaching activities
The departments offer five courses in the master
degree program for public health, and five courses in
the undergraduate program for the Integrated Health
Sciences track.

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1. Graduate Courses, School of Public Health
1) Health and Society I & II: The course highlights
the significance of social determinants of health(SDH) as a key exposure causing social gradientof health. A series of omnibus lectures, each ofwhich focusing a specific topic of SDH (e.g.
income distribution, gender, job stress, anddiscrimination), are provided by 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 studies of health educational
intervention in community, school, and work
places. The case discussion was facilitated byinvited lecturers to reach practical lessons for
effective communication.
3) Health Sociology; Sociology in medicine andsociology applied to health issues are treated in
the systemic course of lectures, covering social
model of health, medical gaze and socializationof health professionals, phenomenology ofchronic ills, and culture and health.
4) Healthcare Management: Adjunctive lecture with
Department of Clinical Epidemiology and Health
Economics. Providing basic skills in financial,strategic, and information management forvision-based healthcare organization administration.
2. Undergraduate Courses, School of Integrated
Health Sciences
1) Introduction to social survey and practice: The
course emphasizes that needs for specific knowledge and subsequent research question define themodes of survey. The course gives the students a
virtual situation where a social survey is required
to obtain data to support some decision making,e.g. market research situation. The students are
asked to define an inquired concept, refine a
research question, design the mode of survey,
and conduct a small pilot survey within the class.
The survey results were reported with some
practical implication, and were opened toin-class discussion.
2) Health sociology:3) Health education:4) Social security and welfare program: Lecture
series on the history and the current systems ofhealth care security and welfare policies in thiscountry.
5) Occupational health management; Lecture series
on risk/needs assessment, strategic managementof health resource, and health promotion intervention in work place.

Research activities
The Department has contributed to an ongoing
research of socioeconomic status and health/functions
among elderly population in the collaboration with the
School of Economics of the University of Tokyo andthe Research Institute of Economic, Industry, andTechnology. The Japanese Study of Ageing andRetirement (J-STAR) is a sister study with the U.S.
Health and Retirement Study, Study of Health, Ageing,
and Retirement in Europe (SHARE), EnglandLongitudinal Survey of Ageing (ELSA), and theirglobal sisters in Asian countries. The scope of JSTAR
is diverse; contribution of health for successful ageing,social economic conditions and access to health care,household economy and its impact on life styles suchas eating habits and nutrition, impact of retirement
onto cognitive function, etc..
Since 2010, the Department has launched anotherpanel study of younger generation, the Japanese studyof Stratification, Health, Income, and Neighborhood(J-SHINE) in collaboration with researcher groups on
neuroscience, economics, sociology, and social
psychology. The aim of this new panel-to-be 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. A preliminary result
suggests that socioeconomic conditions of parents andgrandparents are influential on the sociobehavioral
development of children.
Panel data of these surveys are planned to open for
academic use to a global researcher circle to shareanalytic scheme and to enhance comparative studies

338

so as to better identify common factors as well as
unique factors affecting health 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.

References
1. Lee SL, Hashimoto H, Kohro T, 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 underJapan’s Universal Health-Care Coverage. PLoS
2014 Oct 31;9(10):e111071. doi: 10.1371/journal.
pone.0111071.
2. Kato A, Takada M, Hashimoto H. Reliability andvalidity of the Japanese version of the Self-Stigma
Scale in patients with type 2 diabetes. Health Qual
Life Outcomes. 2014 Dec 12;12(1):179.
3. Tokunaga M, Hashimoto H, Tamiya N. A gap informal long-term care use related to characteristics of caregivers and households, under the
public universal system in Japan: 2001-2010.
Health Policy. 2014 Nov 6. pii: S0168-8510(14)00279-6. doi: 10.1016/j.healthpol.2014.10.015.
4. Takagi D, Kondo N, Takada M, Hashimoto H.
Differences in spousal influence on smoking
cessation by gender and education among
Japanese couples. BMC Public Health. 2014 Nov
19;14:1184. doi: 10.1186/1471-2458-14-1184.
5. Murakami K, Aida J, Ohkubo T, Hashimoto H.
Income-related inequalities in preventive andcurative dental care use among working-age
Japanese adults in urban areas: a cross-sectional
study. BMC Oral Health. 2014 Sep 19;14:117.
doi: 10.1186/1472-6831-14-117.
6. Nishiura C, Hashimoto H. Sleep duration andweight gain: reconsideration by panel data
analysis. J Epidemiol. 2014;24(5):404-9. Epub
2014 Aug 2. PubMed PMID: 25088695; PubMed
Central PMCID: PMC4150012.

7. Kumamaru H, Tsugawa Y, Horiguchi H,
Kumamaru KK, Hashimoto H, Yasunaga H.
Association between hospital case volume andmortality in non-elderly pneumonia patients
stratified by severity: a retrospective cohort study.
BMC Health Serv Res. 2014 Jul 12;14:302. doi:
10.1186/1472-6963-14-302.
8. Ueda M, Kondo N, Takada M, Hashimoto H.
Maternal work conditions, socioeconomic andeducational status, and vaccination of children: acommunity-based household survey in Japan.
Prev Med. 2014 Sep;66:17-21. doi: 10.1016/j.
ypmed.2014.05.018.
9. 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. 2014 May 31. [Epubahead of print] l
10. Miyata H, Gotoh M, Hashimoto H, Motomura N,
Murakami A, Tomotaki A, Hirahara N, Ono M,
Ko C, Iwanaka T. Challenges and prospects of aclinical database linked to the board certification
system. Surg Today. 2014 Nov;44(11):1991-9.
doi: 10.1007/s00595-013-0802-3. Epub 2014 May
23.
11. Takada M, Kondo N, Hashimoto H; J-SHINE
Data Management Committee. Japanese study on
stratification, health, income, and neighborhood:study protocol and profiles of participants. J
Epidemiol. 2014;24(4):334-44. Epub 2014 May
10.
12. Tanaka H, Toyonaga T, Hashimoto H. Functionaland occupational characteristics predictive of a
return to work within 18 months after stroke inJapan: implications for rehabilitation. Int Arch
Occup Environ Health. 2014 May;87(4):445-53.
doi: 10.1007/s00420-013-0883-8.
13. Kondo N. What Has Made Japan Healthy?
-Contributions of local and governmental healthpolicies-. JMAJ(Japan Medical Association
Journal). 2014 January-February;57(No.1):24-7.
14. Yoko A, Iku S, Naoki K, Salina S, Futaba K.
Handwashing and microbial contamination on thepalms of preschool children in Kathmandu, Nepal.
Journal of International Health. 2014;29(2):69-74.

339

15. Tabuchi T, Fujiwara T, Nakayama T, Miyashiro I,
Tsukuma H, Ozaki K, et al. Maternal and paternalindoor or outdoor smoking and the risk of asthma
in their children: A nationwide prospective birthcohort study. Drug Alcohol Depend. 2014 Feb
1;147:103-8.
16. Saito M, Kondo K, Kondo N, Abe A, Ojima T,
Suzuki K, et al. Relative Deprivation, Poverty,
and Subjective Health: JAGES Cross-Sectional
Study. PLoS ONE. 2014;9(10):e111169.
17. 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. 2014 Oct 8.
18. Odonkor CA, Hurst P, Kondo N, Makary MA,
Pronovost PJ. Halting the Revolving Door: How a
Focus on Patient- and Community-Level Risks
May Help Curb Readmissions After Surgery. Am
J Med Qual. 2014 August 7, 2014.
19. 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;234:241-7.
20. Kondo N, Rostila M, Yngwe MA. Risinginequality in mortality among working-age men
and women in Sweden, 1990-2007: a national
registry-based repeated cohort study. J Epidemiol
Community Health. 2014;doi: 10.1136/jech-2013203619.
21. Jwa SC, Fujiwara T, Kondo N. Latent protective
effects of breastfeeding on late childhood
overweight and obesity: A nationwide prospective
study. Obesity. 2014:n/a-n/a.
22. Hirai H, Kondo N, Sasaki R, Iwamuro S, Masuno
K, Ohtsuka R, et al. Distance to retail stores andrisk of being homebound among older adults in acity severely affected by the 2011 Great East
Japan Earthquake. Age Ageing. 2014 October 14,
2014;First published online.
23. Hashimoto M, Suetsugi T, Ichikawa Y, Sunada K,
Nishida K, Kondo N, et al. Assessing therelationship between inundation and diarrhoeal
cases by flood simulations in low-income com-munities of Dhaka City, Bangladesh. HydrologicalResearch Letters. 2014;8(3):96-102.
24. Aihara Y, Oh-oka K, Kondo N, Sharma J,
Shrestha NC, Ishimaru K, et al. Residential Area,
Birth Order, and Dietary Habit May Influence
TSLP Levels in Colostrum: Comparative Study
between Japan and Nepal. Allergology International. 2014;63:283-5.
25. Aihara Y, Oh-oka K, Kondo N, Sharma J,
Ishimaru K, Hara M, et al. Comparison ofcolostrum TGF-β2 levels between lactating
women in Japan and Nepal. Asian Pac J Allergy
Immunol. 2014;32(2):epub ahead of print.

School of Public Health
3. Health Services Sciences

341

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Research Associate
Toki Saito, Ph.D.

Homepage:

http://home.cie.m.u-tokyo.ac.jp:8080/ciemutk

Introduction and Organization
Information engineering in Japan places a great dealof weight on computer hardware, software, and dataprocessing. It is a discipline that seeks objective dataand emphasizes the conception of new methods ofdata transfer, storage, processing, and input/output. It
also targets research on developing computer devices
and systems.
Reviewing the history of the application ofcomputers in medicine, calculating machines forsupporting scientists and technologists first appearedin the 1950s. In the 1960s, computers were used foraccounting and various statistics. The personal
computer appeared in the 1980s and was adopted for
personal use in many professions. The systematizationof large hospitals, such as university hospitals, pushedahead rapidly.
In the 1990s, the computer began to be used as atool to help human thinking, such as in presentations,design, and discovery. When computers became
connected to each other through the internet, thedistribution of information became very easy andrapid, not only within organizations, but alsointernationally.
In 2003, a high-quality, "finished" sequence of thehuman genome was completed. At the dawn of thetwenty-first century, bioinformatics appeared as a new
discipline, one that uses applied mathematics,
informatics, statistics, computer science, and 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
who have special knowledge and skills at aninternational level in order to apply advanced
information technologies to practical projects inclinical medicine and the health sciences. It offers
courses on information system design, development
methodology, evaluation and project management inbiomedicine, health care and public health in the
School of Public Health, and data mining and virtual
reality for clinical decision-making in social medicine.
Famous visiting lecturers and researchers from the
National Cancer Center and other universities havegiven lectures here, furthering our hope of becoming aworld leader in this field.
The education of graduate students is based on
weekly conferences at which the students present the342

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. Nakatomi, H, Miyazaki, H, Tanaka, M, Kin, T,
Yoshino, M, Oyama, H, Usui M, Moriyama H,
Kojima H, Kaga K and Saito, N. (2015).
Improved preservation of function during acoustic
neuroma surgery. Journal of neurosurgery, 122(1),24-33.
2. Yoshino, M., Kin, T., Ito, A., Saito, T., Nakagawa,D., Kamada, K., Mori H, Kunimatsu A, Nakatomi
H, Oyama H and Saito, N. (2014). Diffusion
tensor tractography of normal facial andvestibulocochlear nerves. International journal ofcomputer assisted radiology and surgery, 1-10.
3. Yoshino, M., Kin, T., Saito, T., Nakagawa, D.,
Nakatomi, H., Kunimatsu, A., Oyama H & Saito,
N. (2014). Optimal setting of image bounding box
can improve registration accuracy of diffusion
tensor tractography. International journal ofcomputer assisted radiology and surgery, 9(2),333-339.

Endowed Department

344

Department of Integrated
Traditional Medicine
Project Professor
Tetsuro Okabe, M.D., Ph.D.

Project Associate
Jing Yu, Ph.D,

Hideki Koizumi, M.D., Ph.D.

Homepage http://square.umin.ac.jp/seitai/
Introduction and Organization
In an attempt to investigate the Japanese traditional
herbal medicine, the Department of Integrated
Traditional Medicine was established in 1996 as the
Department of Bioregulatory Function affiliated with
the Department of Medicine and Physical Therapy.
In 1999, the Department of Geriatric Medicine joined
us as an another affiliated Department. Pharmacological actions by medicinal herbs have been
intensively investigated not only on allergic or
autoimmune diseases, but also the disorders associatedwith aging process. Therapeutic experiments ofherbal medicine have been carried out by using animal
disease models to clarify the mechanisms of thepharmacological actions. In additions, the biologicalactions of the herbs have been investigated at cellularlevels to clarify the intracellular signaling pathways
induced by the medicinal herbs.
In 2003, traditional medicine was introduced into corecurriculum of medical education program. Since 2004,
lecture of traditional medicine has been
started in this university as an essential study. The
lectures have been served by this department. For
postgraduate education, seminars of traditional
medicine have been held at the university.
To avoid the confusion of similar names in western
medicine, the name of this department “Department of
Bioregulatory Function” was changed to “Department
of Integrated Traditional Medicine” in 2005.
Together with the change in the department name, westarted the translational studies on the physiology andpathology of the traditional medicine to translate thetraditional medicine into scientific medicine.
Itrequired not only the chemical or pharmacologicalstudies but also the biophysical approaches. In
addition, translation from scientific medicine into the
traditional medicine has been also required for better
understanding the integration of both medicine. For
this purpose, free seminars “traditional medicine as alife science” have been started, in which we analyze
and translate the scientific data into the traditional
medicine and also try to integrate both medicines.
Another research interest has been focused on theanti-aging medicine used in ancient traditional
medicine. Recently, hormone supplemented therapy
has been tried for disorders associated with aging inWestern medicine. Some herbs have been shown toexert their pharmacological actions through receptors
for certain hormones. The studies on this theme havebeen intensively performed at the department.
Postgraduate students have been also engaged in bothbasic and clinical sciences. The department provides awide-ranged clinical, training, and research services.
The weekly official activities of our department are ajournal club on Tuesday and research conferences on
Thursday.

Clinical activities
We have outpatient clinics on Tuesday, Wednesday,and Friday in the Department of General Medicine.

345

The diagnosis is made by the western medicine using
blood examinations and imaging studies. After thescientific diagnosis, patients are diagnosed based on
the instructions of the traditional herbal medicine, andtreated mainly with the medicinal herbs.

Teaching activities
As for under-graduate student education, ourdepartment takes a part in systemic lectures for the 4thyear medical students. In systemic lectures,comprehensive presentation for the understanding ofbasic knowledge about the concept, pathogenesis,
pathology, diagnosis and treatment is performed.
In systemic lectures, we also present clinical cases ofrepresentative cases, and try to discuss with thestudents several points for planning the diagnosis andtreatment. Demonstration of some herbs and typical
recipes is also served during the lectures.
Free seminars “traditional medicine as a life science”
are served, in which we analyze and translate thescientific data into the traditional medicine and also
try to integrate the idea from both medicines.
For international experimental educations, a special
lecture on traditional herbal medicine and demonstration of acupuncture were given for foreign students
from over 40 countries at Harvard Project for Asianand International Relations Tokyo Conference.
Postgraduate students are served with scientificeducation of molecular cell biology and biophysics.
As for the post-graduate clinical education, we
provide clinical lectures regularly on the use of
traditional herbal medicine.

Research activities
Our research field covers from clinical, pharmacological, biological, and biophysical activities of
traditional medicinal herbs. We focus on the molecularmechanisms of cell functions and intracellularsignaling pathways.
Traditional medicinal herbs such as Ginseng has long
been used as an anti-aging agent in Asian countries.
Our laboratory studies molecular mechanisms ofaction by such anti-aging herbs. Ginsenoside Rb1, amajor constituent of Ginseng has been demonstrated
to exert the biological action as a phytoandrogen.
Endocrinological activities of anti-aging herbs areinvestigated using various molecular cell biologicalapproaches including biochemistry, immunochemistry,
molecular biology, molecular genetics such as genetargeting and transgenic mouse approaches, molecularbiophysics.
Much current interest is focused on the therapeuticpotential of hormone replacement therapy (HRT).
However, one of the major adverse reactions of HRT
is considered to promote cancer growth. It is urgent
for us to elucidate the mechanisms of action by theanti-aging herbs and to compare them with those ofhormones. Subsequently, we compare the biologicalactivities of the anti-aging herbs and their counterpart
hormones. We have demonstrated ginsenoside Rb1
and icariin exert the biological activity through its
non-genomic action on androgen receptors. Recently,
we have demonstrated that cinnamaldehyde, a major
constituent of cinnamon selectively stimulates progesterone secretion in human adrenal cells. Our studies
are focused on endocrinological actions of anti-aging
herbs which are exerted through their genomic or
non-genomic actions of steroid hormones.
The spinocerebellar ataxias (SCAs) are clinically andgenetically a heterogeneous group of neurodegenerative disorders. At present, we have no effective
therapeutic tools. SCA6 has been demonstrated to be
an autosomal dominant cerebellar ataxia associatedwith small polyglutamine-dependent expansions in thealpha 1A-voltage calcium channel. Long-term
remission of this genetic disease has been attainedwith medicinal herbs. The findings of our study imply
the therapeutic potential of herbal medicine for thishereditary neurodegenerative disorder. Extensive
investigations are under way to clarify themechanisms. It has been also demonstrated that someherbs are effective against multiple sclerosis,
neuromyelitis optica, glaucoma, epilepsy, Parkinson’s
disease or depression in our laboratory.
It has been reported that some herbal medicines may
be effective for acute episodes of chronic nonspecific
low back pain. Spondylolisthesis is one of thecauses of low back or neck pain. Although surgicaltreatment is often performed for symptomatic
spondylolisthesis, we have succeeded in herbal
therapy for degenerative spondylolisthesis.
Physiology, pathology and therapy of traditional
herbal medicine are based on the principle of the346characteristic systems biology. According to theguideline of the traditional herbal medicine, we haveexamined the clinical effect by systems therapy withmedicinal herbs in patients with bronchial asthma andessential hypertension. Long- term remission has beenobtained in both disorders. Extensive studies are under
way to elucidate the mechanisms by which systems
therapy exerts the therapeutic activities.

References
1.

Wieland LS, Manheimer E, Sampson M,
Barnabas JP, Bouter LM, Cho K, Lee MS, Li X,
Liu J, Moher D, Okabe T, Pienaar ED, Shin BC,
Tharyan P, Tsutani K, van der Windt DA, Berman
BM. Bibliometric and content analysis of the
Cochrane Complementary Medicine Field
specialized register of controlled trials. Syst Rev.
2013 Jul 4;2:51. doi: 10.1186/2046-4053-2-51.

347

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

348

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 2014, we received 37 requests and made6184 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 May 9 in 2014, Dr. Koide gave a lecture forgraduate students of public health, the University ofTokyo at the 6th seminar room on the 13F in the
medical education and research building. The title ofthe lecture was “Medical DB for detecting Adverse
Drug Reactions – Sentinel Project –“ in the series of“Medical Information Systems”. Also, Dr. Koide
lectured to junior students of Integrated Health
Sciences, Faculty of Medicine, the University ofTokyo. The title of the lecture was “Drug life-cycle
and survey” in the series of "pharmacology andtoxicology" at the room number N101, in the 3rd
Building of Medicine on May 27 in 2014. And Dr.
Koide gave a lecture which was entitled"Pharmacoepidemiology and Pharmacovigilance byusing database" in the series of medical common
lectures XXXIII, at the 1st seminar room on 2F of the
medical and education research building on October
31st in 2014. In addition to that, the same lecture
provided by Dr. Koide in the series of“Epidemiological study, Planning and analysis” forjunior students of of Integrated Health Sciences,
Faculty of Medicine, the University of Tokyo, at theroom number N101, in the 3rd Building of Medicine,on October 31, in 2014. Furthermore, Dr. Takanashi

has given a lecture on lipid as a part of clinicaltraining for the 5th and 6th grade's students ofMedicine, the University of Tokyo since 2013.
Also, in the ethical seminars for all researchers
including under and graduate students of medicine, Dr.
Koide lectured on “Personal Information Managementfor Medical Research” on May 16, September 16 in
2014.
And the basic lectures of Medical Writing took
place as an intensive course on August 26-27 in 2014,
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 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 3 in 2014.
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. As the 3rd year of it, the e-learning
system has been evaluated. Therefore, we expand ourscope of human resource development for not only
clinical epidemiology, but also clinical research andtrial.

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

349

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

ofInformationin

2000, is now regarded as a key solution to the problem.
In light of the need for novel approaches, we sought toelucidate 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. We also
elucidated the impact of infection on early
atherosclerosis, along with measuring oxidative stresslevels in stored blood samples.

Clinical

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.
4) In Vivo Analysis on Lipid Metabolism
In order to elucidate the pathophysiological role ofneutral lipid accumulation in metabolic diseases, wetake advantage of mouse models of lipase deficiency
and genetic hyperlipidemia, such as hormone-sensitive
lipase (Lipe) deficient mice, neutral cholesterol esterhydrolase 1 (Nceh1) deficient mice, Ldlr/Apoe andApoa5 deficient mice.
Specifically, our recent findings suggest 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

References
1. Lee SL, Hashimoto H, Kohro T, 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. 2014 Oct 31; 9(10): e111071. doi: 10.1371/journal.pone.0111071.
eCollection 2014.
2. Lee SL, Daimon M, Kawata T, Kohro T, Kimura K,
Nakao T, Koide D, Watanabe M, Yamazaki T,
Komuro I. Estimation of right atrial pressure on
inferior vena cava ultrasound in asian patients. Circ
J. 2014: 78(4): 962-6.

350

Department of Ubiquitous
Preventive Medicine
Associate Professor
Yasushi Imai, M.D., Ph.D. (2014.12〜)
Toru Suzuki, M.D., Ph.D. (〜2014.8)

Assistant Professor
Yuichi Ikeda, M.D., Ph.D. (2014.7〜)
Daigo Sawaki, M.D., Ph.D. (〜2014.5)

Homepage:

http://plaza.umin.ac.jp/upm/

Introduction and Organization
As an official department in the Graduate School of
Medicine of the University of Tokyo, theDepartment of Ubiquitous Preventive Medicine wasestablished in August 1st, 2007, with a donationfrom three pharmaceutical companies, Toa-Eiyo
Ltd., Shionogi & Co., Ltd. and NEC Corporation to
the University (since August 2010, from Shionogi& Co.). Its predecessor is the Clinical BioInformatics Research Unit, which was establishedin 2002 as a government-funded program (BioInformatics Training Program supported by the
Ministry of Education, Culture, Sports, Science andTechnology [MEXT] through Special Coordination
Funds for Promoting Science and Technology).
When the Clinical Bio-Informatics Research Unit
completed its program tenure in 2007, its academic
services were succeeded by our department and theDepartment of Clinical Epidemiology and Systems,
both affiliated with the Department of Cardiovascular Medicine in the Graduate School of
Medicine of the University of Tokyo.
Our department provides clinical as well as
academic support for the Department of Epidemiology and Preventive Medicine, which wasestablished in 2007 within the University of Tokyo
Hospital. In collaboration with our department,

the Department of Clinical Epidemiology and
Systems also support the management of the
Department of Epidemiology and Preventive
Medicine.

Research Activities
Our goal is to create diagnostic and therapeuticbasis for prevention and early detection ofcardiovascular disease by utilizing advanced andhighly efficient techniques of biochemistry andmolecular pharmacology. We especially focus on
the discovery of bioactive substances and diagnostic
biomarkers in order to promote translational
research, which connects basic scientific findings totangible 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
was developed in collaboration with Shimadzu
Corporation. We have already confirmed andpublished its utility in clinical practice (Clin Chem,in press), further, issued press-release from the
University of Tokyo Hospital.
In addition to the development of the diagnostic

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technique as described above, we have alsoestablished several screening systems towards thediscovery of bioactive substances that are involvedin the pathogenesis of cardiovascular disease.
Utilizing these newly developed systems, we will
screen tissue extracts and a small-molecule compound library to identify novel bioactive molecules.
In this way, Ubiquitous Preventive Medicine isan applied science, based on which a comprehensive system is to be developed in an effort topromote 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 andprovides clinical as well 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 theaffiliate Department of Cardiovascular Medicine.

References
Academic Papers in English
1. Suzuki T, Eagle KA, Bossone E, Ballotta A,
Froehlich JB, Isselbacher EM; Medical
management in type B aortic dissection. Ann
Cardiothorac Surg. 4: 413-7, 2014.
2. Dean JH, Woznicki EM, O'Gara P, Montgomery
DG, Trimarchi S, Myrmel T, Pyeritz RE, Harris
KM, Suzuki T, Braverman AC, Hughes GC,
Kline-Rogers E, Nienaber CA, Isselbacher EM,
Eagle KA, and Bossone E. Cocaine Related Aortic
Dissection: Lessons from the International
Registry of Acute Aortic Dissection. Am J Med.
5.005, 2014.
3. Hoff E, Eagle T, Pyeritz RE, Ehrlich M,
Voehringer M, Bossone E, Hutchison S, Peterson
MD, Suzuki T, Greason K, Forteza A,
Montgomery DG, Isselbacher EM, Nienaber CA,
and Eagle KA. Pulse pressure and type A acuteaortic dissection in-hospital outcomes (from theInternational Registry of Acute Aortic Dissection).
Am J Cardiol. 113:1255-1259, 2014

National Conferences
1. 第 5 回 Molecular Cardiovascular Conference II(神戸：2014/9/5-6): 池田祐一、熊谷英敏、Amber Skach、佐藤牧人、柳沢正史. 血中グルココルチコイド濃度の概日変動を制御する副腎皮質内パラクラインシグナル系の同定とその生理的な役割
2. 第 46 回日本動脈硬化学会学術総会 (東京：2014/7/10-11):
Young
Faculty
Initiative
Session：新たなパラダイムへの挑戦．池田祐
一．血中グルココルチコイド濃度の日内変動を制御する新規パラクラインシグナルの同定とその生理学的意義

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Division of Chronic Kidney Disease(CKD) Pathophysiology
Division Chief (Associate Professor)
Reiko Inagi, Ph.D.

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

Postdoctoral Fellow
Shuta Motonishi, 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
Thitinun Anusornvongchai, M.D.
(Department of medicine, Lerdsin Hospital, 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 in

One risk is the possible progression of CKD to

every eight adults. Why has the number of CKD

end-stage kidney failure, which requires renal

patients increased so remarkably? One major cause isreplacement therapy. A second risk is the development

the sharp increase in the number of people withand progression of lifestyle-related diseases, such as

diabetic nephropathy, which is a complication ofheart attack and arteriosclerosis. The kidneys work

diabetes; since 1998, this has been the most important

closely with the heart and other organs, and a decreasecause among diseases which require incipient dialysis.

in renal function causes dysfunction of the heart andAdditional causes include the aging of society andblood vessels. This adverse impact of the progression

other social factors. The kidney is called a silent organ,of CKD on other organs underlines the importance ofand CKD progresses without subjective symptoms. It

the kidneys in maintaining general health. Further,is now evident, however, that asymptomatic CKD

many researchers have also focused on the vicious

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spiral of aging and CKD: aging worsens thewith the mechanisms of CKD progression andprogression of CKD, while CKD accelerates aging.

identification of the mechanism of development

With our modern lifestyles and the super-aging society,and progress of renal anemia.

CKD cannot be separated from lifestyle-relateddiseases, and senility cannot be separated from CKD.

3) Clarifying the impact of kidney aging on CKD
progression in super-aging society4) Identifying factors in the exacerbation of CDK in

Creating a healthy, long-lived society full of energy

patients with diabetes, and developing diagnostic

and vigor requires that the quality of life (QOL) of theand therapeutic drugs targeting such factors.

elderlybe

improved.

In

turn,

total

medicalexpenditures will also be decreased. These are important issues requiring urgent solutions. Against thisResearch Funds
・ Japan Society for the Promotion of Science,

background, the Division of CKD Pathophysiology

Grants-in-Aid for Scientific Research 25461207

was newly established in November 2013 with(to Reiko Inagi, Analysis of pathophysiologicalsupport from Kyowa Hakko Kirin Co., Ltd. The aim

significance of microRNA that regulates hypoxicof the Division is to aid and support the control CKD

and ER stress responses) and 25893045 (to Kumi

and the creation of a healthy, long-lived society. The

Shoji, Identification of the function of Sperm-

Division takes an innovative approach to identifying

associated antigen 4, a novel hypoxia-inducible

the pathophysiology of CKD, and works to develop

factor 1 target, in the kidney)more effective CKD preventive and therapeuticstrategies. Through these research activities, our goal・ Japanese Association of Dialysis Physicians Grant
2012-05 (to R.I.)

is to contribute to the creation of a healthy, long-lived
society in which the elderly can live a happy andAwardsindependent life.
Dr. Shuta Motonishi received the Best Abstract Award
of Japanese Society of Nephrology (at the 57th JSN

Major Research Projects

meeting) and Award for Excellence in the 5th

The Division of CKD Pathophysiology works in

Molecular Nephrology Forum.

collaboration with the Division of Nephrology and
Endocrinology, a part of The University of Tokyo

Dr. Thitinun Anusornvongchai received the President

Graduate School of Medicine (Professor Masaomi

Award of Japanese Society of Pathophysiology in

Nangaku) to conduct basic and clinical research on

Kidney Failure.

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
obtainedtoestablish

new

CKD

treatment

strategies.
2) Clarifying the mechanism of functional change inrenal erythropoietin (EPO)- producing cells, along

References
1. 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. 2014 Nov
25 (in press)

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2. Nordquist L, Friederich-Persson M, Fasching A,
Liss P, Shoji K, Nangaku M, Hansell P, Palm F.
Activation of Hypoxia-Inducible Factors Prevents
Diabetic Nephropathy. J Am Soc Nephrol. 2014
Sep 2 (in press)
3. Kawakami T, Mimura I, Shoji K, Tanaka T,
Nangaku M. Hypoxia and fibrosis in chronic
kidney disease: crossing at pericytes. Kidney Int
Suppl. 2014 Nov;4(1):107-112. Review.
4. Inagi R, Ishimoto Y, Nangaku M. Proteostasis
in endoplasmic reticulum-new mechanisms inkidney disease. Nat Rev Nephrol. 2014 Jul;10(7):369-78. Review.
5. Inagi R. Glycative stress and glyoxalase in kidneydisease and aging. Biochem Soc Trans. 2014 Apr;
42(2):457-60.
6. Shoji K, Tanaka T, Nangaku M. Role of hypoxia
in progressive chronic kidney disease andimplications for therapy. Curr Opin Nephrol
Hypertens. 2014 Mar;23(2):161-8.
7. Jo-Watanabe A, Ohse T, Nishimatsu H, Takahashi
M, Ikeda Y, Wada T, Shirakawa J,Nagai R, Miyata
T, Nagano T, Hirata Y, Inagi R, Nangaku M.
Glyoxalase I reduces glycative and oxidative
stress and prevents age-related endothelial dysfunction through modulation of endothelial nitricoxide synthase phosphorylation. Aging Cell. 2014
Jun; 13(3):519-28.
8. Wada T, Nangaku M, Maruyama S, Imai E, Shoji
K, Kato S, Endo T, Muso E, Kamata K, Yokoyama
H, Fujimoto K, Obata Y, Nishino T, Kato H,
Uchida S, Sasatomi Y, Saito T, Matsuo S. A
multicenter cross-sectional study of circulating
soluble urokinase receptor in Japanese patientswith glomerular disease. Kidney Int. 2014 Mar;85(3):641-8.
9. Inagi R, Shoji K, Nangaku M. Oxidative andendoplasmic reticulum (ER) stress in tissue
fibrosis. Curr Pathobiol Rep 2014; 1: 283-9.

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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. Kanai Y., D. Wang, and N. Hirokawa. KIF 13b
enhances the endocytosis of LRP1 by recruiting
LRP1 to caveolae. J. Cell Biol. 204: 395-408,
2014.
2. Yang W., Y. Tanaka, M. Bundo, and N. Hirokawa.
Antioxidant signaling involving the microtubulemotor KIF12 is an intracellular target of
nutrition excess in beta cells. Dev Cell 31:
202–214, 2014.
3. 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.
4. 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

356

the selective somatodendritic localization of earlyendosomes. J. Neurosci. 35: 5067–5086, 2015.
DOI:10.1523/JNEUROSCI.4240-14.2015.
5. Hirokawa. N. Introduction to the ECR Special
Issue on Molecular Motors. Exp Cell Res 334: 1,
2015.
6. 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.

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Department of Molecular Vascular
Endocrinology
Associate Professor
Masashi Isshiki, M.D, Ph.D.

Associate
Risuke Mizuno, Ph.D.

Homepage http://www.m.u-tokyo.ac.jp/mcm/
Introduction and Organization
The Department of Molecular Vascular Endocrinology was established in the Graduate School of
Medicine in April 2009 by a donation from Novartis
Pharmaceuticals Japan to collaborate with the Department of Nephrology and Endocrinology and theClinical Laboratory.
The vascular system plays an important role in thefunction and maintenance of various organs. Lifestylerelated illnesses such as high blood pressure are
known to cause abnormalities in the blood vessels and,as a result, to cause disorders of important organs likethe heart, kidneys, and brain. Various vasoactive
substances and signal transduction in cells forming thevascular structure are thought to be involved in thisprocess. This department conducts research with theaim of understanding the molecular mechanisms andpathophysiology of vascular disorders brought about
by lifestyle-related illnesses and accumulating knowledge that can be applied to the treatment ofcardiovascular diseases.

Research activities
1. Understanding vascular endothelial function regulatory mechanisms by intracellular Ca2+ signaling
The vasoregulator that we are particularly interested
in is calcium signaling in vascular endothelial cells.
Calcium ions are extremely important signaling
factors that are involved in many vital phenomena. An
important feature of calcium signaling is that it

enables diverse cellular functions through spatiotemporal regulation. We have observed a number ofextremely interesting phenomena using confocal laser
microscope imaging systems. We have reported that,when cultured endothelial cells are stimulated with anagonist such as ATP, the increase in intracellular
calcium spreads to the entire cell in the form ofcalcium waves, starting from the cell edges where
caveolae are abundant (Isshiki et al., PNAS 1998).
Caveloae are invaginations with a diameter of about
100 nm in the cell membrane, and their function has
attracted attention in recent years due to the presenceof a variety of signaling transduction molecules thatare considered to be important in vascular function,such as intracellular calcium regulatory proteins. In
addition, caveolae are dynamic cell membrane
structures, and the sites where they accumulate, which
is where the calcium wave is triggered, contain
substances that accumulate on the upstream side of theflow caused by shear stress and on the opposite side in
the direction of travel during cell migration (Isshiki etal., J Cell Sci 2002). One candidate that has been
proposed as a shear stress sensor is P2x4 receptors on
the cell membrane, and experimental data indicatingthat they are coupled with the production of nitricoxide (NO) in endothelial cells has also been obtained(Yamamoto, Isshiki, et al., Nat Med, 2006). Recently,
we have also been involved in an investigation of therelationship between intracellular calcium dynamics
and endothelial cell function using Fluorescence
Resonance Energy Transfer (FRET). For example,

358

when the amount of calcium in the intracellular
calcium store decreases, there is an effect called
SOCE (store-operated calcium entry) whereby
calcium flows into the cell from outside; we haveshown that this calcium uptake pathway is via the
caveolae membrane and is linked with NO production
due to activation of endothelial nitric oxide synthase(eNOS) present in the membrane (Isshiki et al., J Biol
Chem 2002). NO is deeply involved in vascular tonus
regulation and antiarteriosclerosis; therefore, thispathway is related to the pathology of high bloodpressure and arteriosclerosis, and research in this area
may identify treatment targets. In addition, we havealso been analyzing the relationship between
calcium-dependent molecular regulation and calcium
dynamics directly under the cell membrane, which
may not be obtainable with conventional calcium
indicators, depending on the extracellular calcium
concentration (Isshiki et al., Circ Res 2004).
2. Understanding the pathophysiology of andvasoregulation by STIM1, a new Ca2+ regulatory
molecule
Recently, the important role played by a molecule
called STIM1, which is present in the ER Ca2+ store,
in SOCE control has been discovered, and we havealso been looking at STIM1 in our laboratory toinvestigate its role in endothelial cells.
A study is now underway to investigate STIM1's
relationship with the pathophysiology of vasculardisorders associated with arteriosclerosis and highblood pressure by preparing endothelial-cell-specific
STIM1 knockout mice and analyzing STIM1's effects
on endothelial performance and blood pressure.
3. Searching for new and existing vasoactive
substances and understanding new vasoactive
mechanisms
We are also interested in searching for new
vasoactive substances and understanding new action
mechanisms of existing substances. For example, theinfluence of aldosterone on vascular endothelial function, which is not mediated by transcription mechanisms, has recently been investigated in cultured cells
and by tonus measurements in rat aortic ring (Muto etal., Hypertens Res 2008). Also, we have reported thateplerenone, which is a selective aldosterone antagonist,

improves endothelial function by suppressing theexpression of caveolin, which is an eNOS inhibitor(Muto et al., AHA 2008). Recently, we have also been
examining the effects H2S on vascular function,
which is of physiological and pharmacologicalinterest.
4. Physiological investigation of the contribution oflymphatic vessel function in the pathology ofsalt-sensitive hypertension
Recently, it has been reported that lymph capillary
regeneration in the skin, which is caused by saltloading, is related to the pathology of salt-sensitive
hypertension. However, the effects of salt loading on
the regulatory control mechanism of lymphatic circulation are not yet sufficiently understood. Research iscurrently underway to look at the effects of salt onchanges to the functional properties of collecting
lymphatic vessels that are mainly involved in the
propulsion of lymph, using animal models.

References
Academic Conferences and Lectures
International Conferences
1. Nishimoto, M. Mizuno, R., Isshiki, M. and Fujita
T. Stim1 regulates blood pressure via NO
production in vascular endothelial cells. The 18th
International Vascular Biology Meeting, Apr.
2013, Kyoto
2. Mizuno, R. and Isshiki, M. A high salt dietstrengthens chronotropic effects of lymphaticmechanical activities in mice. Vascular Biology
Oct 20-24, 2013, Hyannis MA, USA359

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),
bladder outlet obstruction (BOO), interstitial cystitis/
bladder pain syndrome(IC/BPS), and underactive
bladder dysfunction, especially focusing on:
1. To elucidate bladder sensory transduction mechanisms
2. To disclose pathophysiology of development of
detrusor overactivity/OAB
3. To find useful biomarkers for IC/BPS
4. To evaluate the effects of metabolic syndrome on
LUT function

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5. To develop novel pharmacological treatment forrefractory LUT dysfunction
6. To establish continence-care system consisted ofmulti-disciplinary professionals to contribute to
the advancement of continence medicine

Publications
1. Aizawa N, 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. 2014
Feb 14. doi: 10.1002/nau.22571. [Epub ahead ofprint] PubMed PMID: 24532414
2. Kamei J, Nishimatsu H, Nakagawa T, Suzuki M,
Fujimura T, Fukuhara H, Igawa Y, Kume H,
Homma Y. Risk factors for septic shock in acuteobstructive pyelonephritis requiring emergency
drainage of the upper urinary tract. Int Urol
Nephrol. 2014 Mar;46(3):493-97.
3. Igawa Y, Kumano S, Aizawa N, Saito Y, Ito H,
Watanabe S, Takahashi N, Tajimi M, Nishimatsu
H, Homma Y. Changes in the function andexpression of T-type and N-type calcium channels
in the rat bladder after bladder outlet obstruction.
J Urol. 2014 Apr;191(4):1159-67.
4. Minagawa T, Aizawa N, Igawa Y, Wyndaele JJ.
The role of transient receptor potential ankyrin 1(TRPA1) channel in activation of single unit
mechanosensitive bladder afferent activities in therat. Neurourol Urodyn. 2014 Jun;33(5):544-9.
5. Yamaguchi O, Marui E, Kakizaki H, Homma Y,
Igawa Y, Takeda M, Nishizawa O, Gotoh M,
Yoshida M, Yokoyama O, Seki N, Ikeda Y,
Ohkawa S. A phase III, randomized, double-blind,placebo-controlled study of the β(3) -adrenoceptor
agonist, mirabegron 50 mg once-daily, inJapanese patients with overactive bladder. BJU Int.
2014 Jun;113(6):951-60.
6. Nishimatsu H, Kitamura T, Yamada D, Nomiya A,
Niimi A, Suzuki M, Fujimura T, Fukuhara H,
Nakagawa T, Enomoto Y, Kume H, Igawa Y,
Homma Y. Improvement of symptoms of aging inmales by a preparation LEOPIN ROYAL
containing aged garlic extract and other five of
natural medicines - comparison with traditional

herbal medicines (Kampo). Aging Male. 2014
Jun;17(2):112-6.
7. Aizawa N, Hedlund P, Füllhase C, Ito H, Homma
Y, Igawa Y. Inhibition of peripheral fatty acidamide hydrolase depresses activities of bladdermechanosensitive nerve fibers of the rat. J Urol.
2014 Sep;192(3):956-63.
8. Iwatsubo E, Suzuki M, Igawa Y, Homma Y.
Individually tailored ultrasound-assisted promptedvoiding for institutionalized older adults withurinary incontinence. Int J Urol. 2014 Dec; 21(12):1253-7.
9. Aizawa N, Ito H, Sugiyama R, Fujimura T, Suzuki
M, Fukuhara H, Homma Y, Igawa Y. Selective
inhibitory effect of imidafenacin and 5hydroxymethyl tolterodine on capsaicin-sensitiveC-fibers of the primary bladder mechanosensitiveafferent nerves in the rat. J Urol. 2014 Sep 11.
doi: 10.1016/j.juro.2014.09.005. [Epub ahead ofprint] PubMed PMID: 25219701.
10. Taguchi S, Fukuhara H, Azuma T, Suzuki M,
Fujimura T, Nakagawa T, Ishikawa A, Kume H,
Igawa Y, Homma Y. Ultra-early versus earlysalvage androgen deprivation therapy for postprostatectomy biochemical recurrence in pT24N0M0 prostate cancer. BMC Urol. 2014 Oct 16;
14:81. doi: 10.1186/1471-2490-14-81. PubMed
PMID: 25323845; PubMed Central PMCID: PMC
4203971.
11. 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. 2014 Nov 6.pii:S15587673(14)00214-6. doi: 10.1016/j.clgc. 2014.09.
007. [Epub ahead of print] PubMed PMID:
25456839.
12. 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 bladder function. J
Urol. 2014 Nov 11. doi:10.1016/j.juro. 2014.11.
005. [Epub ahead of print] PubMed PMID:
25451828.

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13. 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 and cisplatin (DIP) as a potential salvage chemotherapy
for metastatic urothelial carcinoma. Jpn J Clin
Oncol. 2014 Nov 25. pii: hyu201. [Epub ahead ofprint] PubMed PMID: 25425701.

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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. Nakamura Y, Taniguchi H, Mizoguchi K, Ikeda T,
Motoshima K, Yamaguchi H, Nagashima S,
Nakatomi K, Soda M, Mano H, Kohno S.
“Secondary EML4-ALK-positive lung adenocarcinoma in a patient previously treated for acutelymphoblastic leukemia in childhood: a casereport” Jpn J Clin Oncol 44:593-596, 2014.
2. Yasuda T, Ueno T, Fukumura K, Yamato A,
Ando M, Yamaguchi H, Soda M, Kawazu M, Sai
E, Yamashita Y, Murata M, Kiyoi H, Naoe T,
Mano H. “Leukemic evolution of donor-derived
cells harboring IDH2 and DNMT3A mutations
after allogeneic stem cell transplantation”
Leukemia 28:426-428, 2014.
3. Yoshimi A, Toya T, Kawazu M, Ueno T,
Tsukamoto A, Iizuka H, Nakagawa M, Nannya Y,
Arai S, Harada H, Usuki K, Hayashi Y, Ito E,
Kirito K, Nakajima H, Ichikawa M, Mano H,
Kurokawa M. “Recurrent CDC25C mutations
drive malignant transformation in FPD/AML” Nat
Commun 5:4770, 2014.

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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

banks.

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 ofmental disorders remain largely unclear. The
Department of Molecular Psychiatry has been
established at the Graduate School of Medicine,
University of Tokyo from February 2010 to January
2013, by the donation from Astellas Pharma,
Dainippon Sumitomo Pharma, and Yoshitomi Yakuhin,
and from February 2013, by the donation from
Dainippon Sumitomo Pharma, and Yoshitomi Yakuhin.
The aim of this department is to contribute theunderstanding of cause of illness and pathophysiology
of major mental disorders at the molecular level,
through the close collaboration with Department of
Neuropsychiatry at the University of Tokyo.

Publication

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 brain

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
2014,56C:117-121.
2. 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 metabolites in first-episode schizophrenia:
A capillary electrophoresis time-of-flight mass
spectrometry study. Translational Psychiatry 2014,
4:e379.
3. Murata Y, Nishioka M, Bundo M, Sunaga F, Kasai
K, Iwamoto K. Comprehensive DNA methylation
analysis of human neuroblastoma cells treatedwith blonanserin. Neuroscience Letters 2014,
563:123-128.
4. Kubota-Sakashita M, Iwamoto K, Bundo M, Kato
T. A role of ADAR2 and RNA editing ofglutamate receptors in mood disorders andschizophrenia. Molecular Brain 2014,7:5.
5. 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,

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6.

7.

8.

9.

Kato T, Iwamoto K. Increased L1 retrotransposition in the neuronal genome in schizophrenia.
Neuron 2014,81:306-313.
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 2014,79:22-33.
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
2014,23:648-656.
Kato T, Iwamoto K. Comprehensive DNA
methylation and hydroxymethylation analysis in
the human brain and its implication in mental
disorders. Neuropharmacology 2014,80C:133139.
Hayashi-Takagi A, Vawter MP, Iwamoto K.
Peripheral biomarkers revisited: integrative
profiling of peripheral samples for psychiatricresearch. Biological Psychiatry 2014,75:920-928.

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Department of Life Support
Technology (Molten)
Project Associate Professor
Taketoshi Mori, Ph.D.

Project Assistant Professor
Hiroshi Noguchi, Ph.D., 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.
On May 7, 2011, the celebration for department
establishment was held at Gakushi kaikan. Many
people including president of Molten Corp. Kiyoshi
Tamiaki, Prof. Yasuo Ohashi and Prof. Takeyoshi
Dohi attended the party. Both nursing researchers andengineering researches congratulate the establishment.

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 associate projector
and two project assistant professors. We accept
students from Division of Health Science and Nursing.
Accepted two master course students were graduatedat the end of 2013. The supportive department is the
Department of Gerontological Nursing / Wound CareManagement.

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. Yuji Ota,
Ochanomizu University to lecture for Wound Care

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Management II.
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.
In 2014, the staffs in our department supported one
undergraduate student. His graduation thesis theme is“Relationship between in-home activity monitoringdata by pyroelectric sensors and health status among
elderly people living alone”
As for the other education activity, our department
supported management of the second seminar for
nursing science and engineering. The staffs in our
department had engineering-related lectures andintroduction of research using ultrasonography. In
addition, practical training was conducted using
Labview, which is a famous software formeasurement.

Research activities
Our research themes are to investigate causes of
diseases and/or wounds due to daily life activity, andto develop instrument for effective monitoring andpreventing diseases and/or wounds. We study scienceand technology of natural human monitoring, nursing
engineering, and human behavior sensing thoroughly.
We are seeking a new interdisciplinary researchdomain between engineering and nursing, and willing
to realize comfortable daily life through theseresearches.
We are developing the methodology to support healthy
and comfortable daily life by 1) monitoring daily life
naturally, 2) understanding the typical behaviors, and
3) predicting diseases, injuries, and accidents using
various sensing technology.
Main themes of our department are the following:a) Development of monitoring systems for patient on
a bed and vital sign measurement system using
mattressb) Construction of behavior measurement in dailyliving environment using simple sensors andalgorithm for typical behavior pattern extraction
and transition estimation of human behavior
patternc) Three dimensional leg movement measurement
and spatiotemporal 3D leg state measurement for
prevention of foot ulcerd) Clinical research for current status andmanagement 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 mimamori engineering, which is a main
theme in our department, we clarified the relationshipbetween amount of activities monitored by pyroelectric sensors and cognitive functions of older adults
living alone. The sensors are attached on the houses
where the order adults live alone and the activities in
the rooms were captured. The relationship between
health status (e.g., cognitive function and physicalability) and variables calculated from captured sensor
data (amount of activity, the number of outgoing,
duration of outgoing, sleeping time and awake time).
It is clarified that the amount of activities are related
to cognitive functions.
We achieved the prize about the following presentation.
1. Yuka Miura. Presentation Award of the second
annual meeting of nursing science and engineering.
(Domestic conference)
Yuka Miura, Haruka Tohara, Gojiro Nakagami,
Hiroshi Noguchi, Ayano Kumakura, Nami Tomomachi,
Hiromichi Shinozaki, Kenichiro Kobayashi, Takayuki
Saito, Yuto Imai, Taketoshi Mori, Hiromi Sanada.
“Evaluation method of muscle related to opening jaw
function using ultrasonography” In proceedings of thefirst annual meeting of nursing science andengineering. 2014.

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References
1. 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 skinbarrier function. Biol Res Nurs. 2015;17(2):13541.
2. 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;
3. Arias S, Rogeli P, Cardiel E, Sanada H, Mori T,
Noguchi H, Nakagami G. Assessment of threealternating pressure sequences applied to a
dynamic cushion to relieve pressure on seatingareas. Revista mexicana de ingenieria biomedica.
2014;35(3):253-262.
4. Kanazawa T, Nakagami G, Minematsu T, Yamane
T, Huang L, Mugita Y, Noguchi H, Mori T,
Sanada H. Biological responses of threedimensional cultured fibroblasts by sustained
compressive loading include apoptosis andsurvival activity. PLoS One. 2014;9(8):e104676.
5. Takano M, Noguchi H, Oe M, Sanada H, Mori T.
Development and evaluation of a system to assess
the effect of footwear on the in shoe plantarpressure and shear during gait. ROBOMECH
Journal. 2014;1(4).
6. Amemiya A, Noguchi H, Oe M, Ohashi Y, Ueki K,
Kadowaki T, Mori T, Sanada H. Elevated plantarpressure in diabetic patients and its relationshipwith their gait features. Gait & Posture. 2014;40(3):408-14.
7. Minematsu T, Horii M, Oe M, Sugama J, Mugita
Y, Huang L, Nakagami G, Sanada H. Skinblotting: a noninvasive technique for evaluating
physiological skin status. Adv Skin Wound Care.
2014;27(6):272-279.
8. Kato A, Fukazawa Y, Sanada H, Mori T.
Extraction of food-related onomatopoeia fromfood reviews and its application to restaurant
search. JACIII. 2014;18(3):418-428.

9. Miura Y, Nakagami G, Yabunaka K, Tohara H,
Murayama R, Noguchi H, Mori T, Sanada H.
Method for detecting aspiration based on image
prosessing-assisted B-mode video ultranonography. Journal of Nursing Science Engineering.
2014;1(1):12-20.
10. Koyano Y, Nakagami G, Iizaka S, Minematsu T,
Noguchi H, Tamai N, Mugita Y, Kitamura A,
Tabata K, Abe M, Murayama R, Sugama J,
Sanada H. Exploring the prevalence of skin tears
and skin properties related to skin tears in elderly
patients at a long-term medical facility in Japan.
Int Wound J. 2014;.
11. Miura Y, Nakagami G, Yabunaka K, Tohara H,
Murayama R, Noguchi H, Mori T, Sanada H.
Method for detection of aspiration based on
B-mode video ultrasonography. Radiol Phys
Technol. 2014;.
12. Noguchi H, H, a M, Fukui R, Shimosaka M, Mori
T, Sato T, Sanada H. Measurement of dense static
point cloud and online behavior recognition using
horizontal LIDAR and pan rotation of vertical
LIDAR with mirrors. SICE JCMSI. 2014;7(1):12-20.
13. Kitamura A, Nakagmai G, Yoshida M, Noguchi H,
Nishijima Y, Minematsu T, Naito A, Sugawara J,
Shibayama H, Takahashi K, Hakuta A, Umemoto
J, Terada N, Segawa R, Mori T, Sanada H.
Visualization of tumor necrosis factor-α distributions within pressure ulcer tissue using the woundblotting method: a case report and discussion.
WOUNDS. 2014;26(11):323-329.
14. Miura Y, Nakagami G, Tohara H, Murayama R,
Noguchi H, Mori T, Sanada H. B-mode video
ultrasonography for detecting aspiration: two casestudies. Journal of Society of Nursing Practice.
2014;27(1):42-49.

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Department of Youth Mental
HealthAssociate Professor
Tsuyoshi Araki, M.D., Ph.D.

Lecturer
Noriaki Yahata, Ph.D.

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.

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Research activities
Our research field covers Integrative neuroimaging
studies for schizophrenia targeting early intervention
and prevention (IN-STEP), Tokyo teen cohort study,
and the randomized controlled study of earlyintervention.

References
1. 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 and
N-Acetylaspartate Levels in Patients With
Chronic Schizophrenia but not in Those at
Clinical High Risk for Psychosis or With
First-Episode Schizophrenia. Schizophr Bull.
2013 (in press).
2. Nagai T, Tada M, Kirihara K, Yahata N,
Hashimoto R, Araki T and Kasai K: Auditory
mismatch negativity and P3a in response to
duration and frequency changes in the early stagesof psychosis. Schizophr Res, 2013 DOI 10.1016/
j.schres.2013.08.005
3. 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 theoxytocin receptor gene.
Soc Cogn Affect
Neurosci. 2013 (in press).
4. Sato H, Yahata N, Funane T, Takizawa R, Katura
T, Atsumori H, Nishimura Y, Kinoshita A,
Kiguchi M, Koizumi H, Fukuda M & Kasai, K: A
NIRS-fMRI investigation of prefrontal cortex
activity during a working memory task.
Neuroimage. 83C, 158-173 (2013).
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,
Ishii-Takahashi A, Kawakubo Y, Kasai K: Genetic
influences on prefrontal activation during a verbal
fluency task in adults: A twin study based on

multichannel near-infrared spectroscopy. Neuroimage. 2013 Apr 2. [Epub ahead of print]
6. Aoki Y, Orikabe L, Takayanagi Y, Yahata N,
Mozue Y, Sudo Y, Ishii T, Itokawa M, Suzuki M,
Kurachi M, Okazaki Y, Kasai K & Yamasue H:
Volume reductions in frontopolar and left
perisylvian cortices in methamphetamine induced
psychosis.
Schizophr Res. 147(2-3), 355-61(2013).
7. 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. 2013 (in press).
8. Nagai T, Tada M, Kirihara K, Araki T, Jinde S andKasai K: Mismatch negativity as a “translatable”
brain marker toward early intervention for
psychosis: a review. Front. Psychiatry 4:115,
2013 DOI 10.3389/fpsyt.2013.00115
9. Aoki Y, Abe O, Yahata N, Kuwabara H, Natsubori
T, Iwashiro N, Takano Y, Inoue H, Kawakubo Y,
Gonoi W, Sasaki H, Murakami M, Katsura M,
Nippashi Y, Takao H, Kunimatsu A, Matsuzaki H,
Tsuchiya K. J., Kato N, Kasai K & Yamasue H:
Absence of age-related prefrontal NAA change inadults with autism spectrum disorders. Transl
Psychiatry. 2, e178. (2013).
10. Takizawa R, Nishimura Y, Yamasue H, Kasai K:
Anxiety and Performance: The Disparate Roles ofPrefrontal
Subregions
Under
Maintained
Psychological Stress. Cereb Cortex. 2013 Feb 20.
[Epub ahead of print]
11. Araki T, Niznikiewicz M, Kawashima T, Nestor
PG, Shenton ME, McCarley RW: Disruption offunction-structure coupling in brain regions
sub-serving self monitoring in schizophrenia.
Schizophr Res 146: 336-343, 2013 DOI 10.
1016/j.schres.2013.02.028.
12. Nishioka M, Bundo M, Koike S, Takizawa R,
Kakiuchi C, Araki T, Kasai K, Iwamoto K.:
Comprehensive DNA methylation analysis ofperipheral blood cells derived from patients with
first-episode schizophrenia. J Hum Genet 58: 91-7,
2013 DOI 10.1038/jhg.2012.140.

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13. Koike S, Takano Y, Iwashiro N, Satomura Y, Suga
M, Nagai T, Natsubori T, Tada M, Nishimura Y,
Yamasaki S, Takizawa R, Yahata N, Araki T,
Yamasue H, Kasai K: A multimodal approach toinvestigate biomarkers for psychosis in a clinicalsetting: The integrative neuroimaging studies inschizophrenia targeting for early intervention andprevention (IN-STEP) project. Schizophr Res
143: 113-24, 2013 DOI 10.1016/j.schres.2012.
11.012.

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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

Clinical activities

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, Gastroenterology, Surgical oncology & Vascular surgery, and Ophthalmology.
The Department of Immunotherapy Management wasestablished in April 2013 through donations from six
pharmaceuticalcompanies(Mitsubishi-Tanabe,
Bristol-Myers, Chugai, Janssen pharma, Abbvie,
Eisai). The Department of Allergy & Rheumatology,
Dermatology, and Orthopedics work in collaboration.
Not only biologic agents but also small molecules
have been developed in succession. However, it isdifficult to predict the efficacy and toxicity of theseagents by the background characteristics of patientswith rheumatoid arthritis. The aims of this department
are to propose an optimal treatment strategy for eachpatient and to establish a platform to investigate novel
biologics through analyses of immunological changes
by biologics treatments and the relationship between
biologics response and biomarkers or genetic
information.

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 October in 2014, westarted a new outpatient booth exclusively for thosewith psoriatic arthritis on Friday afternoons
comprehensive evaluation of the disease including
accurate diagnosis and monitoring disease activity byclinical 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.

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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. Shoda H, Morita K, Kanda H, Fujio K, Yamamoto
K.: An elderly woman with peripheral spondyloarthritis with aortitis. Mod Rheumatol. 24(2):3536, 2014
2. Inoue M, Shoda H, Seri Y, Kubo K, Kanda H,
Fujio K, Yamamoto K.: Three cases of lupus
nephritis patients with serum interleukin-32γ
detection. Lupus23(11): 1187-91, 2014

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Department of medical researchand the management ofmusculoskeletal pain
Associate Professor
Koh Matsudaira, M.D,Ph.D.

Associate
Hiroyuki Oka, M.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 treating

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musculoskeletal pain and the prognosis through thefollowing methods:
1) Identify risk factors associated with the onset andexacerbation of musculoskeletal pain through anapproach that integrates physical and psychosocial
factors as well as biomechanics;
2) Verify the validity of the standard values ofscreening tools recommended worldwide for their use
in Japan; and3) Evaluate the brain function of people who are on
administrative leave due to low back pain, since thisphenomenon is a major social problem.

that led to a leave of absence from work.
Prospects for future research
We plan to train clinicians with skills in musculoskeletal pain rehabilitation, including specialised
exercise therapy and cognitive behavioural therapy fornonspecific low back pain, which is the most frequent
type of musculoskeletal pain. By collaborating with
the Department of Nursing, we plan to develop simple
tools to prevent low back pain, which will be useful inthe clinical settings and for industrial hygiene.
Moreover, we plan to verify and diagnose the tools’
utility and conduct further research on preventive
tools and therapeutic programmes.

References
Specifically, we will conduct the following research:
1) Explore the risk factors associated with the onset of
low back pain that interferes with work and its
conversion to chronicity by using a cohort of about
2,000 persons from four types of occupations (i.e.
clerical staff, nurses, sales and marketing associates,and personnel in the transportation industry) andcollecting multi-faceted information at baseline;
2) Calculate (on the basis of the prevalence and datafrom approximately 50,000 people in Japan) the
standard values for a screening tool by using aworldwide stratification system that considers
psychosocial factors, namely the subgrouping fortargeted treatment (STarT) back scoring system, inJapanese subjects. Follow-up surveys at 6 months will
be conducted on approximately 2,000 randomly
extracted people who have complaints of low backpain, and a weighted psychological validation of thetool will be performed
3) Elucidate the properties of brain functions inpatients with LSS compared with a control groupcomposed of healthy subjects. In addition, we will
clarify the changes due to interventions by using 18
fluoro-2-deoxyglucose positron emission tomography
images of the brain taken before and after therapeuticinterventions (e.g. exercise and cognitive behaviouraltherapy, which are highly recommended worldwide)
on approximately 15 cases of refractory low back pain

1. Matsudaira K, Konishi H, Miyoshi K, Isomura T,
Inuzuka K. Potential risk factors of persistent low
back pain developing from mild low back pain in
urban Japanese workers. PLos One, 2014 Ape8;
9(4): e93924
2. Hasegawa T, Katsuhira J, Matsudaira K, Iwakiri K,
Maruyama H. Biomechanical Analysis of Low
Back Load when Sneezing. Gait and Posture 40:
670-5, 2014
3. Muraki S, Akune T, En-yo Y, Yoshida M, Tanaka
S, Kawaguchi H, Nakamura K, Oka H, Yoshimura
N. Association of dietary intake with joint space
narrowing and osteophytosis at the knee inJapanese men and women: The ROAD Study.
Mod Rheumatol 24, 236-242, 2014
4. Muraki S, Akune T, Nagata K, Ishimoto Y,
Yoshida M, Tokimura F, Tanaka S, Oka H,
Kawaguchi H, Nakamura K, Yoshimura N.
Association of knee osteoarthritis with onset andresolution of pain and physical functional
disability: The ROAD study. Mod Rheumatol 24:
966-973, 2014
5. Hashizume H, Yoshimura N, Nagata K, Miyazaki
N, Ishimoto Y, Nishiyama R, Oka H, Yamada H,
Yoshida M: Development and evaluation of avideo exercise program for locomotive syndromein the elderly. Mod Rheumatol 24, 250-257, 2014
6. Yoshimura N, Nagata K, Muraki S, Oka H,
Yoshida M, Enyo Y, Kagotani R, Hashizume H,
Yamada H, Ishimoto Y, Teraguchi M, Tanaka S,
Kawaguchi H, Toyama Y, Nakamura K, Akune T:
Prevalence and progression of the radiographic
ossification of posterior longitudinal ligament andits associated factors in the Japanese populations:
A 3-year follow-up of the ROAD study.

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Osteoporos Int 25, 1089-1098, 2014
7. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N: Incidence of certified needed carein the long-term care insurance system and its risk
factors in the elderly of Japanese populationbased cohorts: the ROAD study. Geriatrics &Gerontology International 14, 695-701, 2014
8. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N. Association of physical activities ofdaily living with the incidence of certified need ofcare in the long-term care insurance system ofJapan: the ROAD study. J Orthop Sci 19:489-496,
2014
9. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Nakamura K, Yoshimura N. Exercise habitsduring middle age are associated with lower
prevalence of sarcopenia: the ROAD study.
Osteoporos Int 25:1081-1088, 2014
10. Yamada K, Matsudaira K, Takeshita K, Oka H,
Hara N, Takagi Y: Prevalence of low back pain
as the primary pain site and factors associatedwith low health-related quality of life in a large
Japanese population: a pain-associated crosssectional epidemiological survey. Mod Rheumatol
24, 343-348, 2014
11. Teraguchi M, Yoshimura N, Hashizume H,
Muraki S, Yamada H, Minamide A, Oka H,
Ishimoto Y, Nagata K, Kagotani R, Takiguchi N,
Akune T, Kawaguchi H, Nakamura K, Yoshida M.
Prevalence and distribution of intervertebral discdegeneration over the entire spine in a populationbased cohort: the Wakayama Spine Study.
Osteoarthritis Cartilage 22:104-110, 2014
12. 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, endplate signal change, andSchmorl node with low back pain in a large
population study: the Wakayama Spine Study.
Spine J pii: S1529-9430(14)01758-6. doi: 10.
1016/j.spinee.2014.11.012, 2014
13. 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 magnetic
resonance imaging study: the Wakayama Spine
Study. Spine J 14:2811-2817, 2014
14. Yoshimura N, Akune T, Fujiwara S, Shimizu Y,
Yoshida H, Omori G, Sudo A, Nishiwaki Y,
Yoshida M, Shimokata H, Suzuki T, Muraki S,
Oka H, Nakamura K. Prevalence of knee pain,

lumbar pain and its coexistence in Japanese men
and women: The Longitudinal Cohorts of Motor
System Organ (LOCOMO) study. J Bone Miner
Metab 32:524-532, 2014
15. Ohya J, Miyoshi K, Oka H, Matsudaira K,
Fukushima M, Nagata K. Optimal measurementfor "posterolateral protrusion" of the vertebral
artery at the craniovertebral junction using computed tomography angiography. J Craniovertebr
Junction Spine 5:151-156, 2014
16. Ito H, Takatori Y, Moro T, Oshima H, Oka H,
Tanaka S. Total Hip Arthroplasty After Rotational
Acetabular Osteotomy. J Arthroplasty 2014 Oct 8.
pii: S0883-5403(14)00746-3. doi: 10.1016/j.arth.
2014.10.002, 2014

Endowed Department(22nd Century Medical and Research Center)378

Department of Clinical &Molecular Epidemiology
Project Associate Professor
Takanari Gotoda, M.D., Ph.D.

Project Associate
Takashi Yamamoto, Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/rinsyo_bunshi.html

Introduction and Organization
The Department of Clinical & Molecular
Epidemiology was established in June 2004 as anendowed department (Mitsubishi Tanabe Pharma Co.,
Ltd.) of the Graduate School of Medicine, theUniversity of Tokyo, under supervision of the
Department of Nephrology and Endocrinology of the
University of Tokyo Hospital. Our department also
belongs to the 22nd Century Medical and ResearchCenter, which partly represents the translational
research activities of the University Hospital. At
present, our research laboratory facilities are locatedat the 8th floor of the Central Clinical Service Bldg.2
and at the 10th floor of the Inpatients’ Ward B of the
University Hospital. Dr. Gotoda is entirely responsible
for the management of the department, keeping close
contact and cooperation with the other departments ofthe 22nd Century Medical and Research Center andwith laboratories of the Department of Nephrology
and Endocrinology, and focusing mainly on research
activities.
Our department is established with the main aim of
performing the clinical and epidemiological analysis
on the metabolic syndrome in the Japanese population,of isolating susceptibility gene(s) to metabolic
syndrome through molecular and genetic analysis on
human and rodent animal models, and of contributing
to the development of novel diagnostic method andtherapeutic agents for the prevention and treatment of

the cardiovascular diseases. Above all, recently, we
are focusing on the genetic susceptibility to visceralfat accumulation, a hallmark of the metabolic
syndrome, and also on the genetic susceptibility tohypertension. Furthermore, we are also trying toelucidate the novel mechanistic action of the available
pharmaceutical agents for the treatment of themetabolic syndrome such as the inhibitors of therenin-angiotensin system and the statins.

Clinical activities
Some of the members of our department is closely
involved in clinical services related to both theout-patient and admission departments. We also attend
clinical conferences and contribute to clinicalactivities of the Department of Nephrology and
Endocrinology of the University Hospital, because ourdepartment is under supervision of the Nephrology
and Endocrinology Department. We are also
performing a translational research project using
clinical materials derived from patients withagreement and approval of both the patients and theethics committee of the University Hospital. Also, in
cooperation with outpatient clinics and hospitals
outside, we are collecting and analyzing the clinicaldata on metabolic syndrome from an epidemiologicalstandpoint with the aim of returning the fruitful resultsof the translational research to the clinical practicedepartments.

379

Teaching activities
Our department belongs to the Graduate School of
Medicine and Faculty of Medicine, the University ofTokyo. We are constantly instructing several
postgraduate students and supervising them in order tosucceed in obtaining the medical doctor degrees of the
University of Tokyo. We also contribute to
examination of the applicants for the doctor degrees,and make several lectures for the students in the
Faculty of Medicine at the University of Tokyo as
well.

Research activities
Our research field of interest covers the followings.
 Identification and isolation of novel susceptible
genes and related factors to metabolic syndrome
through systemic molecular and biological analysis
on human and rodent animal models of metabolic
syndrome.
 Performance of clinical and epidemiologicalanalysis with regard to metabolic syndrome.
 Development of novel diagnostic method for risk
factors of cardiovascular diseases.
 Contribution to the development of preventive andtherapeutic novel agents to treat patients withmetabolic syndrome.
 Exploration of novel mechanisms of action ofavailable pharmaceutical agents to treat patientswith cardiovascular diseases.
First of all, with regard to analysis on metabolic
syndrome, we analyzed clinical and epidemiological
data in the Japanese population by means of factor
analysis focusing on metabolic syndrome. The results
indicated that, even in the Japanese population where
severe insulin resistance can hardly be seen andcommon, the presence of insulin resistance is a crucial
factor underlying the clustering of risk factors related
to metabolic syndrome.
Recently, through the genetic analysis of animalmodel of metabolic syndrome, we have successfully
isolated and identified a novel gene underlying
visceral fat accumulation, a hallmark of metabolic
syndrome. Its characterization is described below indetail.
The spontaneously hypertensive rat (SHR) is an
important genetic animal model of hypertension,

dyslipidemia, and insulin resistance closely related tometabolic syndrome. We previously reported thegenetic heterogeneity among SHR strains, mostimportantly, the fact that SHR strains could be divided
into two separate groups according to the presence orabsence of genetic null mutation at the CD36 gene.
Representatively, the SHR/NCrj strain lacks CD36
due to the mutation while the SHR/Izm strain has
normal CD36. Although these two strains are quite
different in terms of visceral fat accumulation, insulin
secretion capacity, kidney weight and proteinuria,
very interestingly, these differences could not beascribed to the CD36 gene mutation, indicating thepresence of another important genetic abnormality. By
performing the so-called QTL (quantitative trait
locus ) analysis on the F2 cross population between
the two SHR strains, we have identified a QTL linked
significantly to epididymal fat weights and bloodpressure located near D1Wox28 on rat chromosome 1.
Next, as the result of a systematic screening of genes
located within the candidate QTL region by means ofgene expression analysis with a Gene-chip microarray,
we have identified the SLC22A18 gene located at thepeak of the QTL region. Interestingly, SHR/NCrj has apoint mutation at the donor splice site of an intron of
the SLC22A18 gene, while SHR/Izm lacking themutation found in SHR/Izm has wild-type SLC22A18,
The SLC22A18 gene is most abundantly expressed inliver and kidney, and it is also expressed ubiquitously,
for example, in the adipose tissue and pancreatic islet
cells. While the physiological function of SLC22A18
remains largely unknown, it is postulated as amembranous protein that would be possibly involvedin the membranous transport. It is also predicted thatthe donor splice site mutation found in SHR/NCrj
should cause the skipping of a single exon encoding
34 amino acids that would be crucial for normal
function of SLC22A18. In fact, the kinetic analysis
using a radio-labeled chemical agent that is postulated
to be an exogenous substrate for SLC22A18 on
isolated adipocytes clearly demonstrated that the
adipocytes derived from SHR/NCrj with the
SLC22A18 defect have significantly altered functionin terms of uptake of the substrate into adipocytes ascompared with those from SHR/Izm, establishing thefunctional significance of the mutation.
Based upon these observations, we hypothesized that

380

the genetic and functional abnormality of SLC22A18
could cause visceral fat accumulation, kidney
impairment, hypertension and impaired insulin
secretion. To test this hypothesis, we have establishedcell lines that either overexpress or underexpress
SLC22A18, and also overexpressed in vivo with useof adenovirus vectors. We are also trying to establish
genetically-engineered mice such as transgenic miceoverexpressing rat SLC22A18 and knockout mice
deficient in the SLC22A18 gene. By analyzing thephenotypes of those genetically-engineered mice, weplan to explore the clue to the etiological mechanismof visceral fat accumulation. Interestingly, since thefunction of SLC22A18 can possibly be regulated bysome synthetic exogenous substrate, verification of
the above hypothesis may open a new way to develop
a novel pharmaceutical agent to treat metabolic
syndrome focusing on SLC22A18 as a new target.
As another important approach to metabolic syndrome,
we have also generated knockout mice deficient in thegene for KAT-1 (kynurenine aminotransferase-1),
which we previously identified a promising candidate
gene of hypertension in SHR. Interestingly, thosehomozygous knockout mice developed hypertension
and manifested insulin resistance, sympathetic
hyperactivity, resistance to diet-induced obesity, anddiabetic insipidus. These observations may serve todevelop a novel pharmaceutical agent to treat
metabolic syndrome focusing on KAT-1 as a newtarget as well.
Finally, we also carry out a series of researchexperiments aiming at exploration of novel
mechanisms of action of available pharmaceuticalagents to treat patients with cardiovascular diseases.

Reference
1. Gotoda T, Shirai K, Ohta T, Kobayashi J,
Yokoyama S, Oikawa S, Bujo H, Ishibashi S, Arai
H, Yamashita S, Harada-Shiba M, Eto M, Hayashi
T, Sone H, Suzuki H, Yamada N; ResearchCommittee for Primary Hyperlipidemia, Researchon Measures against Intractable Diseases by the
Ministry of Health, Labour and Welfare in Japan.
Diagnosis and management of type I and type V
hyperlipoproteinemia. J Atheroscler Thromb.
2012;19:1-12.

2. Arai H, Ishibashi S, Bujo H, Hayashi T,
Yokoyama S, Oikawa S, Kobayashi J, Shirai K,
Ota T, Yamashita S, Gotoda T, Harada-Shiba M,
Sone H, Eto M, Suzuki H, Yamada N; ResearchCommittee for Primary Hyperlipidemia, Researchon Measures against Intractable Diseases by the
Ministry of Health, Labour and Welfare in Japan.
Management of type IIb dyslipidemia. J Atheroscler Thromb. 2012;19:105-14.
3. Yokoyama S, Yamashita S, Ishibashi S, Sone H,
Oikawa S, Shirai K, Ohta T, Bujo H, Kobayashi J,
Arai H, Harada-Shiba M, Eto M, Hayashi T,
Gotoda T, Suzuki H, Yamada N. Background to
discuss guidelines for control of plasma HDLcholesterol in Japan. J Atheroscler Thromb.
2012;19:207-1

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.

Clinical activities
We provide outpatient services for cancer patients. Allinterventions performed in the department are definedby the protocols of the particular clinical trial
approved by the IRB. The following clinical trials areunderway in our department:

382

Dendritic cell therapy
1. UMIN registration number ： UMIN000002136
active, not recruiting
IRB number：2492
Safety, efficacy and immunogenicity of autologous
tumor lysate-pulsed dendritic cell therapy inpatients with advanced renal cell carcinoma
2. UMIN registration number ： UMIN000002837
active, not recruiting
IRB number：2759
Safety, efficacy and immunogenicity of autologous
tumor lysate-pulsed dendritic cell therapy after
resection of stage2A (T2N0,T3N0) esophageal
cancer
3. UMIN registration number ： UMIN000006646
active, not recruiting
IRB number：P2011025-11Z
Safety, efficacy and immunogenicity of concomitant interferon alpha and autologous tumor
lysate-pulsed dendritic cell therapy in patientswith advanced renal cell carcinomaγδ T cell therapy for advanced cancer
4. 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.
5. UMIN registration number ： UMIN000001419
active, not recruiting
IRB number：2120-(1)The efficacy and safety of autologous γδ T celltransfer therapy for esophageal cancer
6. UMIN registration number ： UMIN000004130
active, not recruiting
IRB number：P201019-11Z
Intraperitoneal autologous γδ T cell therapy forrefractory gastric cancer with ascites
7. UMIN registration number ： UMIN000008097
active, not recruiting
IRB number：P201019-11Z
Combination of chemotherapy with docetaxel /cisplatin / fluorouracil (DCF) and autologous γδ Tcell transfer therapy for esophageal cancer.

Adjuvant γδT cell therapy
8. UMIN registration number ： UMIN000000931
active, not recruiting
IRB number：1810-(1)Clinical study to investigate safety and efficacy on
combination of gemcitabine and autologous
gamma/delta T cell transfer therapy after resectionof pancreatic cancer

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
application of new knowledge to clinical practice.

List of Publications
1: Sato Y, Shimizu K, Shinga J, Hidaka M, Kawano
F, Kakimi K, Yamasaki S, Asakura M, Fujii SI.
Characterizationofthemyeloid-derived
suppressor cell subset regulated by NK cells inmalignant lymphoma. Oncoimmunology. 2015
Jan 22; 4(3): e995541. eCollection 2015 Mar. Pub

383

2:

3:

4:

5:

6:

7:

Med PMID: 25949922; PubMed Central PMCID:
PMC4404816.
Kakimi K, Matsushita H, Hosoi A, Miyai M,
Ohara O. CTLs regulate tumor growth via
cytostatic effects rather than cytotoxicity: a few T
cells can influence the growth of many times
more tumor cells. Oncoimmunology. 2014 Dec 3;4(3):e970464. eCollection 2015 Mar. PubMed
PMID: 25949889; PubMed Central PMCID:
PMC4404888.
Matsushita H, Enomoto Y, Kume H, Nakagawa T,
Fukuhara H, Suzuki M, Fujimura T, Homma Y,
Kakimi K. A pilot study of autologous tumor
lysate-loaded dendritic cell vaccination combinedwith sunitinib for metastatic renal cell carcinoma.
J Immunother Cancer. 2014 Aug 19;2:30. doi: 10.
1186/s40425-014-0030-4. eCollection 2014. Pub
Med PMID: 25694811; PubMed Central PMCID:
PMC4331924.
Futami J, Fujiyama H, Kinoshita R, Nonomura H,
Honjo T, Tada H, Matsushita H, Abe Y, Kakimi K.
Denatured mammalian protein mixtures exhibit
unusually high solubility in nucleic acid-free purewater. PLoS One. 2014 Nov 18;9(11):e113295.
doi: 10.1371/journal.pone.0113295. eCollection
2014. PubMed PMID: 25405999; PubMed Central
PMCID: PMC4236158.
Kobayashi T, Kakimi K, Nakayama E, Jimbow K.
Antitumor immunity by magnetic nanoparticlemediated hyperthermia. Nanomedicine (Lond).
2014 Aug;9(11):1715-26. doi: 10.2217/nnm.14.
106. Review. PubMed PMID: 25321171.
Yamada D, Matsushita H, Azuma T, Nakagawa T,
Nagata M, Yamada Y, Suzuki M, Fujimura T,
Fukuhara H, Kume H, Homma Y, Kakimi K.
Granulocyte macrophage colony-stimulating
factor as a predictor of the response of metastatic
renal cell carcinoma to tyrosine kinase inhibitor
therapy. Mol Clin Oncol. 2014 Nov;2(6):1023-1027. Epub 2014 Jul 29. PubMed PMID:
25279192; PubMed Central PMCID: PMC
4179789.
Matsushita H, Hosoi A, Ueha S, Abe J, Fujieda N,
Tomura M, Maekawa R, Matsushima K, Ohara O,
Kakimi K. Cytotoxic T lymphocytes block tumor
growth both by lytic activity and IFNγ-dependentcell-cycle arrest. Cancer Immunol Res. 2015 Jan;3(1):26-36. doi: 10.1158/2326-6066.CIR-14-0098.
Epub 2014 Aug 15. PubMed PMID: 25127875.
8: Wada I, Matsushita H, Noji S, Mori K, Yamashita H,
Nomura S, Shimizu N, Seto Y, Kakimi K.
Intraperitoneal injection of in vitro expanded
Vγ9Vδ2 T cells together with zoledronate for thetreatment of malignant ascites due to gastriccancer. Cancer Med. 2014 Apr;3(2):362-75. doi:
10.1002/cam4.196. Epub 2014 Feb 7. PubMed
PMID: 24515916; PubMed Central PMCID:
PMC3987085.
9: Ichimura T, Morikawa T, Kawai T, Nakagawa T,
Matsushita H, Kakimi K, Kume H, Ishikawa S,
Homma Y, Fukayama M. Prognostic significanceof CD204-positive macrophages in upper urinary
tract cancer. Ann Surg Oncol. 2014 Jun;21(6):2105-12. doi: 10.1245/s10434-014-3503-2. Epub
2014 Feb 4. PubMed PMID: 24492923.
10: Hosoi A, Matsushita H, Shimizu K, Fujii S, Ueha
S, Abe J, Kurachi M, Maekawa R, Matsushima K,
Kakimi K. Adoptive cytotoxic T lymphocyte
therapy triggers a counter-regulatory immunosuppressive mechanism via recruitment of
myeloid-derived suppressor cells. Int J Cancer.
2014 Apr 15;134(8):1810-22. doi:10.1002/ijc.
28506. Epub 2013 Oct 21. PubMed PMID:
24150772.

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
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 a potential 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.

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Department of Integrated
Molecular Science on Metabolic
Diseases
Project Research Associate
Masato Iwabu, M.D., Ph.D. ( ~ September 2014)

Miki Okada-Iwabu, Ph.D. (May 2014 ~ September 2014)

Introduction and Organization
The Department of Integrated Molecular Science on
Metabolic Diseases (DIMSMD) is devoted toclarifying the mechanisms of onset of lifestyle-relateddiseases resulting from interactions between genetic
and environmental factors in the Japanese population
as well as to contributing to the prophylaxis, diagnosis
and treatment of these diseases, in response to thedrastic increase in the number of diabetic patients
which is becoming a major social issue of current
interest. In this regard, the DIMSMD strives toestablish an accurate method through which to predictrisk for the onset of lifestyle-related diseases bytapping into a comprehensive database for genetic andenvironmental factors for these diseases which is
being developed to integrate “Informatics on Genetic
Predisposition to Lifestyle-related Diseases” asgenerated by cutting-edge advances such as single
nucleotide polymorphism analyses with “Informatics
on Environmental Factors for Lifestyle-relatedDiseases” that draw on surveys including detailed
questionnaires on diet intake. The DIMSMD istherefore expected to make significant scientific andsocial contributions by providing effective modalities
for primary prevention of diabetes, moleculardiagnosis of onset of diabetes and its pathology, andoptimal treatment of diabetes, and to play a major role
in reducing the number of newly onset diabetes aswell as in raising the treatment standard for diabetes.
The DIMSMD also aims to develop a system thatallows formulas to be developed to predict therapeutic
response to drugs as well as their safety to be
developed based on information available onenvironmental and genetic factors including gene
expression from patients being treated at University ofTokyo Hospital, and which allows safe and effective
use of drugs being developed in patients withlifestyle-related diseases.
The DIMSSMD has set as its final goal the
installment of a human metabolic disease tissue bankat University of Tokyo Hospital, which draws on an“integrated database” that offers comprehensive
information on gene expression in human hepatic andadipose tissue samples, electronic charts, SNP andlifestyle habits, which will allow validation ofmolecular targets in actual human diseases, design ofa clinical trial system based on SNP and gene
expression profiles, development of models forprediction of therapeutic response based on
environmental and genetic interactions, identificationof molecular targets, discovery of novel therapeutic
agents and safe and effective use of drugs thus
developed in time.
The DIMSMD is thus engaged in daily research
activities and clinical care aimed at contributing to theadvancement of health and medical care in the future.

Research activities
The DIMSMD Research Laboratory aims to elucidate
the molecular mechanisms of lifestyle-related diseases

387such as the metabolic syndrome, diabetes andcardiovascular disease associated with obesity and to
put relevant molecular targets identified in the process
to effective use in the treatment of these diseases. Of
note, the DIMSMD Research Laboratory has animpressive track record in research in this area,
including identification of multiple “key molecules”
implicated in lifestyle-related diseases, such as
adiponectin receptors, which led to an elucidation ofsome of the processes through which lifestyle-relateddiseases develop and progress, based on functional
analyses that tap into developmental engineering and
RNA engineering. The DIMSMD ResearchLaboratory has also been credited with discoveringthat adiponectin is highly active in its high molecularweight form as a ligand to the adiponectin receptors
and that its quantitative measurement is useful in the
diagnosis of insulin resistance and the metabolic
syndrome. Not only that, the DIMSMD ResearchLaboratory has found that, via the adiponectin
receptors, the plant-derived peptide osmotin activates
the AMPK pathway which has a critical role inprotecting against lifestyle-related diseases. Currently,
the DIMSMD Research Laboratory is proactively
engaged in the development of definitive treatments
for lifestyle-related diseases that draw on ligands
specific for the adiponectin receptors.

References
1. Kadowaki T, Yamauchi T, Okada-Iwabu M,
Iwabu M. Adiponectin and its receptors:
Implications for reduction of obesity-associateddiseases and prolongation of longevity. The
Lancet Diabetes and Endocrinology 2, 8-9(2014)
2. Yamauchi T, Iwabu M, Okada-Iwabu M,
Kadowaki T. Adiponectin receptors: A review of
their structure, function and how they work. Best
Pract. Res. Clin. Endocrinol. Metab. 1, 15-23(2014)

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, PhD

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, Wakayama K, Akazawa H, Izumi Y, Isobe
M, Komuro I, Nagai R, Hirata Y. Periodontitis in
cardiovascular disease patients with or without
Marfan syndrome -A possible role of Prevotellaintermedia. PLoS One. 9(4): e95521, 2014.
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. Highincidence of periodontitis in Japanese patientswith abdominal aortic aneurysm. Int Heart J.
55(3); 268-270. 2014.
3. 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 2013 Nov 8. [Epub ahead ofprint]
4. 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 2014 Apr 16. [Epub ahead of print]
5. Tada Y, Ogawa M, Watanabe R, Zempo H,
Takamura C, Suzuki J, Dan T, Miyata T, Isobe M,
Komuro I. Neovascularization induced by hypoxia
inducible transcription factor is associated with
the improvement of cardiac dysfunction inexperimental autoimmune myocarditis. Expert
Opin Investig Drugs. 23(2):149-62, 2014.
6. Zempo H, Sugita Y, Ogawa M, Watanabe R,
Suzuki J, Isobe M. A P2X7 receptor antagonist
attenuates experimental autoimmune myocarditis
via suppressed myocardial CD4+ T andmacrophage infiltration and NADPH oxidase 2/4
expression in mice. Heart Vessels. 2014 May 31.
[Epub ahead of print]
7. Kobayashi N, Suzuki J, Ogawa M, Aoyama N,
Komuro I, Izumi Y, Isobe M. Porphyromonas
gingivalis promotes neointimal formation afterarterial injury through toll-like receptor 2
signaling. Heart Vessels. 29(4): 542-9, 2014.

8. Kuma Y, Usumi-Fujita R, Hosomichi J, Oishi S,
Maeda H, Nagai H, Shimizu Y, Kaneko S, ShitanoC, Suzuki J, Yoshida K, Ono T. Impairment of
nasal airway under intermittent hypoxia during
growth period in rats. Arch Oral Biol. 20;59(11):1139-1145, 2014.
9. Tezuka D, Suzuki J, Isobe M. An oxygen therapy
prevents ventricular arrhythmia in patients withdiastolic heart failure and sleep apnea. J Sleep
Disorder Ther. 3: 3, 2014.
10. 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. 2014 Dec 12. pii:
S1071-9164(14)01344-X. doi: 10.1016/j.cardfail.
2014.12.004. [Epub ahead of print]
11. 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. 2014 Apr 18. [Epubahead of print]
12. Kudo-Sakamoto Y, Akazawa H, Ito K, Takano J,
Yano M, Yabumoto C, Naito AT, Oka T, Lee JK,
Sakata Y, Suzuki J, Saido TC, Komuro I. Calpaindependent cleavage of N-cadherin is involved in
the progression of post-myocardial infarction
remodeling. J Biol Chem. 289(28): 19408-19419,
2014.
13. Sun A, Zou Y, Wang P, Xu D, Gong H, Wang S,
Qin Y, Zhang P, Chen Y, Harada M, Isse T,
Kawamoto T, Fan H, Yang P, Akazawa H, Nagai T,
Takano H, Ping P, Komuro I, Ge J. Mitochondrial
aldehyde dehydrogenase 2 plays protective roles
in heart failure after myocardial infarction via
suppression of the cytosolic JNK/p53 pathway inmice. J Am Heart Assoc. 3(5): e000779, 2014.
14. Yasui H, Lee JK, Yoshida A, Yokoyama T,
Nakanishi H, Miwa K, Naito AT, Oka T, Akazawa
H, Nakai J, Miyagawa S, Sawa Y, Sakata Y,
Komuro I. Excitation propagation in threedimensional
engineered
heartsusing
decellularized extracellular matrix. Biomaterials.
35(27): 7839-50,2014.

390

15. Shimamura M, Nakagami H, Osako MK,
Kurinami H, Koriyama H, Zhengda P, Tomioka H,
Tenma A, Wakayama K, Morishita R. OPG/RANKL/RANK axis is a critical inflammatory
signaling system in ischemic brain in mice. Proc
Natl Acad Sci U S A. 111(22): 8191-6, 2014.
16. Shimamura M, Taniyama Y, Nakagami H,
Katsuragi N, Wakayama K, Koriyama H,
Kurinami H, Tenma A, Tomioka H, Morishita R.
Long-term expression of periostin during thechronic stage of ischemic stroke in mice.
Hypertens Res. 37(6): 494-9, 2014.
17. Maejima Y, Sadoshima J. SUMOylation: A novel
protein quality control modifier in the heart. Circ
Res. 115: 686-689, 2014.
18. Maejima Y, Usui S, Zhai P, Takamura M, Kaneko
S, Zablocki D, Yokota M, Isobe M, Sadoshima J.
MuRF1 negatively regulates pathological cardiac
hypertrophy
throughdownregulationofcalcineurin A. Circ Heart Fail. 7: 479-490, 2014.
19. Ikeda Y, Shirakabe A, Maejima Y, Zhai P,
Sciarretta S, Toli J, Nomura M, Mihara K,
Egashira K, Ohishi M, Abdellatif M, Sadoshima J.
Endogenous Drp1 mediates mitochondrial
autophagy and protects the heart against energy
stress. Circ Res. 2014 Oct 20 [Epub ahead ofprint]
20. Del Re DP, Matsuda T, Zhai P, Maejima Y, Jain
MR, Liu T, Li H, Hsu CP, Sadoshima J. Mst1
promotes cardiac myocyte apoptosis throughphosphorylation and inhibition of Bcl-xL. Mol
Cell. 54: 639-50, 2014.
English Review
1. Suzuki J, Aoyama N, Influence of periodontitis on
abdominal aortic aneurysms. World J Hypertens.
4(3): 25-28, 2014.
2. Akazawa H, Komuro I. Dickkopf-3: a stubborn
protector of cardiac hypertrophy. Cardiovasc Res.
102(1): 6-8, 2014.
3. Oka T, Akazawa H, Naito AT, Komuro I.
Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles inheart failure. Circ Res. 114(3): 565-71, 2014.

391

Department of Ischemic
Circulatory Physiology,
KAATSU training
Associate Professor
Toshiaki Nakajima, M.D., Ph.D.

Assistant Professor
Tomohiro Yasuda, Ph.D.

Research Associate
Taira Fukuda, M.D., Ph.D.

Fellow Researcher
Toshihiro Morita, M.D., Ph.D.

Home page

http://kaatsu.umin.jp/

Introduction of this chair
We investigate the clinical usefulness and basic
mechanisms of KAATSU training for rehabilitation inpatients with various diseases. Especially, the
KAATSU training is applied for muscle training inpatients with cardiovascular, orthostatic dysregulation(OD) and respiratory (COPD) diseases. In addition,
we have examined the clinical benefits of KAATSU
training on cardiac rehabilitation. The KAATSU
training also may be able to be applied to various
kinds of fields such as the muscle training for
astronauts, and severe patients with marked muscle
atrophy in long-term bed rest.

Contents of our study
The KAATSU training is a unique technique of
performing low-load exercises such as resistance
exercises and treadmill with restricted muscle bloodflow that results in an increase of muscle mass andmuscular strength comparable to high-intensity
training. Additionally, the KAATSU trainings canpromote endocrine activities such as growth hormone(GH) secretion. Therefore, KAATSU training may be
an epoch-making rehabilitation training for patientswith various kinds of diseases and old-aged patients.
Also, since KAATSU femoral blood flow restriction
induces the retention of blood flow in lower
extremities, it reduces venous return, and induces
subsequent hemodynamic changes like lower body
negative pressure (LBNP). Thus, KAATSU may partly
provide an orthostatic stimulus, and an effective
countermeasure for cardiovascular deconditioning inweightlessness like LBNP. In our laboratory, we havebeen studying the clinical usefulness of the KAATSU
training and comparing it with the ordinary
rehabilitation. The main targets of our study are as
follows: (1) Clinical usefulness of the KAATSU
training in cardiac rehabilitation. There are many
severe patients with muscle atrophy, especially inintensive care units (ICU) and high-intensive care unit
(HCU), and in our cardiovascular ward. We haveexamined the possibility of KAATSU training formuscle training and early ambulation of these patients.
(2) Clinical usefulness of this training in patients withrespiratory diseases (COPD). There are several

392

mechanisms involving the effects of KAATSU
training including hypoxic effects of skeletal muscles,
GH responses, and shear stress to cardiovascularhemodynamics. Therefore, we have also examined thebasic experimental studies using a variety of methods
using electrophysiology and molecular physiology
techniques. Also, we have investigated the effects ofthis rehabilitation on endothelial function by using
PWV, ABI, and body pletysmography, andmeasurements of blood biomarkers such as endothelial
progenitor cell and high sensitive CRP. We havestarted the cardiac rehabilitation program using
KAATSU resistance training in outpatients withcardiovascular diseases. Finally, the KATTSU training
may be applied to other clinical fields such as
orthopedics and patients with endocrine diseases suchas metabolic syndrome and diabetes mellitus. We hopethat the KAATSU training can be accepted as amethod of new advanced medical technology.

Further studies
We investigate the usefulness and basic
mechanisms of KAATSU training in patients withvarious kinds of diseases. And, we believe thatKAATSU training can provide a clinical benefit to avariety fields for muscle training or muscle strength,
and contributes to improve quality of life in patients
including old persons.

List of papers
1) Minami Y, Kaneda H, Inoue M, Ikutomi M,
Morita T, Nakajima T. Endothelial dysfunction
following drug-eluting stent implantation: A
systematic review of the literature. International
Journal of Cardiology 2013; 165(2): 222-228.
2) Yasuda T, Fukumura K, Fukuda T, Iida H, Imuta
H, Sato Y, Yamasoba T, Nakajima T. Effects of
low-intensity, elastic band resistance exercise
combined with blood flow restriction on muscle
activation. Scandinavian Journal of Medicine andScience in Sports 2014, 24(1); 55-61.
3) Madarame H, Kurano M, Fukumura K, Fukuda T,
Nakajima T. Hemostatic and inflammatory
responses to blood flow-restricted exercise inpatients with ischemic heart diseases: a pilot study.
Clin Physiol Funct Imaging. 2013; 33: 11-7.

4) Yamamoto Y, Morita T, Tanaka T, Ikeda K,
Kikuchi H, Oguri G, Nakamura F, Nakajima T,
Nagai R. Amiodarone inhibits tissue factor
expression in monocytic THP-1 cells. Eur J
Pharmacol. 2013 Feb 15;701(1-3):14-19.
5) Yasuda Y, Fukumura K, Fukuda T, Uchida Y, Iida
H, Meguro M, Sato Y, Yamasoba T, Nakajima T.
Muscle size and arterial stiffness after blood
flow-restricted low-intensity resistance training inolder adults. Scand J Med Sci Sports (in press)
6) Ikeda K, Nakajima T, Yamamoto Y, Takano N,
Tanaka T, Kikuchi H, Oguri G, Morita T,
Nakamura F, Komuro I. Roles of transient
receptor potential canonical (TRPC) channels andreverse-mode Na+/Ca2+ exchanger on cellproliferation in human cardiac fibroblasts: Effectsof transforming growth factor β1. Cell Calcium
2013 Sep;54(3):213-225.
7) Fukuda T, Kurano M, Fukumura K, Yasuda T, Iida
H, Morita T, Yamamoto Y, Takano N, Komuro I,
Nakajima T. Cardiac rehabilitation increases
exercise capacity with a reduction of oxidative
stress. Korean Circ J. 2013 Jul;43(7):481-487.
8) Eshima H, Tanaka Y, Sonobe T, Inagaki T,
Nakajima T, Poole DC, Kano Y. In vivo imaging
of intracellular Ca2+ after muscle contractions anddirect Ca2+ injection in rat skeletal muscle indiabetes. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology
2013 Sep 15;305(6):R610-618.
9) Sahara M, Ikutomi M, Morita T, Minami Y,
Nakajima T, Hirata Y, Nagai R, Sata M. Deletionof Angiotensin-converting Enzyme 2 Promotes
the Development of Atherosclerosis and Arterial
Neointima Formation. Cardiovasc Res. 2013 Nov
4. [Epub ahead of print]
10) Fukuda T, Yasuda T, Fukumura K, Iida H, Morita
T, Sato Y, Nakajima T. Low-intensity kaatsu
resistance exercise using an lelastic band
enhances muscle activation in patients withcardiovascular diseases. Int J KAATSU Training
Res 2013; 9: 1-5.
11) Inoue A, Iwasaki S, Fujimori C, Nakajima T,
Yamasoba T. Developmental changes in theprotective effect of exogenous brain-derived
neurotrophic factor and neurotrophin-3 against

393

ototoxic drugs in cultured rat vestibular ganglion
neurons. Cell and Tissue Res (in press)
12) Yasuda T, Fukumura K, Sato Y, Yamasoba T,
Nakajima T. Effects of detraining after blood flow
restricted low-intensity training on muscle sizeand strength in older adults. Aging Clinical andExperimental Research (in press)
13) Tsutsumi T, Okamoto Y, Takano NK, Wakatsuki D,
Suzuki H, Sezaki T, Iwasawa K, Nakajima T.
Time-frequency analysis of the QRS complex inpatients with ischemic cardiomyopathy andmyocardial infarction. International Jouranal of
Cardiology (in press)
14) Yasuda T, Fykumura 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.
Journal of Gerontology: Biological Sciences (inpress)

394

Department of Translational
Research for Healthcare andClinical Science
Project Associate Professor
Hiroyuki Morita, M.D.,Ph.D.

Project Research Associate
Tomokazu Sumida, 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

395

utilizing the information technology

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)

References
1. Nakayama A, Morita H, Miyata T, Hoshina K,
Nagayama M, Takanashi S, Sumiyoshi T, Komuro
I, Nagai R.
Predictors of mortality after emergency or elective
repair of abdominal aortic aneurysm in a Japanese
population.
Heart Vessels. 29: 65-70, 2014
2. Morita H, Komuro I.
The metabolic syndrome and DYRK1B.
New England Journal of Medicine 371: 785, 2014
3. Morita H, Komuro I.
Somatic mutations in cerebral cortical malformations.
New England Journal of Medicine 371: 2037,
2014

396

Department of Joint Disease
Research
Project Associate Professor
Noriko Yosihmura, 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, andprevention of OA and OP without such epidemiological data.
We therefore established a large-scale nationwide
osteoarthritis/osteoporosis cohort study called ROAD
(Research on Osteoarthritis/osteoporosis Against
Disability) consisted of total 3,040 participants, ofwhich aims at the elucidation of an environmental andgenetic background for bone and joint diseases,
represented by OA and OP.
We have completed the baseline study in 2005-2007,
then 2nd and 3rd follow-ups were performed in 20082010, and 2012-13, respectively. A 4th comprehensive
clinic visit is planned from 2015.

References
1. Yoshida T, Kato J, Inoue I, Yoshimura N, Deguchi
H, Mukoubayashi C, Oka M, Watanabe M,
Enomoto S, Niwa T, Maekita T, Iguchi M, Tamai
H, Utsunomiya H, Yamamichi N, Fujishiro M,
Iwane M, Takeshita T, Ushijima T, Ichinose M:
Cancer development based on chronic active
gastritis and resulting gastric atrophy as assessedby serum levels of pepsinogen and Helicobacter
pylori antibody titer. Int J Cancer 134: 1445-1457,
2014
2. Johansson H, Kanis JA, Odén A, McCloskey E,
Chapurlat RD, Christiansen C, Cummings SR,
Diez-Perez A, Eisman JA, Fujiwara S, Glüer CC,
Goltzman D, Hans D, Khaw KT, Krieg MA,
Kröger H, Lacroix AZ, Lau E, Leslie WD,
Mellström D, Melton LJ 3rd, O'Neill TW, Pasco
JA, Prior JC, Reid DM, Rivadeneira F, van Staa T,
Yoshimura N, Zillikens MC: A meta-analysis of
the association of fracture risk and body massindex in women. J Bone Miner Res 29: 223-233,
2014
3. Yoshimura N, Nagata K, Muraki S, Oka H,
Yoshida M, Enyo Y, Kagotani R, Hashizume H,
Yamada H, Ishimoto Y, Teraguchi M, Tanaka S,

397

Kawaguchi H, Toyama Y, Nakamura K, Akune T:
Prevalence and progression of the radiographic
ossification of posterior longitudinal ligament andits associated factors in the Japanese populations:
A 3-year follow-up of the ROAD study.
Osteoporos Int 25: 1089-1098, 2014
4. Inoue I, Kato J, Tamai H, Iguchi M, Maekita T,
Yoshimura N, Ichinose M: Helicobacter pylori-related chronic gastritis as a risk factor forcolonic neoplasms. World J Gastroenterol 20:
1485-1492, 2014
5. Kanis JA, Johansson H, Oden A, Cooper C,
McCloskey EV; Epidemiology and Quality of Life
Working Group of IOF (Kanis JA, Cooper C,
Adachi J, Borgström F, Clark P, Cummings S,
Diaz-Curiel M, Dimai HP, Harvey N, Hiligsmann
M, Lau E, Lewiecki M, Lips P, Lorenc R,
McCloskey E, Ortolani S, Papioannou A,
Silverman S, Sosa M, Szulc P, Yoshimura N).
Worldwide uptake of FRAX. Arch Osteoporos 9:166, 2014
6. Muraki S, Oka H, Akune T, En-yo Y, Yoshida M,
Sasaki S, Nakamura K, Kawaguchi H, Yoshimura
N: Association of dietary intake with joint space
narrowing and osteophytosis at the knee inJapanese men and women: The ROAD Study.
Mod Rheumatol 24: 236-242, 2014
7. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Nakamura K, Yoshimura N: Exercise habitsduring middle age are associated with lower
prevalence of sarcopenia: the ROAD study.
Osteoporos Int 25: 1081-1088, 2014
8. Muraki S, Yoshimura N, Akune T, Takahashi I,
Fujiwara S: Prevalence, incidence, and progression of lumbar spondylosis by gender and age
strata. Mod Rheumatol 24: 657-661, 2014
9. Hashizume H, Yoshimura N, Nagata K, Miyazaki
N, Ishimoto Y, Nishiyama R, Yamada H, Yoshida
M: Development and evaluation of a video
exercise program for locomotive syndrome in theelderly. Mod Rheumatol 24: 250-257, 2014
10. Nagata K, Yoshida M, Ishimoto Y, Hashizume H,
Yamada H, Yoshimura N: Skipping breakfast andless exercise are risk factors for bone loss ofJapanese young adults: a 3-year follow-up for
medical students. J Bone Miner Metab 32: 420427, 2014

11. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N: Incidence of certified need of carein the long-term care insurance system and its risk
factors in the elderly of Japanese populationbased cohorts: The ROAD study. Geriatr Gerontol
Int 14: 695-701, 2014
12. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N: Association of physical activities ofdaily living with the incidence of certified need ofcare in the long-term care insurance system ofJapan: the ROAD study. J Orthop Sci 19: 489-496,
2014
13. Tanaka S, Kuroda T, Yamazaki Y, Shiraki Y,
Yoshimura N, Shiraki M: Serum 25-hydroxyvitamin D below 25 ng/mL is a risk factor for longbone fracture comparable to bone mineral density
in Japanese postmenopausal women. J Bone
Miner Metab 32: 514-523, 2014
14. Yoshimura N, Akune T, Fujiwara S, Nishiwaki Y,
Shimizu Y, Yoshida H, Sudo A, Omori G, Yoshida
M, Shimokata H, Suzuki T, Muraki S, Oka H,
Nakamura K: Prevalence of knee pain, lumbar
pain and its co-existence in Japanese men andwomen: The Longitudinal Cohorts of Motor
System Organ (LOCOMO) study. J Bone Miner
Metab 32: 524-532, 2014
15. Teraguchi M, Yoshimura N, Hashizume H,
Muraki S, Yamada H, Minamide A, Oka H,
Ishimoto Y, Nagata K, Kagotani R, Takiguchi N,
Akune T, Kawaguchi H, Nakamura K, Yoshida M:
Prevalence and distribution of intervertebral discdegeneration over the entire spine in a populationbased cohort: the Wakayama Spine Study.
Osteoarthritis Cartilage 22: 104-110, 2014
16. Muraki S, Akune T, Nagata K, Ishimoto Y,
Yoshida M, Tokimura F, Tanaka S, Oka H,
Kawaguchi H, Nakamura K, Yoshimura N:
Association of knee osteoarthritis with onset andresolution of pain and physical functional
disability: The ROAD Study. Mod Rheumatol
24(6):966-973, 2014
17. 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 cervical398

myelopathy among subjects with narrow cervicalspinal canal in a population-based magnetic
resonance imaging study: the Wakayama Spine
Study. Spine J 14: 2811-2817, 2014
18. 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, 201519. 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 33:
186-191, 2015
20. 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 whole spine and its association with lumbar
spondylosis and knee osteoarthritis: The ROAD
Study. J Bone Miner Metab 33: 221-229, 2015
21. 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, 201522. 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, 201523. Mure K, Yoshimura N, Hashimoto M, Muraki S,
Oka H, Tanaka S, Kawaguchi H, Nakamura K,
Akune T, Takeshita T: Urinary 8-iso-prostaglandin
F2a as a marker of metabolic risks in the general
Japanese Population: The ROAD Study. Obesity
23,1517-1524, 201524. 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, in press
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, Oka H,
Yoshimura N: Joint space narrowing, body massindex and knee pain: The ROAD study.
Osteoarthritis Cartilage, in press
26. 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, inpress
27. 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, in press
28. Yoshimura N, Musaki S, Oka H, Tanaka S, Ogata
T, Kawaguchi H, Akune T, Nakamura K:
Association between new indices in thelocomotive syndrome risk test and decline inmobility: third survey of the ROAD study. J
Orthop Sci, in press

399

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 2014,
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.

Research activities
We are working on the following activities, widely
contributing to the health of the people by utilizing
medical care information.
1) In January 2015, we held an international
symposium titled "Symposium of utilization of
medical information and personal information
protection" at Iino Hall in Chiyoda-ku. Based on thetiming that the government has announced "Theoutline of system reform regarding utilization of
personal data" and is going to tackle the new
institution building for the protection of personal
information, the symposium was intended to have thepurpose of further understanding regarding utilizationof the medical information and personal information
by performing the discussion among various gathered
position of the parties such as government, researchersof medicine and law, and the patient support groups.
Program on the day was as follows.
Keynote 1: Trend of utilization of medical informationand protection of personal information in Japan.
(Kazuhiro OSHIMA, Insurance Bureau, Ministry of
Health, Labour and Welfare)
Keynote 2: Current situation and challenges of400

utilization of medical information and protection of
personal information in the United States. (Mr. Niall
Brennan, Acting Director, Office of EnterpriseManagement, Center for Medicare & Medicaid
Services, US Federal government)
Panel discussion: "towards the utilization of medical
information and protection of personal information"- Yamamoto Ryuichi, the University of Tokyo.
"Current situation and issues of promotion of theutilization of NDB"
- Hideo YASUNAGA, the University of Tokyo.
"Clinical epidemiology research using the DPC"
- Shinya MATSUDA, University of Occupational andEnvironmental Health. "Regional healthcare and its
future viewed from the analysis of medical information"- Norio HIGUCHI, the University of Tokyo. "Legal
aspects of medical information and personal information protection in the United States and Japan,"- Ikuko YAMAGUCHI, COML. "Medical informationand personal information protection as seen from thepatient's standpoint"2) 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.
3) 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.
4) 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.
5) 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. Matsumoto M, Koike S, Matsubara S, Kashima S,
Ide H, Yasunaga H. Selection and concentration of

401

obstetric facilities in Japan: Longitudinal study
based on national census data. J Obstet Gynaecol
Res. 2014 Dec 29.
2. Chida K, Morohashi G, Fuji H, Magata F,
Fujimura A, Hamada K, Ikarashi D, Yamamoto R.
Implementation and evaluation of an efficient
secure computation system using 'R' for healthcare statistics. J Am Med Inform Assoc. 2014;21:326-331.
3. Yasunobu Nohara, Eiko Kai, Partha Pratim Ghosh,Rafiqul Islam, Ashir Ahmed, Masahiro Kuroda,
Sozo Inoue, Tatsuo Hiramatsu, Michio Kimura,Shuji Shimizu, Kunihisa Kobayashi, Yukino Baba,
Hisashi Kashima, Koji Tsuda, Masashi Sugiyama,
Mathieu Blondel, Naonori Ueda, Masaru
Kitsuregawa, Naoki Nakashima. Health Checkup
and Telemedical Intervention Program for Preventive Medicine in Developing Countries: Verification Study. J Med Internet Res 2015;17:e2.

402

Department of Computational
Diagnostic Radiology andPreventive Medicine
Project Associate Professor
Naoto Hayashi, MD, PhD, 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

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
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 the403

hospital picture archiving and communication system(PACS) for clinical use. Medical images used solely
for research purposes are stored in an independent
PACS installed inside the CDRPM department.
2) Image processing software development
We have structured an integrated software developing
system to facilitate the production of image processing
software. The system is divided into the clinical partand the research part, with the data in the latter being
anonymized. The clinical part consists of case entry
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) Yuan LJ, Takenaka K, Uno K, Ebihara A, Sasaki
K, Komuro T, Sonoda M, Nagai R. Normal andshear strains of the left ventricle in healthy
human subjects measured by two-dimensional
speckle tracking echocardiography. Cardiovasc.
Ultrasound 2014 Feb 11;12:7-7120-12-7.
(2) Nishimura S, Nagasaki M, Okudaira S, Aoki J,
Ohmori T, Ohkawa R, Nakamura K, Igarashi K,
Yamashita H, Eto K, Uno K, Hayashi N,
Kadowaki T, Komuro I, Yatomi Y, Nagai R.
ENPP2 contributes to adipose tissue expansion indiet-induced obesity. Diabetes 2014 Jun 26.
(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 2014 Feb 5.
(4) Takata M, Amiya E, Watanabe M, Omori K, ImaiY, Fujita D, Nishimura H, Kato M, Morota T,

Nawata K, Ozeki A, Watanabe A, Kawarasaki S,
Hosoya Y, Nakao T, Maemura K, Nagai R, Hirata
Y, Komuro I. Impairment of flow-mediateddilation correlates with aortic dilation in patientswith Marfan syndrome. Heart Vessels 2014 Jul;29(4):478-485.
(5) Tomizawa N, Kanno S, Maeda E, Akahane M,
Torigoe R, Ohtomo K. In reply to: Minimizing
the radiation dose in coronary CT angiographyusing prospective ECG-triggering, low tube
voltage and iterative reconstruction technologies.
Jpn.J.Radiol. 2014 Sep 25.
(6) Tomizawa N, Kanno S, Maeda E, Akahane M,
Torigoe R, Ohtomo K. Minimizing theacquisition phase in coronary CT angiographyusing the second generation 320-row CT. Jpn.J.
Radiol. 2014 Jul;32(7):391-396.
(7) Kojima T, Imai Y, Tsushima K, Uno K, Fujiu K,
Iiri T, Nishimatsu H, Suzuki T, Sugiyama H,
Asada K, Nakao T, Yamashita H, Hirata Y, Nagai
R. Temporary dual-chamber pacing can stabilize
hemodynamics during noncardiac surgery in apatient with left ventricular hypertrophy andoutflow obstruction. J.Cardiothorac.Vasc.Anesth.
2014 Feb;28(1):124-127.
(8) Ozeki A, Amiya E, Watanabe M, Hosoya Y,
Takata M, Watanabe A, Kawarasaki S, Nakao T,
Watanabe S, Omori K, Yamada N, Tahara Y,
Hirata Y, Nagai R. Effect of add-on aliskiren to
type 1 angiotensin receptor blocker therapy on
endothelial function and autonomic nervous
system in hypertensive patients with ischemic
heart disease. J.Clin.Hypertens.(Greenwich) 2014
Aug;16(8):591-598.
(9) Goto M, Abe O, Aoki S, Takao H, Hayashi N,
Miyati T, Mori H, Kunimatsu A, Ino K, Yano K,
Ohtomo K. Database of normal Japanese graymatter volumes in the default mode network.
J.Magn.Reson.Imaging 2014 Jan;39(1):132-142.
(10) Takao H, Hayashi N, Ohtomo K. Sex dimorphismin the white matter: fractional anisotropy andbrain size. J.Magn.Reson.Imaging 2014 Apr;
39(4):917-923.
(11) Maeda E, Katsura M, Gonoi W, Yoshikawa T,
Hayashi N, Ohtsu H, Ohtomo K. Abnormal
signal intensities of the seminal vesicles in a

404

screening population. J.Magn.Reson.Imaging
2014 Jun;39(6):1426-1430.
(12) Nemoto M, Yeernuer T, Masutani Y, Nomura Y,
Hanaoka S, Miki S, Yoshikawa T, Hayashi N,
Ohtomo K. Development of automatic visceralfat volume calculation software for CT volumedata. J.Obes. 2014;2014:495084.
(13) Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Takata M, Ozeki A, Watanabe A,
Kawarasaki S, Taniguchi T, Ichimura Y, Toyama
T, Watanabe M, Hirata Y, Nagai R, Komuro I,
Sato S. Clinical correlation of brachial arteryflow-mediated dilation in patients with systemicsclerosis. Mod. Rheumatol. 2014 Jan; 24(1):106111.
(14) Hayakawa YK, Sasaki H, Takao H, Hayashi N,
Kunimatsu A, Ohtomo K, Aoki S. Depressive
symptoms and neuroanatomical structures incommunity-dwelling women: A combined voxelbased morphometry and diffusion tensor imaging
study with tract-based spatial statistics. Neuroimage Clin. 2014 Mar 12;4:481-487.
(15) Takao H, Hayashi N, Ohtomo K. Effects of study
design in multi-scanner voxel-based morphometry studies. Neuroimage 2014 Jan 1;84:133-140.
(16) 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. 2014 Sep 27.

405

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. Muraki S, Akune T, En-yo Y, Yoshida M, Tanaka
S, Kawaguchi H, Nakamura K, Oka H, Yoshimura
N. Association of Dietary Intake with Joint Space
Narrowing and Osteophytosis at the Knee inJapanese Men and Women: The ROAD Study
Modern Rheum 2014;24:236-42.
2. Muraki S, Yoshimura N, Akune T, Sakae Tanaka,
Ikuno Takahashi, Saeko Fujiwara. Prevalence,
Incidence,
andProgressionofLumbarSpondylosis by Gender and Age Strata Modern
Rheum 2014;24:657-61.
3. Yoshimura N, Nagata K, Muraki S, Oka H,
Yoshida M, Enyo Y, Kagotani R, Hashizume H,
Yamada H, Ishimoto Y, Teraguchi M, Tanaka S,
Kawaguchi H, Toyama Y, Nakamura K, Akune T.
Prevalence and progression of radiographic ossification of the posterior longitudinal ligament andassociated factors in the Japanese population: A
3-year follow-up of the ROAD study Osteoporos
Int 2014;25:1089-98
4. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N. Incidence of certified need of carein the long-term care insurance system and its risk
factors in the elderly of Japanese populationbased cohorts: The ROAD study. Geriatr Gerontol
Int 2014 14:695-701.
5. Yoshimura N, Akune T, Fujiwara S, Shimizu Y,
Yoshida H, Omori G, Sudo A, Nishiwaki Y,
Yoshida M, Shimokata H, Suzuki T, Muraki S,
Oka H, Nakamura K. Prevalence of knee pain,
lumbar pain and its co-existence in Japanese men

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.

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and women: The LOCOMO (Longitudinal
Cohorts of Motor System Organ) study. J Bone
Miner Metab. 2014;32:524-32.
6. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Nakamura K, Yoshimura N: Exercise habitsduring middle age are associated with lower
prevalence of sarcopenia: the ROAD study.
Osteoporos Int 2014;25:1081-8.
7. Teraguchi M, Yoshimura N, Hashizume H,
Muraki S, Yamada H, Minamide A, Oka H,
Ishimoto Y, Nagata K, Kagotani R, Takiguchi N,
Akune T, Kawaguchi H, Nakamura K, Yoshida M.
Prevalence and distribution of intervertebral discdegeneration over the entire spine in a
population-based cohort: The Wakayama Spine
Study Osteoarthritis Cartilage 2014;22:104-10.
8. Muraki S, Akune T, Nagata K, Ishimoto Y,
Yoshida M, Tokimura F, Tanaka S, Oka H,
Kawaguchi H, Nakamura K, Yoshimura N.
Association of knee osteoarthritis with onset andresolution of pain and physical functional
disability: The ROAD Study Modern Rheum
2014;24:966-73.
9. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N: Association of physical activities ofdaily living with the incidence of certified need ofcare in the long-term care insurance system ofJapan: the ROAD study. J Orthop Sci 2014;19:489-96.
10. 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. 2015;33:
186-91..
11. 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.

12. 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.
13. 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).
14. 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 three-year follow-up
to the ROAD study Osteoporos Int 2015;26:15161. .
15. 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 Modern Rheum
2015;25:438-48. .
16. 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, endplate signal change, andSchmorl's node with low back pain in a large
population study: the Wakayama Spine Study
Spine J 2015;15:622-8..
17. 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. .
18. 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 (in press).

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19. 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 (in press).
20. 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 inmobility: third survey of the ROAD study J
Orthop Sci (in press).

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Department of Health Care
Safety Management(Tokio Marine & Nichido)
Project Professor
Yasushi Kodama, M.D., LL.M., Ph.D.

Project Assistant Professor
Shoko Ogawa, M.D.

Project Researcher
Tomoko Takahashi Matsuura, M.H.Sc. (until 30th June, 2014)
Maiko Mizuki, M.P.H.
Reiko Segawa, R.N., M.S.

Project Academic Support Specialist
Ryo Amano, JD. (since 16th June until 15th November, 2014)

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
Insurance Co., Ltd.
Public concern regarding malpractice and the medical
related disputes has risen in developed countries
accompany several publicized cases such as the public
inquiry into children’s heart surgery at the Bristol
Royal Infirmary and the accidental chemotherapy
overdoses occurring at the Dana-Farber Cancer
Institute at the end of the 20th century. Reports of themedia in our country concerning malpractice and the
medical related disputes increased suddenly from1999. Fears also rose regarding possible criminal
prosecutions through the mandatory reporting to thepolice provided in the Medical Practitioners Law

Article 21. Some incidents become targets ofinvestigations although several verdicts resulted inacquittals. Nonetheless, there exist various discussions
and some confusion over the intervention of the police
authority and criminal procedures into the process of
medical treatment.
On another front, in medical related disputes
involving civil claims for compensation for damages,
many cases have been dealt with and resolved throughvarious measures such as explanation andreconciliation settlement before becoming a lawsuit.
In spite of such efforts, the number of civil health carelawsuits has kept increasing from the 1970s (about
100 new cases received per year) to 2004 (1110 new
cases per year), with the pace that has doubled every
ten years. Though the number of civil health carelawsuits shows a trend for decrease from 2004 to 2011,
still many medical treatment disputes resulted inlawsuits in 2014, with 877 new cases received and 792

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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.
Risk management of medicalcare nursing (1) What is the risk of medical carenursing?” Welfare and Medical Service Agency“WAM” No. 592, 32 - 33, April 1, 2014
2. Yasushi Kodama. “Healthcare Risk Management(2) Disputes and Communication Risk” Welfare
and Medical Service Agency “WAM” number 593,
32 - 33 May 1, 2014
3. Yasushi Kodama. “Healthcare Risk Management (3) Informed Consent and Patient Risk
Awareness” Welfare and Medical Service Agency“WAM” number 594, 32 - 33 June 1, 2014
4. Yasushi Kodama. “Healthcare Risk Management(4) The proper operation of the Personal Information Protection Law” Welfare and Medical
Service Agency “WAM” number 595, 32 - 33,
July 1, 2014
5. Yasushi Kodama. “Healthcare Risk Management(5) Thoughts on the duty of confidentiality”
Welfare and Medical Service Agency “WAM”
number 596, 32 - 33, August 1, 2014
6. Yasushi Kodama. “Healthcare Risk Management(6) “What is Risk?” Welfare and Medical Service
Agency “WAM” number 597, 32 - 33, September
1, 2014
7. Yasushi Kodama. “Reconsidering the Risk
Management of Social Welfare Corporations” The
Japan National Council of Social Welfare and theManagement Association, social welfare corporations, “Management Association” Vol. 372, 4 - 5,September 1, 2014
8. Yasushi Kodama. “J-CLEAR communication 44
Conflicts of interest in clinical research and a
recent topics” Japan Medical Journal “Weekly
Japan Medical Journal” No. 4715, 38 - 39,
September 6, 2014
9. Yasushi Kodama. Lecture Record “Medical Research and Conflict of Interest” Medical ethics
committee liaison conference “Medical Ethics
48” 75 - 93, January 2014

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10. Yasushi Kodama. “Healthcare Risk Management(7) End-of-life care and legal ‘risk’” Welfare
and Medical Service Agency “WAM” number 598,
32 - 33, October 1, 2014
11. Yasushi Kodama. “Healthcare Risk Management(8) How to develop reliability?” Welfare andMedical Service Agency “WAM” number 599, 32- 33, November 1, 2014
12. Yasushi Kodama. “The task of legal policy inorder to rebuild confidence in health care” IgakuShoin Ltd. November 2014 issue, 854 - 858
13. Yasushi Kodama. “Healthcare Risk Management(9)
Rules and Ethics and Responsibility”
Welfare and Medical Service Agency “WAM”
number 600, 30 - 31, December 1, 2014
14. Yasushi Kodama. “Healthcare Risk Management(10) What will become proof?” Welfare andMedical Service Agency “WAM” number 601, 32- 33, January 1, 201515. Yasushi Kodama. “Healthcare Risk Management(11) What should a doctor say in court? (1)Recent judgments and adversarial model” Welfare
and Medical Service Agency “WAM” number 602,
32 - 33, February 1, 2015
16. Yasushi Kodama. Healthcare Risk Management(12) In order to prepare the legal system of the
future” Welfare and Medical Service Agency“WAM” number 603, 32 - 33, March 1, 2015
Books (in Japanese)
1. Yasushi Kodama. Gastroenterological Medical
Care (Second Edition)”
2. Yasushi Kodama. The Japanese Society of
Gastroenterology Supervision, “Gastroenterological Medical Care (Second Edition)” Edited byan editorial committee, Yasushi Kodama et al
authors 460 - 462, Igaku-Shoin Ltd. October
31, 2014 edition
Conference Presentations
Domestic Meetings (in Japanese)
1. Yasushi Kodama. “Medical Care Trouble andCommunication” 100th General Meeting of theJapanese Society of Gastroenterology
MedicalCare Panel Discussion, Panelist, April 26, 2014
2. Yasushi Kodama. “The present state and problemsof medical practice disputes” Independentadministrative legal entity National Hospital
Agency Hospital director training workshop
lecture, May 15, 2014
3. Yasushi Kodama. “Conflicts of interest in medical
research”
Specified non-profit corporation
Clinical Research Fair Education Evaluation
Agency lecture, May 24, 2014
4. Yasushi Kodama. “About medical practice disputes” Independent administrative legal entity
National Hospital Agency
Hospital director
training workshop lecture, May 29, 2014
5. Yasushi Kodama. “Basic legal knowledge
concerning medical practice disputes - medicalcare safety” Japan Hospital Association Medical
safety supervisor training workshop, June 7, 2014
6. Yasushi Kodama. “On the occasion of The Mid
Staffordshire Inquiries”
The 2014 National
University affiliated hospitals medical safetyseminar lecture, July 2, 2014
7. Yasushi Kodama. “Conflicts of interest in medical
research” 46th Japan Atherosclerosis Society
conference - academic meeting lecture, July 11,
2014
8. Yasushi Kodama. “Conflicts of interest in medical
research” Tokyo Jikei University School of
Medicine Clinical Study seminar lecture, July 28,
2014
9. Yasushi Kodama. “Basic legal knowledge
concerning medical practice disputes - medicalcare safety” Japanese Society for Quality and
Safety in Healthcare Medical safety supervisor
training workshop, lecture, August 8, 2014
10. Yasushi Kodama. “Basic legal knowledge
concerning medical practice disputes - medicalcare safety”
Japanese Nursing Association
Medical safety supervisor training workshop
lecture, September 1, 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, September
6, 2014
12. Yasushi Kodama. “The present state of medicalcare litigation and the problem of medical
records” National Hospital Organization Researchconcerning treatment information management,
September 18, 2014

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13. Yasushi Kodama. “The current state of conflict ofinterest and regulation in clinical research” The63rd Annual Meeting of the East Japan
Association of Orthopaedics and Traumatology
Academic workshop lecture training lecture,
September 20, 2014
14. Yasushi Kodama. “Risk communication seen froma lawyer” Pharmaceutical and Medical Device
Regulatory Science Society of Japan Pharmaceutical Development Business manager Special
training lecture, October 7, 2014
15. Yasushi Kodama. “Doctors - dentists and the legal
system” Health, Labor and Welfare Ministry
Physician re-education group training, October 18,
2014
16. Yasushi Kodama. “About revision of the Medical
Care Law”
Ministry of Health, Labor andWelfare Kyushu Regional Bureau Workshop
concerning patient safety, November 5, 2014
17. Yasushi Kodama. “Basic legal knowledge
concerning medical practice disputes - patient
safety” Japanese Society for Quality and Safety
in Healthcare Medical safety supervisor training
workshop, lecture, November 15, 2014
18. Maiko Mizuki, Masako Suzuki, Kaori Murase,
Shoko Ogawa, Reiko Segawa, Tomoko Matsuura,
Shinji Nagakawa, Ryo Amano, Yasushi Kodama.
“Feedback system in Patient Safety Support
Centers. Through our experience as consultants
and coordinator”. Japanese Society for Quality
and Safety in Healthcare 9th annual scientificmeeting. Nov. 22-24, 2014
19. Reiko Segawa, Maiko Mizuki, Tomoko Matsuura,
Shinji Nagakawa, Shoko Ogawa, Yasushi Kodama.
“Communication with the terminal patients andtheir family. Consideration of their grievances andconcerns received by local government”. JapaneseSociety for Quality and Safety in Healthcare 9th
annual scientific meeting. Nov. 22-24, 201420. Shoko Ogawa, Reiko Segawa, Shinji Nagakawa,
Tomoko Matsuura, Maiko Mizuki, Yasushi
Kodama. “Understandings for the roles and effectsof the Patient Safety Support Centers. Preparationof the questioner how they response to grievancesand concerns.” Japanese Society for Quality and
Safety in Healthcare 9th annual scientific meeting.
Nov. 22-24, 2014

21. Shinji Nagakawa, Maiko Mizuki, Shoko Ogawa,
Reiko Segawa, Yasushi Kodama. “The relationship between health data and the frequency ofcomplaints managed by the Patient Safety Support
Centers in ordinance-designated cities and corecities.” Japanese Society for Quality and Safety in
Healthcare 9th annual scientific meeting. Nov.
22-24, 2014
22. Yasushi Kodama.“A judgment forms a bridge
between “expert knowledge” and “common
sense”” Japanese Association of Medical Law
44th Research Conference Workshop, The way
the participation of experts in medical suits shouldbe (Public announcement planning) lecture,
November 29, 2014”
23. Yasushi Kodama. “The problem of thedevelopment of institutions concerning clinicalresearch - concerning conflict of interest andindustry-university cooperation” 19th Pharmaceutical Product Development Basic Research
Meeting Academic Conference Meeting Symposium, November 29, 2014
24. Yasushi Kodama. “The current state of conflict ofinterest and regulation in clinical research” 35th
Annual Meeting of the Japanese Society ofClinical Pharmacology and Therapeutics education lecture, December 6, 2014
25. Yasushi Kodama. “Introduction to Risk
Management I” National Social Welfare Facility
Manager Conference Beginner Risk Manager
Training Lecture (First Term) Lecture, December 22, 2014
26. Yasushi Kodama. “Introduction to Risk Management
Advanced Level”
National Social
Welfare Facility Manager Conference Advanced
Risk Management training lectures, January 12,
2015
27. Yasushi Kodama. “First response at the time ofan emergency” National Social Welfare Facility
Manager Conference Advanced Risk Management
training lectures, January 14, 201528. Yasushi Kodama. “Concerning newly starting a
medical accident inquiry system” Bar Association Medical Care Symposium, January 29, 201529. Yasushi Kodama. “What should a doctor talkabout in court?” The 20th Annual Meeting of412

the Japan Society of Neurosurgical Emergency
Luncheon Seminar lecture, January 30, 201530. Yasushi Kodama. “The current state of conflict ofinterest and regulation in clinical research” 45th
Annual Japanese Society for Cardiovascular
Surgery academic meeting lecture, February 17,
2015
31. Yasushi Kodama. “The current state of conflictof interest and regulation in clinical research”
Japan Society of Clinical Trials and Research
6th Annual Academic Meeting Lecture, February
20, 2015
International Meetings
1. Shoko Ogawa, Reiko Segawa, Tomoko Matsuura,
Maiko Mizuki, Yasushi Kodama, Mitigating
Miscommunication between Medical Practitioners and Patients. The International Forum on
Quality and Safety in Healthcare Japan 2014.
Poster presentation IP-01. 24th November, 2014.

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Department of Healthcare Quality
Assessment
Associate Professor
Hiroaki Miyata, Ph.D.

Assistant Professor
Ai Tomotaki, R.N., M.S.

Researcher
Hiroki Nogawa, M.D., Ph.D.

Researcher
Norimichi Hirahara, Ph.D.

Researcher
Junichi Okubo

Clerical Staff
Arata Takanashi

Clerical Staff
Chieko Fujimura

Clerical Staff (Secretary)
Nanayo Kyogoku

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.

Health care reform should focus on improving
physical health and healthcare value for patients. As
only medical teams can improve the quality ofhealthcare services in its strict sense, HQA has beencollaborating with various healthcare professional
committees. HQA supports them with systematic datacollection, data management, practical analysis anduseful feedback. Our benchmarking projects are basedon clinical database and they drive quality improvement in each related field. With such positive-sum
competition, patients will receive better healthcare
service, physicians will be rewarded for their
excellence, and healthcare costs will be contained.
Three principles should guide this transformation: (a)the goal is to meet patients’ values, (b) medical

414

practice should be organized around medical
conditions and care cycles, and (c) results — riskadjusted outcomes and costs — must be measured.
HQA has already developed risk models and provided
several practical tools for medical professionals
through joint research projects with Japan
Cardiovascular Surgery Database (JCVSD). One ofthe practical tools is JapanSCORE which allows
doctors to calculate a patient’s risk of mortality andmorbidities. JapanSCORE incorporates JCVSD risk
models that are designed to serve as statistical tools toaccount for the impact of the patient risk factors on
the operative mortality and morbidity. HQA also has
conducted policy analysis and clinical research which
can contribute to healthcare quality improvement
throughout Japan. Value-based competition on the
results have paved the way for a reform thatrecognizes the role of healthcare professionals at theheart of the system.

Research activities
For healthcare quality improvement, a) healthcare
quality must be clearly identified and b) quality
indicators must be set and monitored carefully in eachhealthcare region. A well-designed database systemthat continuously collects clinical data in reliable andvalidated manners is mandatory to identify thehealthcare quality, monitor the quality indicators, andimprove the quality of healthcare services. HQA has
designed and managed nationwide database system incollaboration with the Japan Surgical Society, theJapanese Society for Cardiovascular Surgery, theJapanese Society of Gastroenterological Surgery, andother medical professional societies.
Severity-adjusted indicators must be used forinvestigating clinical outcomes and exploring thesystems that provide the best practices for patients.
HQA has developed risk models and conducted
outcome analyses based on the systematic datacollection. These analyses enable risk assessment andprognosis prediction of cardiovascular surgeries andbenchmarking of the participating facilities in the
database project. This information is useful for
discussion in pre-surgery conference, patients’ better
understanding of treatment as well as promotion ofhealthcare quality improvement.
Also, a new project in collaboration with National
Clinical Database (NCD) has started since 2011.
Today more than 4,100 hospital departments fromaround Japan participate in NCD activities. The
database collects more than 1,300,000 surgical cases
per year.

References
1. Kobayashi H, Miyata H, Gotoh M, Baba H,
Kimura W, Kitagawa Y, Nakagoe T, Shimada M,
Tomita N, Sugihara K, Mori M. Risk model forright hemicolectomy based on 19,070 Japanesepatients in the National Clinical Database. Journalof Gastroenterology: 2013; July.
2. Kuno T, Numasawa Y, Miyata H, Takahashi T,
Sueyoshi K, Ohki T, Negishi K, Kawamura A,
Kohsaka S, Fukuda K. Impact of coronary
dominance on in-hospital outcomes after percutaneous coronary intervention in patients withacute coronary syndrome. PLOS ONE, 2013;8(8):e72672.
3. Saito A, Miyata H, Motomura N, Ono M,
Takamoto S and Japan Cardiovascular Surgery
Database Organization. Propensity-matched analysis of bilateral internal mammary artery versus
single internal mammary artery in 7702 cases ofisolated coronary artery bypass grafting; European
Journal of Cardiothoracic Surgery, Eur J Cardiothorac Surg. Eur J Cardiothorac Surg. 2013;44(4):711-7.
4. Ohno Y, Maekawa Y, Miyata H, Inoue S, Ishikawa
S, Sueyoshi K, Noma S, Kawamura A, Kohsaka S,
Fukuda K. Impact of periprocedural bleeding on
incidence of contrast- Induced acute kidney injury
in patients treated with percutaneous coronary
intervention. J Am Coll Cardiol. 2013;62(14):1260-6.
5. Tokuda Y, Miyata H, Motomura N, Araki Y,
Oshima H, Usui A, Takamoto S; The Japan Adult
Cardiovascular Database Organization. Outcomeof pericardiectomy for constrictive pericarditis inJapan: A nationwide outcome study. Ann Thorac
Surg. 2013;96(2):571-6.

415

6. Kubota H, Miyata H, Motomura N, Ono M,
Takamoto S, Harii K, Oura N, Hirabayashi S, Kyo
S. Deep sternal wound infection after cardiac
surgery. J Cardiothorac Surg. 2013 May 20;8:132.
7. Kaminishi Y, Misawa Y, Kobayashi J, Konishi H,
Miyata H, Motomura N, Takamoto S; Japan
Cardiovascular Surgery Database Organization.
Patient-prosthesis mismatch in patients with aortic
valve replacement. Gen Thorac Cardiovasc Surg.
2013 May;61(5):274-9.
8. Endo A, Kohsaka S, Miyata H, Kawamura A,
Noma S, Suzuki M, Koyama T, Ishikawa S,
Momiyama Y, Nakagawa S, Sueyoshi K, Takagi S,
Takahashi T, Sato Y, Ogawa S, Fukuda K.
Disparity in the application of guideline-based
medical therapy after percutaneous coronary
intervention: analysis from the Japanese prospective multicenter registry. Am J Cardiovasc Drugs.
2013 Apr;13(2):103-12.
9. Numasawa Y, Kohsaka S, Miyata H, Kawamura A,
Noma S, Suzuki M, Nakagawa S, Momiyama Y,
Takahashi T, Sato Y, Fukuda K. Use ofthrombolysis in myocardial infarction risk score
to predict bleeding complications in patients withunstable angina and non-ST elevation myocardial
infarction undergoing percutaneous coronary
intervention. Cardiovasc Interv Ther. 2013 Jan 30.
10. Kodaira M, Kawamura A, Miyata H, Noma S,
Suzuki M, Ishikawa S, Momiyama Y, Nakagawa S,
Sueyoshi K, Takahashi T, Takamoto S, Ogawa S,
Sato Y, Kohsaka S, Fukuda K; For JCD-KICS
investigators. Door to balloon time: How short isenough under highly accessible nationwide insurance coverage? Analysis from the Japanesemulticenter registry. Int J Cardiol. 2013;168(1):534-6.
11. Numasawa Y, Kohsaka S, Miyata H, Kawamura A,
Noma S, Suzuki M, Nakagawa S, Momiyama Y,
Sato Y, Fukuda K. Safety of transradial approachfor percutaneous coronary intervention in relation
to body mass index: A report from a Japanesemulticenter registry. Cardiovasc Interv Ther.
2013;28(3):242-9.
12. Arai T, Yuasa S, Miyata H, Kawamura A,
Maekawa Y, Ishikawa S, Noma S, Inoue S, Sato Y,
Kohsaka S, Fukuda K. Incidence of periprocedural myocardial infarction and cardiac

biomarker testing after percutaneous coronary
intervention in Japan: Results from a multicenter
registry. Heart Vessels. 2013;28(6):714-9.

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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 ofthis research 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
the roles 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), TRIM44 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 a noncoding RNA CTBP1-AS as well as collaborating
factors such as FOXP1, RUNX1 and CtBP1/2. The

417

tumor-promoting effects of APP and CTBP1-AS
have been shown in in vivo models of prostatecancer.
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. Azuma K, Tsukui T, Ikeda K, Shiba S, Nakagawa
K, Okano T, Urano T, Horie-Inoue K, Ouchi Y,
Ikawa M, Inoue S: Liver-specific γ-glutamyl
carboxylase-1 deficient mice display bleeding
diathesis and short life span. PLoS ONE 9,e88643, 2014.
2. Yamaga R, Ikeda K, Boele J, Horie-Inoue K,
Takayama K, Urano T, Kaida K, Carninci P,
Kawai J, Hayashizaki Y, Ouchi Y, de Hoon M,
Inoue S: Systemic identification of estrogenregulated genes in breast cancer cells through cap
analysis of gene expression mapping. Biochem
Biophys Res Commun 447, 531-536, 2014.
3. Urano T, Shiraki M, Sasaki N, Ouchi Y, Inoue S:
Large-scale analysis reveals a functional
single-nucleotide polymorphism in the 5'-flanking
region of PRDM16 gene associated with leanbody mass. Aging Cell 13, 739-743, 2014.
4. Sekiyama K, Waragai M, Akatsu H, Sugama S,
Takenouchi T, Takamatsu Y, Fujita M, Sekigawa
A, Rockenstein E, Inoue S, La Spada A, Masliah

E, Hashimoto M: Disease-Modifying Effect of
Adiponectin in Model of α-Synucleinopathie. Ann
Clin Transl Neurol 1, 479-489, 2014.
5. Fujimura T, Takahashi S, Urano T, Takayama K,
Sugihara T, Obinata D, Yamada Y, Kumagai J,
Kume H, Ouchi Y, Inoue S, Homma Y:
Expression of androgen and estrogen signaling
components and stem cell markers to predictcancer progression and cancer-specific survival inpatients with metastatic prostate cancer. Clin
Cancer Res 20, 4625-4635, 2014.
6. Boele J, Persson H, Shin JW, Ishizu Y, Newie I,
Søkilde R, Hawkins SM, Coarfa C, Ikeda K,
Takayama K, Horie-Inoue K, Ando Y, Burroughs
AM, Sasaki C, Suzuki C, Sakai M, Aoki S,
Ogawa A, Hasegawa A, Lizio M, Kaida K,
Teusink B, Carninci P, Suzuki H, Inoue S,
Gunaratne P, Rovira C, Hayashizaki Y, de Hoon
M: PAPD5-mediated 3' adenylation andsubsequent degradation of oncomiR miR-21 is
disrupted in proliferative disease. Proc Natl Acad
Sci U S A 111, 11467-11472, 2014.
7. Urano T, Shiraki M, Saito M, Sasaki N, Ouchi Y,
Inoue S: Polymorphism of SLC25A32, the folatetransporter gene, is associated with plasma folate
levels and bone fractures in Japanese postmenopausal women. Geriatric Gerontol Int 14,
942-946, 2014.
8. Obinata D, Ito A, Fujiwara K, Takayama K,
Ashikari D, Murata Y, Yamaguchi K, Urano T,
Fujimura T, Fukuda N, Soma M, Watanabe T,
Nagase H, Inoue S, Takahashi S: Pyrroleimidazole polyamide targeted to break fusion sites
in TMPRSS2 and ERG gene fusion represses
prostate tumor growth. Cancer Sci 105, 12721278, 2014.
9. Maruyama Y, Miyazaki T, Ikeda K, Okumura T,
Sato W, Horie-Inoue K, Okamoto K, Takeda S,
Inoue S: Short hairpin RNA library-based
functional screening identified ribosomal protein
L31 that modulates prostate cancer cell growth via
p53 pathway. PLoS ONE 9, e108743, 2014.
10. Miyazaki T, Ikeda K, Horie-Inoue K, Inoue S:
Amyloid precursor protein regulates migrationand metalloproteinase gene expression in prostatecancer cells. Biochem Biophys Res Commun 452,828-833, 2014.

418

11. Miyazaki T, Ikeda K, Horie-Inoue K, Kondo T,
Takahashi S, Inoue S: EBAG9 modulates hostimmune defense against tumor formation andmetastasis by regulating cytotoxic activity of T
lymphocytes. Oncogenesis 3, e126, 2014.
12. Takayama K, Suzuki T, Tsutsumi S, Fujimura T,
Takahashi S, Homma Y, Urano T, Aburatani H,
Inoue S: Integrative analysis of FOXP1 function
reveals a tumor suppressive effect in prostatecancer. Mol Endocrinol 28, 2012-2024, 2014.
13. Takayama K, Suzuki T, Fujimura T, Urano T,
Takahashi S, Homma Y, Inoue S: CtBP2
modulates the androgen receptor to promote
prostate cancer progression. Cancer Res 74,
6542-6553, 2014.
14. Tsuchihashi T, Mori K, Horie-Inoue K, Okazaki
Y, Awata T, Inoue S, Yoneya S: Prognostic
phenotypic and genotypic factors associated withphotodynamic therapy response in patients withage-related
maculardegeneration.
Clin
Ophthalmol 8, 2471-2478, 2014.
15. Shiba S, Ikeda K, Azuma K, Hasegawa T,
Amizuka N, Horie-Inoue K, Inoue S: γ-Glutamyl
carboxylase in osteoblasts regulates glucose
metabolism in mice. Biochem Biophys Res
Commun 453, 350-355, 2014.
16. Ikeda K, Horie-Inoue K, Inoue S: Analysis of
TFRNs Associated with Steroid HormoneRelated Cancers. (2014) Methods Mol Biol
Vol.1164, “Transcription Factor Regulatory
Networks”, Springer Science+Business Media,
New York, (pp. 197-209)

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Department of Clinical Trial DataManagement
Project Professor
Takuhiro Yamaguchi, Ph.D.

Project Assistant Professor
Tempei Miyaji, M.S.

Project Researcher
Hiroshi Ohtsu, M.S.

Homepage

http://ctdm.umin.jp/

Introduction and Organization
Why we discuss Clinical Data Management (CDM)?
The reason why the concept of CDM is important has
not been fully discussed and educated in Japan. Our
department was established to answer this question.
The Department of Clinical Trial Data Management
was established in 2007 and carries out educationaland research activities on CDM in collaboration withThe Department of Biostatistics and The ClinicalResearch Support Center in University of Tokyo.
As compared to the situation of CDM in the UnitedStates and Europe, technical aspects (data collection,
entry, check…) have been mainly focused in Japan but
the essence of CDM is to ensure quality of clinicaldata to appropriate level for fair and scientificevaluation. This has not been recognized in manyeducational activities. CDM should be defined as atechnical system to conduct clinical trials scientifically,
ethically and efficiently and to draw correctconclusion and also as a research discipline withtheory and practice that applies statistics, quality
control and clinical knowledge. It can optimize thewhole clinical trial process, keep the level of data
quality appropriately and calculate the trial cost.
One of our missions is to activate researches on CDM
aimed at improving the quality of clinical trials. The
other is to produce data managers trained under the
new education system which can look around all theclinical trial process to adapt rapid change of medical
environment and recent increase of e-clinical trials in
the world.

Teaching activities
1. Development of systematic educational programsof CDM and holding of seminars, which include; Design of clinical trials
 CDM
 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 areincluded as biostatisticians or clinical data
managers.

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Research activities
In addition to activities described above, we aredeveloping common tool for clinical research such as
Standardized Operating Procedures (SOPs) in
conducting clinical research.
Research on Clinical Data Interchange Standards
Consortium (CDISC) in collaboration with University
Hospital Medical Information Network (UMIN) is
actively ongoing. The mission of CDISC is to develop
and support global, platform-independent data standards that enable information system interoperability to
improve medical research and related areas of healthcare and we are challenging to convert several academic clinical trial data to CDISC Standards formats.
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 with other universities andmedical institutions for several clinical research.
Finally, as the collaborative department of the ClinicalResearch Support Center (CresCent), we also involvedin their projects as biostatisticians and clinical datamangers.

3.

4.

5.

6.

7.

References
1. Taira N, Iwata H, Hasegawa Y, Sakai T, Higaki K,
Kihara K, Yamaguchi T, Ohsumi S, Shimozuma K,
Ohashi Y. Health-related quality of life andpsychological distress during neoadjuvant
endocrine therapy with letrozole to determine
endocrine responsiveness in postmenopausal
breast cancer. Breast Cancer Res Treat. 2014
May;145(1):155-64.
2. Ooba N, Sato T, Wakana A, Orii T, Kitamura M,
Kokan A, Kurata H, Shimodozono Y, Matsui K,
Yoshida H, Yamaguchi T, Kageyama S, Kubota K.
A prospective stratified case-cohort study on

8.

9.

statins and multiple adverse events in Japan.
PLoS One. 2014 May 8;9(5):e96919.
Hidaka H, Yamaguchi T, Hasegawa J, Yano H,
Kakuta R, Ozawa D, Nomura K, Katori Y.
Clinical and bacteriological influence of diabetes
mellitus on deep neck infection: A systematic
review and meta-analysis. Head Neck. 2014
May 21.
Soeda H, Shimodaira H, Gamoh M, Ando H,
Isobe H, Suto T, Takahashi S, Kakudo Y, Amagai
K, Mori T, Watanabe M, Yamaguchi T, Kato S,
Ishioka C. Phase II trial of cetuximab plus
irinotecan for oxaliplatin- and irinotecan-based
chemotherapy-refractory patients with advanced
and/or metastatic colorectal cancer: evaluation ofefficacy and safety based on KRAS mutation
status (T-CORE0801). Oncology. 2014;87(1):720.
Maeda E, Katsura M, Gonoi W, Yoshikawa T,
Hayashi N, Ohtsu H, Ohtomo K. Abnormal signal
intensities of the seminal vesicles in a screening
population. J Magn Reson Imaging. 2014 Jun;
39(6):1426-30.
Sugita S, Chikuda H, Kadono Y, Ohtsu H,
Takeshita K, Nishino J, Tohma S,Tanaka S.
Clinical characteristics of rheumatoid arthritis
patients undergoing cervical spine surgery: ananalysis of National Database of Rheumatic
Diseases in Japan. BMC Musculoskelet Disord.
2014 Jun 13;15:203.
Yamamoto M, Watanabe E, Suzuki T, Yamazaki T,
Ohtsu H, Ozaki Y, Ogawa S,Yamashita T;
J-RHYTHM II Investigators. Association between
the quality of life and asymptomatic episodes ofparoxysmal atrial fibrillation in the J-RHYTHM II
study. J Cardiol. 2014 Jul;64(1):64-9.
Morita T, Sato K, Miyashita M, Yamagishi A,
Kizawa Y, Shima Y, Kinoshita H, Suzuki S,
Shirahige Y, Yamaguchi T, Eguchi K. Does aregional comprehensive palliative care program
improve pain in outpatient cancer patients?
Support Care Cancer. 2014 Sep;22(9):2445-55.
Yamagishi A, Sato K, Miyashita M, Shima Y,
Kizawa Y, Umeda M, Kinoshita H, Shirahige Y,
Akiyama M, Yamaguchi T, Morita T. Changes in
Quality of Care and Quality of Life of Outpatients
With Advanced Cancer After a Regional Palliative421

Care Intervention Program. J Pain Symptom
Manage. 2014 Oct;48(4):602-10.
10. Shiraya T, Kato S, Shigeeda T, Yamaguchi T,
Kaiya T. Comparison of burn size after retinal
photocoagulation by conventional and high-power
short-duration methods. Acta Ophthalmol. 2014
Nov;92(7):e585-6.
11. Ishiki H, Iwase S, Gyoda Y, Kanai Y, Ariyoshi K,
Miyaji T, Tahara Y, Kawaguchi T, Chinzei M andYamaguchi T. Oral Nutritional Support Can
Shorten the Duration of Parenteral Hydration in
End-of-Life Cancer Patients: A Randomized
Controlled Trial. Nutr Cancer. 2015;67(1):105-11.
12. Ando K, Ohtsu H, Uchida S, Kaname S, Arakawa
Y, Fujita T, EVALUATE Study Group. Antialbuminuric effect of the aldosterone blocker
eplerenone in non-diabetic hypertensive patientswith albuminuria: a double-blind, randomised,
placebo-controlled trial. The lancet Diabetes &endocrinology 2014 Dec;2(12):944-53.
13. 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 Adenocarcinomaof the Lung? Ann Thorac Cardiovasc Surg. 2015
Feb 20;21(1):8-13.

422

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 evenexperienced experts of new drug development in thepharmaceutical industry.
Pharmacology andPharmacokinetics 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 andunder-graduates 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

423

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 theconstructed library, differences of peptide repertoire
presented by HLA proteins in the presence or absenceof a compound 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. Ito N, Ito K, Ikebuchi Y, Kito T, Miyata H,
Toyoda Y, Takada T, Hisaka A, Honma M, Oka A,
Kusuhara

H,

SuzukiH.

Organic

cationtransporter/solute carrier family 22a is involved in
drug transfer into milk in mice. J Pharm Sci. 2014
Oct;103(10):3342-8.
2. Honma M, Ikebuchi Y, Kariya Y, Suzuki H.
Establishment of optimized in vitro assay methods
for evaluating osteocyte functions. J Bone Miner
Metab. 2015 Jan;33(1):73-84.
3. Takeuchi K, Ohishi M, Endo K, Suzumura K,
Naraoka H, Ohata T, Seki J, Miyamae Y, Honma
M, Soga T. Hydroxyproline, a serum biomarker
candidate for gastric ulcer in rats: a comparison
study of metabolic analysis of gastric ulcer
models induced by ethanol, stress, and aspirin.
Biomark Insights. 2014 Jul 27;9:61-6.

424

Department of
Therapeutic Strategy forHeart Failure
Project Professor
Koichiro Kinugawa, M.D.

Project Research Assosiate
Teruhiko Imamura, M.D

Project Researcher
Shunei Kyo, M.D.
Naoko Kato

Project Academic Support Specialist
Ikuko Okada

Homepage

http: http://plaza.umin.ac.jp/~heart-f/

Introduction and Organization
The Department of Therapeutic Strategy for Heart
Failure (TSHF) in the University of Tokyo Hospital
was established by the support of the Department of
Cardiac Surgery and the Department of Cardiovascular Medicine of the University of Tokyo 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 thirteen companies.

Clinical Activities
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, Shinsyu University
Hospital, Akita University Hospital, Gunma
Prefectural Cardiovascular Center, and Nagoya
Tokusyukai Hospital.

425

3. Waon Therapy
Waon Therapy is innovative physiotherapy forend-stage heart failure developed by Professor Chuwa
Tei. In cooperation with Kagoshima University
Hospital, We performed Waon therapy for various
numbers of patients in Japan.

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
Board Examination by 10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments forheart failure, it is essential for our department of the
University to have active research programs in clinicaland basic subjects related to assisted circulations andheart transplantation. We created highly active
research programs in the every field of medical 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 CP 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. Kinugawa K, Sato N, Inomata T, Shimakawa t,
Iwatake N, Mizuguchi K. Efficacy and Safety ofTolvaptan in Heart Failure Patients with Volume
Overload - An InterimResultofPostMarketing
Surveillance in Japan-. Circ J. 2014;78(4):844-52.
2. Kinugawa K, Nagai R, Inoue H, Atarashi H, Seino
Y, Yamashita T, et al. Impacts of patient characteristics on the effectiveness of landiolol in AF/AFL
patients complicated with LV dysfunction: subgroup analysis of the J-Land study. Advances in
Therapy. 2014;31:426-39.
3. Kimura M, Kinoshita O, Nawata K, Nishimura T,
Hatano M, Imamura T, et al. Midterm outcome of
implantable left ventricular assist devices as abridge to transplantation: Single-center experiencein Japan. J Cardiol. 2014.
4. Kato N, Kinugawa K, Imamura T, Maki H, Inaba
T, Muraoka H, et al. Differential Impacts ofAchieved Heart Rate and Achieved Dose of
β-blocker on Clinical Outcomes in Heart Failure
with and without Atrial Fibrillation. Int J Cardiol.
2014;173:331-3.
5. Kato N, Jaarsma T, Kinugawa K. Impacts ofComorbidities on Economic and Health Outcomesin Patients with Cardiovascular Disease. Circ J.
2014;78:588-9.
6. Imamura T, Koichiro Kinugawa, Murasawa T,
Kagami Y, Endo M, Muraoka H, et al. Cardiac

426

Allograft Vasculopathy can be Distinguished fromDonor-transmitted Coronary Atherosclerosis by
Optical Coherence Tomography Imaging in Heart
Transplantation Recipient – Double Layered
Intimal Thickness. Int Heart J. 2014;55:178-80.
7. Imamura T, Kinugawa K, Ohtani T, Sakata Y,
Taiki H, Kinugawa S, et al. Assessment of Qualityof Life during Long-term Treatment of Tolvaptan
in Refractory Heart Failure - Design andRationale of the AQUA-TLV Study. Int Heart J.
2014;55:264-367.
8. Imamura T, Kinugawa K, Nitta D, Fujino T, Inaba
T, Maki H, et al. Is the Internal Jugular Vein or
Femoral Vein a Better Approach Site forEndomyocardial Biopsy in Heart Transplant
Recipients? Int Heart J. 2014.
9. Imamura T, Kinugawa K, Nitta D, Fujino T, Inaba
T, Maki H, et al. Lower Rotation Speed Stimulates
Sympathetic Activation during Continuous Flow
Left Ventricular Assist Device Treatment. J Artif
Organs. 2014;Epub Oct 22.
10. Imamura T, Kinugawa K, Minatsuki S, Muraoka
H, Kato N, Inaba T, et al. Urine Sodium Excretion
after Tolvaptan Administration is Dependent uponBaseline Serum Sodium Levels- A Possible
Explanation for the Improvement of Hyponatremia with Scarce Chance of Hypernatremia bya Vasopressin Receptor Antagonist. Int Heart J.
2014;55:131-7.
11. Imamura T, Kinugawa K, Kato N, Muraoka H,
Fujino T, Inaba T, et al. Late-Onset Right
Ventricular Failure Emerges in Patients with
Preoperative Small Left Ventricle after
Implantation of Continuous Flow Left Ventricular
Assist Device. Circ J. 2014;78:625-33.
12. Imamura T, Kinugawa K, Hatano M, Fujino T,
Muraoka H, Inaba T, et al. Preoperative Betablocker Treatment is a Key for Deciding Left
Ventricular Assist Device Implantation Strategy
Targeting Bridge to Recovery. J Artif Organs.
2014;17:23-32.
13. Imamura T, Kinugawa K, Hatano M, Fujino T,
Inaba T, Maki H, et al. Low Cardiac Output
Stimulates Vasopressin Release in Patients with
Stage D Heart Failure – Its Relevance to Poor
Prognosis and Reversal by Surgical Treatment.
Circ J. 2014;78(9):2259-67.

14. Imamura T, Kinugawa K, Hatano M, Fujino T,
Inaba T, Maki H, et al. Status 2 Patients Had Poor
Prognosis Without Mechanical Circulatory
Support &ndash; Indications for Device Implantation &ndash. Circulation Journal. 2014;78(6):1396-404.
15. Imamura T, Kinugawa K, Fujino T, Inaba T, Maki
H, Hatano M, et al. Increased Urine Aquaporin-2
Levels Relative to Plasma Arginine Vasopressin isa Novel Marker of Response to Tolvaptan inPatients with Decompensated Heart Failure. Circ J.
2014;78(9):2240-9.
16. Imamura T, Kinugawa K, Fujino T, Inaba T, Maki
H, Hatano M, et al. Recipients with Shorter
Cardiopulmonary Bypass Time Achieve Improvement of Parasympathetic Reinnervation within 6
Months after Heart Transplantation. Int Heart J.
2014;55:440-4.
17. Fujino T, Kinugawa K, Hatano M, Imamura T,
Muraoka H, Minatsuki S, et al. Low bloodpressure, low serum cholesterol and anemia
predict early necessity of ventricular assist device
implantation in patients with advanced heart
failure at the time of referral from non-ventricularassist device institutes. Circ J. 2014;78:2882-9.
18. Imamura T.Aquaporin-2-guided tolvaptan therapy
in patients with congestive heart failure
accompanied by chronic kidney disease. Int HeartJ. 2014 Nov 13;55(6):482-3. Epub 2014 Oct 16.
No abstract available.J Artif Organs. 2015 Jan 21.

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Department of Molecular
Medicinal Sciences on Metabolic
Regulation
Project Associate Professor
Hiroaki Okazaki, M.D., Ph.D. (〜2014. Apr.)

Project Research Associate
Miki Okada-Iwabu, Ph.D. (〜2014. Apr.)

Introduction and Organization
Diabetes is currently estimated to affect some 9.5
million patients or 20.5 million individuals including
those at risk and thus has become a major social issueof concern in Japan. Indeed, as it continues to spreadworldwide, diabetes has become such an epidemic thatthe development of novel, groundbreaking, antidiabetic drugs is eagerly awaited.
While diabetes treatment has come to employ antidiabetic drugs with diverse mechanisms of action over
the years, the development of “radical” treatments forlifestyle-related diseases has become an arena offierce competition globally, as their arrival continues
to be eagerly anticipated.
Against this background, the present course aims to
explore, as part of our endeavor to elucidate themechanism of onset of diabetes, potential anti-diabetic
synthetic small molecules and their mechanisms ofaction and target molecules, and to discover/develop
breakthrough anti-diabetic drugs.
Launched in May 2011, this course aims to develop
innovative anti-diabetic drugs based on molecularinsights into the mechanisms of onset of diabetes, inclose collaboration with its parent course, Department
of Diabetes and Metabolic Diseases, Graduate Schoolof Medicine, The University of Tokyo, working

around the clock to bring innovative drugs into theclinical arena thus contributing to society at large.

Research activities
The objective of the course will be to explore andoptimize potential anti-diabetic synthetic small
compounds for clinical application as novel treatments
for diabetes/lifestyle-related diseases.
A unique screening/assay system of our own devising
is currently being exploited to the hilt to help explore
and analyze a wide array of synthetic small compounds with anti-diabetic potential, together with its
spin-off in vitro systems drawing on cultured cells andcell-free systems and in vivo systems drawing on
mouse models of obesity and type 2 diabetes andgenetically modified animals.
We believe that furthering research along these lines
will bring within reach “radical” treatments fordiabetes and lifestyle-related diseases with long-term
insulin-sensitizing and anti-atherosclerotic effects.
Last but not least, our drug discovery/development
research endeavors are not limited diabetes andlifestyle-related diseases but include their relateddiseases, such as cancer and Alzheimer’s disease,which evidence from Japan and overseas suggests
represent potential targets for novel drug development,

428

to make research contributions that help advance
healthcare toward the next century.

References(1) Kadowaki T, Yamauchi T, Okada-Iwabu M,
Iwabu M. Adiponectin and its receptors:
Implications for reduction of obesity-associateddiseases and prolongation of longevity. The Lancet
Diabetes and Endocrinology 2, 8-9 (2014)(2) Yamauchi T, Iwabu M, Okada-Iwabu M,
Kadowaki T. Adiponectin receptors: A review of
their structure, function and how they work. Best
Pract. Res. Clin. Endocrinol. Metab. 1, 15-23(2014)

Social Cooperation Program430

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

Research activities

The Department of Lipidomics was established in
April 2011, funded by Shimadzu Corp. and Ono
Pharmaceutical Co., Ltd. The objective of the laboratory is to establish and improve mass spectrometrybased lipidomics methodologies, and its application tobiomedical studies including basic lipid biology as
well as clinical research.
The laboratory was started by 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.
in Mar. 2015), two guest researchers and two technicalassistants.

Our research interests cover following topics.

Teaching activities
The department staffs gave several lectures forundergraduate and graduate students. For undergraduate students, Drs. Shimizu and Kita delivered
several lectures on biochemistry. Dr. Kita gave
lectures on “Proteome and metabolome” for master’s
students and “Principles and Applications of Mass
Spectrometry” for doctoral students. Dr. Tokumasu
gave a lecture, “Principle of Malaria” as a partof ”Tropical Medicine” in International Health
Department.

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 physiologicallyimportant molecules. Comprehensive analysis of
known lipid mediators is a useful, unbiased method in
disease mechanism studies, and the lipid mediator
profile is a useful parameter that characterizes diseasestatus as well. We have developed an original
multiplex quantification method for trace amounts oflipid mediators using liquid chromatography-tandem
mass spectrometry (LC-MS/MS). We are developing
more sensitive 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 high-level
integration of chromatography and mass spectrometry,
which ensures lipid separation, semi-quantitative detection, and identification. We are collaborating withindustries to solve known difficulties in lipid chromatography, develop differential analysis and featureextraction methods, and establish an intelligent
analytical system linked with lipid database.

431

Methods for clinical samples
Clinical samples such as blood, urine, feces, andtissue biopsies vary much as compared with controlled
animal studies. Furthermore, sampling and storage
conditions are not always optimized for lipid analysis.
We are developing techniques for handling clinicalsamples 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, it is not sufficient to investigate the status oflipid metabolic pathway, because changes inmetabolic flux do not always reflect to static amountof metabolites. To overcome this, we develop aflux-oriented lipidomics analysis using stable-isotope
tracers.
Lipid biomarker/lipid mediator discovery using
animal models
Appling the latest lipidomics technologies to theanalysis of the animal models of various diseases
including metabolic disease, we are trying to discovernovel lipid biomarkers. We also analyze various genedeficient 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 a 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 to 600,000 victims eachyear. Developments of anti-malarial drug have beenhampered by quick emergence of drug resistantparasites. To better understand malaria parasite
biology and drug resistance mechanisms, we study

molecular pathways of lipid membrane system andbiophysical properties of membrane responsible formalaria protein delivery to the host erythrocyte
membrane. Since parasites develop inside humanerythrocytes, clean separation of parasite from thehost cell and precise biochemical analyses are often
difficult task. In our laboratory, we combine lipid
profiling techniques, a high-resolution fluorescencemicroscopy, and advanced biophysical analyses toachieve our research objectives.

References
1. Asahara M, Ito N, Yokomizo T, Nakamura M,
Shimizu T, Yamada Y. The absence of the leukotriene B4 receptor BLT1 attenuates peripheral
inflammation and spinal nociceptive processing
following intraplantar formalin injury. MolecularPain, 11.11 (2015)
2. 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)
3. 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)
4. 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)
5. 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.
Lipid Res., 55, 1386-1396 (2014)
6. Harayama T, Eto M, Shindou H, Kita Y, Otsubo E,
Hishikawa D, Ishii S, Sakimura K, Mishina M,
Shimizu T. Lysophospholipid acyltransferases

432

mediate phosphatidylcholine diversification toachieve the physical properties required in vivo.
Cell Metab., 20, 295-305 (2014)
7. 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)
8. 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)
9. 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)
10. 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)
11. 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)12. 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)

433

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.

Websitehttp://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 ofengineering.
Tokuno Shinichi Project Associate Professor, taking
advantage of his expertise, supports the lecture ofdisaster medicine in emergency medicine.

Research activities
It includes voluntary component such as language
and involuntary component which is mainly derived
from the autonomic nervous in voice. Voice emotion
recognition technology which recognizes an emotionof the speaker by assessing patterning the involuntarycomponent has already been established. Our research
forces on the assessment of the medical validity of theverbal analysis of pathophysiology technology (PST:
Psychoanalysis System Technology) which measure
the health of mind (depressive or manic) from thevoice, and the research for the society implementationof this technology. Additionally, we will further
develop this technology, and try to applicate it to theother diseases.
 Research for medical verification and social
implementation of depression evaluation by voice

434

1)

2)

3)

4)

5)



1)

2)

3)

Voice comparison of healthy subjects and patients
Currently, by analyzing the voice for long term
about two weeks, it was possible to substantially
identify the voice of patients and healthy subjects.
In the future, to increase the accuracy, we will
increase the number of cases.
A study on the monitoring of health status byvoice using a smartphone
As a pre-stage of society implementation, aprospective study of long-term use by volunteers
scheduled to start in 2015 summer.
Use in industrial hygiene field of stress check byvoice
As research for social implementation, we arepreparing a study to use our technology in thecontext of industrial hygiene.
Verification in other languages
In order to confirm the usefulness of languages
other than Japanese, we are preparing a joint
research of the speech database of the foreign
languages and other countries.
The detailed study by multicenter study
Because of the robustness evaluation oftechnology, joint research in the multi-center isplanned.
Application of the verbal analysis ofpathophysiology technology to other than the
stress-depression
sleep apnea syndrome
By the analysis of voice in the awakening andsnoring in falling asleep of the patients who have
sleep apnea syndrome, we have done research on
the measurement of the quality of sleep.
Cerebral infarction
We are conducting research to capture thechange of voice due to cerebral infarction.
OthersWe are preparing for research for several
disease such as mental disorders (PTSD ·schizophrenia),
neurologicaldisorders(Parkinson's disease), dementia (including;Alzheimer's disease), cardiovascular disease(ischemic heart disease) respiratory disease(COPD · asthma), metabolic diseases (diabetes,gout), for such as otolaryngology disease (tongue
adhesion disease, vocal cord polyp), I'm
preparing for research.



A study for the effects of driving a car on thehealth of maind
We 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. Stress Evaluation by Voice: From Prevention toTreatment in Mental Health Care. Tokuno S.
Econophysics, Sociophysics & other Multidisciplinary Sciences Journal (in press)
2. Development of Verbal Analysis Pathophysiology,
S Mitsuyoshi, Econophysics, Sociophysics &other Multidisciplinary Sciences Journal (in press)
3. The novel technology of stress check for the nurse,
S Tokuno, Nurshing; 35(9): pp67-76 07/2015(Japanese)
4. 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.
5. Check again! ECG monitor mastering guide, S
Tokuno, Nurshing; 34(11): pp59-69 09/2014(Japanese)

435

Functional Regulation of
Adipocytes
Project Associate Professor
Hironori Waki, M.D., Ph.D.

Project Lecturer
Takuya Sugiyama, M.D., Ph.D.

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
next-generation sequencer (NGS)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 of436binding 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 inadipocytes in normal and disease states, particularly
focusing on adipocyte-specific transcription regulatory 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 themetabolic syndrome by using comprehensive
epigenomic, genomic, biochemical and genetic
engineering approaches.

References
1. Benitez CM, Qu K, Sugiyama T, Pauerstein PT,
Liu Y, Tsai J, Gu X, Ghodasara A, Arda HE,
Zhang J, Dekker JD, Tucker HO, Chang HY, Kim
SK. An integrated cell purification and genomics
strategy reveals multiple regulators of pancreas
development. PLoS Genet. 2014 Oct 16;10(10):e1004645. doi: 10.1371/journal.pgen.1004645.
eCollection 2014 Oct. PubMed PMID: 25330008;
PubMed Central PMCID: PMC4199491

437

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., Rika Arai, 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
who wish 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.
The following are the members from various
departments at the University of Tokyo: Ryoko
Murayama (Project Associate Professor; from Department of Nursing) and Makoto Oe (Project Lecturer;
from Department of Gerontological Nursing/Wound
Care Management) as well as Hidenori Tanabe andRika Arai (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,Gerontological Nursing I and Gerontological Nursing

438

II, for undergraduates, master course students, or
PhD course students with the Department ofGerontological Nursing/Wound Care management.
The followings were Master’s themes in 2013;“Is thrombus with subcutaneous edema detected byultrasonography related to peripheral intravenous
catheter failure?”

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 2014
• 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 forprevention 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 2nd Conference of Nursing
Science and Engineering“Observation of intravascular lumen variation
after infusion therapy using ultrasonography”•
Best Poster Award: Science & Technology,
Australian Wound Management Association
National Conference 2014
“Variations in the healing course of diabetic footulcers based on the Kobe classification”

References
1. Oe M, Takehara K, Ohashi Y, Mugita Y,
Murayama R, Komiyama C, Ueki k, Kadowaki T,
Sanada H. The incidence of foot ulcers in patientswith diabetes at a university hospital in Tokyo
over a 5 year period, Diabetology International
2015;6(1):55-59.
2. Oe M, Ohashi Y, Amemiya A, Yamada A, Iizuka Y,
Kadowaki T, Sanada H. Foot complications indiabetes mellitus: comparison of Chinese andJapanese patients. Japanese Journal of Foot Care.
2015; 13(1): 19-23.
3. 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. 2015
4. Tsunemi Y, Takehara K, Oe M, Sanada H,
Kawashima M. Diagnostic Accuracy of Tinea
Unguium Based on Clinical Observation, The
Journal of Dermatology. 2015;42(2):221-22.
5. Yabunaka K, Murayama R, Takahashi T, Tanabe
H, Kawamoto A, Oe M, Arai R, Sanada H.
Ultrasonographic appearance of infusion via the439

peripheral intravenous catheters. Journal of
Nursing Science Engineering. 2015;2(1):40-46.
6. Shiraishi M, Haruna M, Matsuzaki M, Ota E,
Murayama R, Sasaki S, Yeo S, Murashima S.
Relationship between plasma total homocysteinelevel and dietary caffeine and vitamin B6 intakes
in pregnant women. Nurs Health Sci. 2014
Jun;16(2):164-70.
7. Matsuzaki M, Haruna M, Ota E, Murayama R,
Yamaguchi T, Shioji I, Sasaki S, Yamaguchi T,
Murashima S. Effects of lifestyle factors on
urinary oxidative stress and serum antioxidant
markers in pregnant Japanese womes: A cohort
study. BioSience Trends. 2014; 8(3): 176-184.
8. Takano M, Noguchi H, Oe M, Sanada H, Mori T.
Development and evaluation of a system to assess
the effect of footwear on the in shoe plantar pressure and shear during gait. ROBOMECH Journal.
2014;1:4. doi:10.1186/s40648-014-0004-9.
9. Amemiya A, Noguchi H, Oe M, Ohashi Y, Ueki K,
Kadowaki T, Mori T, Sanada H. Elevated plantarpressure in diabetic patients and its relationshipwith their gait features. Gait & Posture. 2014
Jul;40(3):408-14.
10. Yotsu RR, Pham NM, Oe M, Nagase T, Sanada H,
Hara H, Fukuda S, Fujitani J, Yamamoto-Honda R,
Kajio H, Noda M, Tamaki T.Comparison ofcharacteristics and healing course of diabetic footulcers by etiological classification: Neuropathic,ischemic, and neuro-ischemic type.J Diabetes
Complications. 2014 Jul-Aug;28(4):528-35.
11. Minematsu T, Horii M, Oe M, Sugama J, Mugita
Y, Huang L, Nakagami G, Sanada H. Skinblotting: a noninvasive technique for evaluating
physiological skin status. Adv Skin Wound Care.
2014 Jun;27(6):272-9.
12. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R. Demographic and lifestyle factors associatedwith vitamin D status in pregnant Japanesewomen. Journal of Nutritional Science andVitaminology (Tokyo). 2014; 60(6): 420-8.

Social Cooperation Program(22nd Century Medical and Research Center)441

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 virtually combined
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 healthinformation space.” We particularly focus on better
clinical outcomes in various medical/healthcare fields,
as well as the efficacy, safety, and security achievedby these innovative systems.

Research activities
We have been working on the specific projects
discussed below since this department was establishedin 2009; our systems have reached the stage of clinicalvalidation. Furthermore, we are collaborating inresearch with several laboratories both inside andoutside the campus, seeking further frontier fields ininterdisciplinary research and practical medicine/
healthcare fields. Through development of these
specific systems, we also aim to establish a systematic
methodology for creating solutions for virtual
ubiquitous health information space.
1. A 12-lead ECG system based on cloud computing
for emergency care

Treatment of cardiovascular disease inside medical
facilities has improved dramatically in recent years.
However, treatment of acute cardiovascular disease
before patients arrive at those facilities has not kept
pace. In order to fill this gap, we have developed anovel ECG system—“Mobile Cloud-based ECG(MCECG)”—that appears a clinically valid approachto this problem. MCECG is a cloud-computing systemwith wireless-transmission ECG units, whose clinicalusefulness is due to the cloud-based server, allowing
cardiovascular specialists inside medical facilities togive outside emergency caregivers diagnosis andtreatment guidance. Ongoing studies include practicaluse of MCECG in the clinical setting of emergency
care. We are collaborating with Kitasato University,
Oita University, and Hokuto hospital. Clinical studies
demonstrated the effectiveness of MCECG in
improved prognostic outcome of patients withcardiovascular disease. And, based on these research
results, the system has been put to practical use. NTT
DOCOMO provides the system commercially.
2. DialBetics: A novel smartphone-based selfmanagement support system for type 2 diabetic
patients
It is fundamentally important for diabetic patients tomaintain an appropriate balance of diet and exercise,although a clear way to achieve that goal has not yet
been established. To help achieve it, we developed anovel smartphone-based self-management support
system for type 2 diabetic patients. This new system442

automatically stratifies each patient's biometric dataaccording to medical risk-evaluation criteria. The
data—blood glucose, blood pressure, food intake andexercise—are measured at home by the patients with
devices whose sensors automatically send the data to
the DialBetics server. The system’s stratificationengine feeds back the raw data and the readings’ risk
levels to the patients. The readings are also sent tothe administrator—but only if the risk levels are sohigh that patients must be urged to consult their healthprofessionals as soon as possible. Even though theefficacy of telemedicine is generally granted, the fear
has been that it may increase the burden on healthcare
workers, making it difficult to maintain and promote.
This new system was developed specifically to
overcome this kind of apprehension, actually reducing
the burden on health care workers. We conducted aclinical study with 56 diabetes patients, its protocol
approved by the ethics committee. A full paper
reported the safety and efficacy of DialBetics in the
Journal of Diabetes Science and Technology. We also
promote the system in collaboration with a researchlaboratory in the Faculty of Engineering. We plan to
conduct a new, more comprehensive clinical study as
an advanced medical technology program at the
University of Tokyo to obtain healthcare coverage ofthe system.
3. Integrated System on Smartphone for a Personal
Health Record platform
Various kinds of personal health record systems(PHR) have been developed to promote healthcareawareness among patients. We have developed a novel
PHR system based on mobile ICT and cloudcomputing as a potential platform for medical/
healthcare information to improve patients’ health. My
Health Diary is now available at the Google Store.
4. Smartphone-based self-management system fordialysis patients
Intake of water, potassium, and phosphate affectchange of body weight, serum potassium andphosphate level, all of them values associated with thesurvival of dialysis patients. We developed SMART-D
to support patients’ self-management in order to improve long-term survival of those patients. Patientscan check their lab data—serum potassium andphosphate level—and change of body weight by using
the system; if the values meet the level suggested by
the guidelines, patients will be more motivated toadhere to healthy behavior; alternatively, if the values
do not meet the suggested level, patients should try tomodify their behavior in order to achieve thetreatment goals. A two-week pilot study of 20
dialysis patients was conducted, showing that qualityof life tended to improve for the patients who used
SMART-D, compared with that for the control patients.
We plan to do a longer study with a larger number ofpatients.

Future directions
We will continue development and validation of the
projects we have described, focusing particularly on
those aspects that affect clinical efficacy—which, atleast in part, has already been proven in practice. In
addition to questions of health care in our university
hospital outpatient/ward, we will undertake joint
research projects to examine various other models of
health care, such as community and home health care.
Our goal is to develop a cyberspace that satisfies not
only medical professionals’ needs but also patients’needs; we will move onto establishing virtual
cyberspace—telehealth space—supported by medical
informatics and clinical medicine.

References
1. Waki K, Fujita H, Uchimura Y, Omae K, Aramaki
E, Kato S, Lee H, Kobayashi H, Kadowaki T, Ohe
K. DialBetics: A Novel Smartphone-based Selfmanagement Support System for Type 2 Diabetes
Patients. J Diabetes Sci Technol. 2014 Mar 13;
8(2):209-215.
2. Aizawa K, Maeda K, Ogawa M, Sato Y,
Kasamatsu M, Waki K, Takimoto H. Comparative
Study of the Routine Daily Usability of FoodLog:
A Smartphone-based Food Recording Tool
Assisted by Image Retrieval. J Diabetes Sci
Technol. 2014 Feb 14;8(2):203-208.
3. Fujimoto H, Suzuki T, Aizawa K, Sawaki D,
Ishida J, Ando J, Fujita H, Komuro I, Nagai R
Processed B-type natriuretic peptide is abiomarker of postinterventional restenosis in443

ischemic heart disease. Clin Chem. 2013 Sep; 59(9):1330-7.
4. Hasumi E, Iwata H, Kohro T, Manabe I,
Kinugawa K, Morisaki N, Ando J, Sawaki D,
Takahashi M, Fujita H, Yamashita H, Ako J,
Hirata Y, Komuro I, Nagai R Diagnostic
implication of change in b-type natriuretic peptide(BNP) for prediction of subsequent target lesion
revascularization following silorimus-eluting stent
deployment. Int J Cardiol. 2013 Jan 7.
5. Nakayama A, Morita H, Ando J, Fujita H, Ohtsu
H, Nagai R Adverse cardiovascular outcomes
associated with concurrent use of clopidogrel orticlopidine and proton-pump inhibitors in patients
undergoing percutaneous coronary intervention.
Heart Vessels. 2013 May;28(3):292-300.
6. Waki K, Sugawara Y, Mizuta K, Taniguchi M,
Ozawa M, Hirata M, Nozawa M, Kaneko J,
Takahashi K, Kadowaki T, Terasaki PI, andKokudo N. Predicting Operational Tolerance inPediatric Living-Donor Liver Transplantation by
Absence of HLA Antibodies. Transplantation.
2013 Jan 15;95(1):177-83.
7. Hayakawa M, Uchimura Y, Omae K, Waki K,
Fujita H, Ohe K. A Smartphone-based Medication
Self-management System with Realtime Medication Monitoring. Appl Clin Inform. 2013 Jan 30;
4(1):37-52.
8. Takeuchi I, Fujita H, Ohe K, Imaki R, Sato N,
Soma K, Niwano S, Izumi T. Initial experience ofmobile cloud ECG system contributing to theshortening of door to balloon time in an acute
myocardial infarction patient. Int Heart J.2013;
54(1):45-7
9. Waki K, Fujita H, Uchimura Y, Aramaki E, Omae
K, Kadowaki T, Ohe K DialBetics: smartphonebased self-management for type 2 diabetes
patients. J Diabetes Sci Technol. 2012 Jul 1; 6(4):983-5.
10. Nakayama A, Morita H, Miyata T, Ando J, Fujita
H, Ohtsu H, Akai T, Hoshina K, Nagayama M,
Takanashi S, Sumiyoshi T, Nagai R Inverse
association between the existence of coronary
artery disease and progression of abdominal aortic
aneurysm. Atherosclerosis. 2012 May; 222(1):278-83.

11. Kimura K, Takenaka K, Ebihara A, Okano T, Uno
K, Fukuda N, Ando J, Fujita H, Morita H, Yatomi
Y, Nagai R Speckle tracking global strain rate E/E'
predicts LV filling pressure more accurately than
traditional tissue Doppler E/E'. Echocardiography.
2012 Apr;29(4):404-10.
12. Myojo M, Iwata H, Kohro T, Sato H, Kiyosue A,
Ando J, Sawaki D, Takahashi M, Fujita H, Hirata
Y, Nagai R Prognostic implication of macrocytosis on adverse outcomes after coronary
intervention. Atherosclerosis. 2012 Mar; 221(1):148-53.
13. Kohro T, Iwata H, Fujiu K, Manabe I, Fujita H,
Haraguchi G, Morino Y, Oguri A, Ikenouchi H,
Kurabayashi M, Ikari Y, Isobe M, Ohe K, Nagai R
Development and implementation of an advanced
coronary angiography and intervention databasesystem. Int Heart J. 2012;53(1):35-42.
14. Oba S, Noda M, Waki K, Nanri A, Kato M,
Takahashi Y, Poudel-Tandukar K, Matsushita Y,
Inoue M, Mizoue T, Tsugane S; Japan Public
Health Center-Based Prospective Study Group.
Smoking cessation increases short-term risk oftype 2 diabetes irrespective of weight gain: theJapan Public Health Center-Based Prospective
Study. PLoS One. 2012;7(2):e17061.
15. Ohe H, Waki K, Yoshitomi M, Morimoto T,
Nafady-Hego H, Satoda N, Li Y, Zhao X,
Sakaguchi S, Uemoto S, Bishop GA, Koshiba T
Factors affecting operational tolerance after
pediatric living-donor liver transplantation:
impact of early post-transplant events and HLA
match. Transpl Int. 2012 Jan;25(1):97-106.
16. Waki K, Sugawara Y, Kokudo N, Kadowaki T
Long-term pancreas allograft survival insimultaneous pancreas-kidney trans- plantation byera. Clin Transpl. 2012:13-22.

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

446

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., Makoto Kaneko, M.D., Akiko Masuda, M.D., Makoto Kurano, 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 andhigh-quality 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 2014, over 5,230,847

serum enzyme tests (such as AST and ALT), and581,760 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, gene analysis tests and urinalysis.
In 2014, 1,236,181 samples were examined forcomplete blood cell counts, cell surface marker
analysis, prothrombin time, fibrinogen, glucose, andHbA1C tests, and 254,979 urine samples were
examined.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2014, 49,035 ECG, 23,633
pulmonary function tests, 10,915 echocardiography
tests, 14,723 abdominal echography tests, and 10,539
EEG were performed.
The Hospital Ward Section
This section has been recently founded and is incharge of laboratory tests, mainly ECG, forseriously-ill, hospitalized patients. In the future, this447

section is going to be further expanded since there isso much 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.

3.

4.

5.

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.

6.

7.

8.

References
Original article:
1. Daikoku, T., Yatomi, Y., Yumoto, M. Implicit andexplicit statistical learning of tone sequences
across spectral shifts. Neuropsychologia. 63: 194204, 2014.
2. Enooku, K., Nakagawa, H., Soroida, Y., Ohkawa,
R., Kageyama, Y., Uranbileg, B., Watanabe, N.,
Tateishi, R., Yoshida, H., Koike, K., Yatomi, Y.,

9.

Ikeda, H. Increased serum mitochondrial creatine
kinase activity as a risk for hepatocarcinogenesis
in chronic hepatitis C patients. Int. J. Cancer 135:
871-879, 2014.
Ichinose, J., Watanabe, K., Sano, A., Nagase, T.,
Nakajima, J., Fukayama, M., Yatomi, Y., Ohishi,N., Takai, D. Alternative polyadenylation isassociated with lower expression of PABPN1 andpoor prognosis in non-small cell lung cancer.
Cancer Sci. 105: 1135-1141, 2014.
Iida, Y., H. Tsuno, N., Kishikawa, J., Kaneko, K.,
Murono, K., Kawai, K., Ikeda, T., Ishihara, S.,
Yamaguchi, H., Sunami, E., Kitayama, J., Yatomi,Y., Watanabe, T. Lysophosphatidylserine Stimulates Chemotactic Migration of Colorectal Cancer
Cells Through GPR34 and PI3K/Akt Pathway.
Anticancer Res. 34: 5465-5472, 2014.
Iino, J., Osada, M., Kurano, M., Kaneko, M.,
Ohkawa, R,. Satoh, Y., Okubo, S., Ozaki, Y.,
Tozuka, M., Tsuno, N.H., Yatomi, Y. Plateletderived sphingosine 1-phosphate induces migration of Jurkat T cells. Lipids Health Dis. 13: 150,
2014.
Ito, S., Iwaki, S. Kondo, R., Satoh, M., Iwabuchi,
K., Ohkawa, R., Mishima, Y., Yatomi, Y.,
Furumoto, T., Tsutsui, H., Fujii, S. TNF-α
production in NKT cell hybridoma is regulated bysphingosine-1-phosphate: implications for inflammation in atherosclerosis. Coron Artery Dis. 25:
311-320, 2014.
Jimbo, R., Kawakami-Mori, F., Mu, S., Hirohama,D., Majtan, B., Shimizu, Y., Yatomi, Y., Fukumoto,S., Fujita, T., Shimosawa, T. Fibroblast growth
factor 23 accelerates phosphate-induced vascular
calcification in absence of Klotho deficiency.
Kidney Int. 85: 1103-1111, 2014.
Kobayashi, T., Seo, S., Morita, S., Goto, A.,
Masuda, A., Shimizu, N., Nishida, M., Nunobe, S.,
Ichikawa, M., Takazawa, Y., Seto, Y., Fukayama,M., Kurokawa, M. Esophageal intramucosal
hematoma after peripheral blood stem cell transplantation: case report and review of literature. Int.
J. Clin. Exp. Pathol. 7: 2690-2694, 2014.
Kondo, M., Ishizawa, T., Enooku, K., Tokuhara,Y., Ohkawa, R., Uranbileg, B., Nakagawa, H.,
Tateishi, R., Yoshida, H., Kokudo, N., Koike, K.,
Yatomi, Y., Ikeda, H. Increased serum autotaxin

448

levels in hepatocellular carcinoma patients werecaused by background liver fibrosis but not by
carcinoma. Clin. Chim. Acta. 433: 128-134, 2014.
10. Kono, R., Kanozawa, K., Shimosawa, T., Tayama,Y., Matsuda, A., Hasegawa, H., Mitarai, T.
Adrenomedullin in peritoneal effluent expressedby peritoneal mesothelial cells. Clin. Exp.
Nephrol. 18: 124-129, 2014.
11. Kurano, M., Hara, M., Tsuneyama, K., Sakoda, H.,
Shimizu, T., Tsukamoto, K., Ikeda, H., Yatomi, Y.
Induction of insulin secretion by apolipoprotein M,
a carrier for sphingosine 1-phosphate. Biochim.
Biophys. Acta. 1841: 1217-1226, 2014.
12. Mitome-Mishima, Y., Miyamoto, N., Tanaka, R.,
Shimosawa,T., Oishi, H., Arai, H., Hattori, N., andUrabe, T. Adrenomedullin Deficiency and Aging
Exacerbate Ischemic White Matter Injury after
Prolonged Cerebral Hypoperfusion in Mice.
Biomed Res. Int. 2014: 861632, 2014.
13. Nagai, H., Kuwahira, I., Schwenke, D.O.,
Tsuchimochi, H., Nara, A., Inagaki, T., Ogura, S.,
Fujii, Y., Umetani, K., Shimosawa, T., Yoshida, K.,
Pearson, J.T., Uemura, K., Shirai, M. β2Adrenergic Receptor-Dependent Attenuation ofHypoxic Pulmonary Vasoconstriction Prevents
Progression of Pulmonary Arterial Hypertension
in Intermittent Hypoxic Rats. PLoS One 9:e110693, 2014.
14. Nishimura, S., Nagasaki, M., Okudaira, S., Aoki,
J., Ohmori, T., Ohkawa, R., Nakamura, K.,
Igarashi, K., Yamashita, H., Eto, K., Uno, K.,
Hayashi, N., Kadowaki, T., Komuro, I., Yatomi, Y.,
Nagai, R. ENPP2 Contributes to Adipose Tissue
Expansion and Insulin Resistance in Diet-Induced
Obesity. Diabetes. 63: 4154-4164, 2014.
15. Nojiri, T., Kurano,M., Tokuhara, Y., Ohkubo, S.,
Hara, M., Ikeda, H., Tsukamoto, K., Yatomi, Y.
Modulation of sphingosine-1-phosphate andapolipoprotein M levels in the plasma, liver andkidneys in streptozotocin-induced diabetic mice. J.
Diabetes Investig. 5: 639-648, 2014.
16. Ogura, M., Ichikawa, M., Masuda, A., Kandabashi,K., Nannya, Y., Kurokawa, M. A mixed-typeautoimmune hemolytic anemia with immune
thrombocytopenia related with myositis and posttransplantation lymphoproliferative disorder. Ann.
Hematol. 93: 869-871, 2014.

17. Satoh Y., Masuda A., Jona M., Nannya Y., Yokota
H., Kurokawa M., Yatomi Y.
Heparin-mediated inhibition of PCR in theaccelerated phase of chronic myeloid leukaemia
characterised by abundant basophilia. Eur. J.
Haematol. 92: 456-457, 2014.
18. Tokuhara, Y., Shukuya, K., Tanaka, M., Mouri, M.,
Ohkawa, R., Fujishiro, M., Takahashi, T., Okubo,
S., Yokota, H., Kurano, M., Ikeda, H., Yamaguchi,
S., Inagaki, S., Ishige-Wada, M., Usui, H., Yatomi,Y., Shimosawa, T. Detection of novel visible-lightregion absorbance peaks in the urine after
alkalization in patients with alkaptonuria. PLoS
One 9: e86606, 2014.
19. Uranbileg, B., Enooku, K., Soroida, Y., Ohkawa,
R., Kudo, Y., Nakagawa, H., Tateishi, R., Yoshida,
H., Shinzawa, S., Moriya, K., Ohtomo, N.,
Nishikawa, T., Inoue, Y., Tomiya, T., Koike, K.,
Yatomi, Y., Ikeda, H. High ubiquitous mitochondrial creatine kinase expression in hepatocellular
carcinoma denotes a poor prognosis with highlymalignant potential. Int. J. Cancer 134: 21892198, 2014.
20. Fukuda, N., Itatani, K., Kimura, K., Ebihara, A.,
Negishi, K., Uno, K., Miyaji, K., Kurabayashi, M.,
Takenaka, K. Prolonged vortex formation during
the ejection period in the left ventricle with low
ejection fraction: a study by vector flow mapping
J Med Ultrasonics. 41:301–310, 2014.
21. Yuan, LJ., Takenaka, K., Uno, K., Ebihara, A.,
Sasaki, K., Komuro, T., Sonoda, M., Nagai, R .
Normal and shear strains of the left ventricle inhealthy human subjects measured by twodimensional speckle tracking echocardiography.
Cardiovasc Ultrasound. 12:7, 2014.
22. Ueno, Y., Yamashiro, K., Tanaka, Y., Watanabe,
M., Shimada, Y., Kuroki, T., Miyamoto, N.,
Daimon, M., Tanaka, R., Miyauchi, K., Daida, H.,
Hattori, N., Urabe, T. Rationale and design of
EPISTEME trial: Efficacy of post- stroke
intensive rosuvastatin treatment for aortogenic
embolic stroke. Cardiovasc Drugs Ther 28:79-85,
2014.
23. Chiang, SJ., Daimon, M., Ishii, K., Kawata, T.,
Miyazaki, S., Hirose, K., Ichikawa, R., Miyauchi,
K., Yeh, MH., Chang, NC., Daida, H. Assessmentof Elevated Levels and Rapid Changes of Left

449

Ventricular Filling Pressure Using a Novel Global
Strain Imaging Diastolic Index. Circ J. 78:419427, 2014.
24. Lee, S., Daimon, M., Kawata, T., Kohro, T.,
Kimura, K., Nakao, T., Koide, D., Watanabe, M.,
Yamazaki, T., Komuro, I. Estimation of Right
Atrial Pressure by Inferior Vena Cava Ultrasoundin an Asian Population. Circ J. 78:962-966, 2014.
25. Maruyama, M., Daimon, M., Kawata, T., Kasai, T.,
Ichikawa, R., Miyazaki, S., Ohmura, H.,
Yamamoto, T., Amano, A., Daida, H. Early
Hemodynamic Performance of the Trifecta
Bioprostheic Valve in Patients with Aortic Valve
Disease: An Initial Single-center Experience inJapan. Circ J. 78:1372-1378, 2014.
26. Sasaki, S., Daimon, M., Kawata, T., Miyazaki, S.,
Ichikawa, R., Maruyama, M., Chiang, SJ., Mahara,K., Watanabe, H., Sumiyoshi, T., Tomoike, H.,
Daida, H.. Factors Responsible for ElevatedPlasma B-type Natriuretic Peptide Levels in
Severe Aortic Stenosis: Comparison between
Elderly and Younger Patients. J Cardiol. 64:
476-481, 2014.
27. Koyama, K., Daimon, M., Semba, H., Wang, JH.,
Uno, K., Kawata, T., Nakao, T., Kimura, K.,
Komuro, I. Mitral Valve Thickening in Cogan’s
Syndrome. J Echocardiogr. 14: 123-124, 2014
Review article:
1. Jimbo, R., Shimosawa, T. Cardiovascular Risk
Factors and Chronic Kidney Disease−FGF23: A
Key Molecule in the Cardiovascular Disease. Int.
J. Hypertens. 2014: 9, 2014.
2. Kaneko, M., Wanaka, K., Tsuno, N.H., Kanno, N.,
Nonobe, R., Takahashi, C., Matsuo, T., Okazaki,
H., Yatomi, Y. The diagnosis and management of
heparin-induced thrombocytopenia in Japan. ISBT
Sci. Ser. 9: 210–216, 2014.
3. Kawakami-Mori F, Shimosawa, T. Oxidative
Stress and Mineralocorticoid Receptor Signaling
in the Brain: Possible Therapeutic Targets for
Dementia. Ann Clin Exp Hypertension 2: 1015,
2014.
4. Ogura, S., Shimosawa, T. Oxidative stress andorgan damages. Curr. Hypertens. Rep. 16: 452,
2014.

450

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
Kazuhiro Fukatsu. M.D., Ph.D.

Lecturer
Takami Komatsu, M.D., Ph.D.
Ryoji Fukushima, M.D., Ph.D.

Associate
Saito Yuhei, M.S.
Satoshi Murakoshi, M.D., Ph.D.

Homepage

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

Introduction and Organization
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 and 11,150 operations were
performed in 2006, 2007, 2008, 2009 2010, 2011,2012, 2013 and 2014 fiscal year, respectively. The
number of operations in 2014 fiscal year counts forapproximately 1.8 times comparing to that in 2001.
These days more and more patients undergo theoperation, using endoscopic technique, such as
laparoscopy/thoracoscopy-assisted operation. There is451

also 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 acirculating nurse. It consists of lectures of aseptic
techniques, de-contamination/sterilization methods,

452

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（2014）
1. Mitsui T, Fukatsu K, Yanagawa M, Amenomori S,
Ogawa E, Fukuda T, Murakoshi S, Moriya T,
Yasuhara H, Seto Y. Truncal vagotomy temporarily decreases the pro- and anti-inflammatory
cytokine levels in the small intestine. Surg Today.
2014; 44(6):1123-7.
2. 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; 15(1):50-7.
3. Fukatsu K. Impact of the feeding route on gut
mucosal immunity. Curr Opin Clin Nutr Metab
Care. 2014; 17(2):164-70.
4. 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; 155(4):711-8.
5. 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; 38(11):3015-22.
6. Kishii K, Kikuchi K, Matsuda N, Yoshida A,
Okuzumi K, Uetera Y, Yasuhara H, Moriya K.
Evaluation of matrix-assisted laser desorption
ionization-time of flight mass spectrometry for453

species identification of Acinetobacter strains
isolated from blood cultures. Clinical Microbiol
Infect 2014; 20(5): 424-30
7. Saito Y, Kobayashi H, Uetera Y, Yasuhara H,
Kajiura T, Okubo T. Microbial contamination ofsurgical instruments used for laparotomy. Am J
Inf Cont 2014; 42(1): 43-7
8. Kishii K, Kikuchi K, Yoshida A, Okuzumi K,
Uetera Y, Yasuhara H, Moriya K. Antimicrobial
susceptibility profile of Acinetobacter species
isolated from blood cultures in two Japanese
university hospitals. Microbiol Immunol 2014;
58(2):142-6.
9. Furuya Y, Yasuhara H. Abrupt vominting and painwith abdominal mass. JAMA Surg. 2014; 149(9):987-8.

454

Department of Clinical Radiology
Professor (department manager)
Kuni Ohtomo, M.D., Ph.D.

Lecturer (vice manager)
Jiro Sato, M.D.

Assistant Professor
Masaki Katsura, M.D., Ph.D.

Homepage

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

Introduction and Organization
In the Department of Clinical Radiology, clinicalservices on Diagnostic Radiology (imaging andintervention), Radiation Oncology (radiotherapy),
Nuclear Medicine and the Radiation Safety Control
System are provided in cooperation with radiology
technologists and nurses. Present constituent members
are as follows: three medical doctors, 73 radiological
technicians and 1 technical official of the radiation
control. The staff members of the Department ofRadiology (teachers, the graduate school students,
medical staffs, and the clinical trainees) join this. In
addition, the doctors of other departments and thenurses cooperate and are also engaged in the clinicalradiology activities.
Department of Clinical Radiology is actively
participating in the following projects. 1) PACS: We
have recently developed a radiology information
system (RIS) networking with hospital information
system (HIS) and PACS (picture archiving andcommunicating system). The PACS of the whole
hospital (the film-less imaging system) wasestablished in 2003. The new reporting system wasinstalled in 2002. 2) Radiation Safety Control:
Stimulated by the need for evaluating the individualaccumulated exposure dose by medical radiation, we
have started a working group to solve this problem.
We aim to provide the accumulated exposure dose
data on RIS. 3) Image Computing & Analysis
Laboratory: The clinical section of this project islocated at the reading room in the Diagnostic
Radiology Section. The main services are processingof volume image data into clinical 3D-images andanalysis of imaging data. 4) Researches on new
radiology techniques: Ongoing collaborative researches are as follows: image-guided radiation
therapy, clinical PET, multi-detector row CT, 3-Tesla
MRI, flat panel detector.

Clinical activities
1) Diagnostic Radiology:
The section of diagnostic radiology is responsible
for all the clinical examinations of CT, MRI, andangiography and vascular interventional procedures
except for cardiac and peripheral arterial studies. Allof these examinations are performed under therequests of clinicians. Over one hundred and fifty CT
examinations are performed using six MDCT scanners
each day. Interventional procedure such as
percutaneous biopsy and abscess drainage are alsodone by CT guidance. About sixty MR examinations
are done using four of 1.5-Tesla and two 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,455

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.

456

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.,

Takehito Yamamoto, Ph.D.

Homepage

http://plaza.umin.ac.jp/~todaiyak/

Introduction and Organization
We have 10 faculty members, 72 pharmacy staffs,
and 10 graduate students and 3 undergraduate students
from the faculty of pharmaceutical sciences and 1
graduate students from the faculty of medicine (as ofJanuary 1st, 2015). 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457

medicines and other materials used in our
department. This section also takes statistics ofevery information of drug affairs. Drug management section takes care of supplying and safekeeping of all the in-hospital medicines (2,393
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 ofpatient’s 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 2014)
Number of items on in-hospital formulary: 2,393
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
436,790 ps.
(outside :351,361 ps.)(inside :85,429 ps.)out-patient chemotherapy:
11,199 ps.
in-patients :236,345 ps.
injection drugs:
220,599 ps.
IVH:
5,284 ps.
chemotherapy:
11,546 pp.
TDM consultations (annual) :15,688 pp.
Numbers of hospital pharmaceutical cares (annual):
16,575 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458

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
2014, 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
2014, 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, andestablishment 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
to prevent / treat the adverse effect.
5. Absolute quantification of factors determining thepharmacokinetic profiles of drugs and its
application to clinical pharmacokinetics andpharmacology field.

Publications
Research
It is evident that the molecular function ofparticular element cannot always be assigned to only
one function at whole body level, because one to one
simple correspondence is not common in our body. It
is also true that the understanding of the relationshipbetween drug and its ultimate target is not sufficient topredict the pharmacological/toxicological effects. We
need to understand not only the detailed molecularmachinery of drug target, but also its environment
surrounding the target (ex. other associated proteins,
signaling molecules, etc.), where and when it works,
and finally how it behaves as functional unit in our
body. This is a basic idea trying to understand “livingbody” as “system”. By further promoting this idea to“system pharmacology”, we will be able to identify amolecular target which is related to the pharmacological/toxicological output in clinical situation or evenat early drug development stage. Based on suchconcept, following projects are now ongoing:

1. Abe T, Yanagihara Y, Uchino T, Oriyama T,
Komatsu M, Nakajima K, Suzuki H. Evaluation of
the pharmaceutical characteristics of various
enteric-coated aspirin tablets under different
storage conditions. Chem Pharm Bull (Tokyo).
62(7):617-26. 2014.
2. Granot T, Yamanashi Y, Meruelo D. Sindbis viral
vectors transiently deliver tumor-associatedantigens to lymph nodes and elicit diversified
antitumor cd8+ t-cell immunity. Mol Ther. 22(1):112-22. 2014.
3. Hisaka A, Nakamura M, Tsukihashi A, Koh S,
Suzuki H. Assessment of intestinal availability(fg) of substrate drugs of cytochrome p450s by
analyzing changes in pharmacokinetic properties
caused by drug-drug interactions. Drug Metab
Dispos. 42(10):1640-5. 2014.
4. Honma M, Ikebuchi Y, Kariya Y, Suzuki H.
Regulatory mechanisms of rankl presentation to459

osteoclast precursors. Curr Osteoporos Rep. 12(1):115-20. 2014.
5. Ito N, Ito K, Ikebuchi Y, Kito T, Miyata H,
Toyoda Y, Takada T, Hisaka A, Honma M, Oka A,
Kusuhara H, Suzuki H. Organic cationtransporter/solute carrier family 22a is involved in
drug transfer into milk in mice. J Pharm Sci. 103(10):3342-8. 2014.
6. Matsuo H, Nakayama A, Sakiyama M, Chiba T,
Shimizu S, Kawamura Y, Nakashima H,
Nakamura T, Takada Y, Oikawa Y, Takada T,
Nakaoka H, Abe J, Inoue H, Wakai K, Kawai S,
Guang Y, Nakagawa H, Ito T, Niwa K, Yamamoto
K, Sakurai Y, Suzuki H, Hosoya T, Ichida K,
Shimizu T, Shinomiya N. Abcg2 dysfunction
causes hyperuricemia due to both renal urate
underexcretion and renal urate overload. Sci Rep.
4:3755. 2014.
7. Matsuo H, Takada T, Nakayama A, Shimizu T,
Sakiyama M, Shimizu S, Chiba T, Nakashima H,
Nakamura T, Takada Y, Sakurai Y, Hosoya T,
Shinomiya N, Ichida K. Abcg2 dysfunction
increases the risk of renal overload hyperuricemia.
Nucleosides Nucleotides Nucleic Acids. 33(4-6):
266-74. 2014.
8. Nakayama A, Matsuo H, Nakaoka H, Nakamura T,
Nakashima H, Takada Y, Oikawa Y, Takada T,
Sakiyama M, Shimizu S, Kawamura Y, Chiba T,
Abe J, Wakai K, Kawai S, Okada R, Tamura T,
Shichijo Y, Akashi A, Suzuki H, Hosoya T,
Sakurai Y, Ichida K, Shinomiya N. Common
dysfunctional variants of abcg2 have stronger
impact on hyperuricemia progression than typicalenvironmental risk factors. Sci Rep. 4:5227. 2014.
9. Ohno Y, Yamada M, Yamaguchi R, Hisaka A,
Suzuki H. Persistent drug interaction between
aprepitant and warfarin in patients receiving
anticancer chemotherapy. Int J Clin Pharm. 36(6):1134-7. 2014.
10. Panthee N, Ono M, Morota T, Tanaka T, Itoda Y,
Ikemura M, Yamamoto T, Suzuki H, Saito A,
Motomura N. Paraplegia prevention by oral
pretreatment with memantine in a rabbit model. J
Thorac Cardiovasc Surg. 148(4):1732-8. 2014.
11. Sakiyama M, Matsuo H, Shimizu S, Chiba T,
Nakayama A, Takada Y, Nakamura T, Takada T,
Morita E, Naito M, Wakai K, Inoue H, Tatsukawa

S, Sato J, Shimono K, Makino T, Satoh T, Suzuki
H, Kanai Y, Hamajima N, Sakurai Y, Ichida K,
Shimizu T, Shinomiya N. A common variant ofleucine-rich repeat-containing 16a (lrrc16a) geneis associated with gout susceptibility. Hum Cell.
27(1):1-4. 2014.
12. Sakiyama M, Matsuo H, Shimizu S, Nakashima H,
Nakayama A, Chiba T, Naito M, Takada T, Suzuki
H, Hamajima N, Ichida K, Shimizu T, Shinomiya
N. A common variant of organic anion transporter
4 (oat4/slc22a11) gene is associated with renal
underexcretion type gout. Drug Metab Pharmacokinet. 29(2):208-10. 2014.
13. Sakiyama M, Matsuo H, Takada Y, Nakamura T,
Nakayama A, Takada T, Kitajiri S, Wakai K,
Suzuki H, Shinomiya N. Ethnic differences in
atp-binding cassette transporter, sub-family g,member 2 (abcg2/bcrp): Genotype combinations
and estimated functions. Drug Metab Pharmacokinet. 29(6):490-2. 2014.
14. Suzuki S, Shuto T, Sato T, Kaneko M, Takada T,
Suico MA, Cyr DM, Suzuki H, Kai H. Inhibitionof post-translational n-glycosylation by hrd1 that
controls the fate of abcg5/8 transporter. Sci Rep.
4:4258. 2014.
15. Takada T, Ichida K, Matsuo H, Nakayama A,
Murakami K, Yamanashi Y, Kasuga H, Shinomiya
N, Suzuki H. Abcg2 dysfunction increases serum
uric acid by decreased intestinal urate excretion.
Nucleosides Nucleotides Nucleic Acids. 33(4-6):
275-81. 2014.

460

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 andout-patient care for pregnant women including theactivities in the delivery units.

Activities
Total number of delivery cases was 997 in 2014.
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.]

461

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 and orthoptists
who had belonged to other departments in the
University of Tokyo Hospital were included in our
department. From 2009, a speech therapist added toour department, and now two therapists performtherapy for patients with aphasia, dysarthria, anddysphagia.

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 the462

subjects on rehabilitation for disorders such ascerebrovascular disturbances, respiratory disorders,
neuromuscular diseases, bone and joint diseases, andpediatric disorders as well as on outline ofrehabilitation, and amputation/prostheses. We haveprovided a clinical practice in small group, so-calledclinical clerkship for 5th year students from
Wednesday to Friday every week. They experience a
few patients and learn how to take a patients’ history,
physical findings, functional evaluation, and how toplan rehabilitation programs. We have introduced a
few of elective students for elective clinical clerkshipto our collaborating hospitals with specialized
rehabilitation ward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with other departments in our hospital, other faculties in our university,and institutions outside the University of Tokyo. The
ongoing and scheduled projects are as follows.
1) 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. Zhang Y, Haga N: Skeletal complications incongenital insensitivity to pain with anhidrosis: acase series of 14 patients and review of articles
published in Japanese. J Orthop Sci 19: 827-831,
2014
2. Nagata E, Kano H, Kato F, Yamaguchi R,
Nakashima S, Takayama S, Kosaki R, Tonoki H,
Mizuno S, Watanabe S, Yoshiura K, Kosho T,
Hasegawa T, Kimizuka M, Suzuki A, Shimizu K,
Ohashi H, Haga N, Numabe H, Horii E, Nagai T,
Yoshihashi H, Nishimura G, Toda T, Takada S,
Yokoyama S, Asahara H, Sano S, Fukami M,
Ikegawa S, Ogata T: Japanese founder duplications/triplications involving BHLHA9 are associatedwith split-hand/foot malformation with or without
long bone deficiency and Gollop-Wolfgang
complex. Orphanet J Rare Dis 9: 125, 2014
3. Goto M, Takedani H, Haga N, Kubota M,
Ishiyama M, Ito S, Nitta O: Self-monitoring has
potential for home exercise programs in patientswith hemophilia. Haemophilia 20: e121-127, 2014
4. Inokuchi H, Yasunaga H, Nakahara Y, Horiguchi
H, Ogata N, Fujitani J, Matsuda S, Fushimi K,
Haga N: Effect of rehabilitation on mortality ofpatients with Guillain-Barre syndrome: apropensity-matched analysis using a nationwide
database. Eur J Phys Rehabil Med 50: 439-446,
2014
5. Mishima K, Kitoh H, Haga N, Nakashima Y,
Kamizono J, Katagiri T, Susami T, Matsushita M,
Ishiguro N: Radiographic characteristics of thehand and cervical spine in fibrodysplasia
ossificans progressiva. Intractable Rare Dis Res 3:46-51, 2014
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. 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, published online

463

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, 2 hydrogen peroxide plasma sterilizers.

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: 30085 for surgical center,
13693 for wards and outpatient clinics in 2012).
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 6857 in 2012.

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. 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

464

2.

3.

4.

5.

6.

Complications During Parenteral Nutrition. Ann
Surg. 2012 Nov 26. [Epub ahead of print]
Fukatsu K. The long road to optimizing theparenteral provision of nutrients. JPEN J Parenter
Enteral Nutr. 2012 Mar;36(2):157-8.
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.
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.
Fukatsu K. Friend or foe? Linkage between
hormonal response and innate immunity. J Surg
Res. 2012 Jan;172(1):83-4.
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.

465

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.,

Lecturer (Hospital)
Masako Ikemura, M.D., Ph.D.

Aya Shinozaki-Ushiku, M.D., Ph.D. *Associate
Yukako Shintani, M.D., Ph.D.

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

Akimasa Hayashi, M.D., Ph.D.,
Shogo Tajima, M.D. *Mariko Tanaka, M.D., Ph.D. *Clinical Fellow
Makiko Ogawa, M.D.,

Homepage

Kei Oide, M.D.,

Ryohei Kuroda, M.D.

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.
The proper staffs in the Division of Diagnostic
Pathology include a lecturer, five associates, and threeclinical staffs. Dr. Shintani learned cardiovascularpathology in Massachusetts General Hospital from 11,
Nov. to 12, Dec.
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. We held the first seminar on March 28-29,
2015.

Clinical activities (diagnostic
pathology and autopsy)
The annual statistics of the pathologic practice in 2014
fiscal year consisted of 16,581 cases of histological466

examination (22,951 specimens), 18,851 cases ofcytology, 826 of frozen histology, 464 of
intra-operative cytology, 61 cases of autopsy (17.9%of the autopsy rate), and 1 autopsy case from otherhospitals.
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 and Tanaka), male
genitourinary (Dr. Morikawa) and female genitaltracts (Dr. Sasaki), breast (Dr. Ikemura), and bone andsoft tissues (Dr. Ushiku). Biopsy conferences are also
held in the cases of kidney (Dr. Shintani in charge),
skin (Dr. Shinozaki-Ushiku) and GI tract (Dr. Abe).
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.
We continue to participate in the autopsy
assessment for “The Model Project for Inspection andAnalysis of the Deaths Related to Medical Treatment(DRMT)”.

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
nine junior residents (total 32 months) in 2014 fortheir second year program of the internship.

Teaching activities

See the corresponding section of Department of
Pathology and Diagnostic Pathology(1) Furuta T, Kiryu S, Yamada H, Hosoi M,
Kurokawa M, Morikawa T, Shibahara J, Ohtomo
K. Erdheim-Chester disease with an 18Ffluorodeoxyglucose-avid breast mass and BRAF
V600E mutation. Jpn J Radiol. 2014 May; 32(5):282-7.
(2) Hangai S, Yoshimi A, Hosoi A, Matsusaka K,
Ichikawa M, Fukayama M, Kurokawa M. An

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.

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, 24, 25 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 are also
developing diagnostic and therapeutic methods usingcancer specific antibodies in collaboration with
Departments of Radiology and Upper GI tract Surgery,and Genome Science Division, Research Center for
Advanced Science and Technology, the University ofTokyo (Drs. Ikemura, Ushiku, and Abe). 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.

References (Case Reports Only)

467

(3)

(4)

(5)

(6)

(7)

(8)

(9)

indeterminate result of QuantiFERON- TB Gold
In-Tube for military tuberculosis due to a highlevel of IFN-γ production. Int J Hematol. 2014
Apr;99(4):523-6.
Harada N, Ishizawa T, Inoue Y, Aoki T, Sakamoto
Y, Hasegawa K, Sugawara Y, Tanaka M,
Fukayama M, Kokudo N. Acoustic radiation force
impulse imaging of the pancreas for estimation ofpathologic fibrosis and risk of postoperative
pancreatic fistula. J Am Coll Surg. 2014 Nov ;219(5):887-94.e5.
Harada S, Yamazaki S, Nakamura F, Morita K,
Yoshimi A, Shinozaki-Ushiku A, Fukayama M,
Kurokawa
M.
Autoimmune
neutropenia
preceding Helicobacter pylori-negative MALT
lymphoma with nodal dissemination. Int J Clin
Exp Pathol. 2014 Aug; 7(9):6386-90.
Honda A, Nakamura F, Nannya Y, Shintani Y,
Fukayama M, Ichikawa M, Kurokawa M.
Pulmonary lymphocyte-rich classical Hodgkin
lymphoma with early response to ABVD therapy.
Ann Hematol. 2014 Jun; 93(6):1073-4.
Ikemura M, Maeda E, Hatao F, Aikou S, Seto Y,
Fukayama
M.Plexiform
angiomyxoid
myofibroblastic tumor (PAMT) of the stomach. A
case report focusing on its characteristic growth
pattern. Int J Clin Exp Pathol. 2014 Jan; 7(2):685-9.
Inoue T, Oda K, Arimoto T, Samejima T,
Takazawa Y, Maeda D, Fukayama M, Kawana K,
Osuga Y, Fujii T. Xanthogranulomatous inflammation of the perimetrium with infiltration into
the uterine myometrium in a postmenopausal
woman: a case report. BMC Womens Health.
2014 Jul 15;14:82.
Kobayashi T, Seo S, Morita S, Goto A, Masuda A,
Shimizu N, Nishida M, Nunobe S, Ichikawa M,
Takazawa Y, Seto Y, Fukayama M, Kurokawa M.
Esophageal intramucosal hematoma after
peripheral blood stem cell transplantation: casereport and review of literature. Int J Clin Exp
Pathol. 2014 Apr 15;7(5):2690-4.
Kogure Y, Nakamura F, Shinozaki-Ushiku A,
Watanabe A, Kamei K, Yoshizato T, Nannya Y,
Fukayama M, Kurokawa M. Pulmonary mucormycosis with embolism: two autopsied cases ofacute myeloid leukemia. Int J Clin Exp Pathol.
2014 May; 7(6):3449-53.
(10) Kume A, Morikawa T, Ogawa M, Yamashita A,
Yamaguchi S, Fukayama M. Congenital neuroblastoma with placental involvement. Int J Clin
Exp Pathol. 2014 Oct; 7(11):8198-204.
(11) Makise N, Morikawa T, Takeshima Y, Homma Y,
Fukayama M. A case of urinary bladder urothelial
carcinoma with squamous, glandular, and plasmacytoid differentiation. Case Rep Oncol. 2014
May; 7(2):362-8.
(12) Mine S, Suzuki K, Sato Y, Fukumoto H, Kataoka
M, Inoue N, Ohbayashi C, Hasegawa H, Sata T,
Fukayama M, Katano H. Evidence for humanherpesvirus-6B infection of regulatory T-cells inacute systemic lymphadenitis in an immunocompetent adult with the drug reaction witheosinophilia and systemic symptoms syndrome: acase report. J Clin Virol. 2014 Nov; 61(3):448-52.
(13) Mukaiyama Y, Suzuki M, Morikawa T, Mori Y,
Takeshima Y, Fujimura T, Fukuhara H, Nakagawa
T, Nishimatsu H, Kume H, Homma Y. Multiple
primary malignant neoplasms of the glottis, renal
pelvis, urinary bladder, oral floor, prostate, andesophagus in a Japanese male patient: a casereport. World J Surg Oncol. 2014 Sep; 12:294.
(14) Nakaya T, Morita K, Kurata A, Ushiku T,
Igarashi T, Kuroda M, Fukayama M. Multifocal
kaposiform hemangio- endothelioma in multiple
visceral organs: an autopsy of 9-day-old female
baby. Hum Pathol. 2014 Aug; 45(8):1773-7.
(15) Numakura S, Morikawa T, Ushiku T, Toyoshima
T, Fukayama M. Langerhans cell histiocytosis of
the urinary bladder in a patient with bladdercancer previously treated with intravesicalBacillus Calmette-Guérin therapy. Pathol Res
Pract. 2014 Feb;210(2):123-6.
(16) Nozawa H, Kanazawa T, Tanaka T, Takahashi M,
Ishihara S, Sunami E, Kitayama J, Ikemura M,
Komuro I, Watanabe T. Laparoscopic resection ofa gastrointestinal stromal tumor of the lower
rectum in a patient with coronary artery disease
following long-term neoadjuvant imatinib
treatment and anticoagulation therapy. World J
Surg Oncol. 2014 Jul; 12:211.
(17) Oda K, Ikeda Y, Maeda D, Arimoto T, Kawana K,
Fukayama M, Osuga Y, Fujii T. Huge pyogenic

468

cervical cyst with endometriosis, developing
13 years after myomectomy at the lower uterine
segment: a case report. BMC Womens Health.
2014 Sep;14:104.
(18) Ogawa M, Morikawa T, Toyoshima T, Fukayama
M. Squamous cell carcinoma in a duplicated renal
pelvis. Int J Clin Exp Pathol. 2014 Oct;7(11):7957-61.
(19) Sasaki T, Isayama H, Aoki T, Tanaka M, Hamada
T, Nakai Y, Sakamoto Y, Hasegawa K, Morikawa
T, Fukayama M, Kokudo N, Koike K. A R0
resection case of initially unresectable metastatic
pancreatic cancer downstaged by FOLFIRINOX
therapy. Pancreas. 2014 Aug;43(6):972-4.
(20) Tanaka M, Ushiku T, Ikemura M, Shibahara J,
Seto Y, Fukayama M. Esophageal adenocarcinoma arising in cervical inlet patch withsynchronous Barrett's esophagus-related dysplasia. Pathol Int. 2014 Aug; 64(8):397-401.
(21) Tsukamoto A, Nakamura F, Nannya Y, Kobayashi
Y, Shibahara J, Ichikawa M, Fukayama M, Koike
K, Kurokawa M. MALT lymphoma of the small
bowel with protein-losing enteropathy. Int J
Hematol. 2014 Feb; 99(2):198-201.
(22) Tsuzuki S, Fukumoto H, Mine S, Sato N,
Mochizuki M, Hasegawa H, Sekizuka T, Kuroda
M, Matsushita T, Katano H. Detection oftrichodysplasia spinulosa- associated polyomavirus in a fatal case of myocarditis in a sevenmonth-old girl. Int J Clin Exp Pathol. 2014 Jul;
7(8):5308-12.
(23) Yagi H, Amiya E, Ando J, Watanabe M, Yanaba K,
Ikemura M, Fukayama M, Komuro I. In-stentrestenosis exacerbated by drug-induced severe
eosinophilia after second-generation drug-eluting
stent implantation. Am J Case Rep. 2014 Sep; 15:397-400.
(24) Yamagata Y, Ando Y, Matsusaka K, Karube H,
Onoyama H, Aikou S, Yamashita H, Mori K,
Nomura S, Fukayama M, Seto Y. Poorly
differentiated mesenteric carcinoma of unknown
primary site detected by abscess formation: casereport. World J Surg Oncol. 2014 Jan;12:4(25) Yasutake T, Kiryu S, Akai H, Watadani T,
Akahane M, Tomizawa N, Gonoi W, Ikemura M,
Takahashi M, Matuoka Y, Ohtomo K. MR
imaging of carcinosarcoma of the liver using

Gd-EOB-DTPA. Magn Reson Med Sci. 2014;13(2): 117-21.

469

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 136 corneal
transplantations were performed in 2014. 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.

470

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. Kimoto M, Shima N, Yamaguchi M, Hiraoka Y,
Amano S, Yamagami S. Invest Ophthalmol Vis
Sci.Development of a bioengineered corneal
endothelial cell sheet to fit the corneal curvature.
55:2337-43, 2014.
2. Mimura T, Ichinose T, Yamagami S, Fujishima H,
Kamei Y, Goto M, Takada S, Matsubara M.
Airborne particulate matter (PM2.5) and theprevalence of allergic conjunctivitis in Japan. Sci
Total Environ. 487:493-9, 2014.
3. Mimura T, Yamagami S, Fujishima H, Noma H,
Kamei Y, Goto M, Kondo A, Matsubara
M.Sensitization to Asian dust and allergic rhinoconjunctivitis. Environ Res. 132:220-5, 2014.
4. Yoshida J, Oshikata-Miyazaki A, Yokoo S,
Yamagami S, Takezawa T, Amano S. Development and evaluation of porcine atelocollagen
vitrigel membrane with a spherical curve andtransplantable artificial corneal endothelial grafts.
Invest Ophthalmol Vis Sci. 55:4975-81, 2014.
5. Haruki T, Miyazaki D, Matsuura K, Terasaka Y,
Noguchi Y, Inoue Y, Yamagami S. Comparison of
toxicities of moxifloxacin, cefuroxime, andlevofloxacin to corneal endothelial cells in vitro. J
Cataract Refract Surg. 40:1872-8, 2014.
6. Kimakura M, Usui T, Yokoo S, Nakagawa S,
Yamagami S, Amano S. Toxicity of topicalantifungal agents to stratified human cultivatedcorneal epithelial sheets. J Ocul Pharmacol Ther.
30:810-4, 2014.

471

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Motohiro Kato, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Assistant Professor
Kensuke Narukawa, M.D., Ph.D. (Hematology-Oncology)
Kazuhiro Toyama, 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 830 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 2014, 14 patients (including 6 children) received
autologous HSCT and 23 patients (including 6
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.

472

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.

3.

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. Kobayashi T, Seo S, Morita S, Goto A, Masuda A,
Shimizu N, Nishida M, Nunobe S, Ichikawa M,
Takazawa Y, Seto Y, Fukayama M, Kurokawa M.
Esophageal intramucosal hematoma after peripheral blood stem cell transplantation: case reportand review of literature. Int J Clin Exp Pathol
2014; 7: 2690-4.
2. Kogure Y, Nakamura F, Nukina A, Kamikubo Y,
Ichikawa M, Kamikubo Y, Kurokawa M.
Catheter-related septic shock by Micrococcus in

4.

5.

6.

an autologous hematopoietic stem cell transplantation recipient. Am J Infect Control 2014;
42: 87.
Nannya Y, Shinohara A, Ichikawa M, Kurokawa
M. Serial profile of vitamins and trace elements
during the acute phase of allogeneic stem celltransplantation. Biol Blood Marrow Transplant
2014; 20: 430-4.
Nasu R, Nannya Y, Shinohara A, Ichikawa M,
Kurokawa M. Favorable outcomes of tacrolimus
compared with cyclosporine A for GVHD
prophylaxis in HSCT for standard-risk hematological diseases. Ann Hematol 2014; 93: 1215-23.
Ogura M, Ichikawa M, Masuda A, Kandabashi K,
Nannya Y, Kurokawa M. A mixed-typeautoimmune hemolytic anemia with immune
thrombocytopenia related with myositis and posttransplantation lymphoproliferative disorder. Ann
Hematol 2014; 93: 869-71.
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 in patients withpediatric myelodysplastic syndrome and myeloproliferative neoplasms. Pediatr Blood Cancer 2014;
61: 1860-6.

473

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. The endoscopic rooms moved to the newbuilding in Oct. 2006.

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. Enteroscopy by using capsule endoscopes
and balloon-assisted endoscopes are rapidly increasing
in number. Additionally, image enhanced endoscopy
for detail inspection and therapeutic endoscopy,

including endoscopic submucosal dissection foresophageal, gastric and colorectal tumors, are majoradvanced fields. Our recent clinical activities are
summarized in Table 1.
Another important activity of our department is thedisinfection and maintenance of endoscopic
apparatuses used in other units including 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.

474

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
2005

2006

2007

2008

2009

EGD*
Colonoscopy
Bronchoscopy
EUS**Enteroscopy
Laryngoscopy
Colposcopy

8265
4084
212
461
89
88

8131
4327
201
438
127
58

8796
4360
201
484
91
117

9822
4679
165
402
133
63
256

10262
4996
226
518
181
75
307

Total

13199

13282

14043

15520

16566

2010
10556
5152
255
551
311
70
361
17256

2011
10963
5208
197
630
282
108
378
17764

2012
11376
5688
196
698
282
83
365
18688

2013
11840
6000
169
763
375
128
404
19679

2014
11740
6043
218
766
396
102
327
19592

*Esophagogastroduodenoscopy, **Endoscopic ultrasonography

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

5.

References
1. Kodashima S, Fujishiro M, Ono S, Niimi K,
Mochizuki S, Asada-Hirayama I, Konno-Shimizu
M, Matsuda R, Minatsuki C, Nakayama C,
Takahashi Y, Sakaguchi Y, Yamamichi N, Tanaka
C, Koike K. Evaluation of a new image-enhanced
endoscopic technology using band-limited lightfor detection of esophageal squamous cell
carcinoma. Dig Endosc 2014; 26: 164–171
2. Takahashi Y, Yamamichi N, Shimamoto T,
Mochizuki S, Fujishiro M, Takeuchi C, Sakaguchi
Y, Niimi K, Ono S, Kodashima S, Mitsushima T,
Koike K. Helicobacter pylori infection ispositively associated with gallstones: a large-scalecross-sectional study in Japan. J Gastroenterol.
2014 May;49(5):882-9.
3. Shimamoto T, Yamamichi N, Kodashima S,
Takahashi Y, Fujishiro M, Oka M, Mitsushima T,
Koike K. No association of coffee consumption
with gastric ulcer, duodenal ulcer, reflux
esophagitis, and non-erosive reflux disease: across-sectional study of 8,013 healthy subjects inJapan. PLoS One. 2013 Jun 12;8(6):e65996.
4. Fujishiro M, Kaminishi M, Hiki N, Oda I,
Fujisaki J, Uedo N, Kaise M, Tanabe S, Iguchi M,
Matsuhashi N, Nomura S, Tajiri H, Yahagi N,
Suzuki H. Efficacy of spraying l-menthol solution
during endoscopic treatment of early gastriccancer: a phase III, multicenter, randomized,

6.

7.

8.

double-blind,placebo-controlled
study.
J
Gastroenterol. 2014 Mar;49(3):446-54.
Mitsui T, Niimi K, Yamashita H, Goto O, Aikou S,
Hatao F, Wada I, Shimizu N, Fujishiro M, Koike
K, Seto Y. Non-exposed endoscopic wallinversion surgery as a novel partial gastrectomy
technique. Gastric Cancer. 2014 Jul;17(3):594-9.
Yoshida T, Kato J, Inoue I, Yoshimura N, Deguchi
H, Mukoubayashi C, Oka M, Watanabe M,
Enomoto S, Niwa T, Maekita T, Iguchi M, Tamai
H, Utsunomiya H, Yamamichi N, Fujishiro M,
Iwane M, Takeshita T, Ushijima T, Ichinose M.
Cancer development based on chronic active
gastritis and resulting gastric atrophy as assessedby serum levels of pepsinogen and Helicobacter
pylori antibody titer. Int J Cancer. 2014 Mar 15;
134(6):1445-57.
Tsuji Y, Ohata K, Gunji T, Shozushima M,
Hamanaka J, Ohno A, Ito T, Yamamichi N,
Fujishiro M, Matsuhashi N, Koike K Endoscopic
tissue shielding method with polyglycolic acidsheets and fibrin glue to cover wounds aftercolorectal endoscopic submucosal dissection(with video). Gastrointest Endosc. 2014 Jan;
79(1):151-5.
Arezzo A, Passera R, Saito Y, Sakamoto T,
Kobayashi N, Sakamoto N, Yoshida N, Naito Y,
Fujishiro M, Niimi K, Ohya T, Ohata K, Okamura
S, Iizuka S, Takeuchi Y, Uedo N, Fusaroli P,
Bonino MA, Verra M, Morino M.Systematic
review and meta-analysis of endoscopic submucosal dissection versus transanal endoscopic
microsurgery for large noninvasive rectal lesions.
Surg Endosc. 2014 Feb;28(2):427-38.

475

9. Fujimoto K, Fujishiro M, Kato M, Higuchi K,
Iwakiri R, Sakamoto C, Uchiyama S, Kashiwagi
A, Ogawa H, Murakami K, Mine T, Yoshino J,
Kinoshita Y, Ichinose M, Matsui T. Guidelines for
gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc. 2014
Jan;26(1):1-14.
10. Tsuji Y, Gunji T, Sato H, Ono A, Ito T, Ohata K,
Yamamichi N, Fujishiro M, Matsuhashi N, Koike
K. Antithrombotic drug does not affect thepositive predictive value of an immunochemical
fecal occult blood test. Dig Endosc. 2014 May;
26(3):424-9.
11. Tachimori Y, Ozawa S, Fujishiro M, Matsubara H,
Numasaki H, Oyama T, Shinoda M, Toh Y,
Udagawa H, Uno T. Comprehensive registry ofesophageal cancer in Japan, 2005. Esophagus
2014 Jan;11(1): 1-20.
12. Tachimori Y, Ozawa S, Fujishiro M, Matsubara H,
Numasaki H, Oyama T, Shinoda M, Toh Y,
Udagawa H, Uno T. Comprehensive Registry of
Esophageal Cancer in Japan, 2006. Esophagus
Esophagus 2014 Jan;11(1): 21-47.
13. Neumann H, Fujishiro M, Wilcox CM,
Mönkemüller K. Present and future perspectivesof virtual chromoendoscopy with i-scan andoptical enhancement technology. Dig Endosc.
2014; 26 (Suppl. 1): 43–51
14. Yamamichi N, Shimamoto T, Sakaguchi Y,
Takahashi Y, Kodashima S, Nakayama C,
Minatsuki C, Ono S, Mochizuki S, Matsuda R,
Asada-Hirayama I, Niimi K, Fujishiro M, Tsuji Y,
Takeuchi C, Kakimoto H, Goto O, Mitsushima T,
Koike K. Categorization of upper gastrointestinal
symptoms is useful in predicting backgroundfactors and studying effects and usages ofdigestive drugs. PLoS One. 2014 Feb 5;9(2):e88277.
15. Ono S, Tsuji Y, Fujishiro M, Kodashima S,
Yamamichi N, Koike K. An effective techniquefor delivery of polyglycolic acid sheet afterendoscopic submucosal dissection of theesophagus: the clip and pull method. Endoscopy.
2014;46 Suppl 1 UCTN:E44-5.
16. Xue H, Gong S, Shen Y, Tan H, Fujishiro M, Dai J,
Zhao Y, Ge Z. The learning effect of a training
programme on the diagnosis of oesophageal

lesions by narrow band imaging magnification
among endoscopists of varying experience. Dig
Liver Dis. 2014 Jul;46(7):609-15.
17. Ono S, Niimi K, Fujishiro M, Takahashi Y,
Sakaguchi Y, Nakayama C, Minatsuki C, Matsuda
R, Hirayama-Asada I, Tsuji Y, Mochizuki S,
Kodashima S, Yamamichi N, Ozeki A, Matsumoto
L, Ohike Y, Yamazaki T, Koike K. Evaluation ofpreferable insertion routes for esophagogastroduodenoscopy using ultrathin endoscopes. WorldJ Gastroenterol. 2014 May 7;20(17):5045-50.
18. Iwakiri R, Higuchi K, Kato M, Fujishiro M,
Kinoshita Y, Watanabe T, Takeuchi T, Yamauchi
M, Sanomura M, Nakagawa H, Sugisaki N, Okada
Y, Ogawa H, Arakawa T, Fujimoto K.
Randomised clinical trial: prevention ofrecurrence of peptic ulcers by rabeprazole inpatients taking low-dose aspirin. Aliment
Pharmacol Ther. 2014 Oct;40(7):780-95.
19. Kageyama-Yahara N, Yamamichi N, Takahashi Y,
Nakayama C, Shiogama K, Inada KI, KonnoShimizu M, Kodashima S, Fujishiro M, Tsutsumi
Y, Ichinose M, Koike K. Gli Regulates MUC5AC
Transcription in Human Gastrointestinal Cells.
PLoS One. 2014 Aug 28;9(8):e106106.
20. Saito I, Tsuji Y, Sakaguchi Y, Niimi K, Ono S,
Kodashima S, Yamamichi N, Fujishiro M, Koike
K. Complications related to gastric endoscopic
submucosal dissection and their managements.
Clin Endosc 2014;47:398-403
21. Yamamichi N, Hirano C, Shimamoto T, Minatsuki
C, Takahashi Y, Nakayama C, Matsuda R,
Fujishiro M, Konno-Shimizu M, Kato J,
Kodashima S, Ono S, Niimi K, Mochizuki S,
Tsuji Y, Sakaguchi Y, Asada-Hirayama I, Takeuchi
C, Yakabi S, Kakimoto H, Wada R, Mitsushima T,
Ichinose M, Koike K. Associated factors ofatrophic gastritis diagnosed by double-contrast
upper gastrointestinal barium x-ray radiography: across-sectional study analyzing 6,901 healthy
subjects in Japan. PLoS One. 2014 Oct 24;9(10):e111359.
22. Tsuji Y, Fujishiro M, Kodashima S, Niimi K, Ono
S, Yamamichi N, Koike K. Desirable training ofendoscopic submucosal dissection: further spreadworldwide. Ann Transl Med. 2014 Mar;2(3):27.

476

23. Yoshida S, Isayama H, Koike K. Palliative
self-expandable metallic stent placement forcolorectal obstruction caused by an extracolonicmalignancy Gastrointest Interv 2014; 3:75–79
24. Sasaki T, Isayama H, Yoshida S, Nakai Y,
Yamashita H, Seto Y, Koike K. Endoscopic
trimming of a migrated gastroduodenal stent using
a loop cutter and a two-channel endoscope.
Endoscopy. 2014 Oct;46 Suppl 1 UCTN:E462-3.
25. Yamaji Y, Isomura Y, Yoshida S, Yamada A,
Hirata Y, Koike K. Randomized controlled trial
comparing the efficacy of mosapride plus
omeprazole combination therapy to omeprazole
monotherapy in gastroesophageal reflux disease.
JDigDis. 2014Sep;15(9):469-76.
26. Isomura Y, Yamaji Y, Yamada A, Watanabe Y,
Suzuki H, Kobayashi Y, Yoshida S, Watabe H,
Hirata Y, Yoshida H, Koike K. Irsogladine
improves small-intestinal injuries in regular users
of nonsteroidal anti-inflammatory drugs. Gastrointest Endosc. 2014 Jul;80(1):118-25.

477

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.

2.

3.
4.

5.
6.
7.

Teaching activities
1.

2.
3.
4.

Clinical activities
1.

Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).

Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does
not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.
DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
LDL apheresis for nephrotic syndrome and ASO
patients.
White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.

5.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acutekidney injury and acute renal failure.
Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course to
second year residents on request.
Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRT

478

6.

Pocket Manual]. English and Chinese version of“Apheresis Pocket Manual” is available for
global experts of Apheresis therapy.
Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.

2.
3.
4.
5.
6.
7.
8.

4.

Postoperative polymyxin B hemoperfusion andmortality in patients with abdominal septic
shock: a propensity-matched analysis. Crit. CareMed. 42, 1187-1193 (2014)

2.

3.

Iwagami M., Yasunaga H., Doi K., Noiri E. Is
postoperative polymyxin B hemoperfusion for

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.
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].

abdominal septic shock really ineffective? :Response to Hashiguchi and Iba. Crit. Care Med.
42, e597-e598 (2014)
6.

Doi K., Ishizu T., Tsukamoto-Sumida M., Hiruma
T., Yamashita T., Ogasawara E., Hamasaki Y.,
Yahagi N., Nangaku M., Noiri E. The highmobility group protein B1-Toll-like receptor 4
pathway contributes to the acute lung injury
induced by bilateral nephrectomy. Kidney Int. 86,
316-326 (2014)

7.

Ito T., Hanafusa N., Fukui M., Yamamoto H.,
Watanabe K., Noiri E., Iwase S., Miyagawa K.,
Fujita T., Nangaku M. Single center experienceof cell-free and concentrated ascites reinfusion
therapy in malignancy related ascites. Ther.
Apher. Dial. 18, 87-92 (2014)8.

Hanafusa N., Noiri E., Nangaku M. Vascularaccess puncture under ultrasound guidance. Ther.

References
1.

Iwagami M., Yasunaga H., Doi K., Horiguchi H.,
Fushimi K., Matsubara T., Yahagi N., Noiri E.

5.

Research activities
1.

tetraamino fullerene. Sci. Rep. 4: 4916 (2014)

Apher. Dial. 18, 213-214 (2014)

Sumida M., Doi K., Kinoshita O., Kimura M.,

9.

Fujita D., Takahashi M., Doi K., Abe M., Tazaki

Ono M., Hamasaki Y., Matsubara T., Ishii T.,

J., Kiyosue A., Myojo M., Ando J., Fujita H.,

Yahagi N., Nangaku M., Noiri E. Perioperative

Noiri E., Sugaya T., Hirata Y., Komuro I.

plasma neutrophil gelatinase-associated lipocalin

Response of urinary liver-type fatty acid-binding

measurement in patients who undergo left

protein to contrast media administration has aventricular assist device implantation surgery.

potential to predict one-year renal outcome in

Circ. J. 78:1891-1899 (2014)

patients with ischemic heart disease. Heart

Nakamura K., Inokuchi R, Doi K, Fukuda T,

Vessels 2014 [PMID: 2455 4043]

Tokunaga K, Nakajima S, Noiri E, Yahagi N.

10. Doi K., Noiri E., Nangaku M., Yahagi N.,

Specific ketoacidosis. Intern. Med. 53, 1071-

Jayakumar C., Ramesh G. Repulsive guidance

1073 (2014)

cue semaphorin 3A in urine predicts the

Minami K., Okamoto K., Doi K., Harano K.,

progression of acute kidney injury in adult

Noiri E., Nakamura E. siRNA delivery targeting

patients from a mixed intensive care unit.

toNephrol. Dial. Transplant. 29: 73-80 (2014)

the

lung

accumulation

and

via

agglutination-induced

clearanceofcationic

11. Hamasaki Y., Doi K., Tanaka M., Kume H.,

479

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. 15: 173, (2014)
12. 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: 381-185, (2014)
13. Yamashita T, Doi K, Hamasaki Y, Matsubara T,
Ishii T, Yahagi N, Nangaku M, Noiri E.
Evaluationofurinary

tissueinhibitorofmetalloproteinase-2 in acute kidney injury: aprospective observational study. Crit. Care 18:716 (2014)
14. Hiruma T., Asada T., Yamamoto M., Inokuchi R.,
Matsubara T., Ishii T., Sumda M., Isshiki R.,
Mayumi K., Noiri E., Nangaku M., Yahagi N.,
Doi K. Mortality prediction by acute kidney
injury biomarkers in comparison with serum
creatinine. Biomarkers 19: 646-651 (2014)

480

Clinical Research Support Center
Professor
Tsutomu Yamazaki, M.D., Ph.D.

Associate Professor
Yoshihiro Arakawa, Ph.D.

Project Associate Professor
Takashi Moritoyo, M.D., Ph.D.

Project Lecturer
Tetsuya Ueda, M.D., Ph.D.

Research Associate
Shuichi Kawarasaki, M.D., Ph.D.
Munenori Takata, M.D., Ph.D.
Yukari Uemura, Ph.D.

Project Research Associate
Akiko Kishi Svensson, M.D., Ph.D.
University Hospital Clinical Trial Alliance (UHCT Alliance)

Homepage

http://www.cresc.h.u-tokyo.ac.jp/

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 division of the hospital and supports not only
industry-sponsored, but also investigator-initiated,clinical trials. Institutional guidelines, forms andtemplates for investigator-initiated clinical trials wereprepared in 2002 according to the principle of the
ICH-GCP and made available to the public on our
website, aiming at the contribution to the improvement of clinical trials in Japan. The support wasprovided to the investigators mainly in terms ofprotocol development and protection of research
participants.
With the increasing volume of clinical research

conducted in our hospital, demand mounted for the
structural framework to support investigator-initiated,
especially multicenter, trials.
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 demands, the former
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

481

Coordinating Unit, which provides coordinating
functions for research such as multicenter trials.
Site Coordinating Unit is comprised of theinstitutional review board (IRB) Secretariat Division,
Investigational Drug/Information Control Division
and Clinical Research Coordinator Division, eachcharged with IRB secretarial affairs, handling of drugs
for clinical trials and assistance with safety
information reporting, and clinical researchcoordinator 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 now support
both trials registered or not registered for marketing
approval, and, therefore, can provide seamless support
to research in any phase of development.
As of March 2015, the Center staff includes aprofessor, an associate professor, a project associate
professor, a project lecturer, 3 assistant professors, a
project assistant professor, 12 pharmacists, 20 nurses(full-time equivalent, FTE), 8 laboratory technicians(FTE), 3 clinical psychologists, 6 project specialists
and 5 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>
To further improve the quality of trials or clinicalresearch (which includes compassionate use ofunapproved drugs) respecting the principles of the
globally standard ICH-GCP, we have laid down and asneeded revised the in-house guidelines or SOPs. These
documents include those relating to preparation of thestudy protocol or informed consent form, implementation of research, and handling of costs to trial
participants.
For secure process of the applications of industrysponsored clinical trials to IRB, we hold a preliminary
hearing system (named as “protocol presentation”)
before IRB.
The items processed by the Center as the IRB
secretariat in fiscal 2014 included, as for industrysponsored trials for marketing approval, 39 new
protocol applications, 70 study extension applications,375 protocol amendment applications, 930 SAE/safety
information reports, 46 study closure or termination
reports. As for investigator-initiated clinical research,
the Center processed 65 new protocols (including 20
applications for compassionate use of unapproved
drugs), 192 applications for protocol amendment, 282
SAE/safety information reports, 70 reports for study
closure or termination.
Protocol presentations of industry-sponsored trials
prior to application to IRB totaled 14 applications.
Preliminary
consultation
andguidanceforinvestigator-initiated research application including
cases of compassionate totaled 52 and 13 applications,
respectively.
Clinical Research Support Center managed
drug/device inventory for 118 clinical trials forregulatory approval, 4 postmarketing trials, 5 trials ofdevices, 31 investigator-initiated clinical trials, andone case of compassionate use in fiscal 2014. The
number of prescriptions processed was 1137 for trials
for approval and postmarketing trials combined, 1034
for investigator-initiated clinical trials. We are
currently managing trial drugs centrally for 4
multicenter trials. We masked investigational drugs
for 2 double-blind placebo controlled trials. We arealso in charge of the primary review of clinical trial
safety information and of maintaining the database on
clinical trials in general.

482

Clinical research coordinators (CRC) of the Center
have been supporting as a principle all clinical trials
for approval and postmarketing trials since 2002. We
started supporting in part investigator-initiated trials in
2004. In 2005 we started providing CRC support toinvestigator-initiated trials on a beneficiary-pays basis.
CRCs exclusively involved in investigator-initiatedtrials have been employed as needed. The number oftrial participants that CRCs interacted with was 5150
in 2014. The number of monitoring visits was 638 in
2014.
As part of patient awareness campaign activity, we
continued updating the Center homepage, preparedleaflets and distributed them at outpatient receptions.
The leaflets contain information about trials 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>
At Central Coordinating Unit, which wasestablished in the Center in 2010, 21 projects as ofMarch 2015 were adopted for support by the Unit
including project management, data management etc.
In cases of investigator-initiated post-market clinical
trials financially supported by pharmaceuticalcompanies, potential conflicts of interest weremanaged by introducing the funds directly to theCenter with contracts and by developing protocols
with scientific designs and conducting them
independently to the fund sponsors. In the firstinvestigator-initiated registered clinical trial of
medical device, the clinical trial notification was
submitted to the regulatory authority, PMDA, in
February 2012 followed by manufacturing andmarketing approval application submission in
November 2014. The device was then approved in
June
18th
2015.
And
in
the
secondinvestigator-initiated registered clinical trial which
was a first-in-human study, the clinical trial
notification was submitted to PMDA in December
2012 and the trial finished in March 2014.
<P1 Unit>
After the P1 Unit was established in May 2012, wearranged for starting clinical trials the preparation of

SOPs, manuals and forms, the establishment of
in-house collaboration system, the on-the-job trainingof the staff and the recruitment system of healthy
volunteers. The practical use of P1 unit started withthe first clinical trial in October 2012. In 2013, we
conducted the first-in-human clinical trials for ourown compound that are expected to modify thedisease progression of Alzheimer’s disease. In 2014,
we conducted five clinical trials including theindependent clinical study for a medical device, abioequivalence study, a first-in human clinical trial, apost-marketing clinical trial and a clinicalpharmacological trial.
< University Hospital Clinical Trial Alliance>
To cope with the so-called `drug lag problem`
relating to the drugs unapproved in Japan,
participation in global trials was an urgent necessity.
For this purpose, University Hospital Clinical Trial
Alliance (UHCT Alliance) comprised of 6 national
university hospitals (The University of Tokyo, Niigata
University, Gunma University, Tsukuba University,
Tokyo Medical and Dental University and Chiba
University) located in the central part of Japan wasestablished in 2006 and has since been incollaboration toward improvement of clinical trial
environments. The Alliance Office was based in the
University of Tokyo Hospital. In Alliance anorganizational structure has been established that cancooperatively attract trials and smoothly process themfor IRB approval. A course to educate the staff in
preparation for global trials 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.
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 clinical483

research.
Until the end of March 2014, 70 protocols wereintroduced to the Alliance including 40 multinational
trials. The Alliance helped to assess feasibility in 15
trials and to select the participating sites in 47.
Cooperative protocol presentation (hearing) sessions
were held for 37 protocols. Based on the data of 20
trials, 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 99 projects asof June 2015, and also commercially available withthe brand name ‘HOPE eACReSS’ of Fujitsu
Corporation.
<National University Hospital Clinical Research
Initiative>
In October 2012, National University Hospital
Clinical Research Initiative (NUH-CRI) wasestablished with our leading role and included allnational university hospitals in Japan (42 universities
and 45 hospitals). The office of the Initiative was also
taken charge of by the Alliance Office since thepreparatory meeting in July 2012. First general
meeting was held in January 2013 in Tokyo Medical
and Dental University and the second meeting washeld for two days in February 2014 in The Universityof Tokyo. The third meeting was held for two days in
January 2015 in The University of Tokyo.

Education/Training
The Center has been accepting M3 and M4 students
for two day training course in ‘Clinical Clerkship’since it become mandatory in 2013.
We accepted 10 graduate students (enrolled in
Master’s and Doctoral courses) in the Faculty of
Medicine, Graduate School of Pharmaceutical
Sciences and the School of Engineering, who took
Medical Innovation Initiative course. Medical
Innovation Initiative is part of “Fostering Medical
Researcher of the Future” project adopted by MEXT

(Ministry of Education, Culture, Sports andTechnology). In addition, we accepted 12 students
enrolled in Graduate School and Faculty of
Pharmaceutical Sciences, both from inside and outside
the university.
Nine resident physicians underwent one-monthtraining at the Center, as a part of the M.D.
residency-training program.
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 participate.
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 workshops with 8 alliance
universities in the Kanto Koshinetsu area, consistingof writing clinical research protocol, data management
and monitoring workshop. Workshops were attended
by 42, 82 and 69 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.
Besides“Research
EthicsSeminars”
forinvestigators have been provided three times a year
since the fiscal year 2003, as well as open seminars
for clinical investigator once a year.

Research Activities
An endowed course on clinical trial data
management was opened in April 2007 with thecooperation from the Center and the Biostatistics
Department, Graduate School of Medicine, conducting research and education on data management and484

biostatistics focused on practical application to trials.
The Center was involved in 40 presentations inscientific meetings, of which 27 were as presenters,and 28 invited lectures in fiscal 2014 and 45 publishedpapers in 2014.

Publications
1)

2)

3)

4)

5)

6)

Lee, S.L., Daimon M., Kawata T., Kohro T.,
Kimura K., Nakao T., Koide D., Watanabe M.,
Yamazaki T., Komuro I.: Estimation of Right
Atrial Pressure on Inferior Vena Cava Ultrasoundin Asian Patients. Circ J. 78(4):962-966,2014
Yamamoto M., Watanabe E., Suzuki T., YamazakiT., Ohtsu H., Ozaki Y., Ogawa S., Yamashita T.,
J-RHYTHM Ⅱ
Investigators: Association
between the quality of life and asymptomatic
episodes of paroxysmal atrial fibrillation in the
J-RHYTHM Ⅱ study. J Cardiol.64(1):64-9,
2014
Yokoi H., Nohara R., Daida H., Hata M., Kaku K.,
Kawamori R., Kishimoto J., Kurabayashi M.,
Masuda I., Sakuma I., Yamazaki T., Yoshida M.,
for the Justification for Athrosclerosis Regression
Treatment (JART) Investigators: Change in
Carotid Intima-Media Thickness in a High-Risk
Group of Patients by Intensive Lipid-Lowering
Theraphy With Rosuvastatin Subanalysis of the
JART Study. Int Heart J. 55(2):146-152,2014
Ono S., Niimi K., Fujishiro M., Takahashi Y.,
Sakaguchi Y., Nakayama C., Minatsuki C.,
Matsuda R., Hirayama-Asada I., Tsuji Y.,
Mochizuki S., Kodashima S., Yamamichi N.,
Ozeki A., Matsumoto L., Ohike Y., Yamazaki T.,
Koike K.: Evaluation of preterable insertion
routes for using ultrathin endoscopes. World J
Gastroenterol. 20(17):5045-50,2014
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
Kuga K., Yamasaki H., Hattori A., Xu DZ.,
Watanabe S., Arimoto T., Aonuma K., Kohro T.,
Yamazaki T., Nagai R.: Prognosis of Myocardial

Infarction With Left Ventricular Dysfunction in
the Coronary Revascularization Era -Subanalysisof the Japanese Coronary Artery Disease (JCAD)
Study-. Circ J. 78(10):2483-91, 2014
7) Daida H., Nohara R., Hata M., Kaku K.,
Kawamori R., Kishimoto J., Kurabayashi M.,
Masuda I., Sakuma I., Yamazaki T., Yokoi H. andYoshida M. for the Justification for
Atherosclerosis Regression Treatment (JART)
Investigators: Can Intensive Lipid-Lowering
Therapy Improve the Carotid Intima-Media
Thickness in Japanese Subjects Under Primary
Prevention for Cardiovascular Disease?: The
JART and JART Extension Subanalysis. J
Atheroscler Thromb. 21(7):739-54,2014
8) Inagaki N., Ueki K., Tanizawa Y., Watada H.,
Nakamura J., Shimomura I., Nishimura R.,
Yamazaki T., Kadowaki T.: Protocol for alarge-scale prospective observational study withalogliptin in patients with type 2 diabetes:
J-BRAND Registry.BMJ.4:e004760.doi:10,20149) 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 e111071:9,201410) 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
11) Ando K, Ohtsu H, Uchida S, Kaname S, Arakawa
Y, Fujita T; EVALUATE Study Group.:Anti-albuminuric effect of the aldosterone
blocker eplerenone in non-diabetic hypertensive
patients with albuminuria: a double-blind,randomized, placebo-controlled trial. Lancet
Diabetes Endocrinol, 2(12):944-955 (2014)12) Hosoya T, Kimura K, Itoh S, Inaba M, Uchida S,
Tomino Y, Makino H, Matsuo S, Yamamoto T,
Ohno I, Shibagaki Y, Iimuro S, Imai N,
Kuwabara M, Hayakawa H. The effect offebuxostat to prevent a further reduction in renal

485

13)

14)

15)

16)

17)

18)

function of patients with hyperuricemia who havenever had gout and are complicated by chronic
kidney disease stage 3: study protocol for a
multicenter randomized controlled study. Trials.
2014 Jan 16;15:26.doi:10.1186/1745-6215-15-26.
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.
Imai H., Watanabe M., Fujita T., Watanabe H.,
Harada K., Moritoyo T.; ANTCliPh (Academic
Network for Trials in Clinical Pharmacology )Trial 04 Study Group: Pharmacokinetics ofteriparatide after subcutaneous administration tovolunteers with renal failure: a pilot study. Int. J.
Clin. Pharmacol. Ther. 52:166-174, 2014.
Watanabe S, Amiya E, Watanabe M, Takata M,
Ozeki A, Watanabe A, Kawarasaki S, Nakao T,
Hosoya Y, Nagata K, Nagai R, Komuro I.
Elevated C-reactive protein levels and enhanced
high frequency vasomotion in patients withischemic heartdisease during brachial flowmediated dilation. PLoS One. 2014 Oct 9;9(10):e110013. doi: 10.1371
Ozeki A, Amiya E, Watanabe M, Hosoya Y,
Takata M, Watanabe A, Kawarasaki S, Nakao T,
Watanabe S, Omori K, Yamada N, Tahara Y,
Hirata Y, Nagai R. Effect of add-on aliskiren to
type 1 angiotensin receptor blocker therapy on
endothelial function and autonomic nervous
system in hypertensive patients with ischemic
heart disease. J Clin Hypertens (Greenwich).
2014 Aug;16(8):591-8.
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.
Amiya E, Watanabe M, Takata M, Nakao T,
Hosoya Y, Watanabe S, Nagai R, Komuro I.
Diurnal body temperature rise is reduced indiabetes with autonomic neuropathy. Clin Auton

19)

20)

21)

22)

23)

24)

Res. 2014 Apr;24(2):95-7.
Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Takata M, Ozeki A, Watanabe A,
Kawarasaki S, Taniguchi T, Ichimura Y, Toyama
T, Watanabe M, Hirata Y, Nagai R, Komuro I,
Sato S. Clinical correlation of brachial arteryflow-mediated dilation in patients with systemicsclerosis. Mod Rheumatol. 2014. Jan;24(1):106-11.
Takata M, Amiya E, Watanabe M, Omori K, ImaiY, Fujita D, Nishimura H, Kato M, Morota T,
Nawata K, Ozeki A, Watanabe A, Kawarasaki S,
Hosoya Y, Nakao T, Maemura K, Nagai R, Hirata
Y, Komuro I. Impairment of flow-mediateddilation correlates with aortic dilation in patientswith Marfan syndrome. Heart Vessels. 2014 Jul;29(4):478-85.
Akizawa T, Saito A, Gejyo F, Suzuki M,
Nishizawa Y, Tomino Y, Tsubakihara Y, Akiba T,
Hirakata H, Watanabe Y, Kawanishi H, Bessho M,
Udagawa Y, Aoki K, Uemura Y, Ohashi Y, andthe JET Study Group. Low hemoglobin levels
and hypo-responsiveness to erythropoiesisstimulating agent associated with poor survival inincident Japanese hemodialysis patients. Ther
Apher Dial. 2014; 18(5):404-13.
Ohta h, Uemura Y, Nakamura T, Fukunaga M,
Ohashi Y, Hosoi T, Mori S, Sugimoto T, Itoi E,
Orimo H, Shiraki M, for the Adequate Treatmentof Osteoporosis (A-TOP) Research Group. Serum
25-hydroxyvitaminD level as an independent
determinant of quality of life in osteoporosis witha high risk for fracture. Clin Ther. 2014; 36(2):225-35.
Ito S, Uenishi K, Ishida H, Uemura Y, Kodama
M, Fukuoka H. Relationships between birthweight and serum cholesterol levels in 2 healthy
Japanese late adolescents. J Nutr Sci Vitaminol.
2014; 60(2):108-13.
Akizawa T, Saito A, Gejyo F, Suzuki M,
Nishizawa Y, Tomino Y, Tsubakihara Y, Akiba
T, Hirakata H, Watanabe Y, Kawanishi H,
Bessho M, Udagawa Y, Aoki K, Uemura Y,
Ohashi Y, and the Co-JET Study Group. Impactsof recombinant human erythropoietin treatment
during predialysis periods on the progression ofchronic kidney disease in a large-scale cohort

486

study (Co-JET study). Ther Apher Dial. 2014;
18(2): 140-8.
25) Tanaka S, Miyazaki T, Uemura Y, Kuroda T,
Miyakawa N, Nakamura T, Fukunaga M, Ohashi Y,
Ohta H, Mori S, Hagino H, Hosoi T, Sugimoto T,
Itoi E, Orimo H, Shiraki M. Design of arandomized clinical trial of concurrent treatment
with vitamin K2 and risedronate compared to
risedronate alone in osteoporotic patients: JapaneseOsteoporosis Intervention Trial-03 (JOINT-03). J
Bone Mineral Metab. 2014; 32(3): 298-304.
26) 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.

487

University Hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Instructor
Hirono Ishikawa, Ph.D.

Homepage

http://www.umin.ac.jp/umin/

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
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488

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 410,000
registrants, and approximately 93,000,000 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
VHP:
Visible Human Project Image Data
EPOC:
Evaluation System of Postgraduate
Clinical Training

Debut:

Dental Training Evaluation andTabulation System

 Medical Examination and Treatment
http://www.umin.ac.jp/uhosp/• Intoxication database• Medical supplies and materials database• Drug information text database for patients• Drug information text database forpharmacists• Standardized nursing procedures database• Ministry of Education, Culture, Sports,
Science and Technology document public
information system• Basic hospital statistics database• National university hospital-related medical
dispute report• Collection of advanced medical procedures
application• 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• Video-on-demand (VOD) and streaming
service(3) Communication support• E-mail• Listserv• Discussion board• File exchange

Teaching Activities
Please refer to Department of Health Communication
for information about graduate and undergraduate
education.

489

Research Activities
Please refer to Department of Health Communication
for information about research activities.

References
Please refer to Department of Health Communication.

490

Organ Transplantation Service
Director and Professor
Norihiro KOKUDO

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/1512ishokugeka/index.html

The University of Tokyo Hospital has aggressively
performed organ transplantation. In 1966, the firstkidney transplantation in Japan was performed. In
1996, the first living donor liver transplantation was
performed. Organ Transplant Service started tofunction since 2003. Until today, more than 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.

491

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.

492

Center for Epidemiology andPreventive Medicine
Director & Professor
Tsutomu Yamazaki, M.D., Ph.D. (Clinical Research Support Center)

Associate Professor
Toru Suzuki, 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.,
Yuichi Ikeda, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)
Daigo Sawaki, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)
Yoshiko Mizuno,M.D., Ph.D. (Department of Clinical Epidemiology and Systems)
Mikio Takanashi, M.D., Ph.D. (Department of Clinical Epidemiology and Systems)
Atuko Nakayama, M.D., Ph.D. (Caradiovascular 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 clinicaldata and health-related information to develop more
efficient models for disease management, 3) by doing
the above 1) and 2), to promote preventive medicine
and medicine 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

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the Department of Clinical Epidemiology and Systems
and the Department of Ubiquitous Preventive
Medicine. In addition, examinations in the Department
are administered in collaboration with three Central
Clinical Facilities (Clinical Laboratory Center,
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) 2014from April 1, to March 31,
2015, the total number of examinees (who had basic
examinations and optional examinations) was 7,583,
including 2,705 in basic examinations, 555 incomplete cardiovascular examinations, 13 in home
blood pressure screening, 687 in complete cerebrovascular examinations, 104 in check up dementia,
353in colorectal cancer screening, 426 in uterine
cancer screening, 588 in breast cancer screening,
611in lung cancer screening, 1025 in tumor marker
diagnosis, 434 in estimation of gastric cancer risk, 9 inupper gastrointestinal endoscopy (later), and 73 inoral/dental examinations.

494

When examinees visit other departments in our
hospital for a work-up or treatment, we write a letterof referral by request. In the FY 2014, we issued 951
letters of referral to other departments in our hospitaland 46 to other hospitals.
We have expanded our public relations efforts andduring the FY 2013 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. Lee SL., Daimon M., Kawata T., Kohro T., Kimura
K., Nakao T., Koide D., Watanabe M., Yamazaki T.,
Komuro I.: Estimation of Right Atrial Pressure on
Inferior Vena Cava Ultrasound in Asian Patients.
Circ J. 78(4):962-966,2014
2. Yamamoto M., Watanabe E., Suzuki T., Yamazaki T.,
Ohtsu H., Ozaki Y., Ogawa S., Yamashita T.,
J-RHYTHM Ⅱ Investigators: Association between
the quality of life and asymptomatic episodes ofparoxysmal atrial fibrillation in the J-RHYTHM Ⅱ
study. J Cardiol.64(1):64-9,2014
3. Yokoi H., Nohara R., Daida H., Hata M., Kaku K.,
Kawamori R., Kishimoto J., Kurabayashi M.,
Masuda I., Sakuma I., Yamazaki T., Yoshida M., for
the Justification for Athrosclerosis Regression
Treatment (JART) Investigators: Change in Carotid
Intima-Media Thickness in a High-Risk Group ofPatients by Intensive Lipid-Lowering Theraphy
With Rosuvastatin Subanalysis of the JART Study.
Int Heart J. 55(2):146-152,2014
4. Ono S., Niimi K., Fujishiro M., Takahashi Y.,
Sakaguchi Y., Nakayama C., Minatsuki C., Matsuda
R., Hirayama-Asada I., Tsuji Y., Mochizuki S.,
Kodashima S., Yamamichi N., Ozeki A., Matsumoto
L., Ohike Y., Yamazaki T., Koike K.: Evaluation ofpreterable insertion routes for using ultrathin
endoscopes. World J Gastroenterol. 20(17):5045-50,
2014
5. Yoshii H., Onuma T., Yamazaki T., Watada H.,
Matsuhisa M., Matsumoto M., Kitagawa a K,
Kitakaze M., Yamasaki Y., Kawamori R.: Effects of

Pioglitazone on Macrovascular Events in Patientswith Type 2 Diabetes Mellitus at High Risk of
Stroke: The PROFIT-J Study. J Atheroscler Thromb.
21(6):563-73,2014
6. Kuga K., Yamasaki H., Hattori A., Xu DZ.,
Watanabe S., Arimoto T., Aonuma K., Kohro T.,
Yamazaki T., Nagai R.: Prognosis of Myocardial
Infarction With Left Ventricular Dysfunction in theCoronary Revascularization Era -Subanalysis of theJapanese Coronary Artery Disease (JCAD) Study-.
Circ J. 78(10):2483-91, 2014
7. Daida H., Nohara R., Hata M., Kaku K., Kawamori
R., Kishimoto J., Kurabayashi M., Masuda I.,
Sakuma I., Yamazaki T., Yokoi H. and Yoshida M.
for the Justification for Atherosclerosis Regression
Treatment (JART) Investigators: Can Intensive
Lipid-Lowering Therapy Improve the Carotid
Intima-Media Thickness in Japanese Subjects Under
Primary Prevention for Cardiovascular Disease?:
The JART and JART Extension Subanalysis. J
Atheroscler Thromb. 21(7):739-54,2014
8. Inagaki N., Ueki K., Tanizawa Y., Watada H.,
Nakamura J., Shimomura I., Nishimura R.,
Yamazaki T., Kadowaki T.: Protocol for a large-scale
prospective observational study with alogliptin inpatients with type 2 diabetes: J-BRAND Registry.
BMJ.4:e004760.doi:10,2014
9. Lee SL., 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
10. 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):251020,2014
11. Suzuki T, Eagle KA, Bossone E, Ballotta A,
Froehlich JB, Isselbacher EM. Medical management
in type B aortic dissection. Ann Cardiothorac Surg.
4:413-7, 201412. Hoff E, Eagle T, Pyeritz RE, Ehrlich M, Voehringer
M, Bossone E, Hutchison S, Peterson MD,Suzuki T,495

Greason K, Forteza A, Montgomery DG, Isselbacher
EM, Nienaber CA, and Eagle KA. Pulse pressure
and type A acute aortic dissection in-hospitaloutcomes (from the International Registry of Acute
Aortic Dissection). Am J Cardiol 113:1255-1259,
2014
13. Ozeki A, Amiya E, Watanabe M, Hosoya Y, Takata
M, Watanabe A, Kawarasaki S, Nakao T, Watanabe
S, Omori K, Yamada N, Tahara Y, Hirata Y, Nagai R.
Effect of Add-on Aliskiren to AT1-receptor blocker
on Endothelial Function and Autonomic Nervous
System in Hypertensive Patients with Ischemic
Heart Disease. J Clin Hypertens. 2014 Aug;16(8):591-8
14. Yamamichi N, Shimamoto T, Sakaguchi Y,
Takahashi Y, Kodashima S, Nakayama C, Minatsuki
C, Ono S, Mochizuki S, Matsuda R,
Asada-Hirayama I, Niimi K, Fujishiro M, Tsuji Y,
Takeuchi C, Kakimoto H, Goto O, Mitsushima T,
Koike K. Categorization of upper gastrointestinal
symptoms is useful in predicting background factors
and studying effects and usages of digestive drugs.
PLoS One. 2014 Feb 5;9(2):e88277.
15. Yamamichi N, Hirano C, Shimamoto T, Minatsuki C,
Takahashi Y, Nakayama C, Matsuda R, Fujishiro M,
Konno-Shimizu <, Kato J, Kodashima S, Ono S,
Niimi K, Mochizuki S, Tsuji T, Sakaguchi Y, AsadaHirayama I, Takeuchi C, Yakabi S, Kakimoto H,
Wada R, Mitsushima T, Ichinose M, Koike K.
Associated factors of atrophic gastritis diagnosed bydouble-contrast upper gastrointestinal barium X-ray
radiography: a cross-sectional study analyzing 6,901
healthy subjects in Japan. PLoS One. 2014 in press
16. Kodashima S, Fujishiro M, Ono S, Niimi K,
Mochizuki S, Asada-Hirayama I, Konno-Shimizu M,
Matsuda R, Minatsuki C, Nakayama C, Takahashi Y,
Sakaguchi Y, Yamamichi N, Tanaka C, Koike K.
Evaluation of a new image-enhanced endoscopic
technology using band-limited light for detection ofesophageal squamous cell carcinoma. Dig Endosc.
2014 Mar;26(2):164-71
17. Arezzo A, Passera R, Saito Y, Sakamoto T,
Kobayashi N, Sakamoto N, Yoshida N, Naito Y,
Fujishiro M, Niimi K, Ohya T, Ohata K, Okamura S,
Iizuka S, Takeuchi Y, Uedo N, Fusaroli P, Bonino
MA, Verra M, Morino M. Systematic review andmeta-analysis of endoscopic submucosal dissection

versus transanal endoscopic microsurgery for large
noninvasive rectal lesions. Surg Endosc. 2014 Feb;
28(2):427-38.
18. Tsuji Y, Fujishiro M, Kodashima S, Ono S, Niimi K,
Mochizuki S, Asada-Hirayama I, Matsuda R,
Minsatsuki C, Nakayama C, Takahashi Y, Sakaguchi
Y, Yamamichi N, Koike K. Polyglycolic acidsheets and fibrin glue decrease the risk of bleeding
after endoscopic submucosal dissection of gastricneoplasms (with video). Gastrointest Endosc. 2014
in press
19. Tsuji Y, Fujishiro M, Kodashima S, Niimi K, Ono S,
Yamamichi N, Koike K. Desirable training ofendoscopic submucosal dissection: further spreadworldwide. Ann Transl Med 2014;2(3):27
20. Mitsui T, Niimi K, Yamashita H, Goto O, Aikou S,
Hatao F, Wada I, Shimizu N, Fujishiro M, Koike K,
Seto Y. Non-exposed endoscopic wall-inversion
surgery as a novel partial gastrectomy technique.
Gastric Cancer. 2014 Jul;17(3):594-9.
21. Saito I, Tsuji Y, Sakaguchi Y, Niimi K, Ono S,
Kodashima S, Yamamichi N, Fujishiro M, Koike K.
Complications Related to Gastric Endoscopic
Submucosal Dissection and Their Managements.
Clin Endosc 2014;47:398-403.
22. 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. 2014 in press
23. Takahashi Y, Yamamichi N, Shimamoto T,
Mochizuki S, Fujishiro M, Takeuchi C, Sakaguchi Y,
Niimi K, Ono S, Kodashima S, Mitsushima T, Koike
K. Helicobacter pylori infection is positively associated with gallstones: a large-scale cross-sectional
study in Japan. J Gastroenterol. 2014 May;49(5):882-9.
International Conferences
1. Epidemiology and Prevention/Nutrition, Physical
Activity and Metabolism, 2014 Scientific Sessions(San Francisco U.S.A:2014/3/18-21)
・Lee S., Hashimoto H., Yasunaga H., Horiguchi H.,
Kohro T., Iimuro S., Koide D., Komuro I., Yamazaki
T.

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2.

3.

4.

5.

6.

7.

Impact Of Income Level On The Care Of Senile
Aortic Stenosis Under Universal Health Coverage
European Society of Cardiology Congress(Barcelona Spain:2014/8/30-9/3)
・Lee L. S., Yasunaga H., Matsui H., Kohro H.,
Koide D., Yamazaki T., Komuro I.
Hoptial volume has significant impact on mortality
with cardiogenic shock patients who are in need ofmechanical circulatory support
European Society of Cardiology Congress(Barcelona Spain:2014/8/30-9/3)
・Lee L. S., Kojima T., Yasunaga H., Matsui H.,
Kohro T., Koide D., Fujiu K., Yamazaki T., Komuro
I.
Impact of hospital volume on complication rate ofcatheter ablation in patients with atrial fibrillation
Keystone symposia (Whistler, Canada: 2014/3/1621)
・ Ozeki A, Watanabe M, Manabe I, Imai Y,
Watanabe A, Kawarasaki S, Maemura K, Yamazaki
T, Nagai R, Komuro I. ARID5B expression may
affect susceptibility to atherosclerosis and diabetes
mellitus by regulating adiponectin expression level
through PPRE in the promoter.
United European Gastroenterology Week. (Vienna,
Austria :2014/10/18-22)
・Keiko Niimi, Susumu Aikou, Yoshiki, Sakaguchi,
Sinya Kodashima, Nobutake Yamamichi, Hiroharu
Yamashita, Mitsuhiro Fujishiro, Yasuyuki Seto,
Kazuhiko Koike.
Non-exposed endoscopic
wall-inversion surgery (NEWS) as a novel
full-thickness resection technique for gastric tumor.
Asia Pacific Digestive Week. (Bali, Indoneshia:
2014/11/22-25)
・Keiko Niimi, Osamu Goto, Kazumichi Kawakubo,
Yosuke Nakai, Chihiro Minatsuki, Itsuko AsadaHirayama, Satoshi Mochizuki, Satoshi Ono, Shinya
Kodashima, Nobutake Yamamichi, Hiroyuki
Isayama, Mitsuhiro Fujishiro, Kazuhiko Koike.
Learning Curve For Endoscopic Ultrasound Guided
Fine Needle Aspiration Of Gastrointestinal Submucosal Tumors.
The 4th International Symposium on Chylomicrons
in Disease (March 29-30 2014, Tokyo, Japan)
Hiroaki Okazaki, Mikio Takanashi, Guosheng Liang“Molecular regulation of diabetic hyperlipidemia”“A critical role of hormone-sensitive lipase in

streptozotocin-induced diabetic hypertriglyceridemia”
8. 9th Metabolic Syndrome, Type 2 Diabetes andAtherosclerosis Congress（September 12-14 2014,
Kyoto, Japan）
Mikio Takanashi, Satoru Takase, Akari Noda,
Yoshino Taira, Sachiko Okazaki, Futoshi Shionoiri,
Yoko IIzuka, Jun-ichi Osuga, Shun Ishibashi,
Takashi Kadowaki, Hiroaki Okazaki“A critical role of hormone-sensitive lipase in
streptozotocin-induced diabetic hypertriglyceridemia”

497

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.,

Keiichi Hishikawa, M.D., Ph.D.,

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

Satoru Yamagami, M.D., Ph.D.

Research Associates
Makoto Komura, M.D., Ph.D.,

Osamu Takase, M.D., Ph.D.

Yuko Fujihara, D.D.S., 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 fortreatment 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 healthcare CO., Ltd.
July, 2002 Department of Vascular Regeneration
founded by a donation from Daiichi Pharmaceutical

498

Co., Ltd.
July, 2002 Department of Bone & Cartilage
Regenerative Medicine founded by a donation from
TAKEDA Chemical Industries., Ltd.
September, 2002 Department of Regeneration
Medicine for Hematopoiesis founded by a donationfrom KIRIN Brewery Co., Ltd.
November, 2002 Department of Clinical Renal
Regeneration founded by a donation from MOCHIDA
Pharmaceutical Co., Ltd.
November, 2002 Department of MENICON
Cartilage & Bone Regeneration founded by a donationfrom MENICON Co., Ltd.
March, 2003 The Cell Processing Center set up on
the 8th floor of the In-patient Ward B.
June, 2005 Department of Corneal Tissue
Regeneration was renewed by a donation fromAMNIO TEC 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 ofpediatric surgery.
July, 2007 Department of Bone & Cartilage
Regenerativen Medicine was renewed by a donationfrom Eli Lilly Japan K.K.
March, 2012 Department of Advanced Nephlorogy
and Regenerative Medicine founded by a donationfrom Zenjinkai.

Research activities
As for corneal regeneration, we aim at constructionof regenerated cornea, clinical application of more
improved corneal epithelial sheet transplantation forocular surface reconstruction, and establishment andclinical application of corneal endotheliumtransplantation.
To achieve these goals, 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. We perform a
research to make it possible to create regenerative
tissues with low cost. This should be useful togenerate industries of regenerative medicine.
As for vascular regeneration, we aim atestablishment 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.

499

As for renal regeneration, we aim at specificmethod to differentiate human iPS cells to kidney cells.
To achieve these goals, we are conducting epigenetic
analysis of human kidney derived iPS cells.
Moreover, we are trying to establish 3-D culture
system for safe clinical application of human iPS cells,
and determining new target of cancer therapy bycomprehensive epigenetic analysis of cancer dereived
iPS cells.
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
preparing for an investigator-initiated clinical trial “Aclinical trial for the validation of safety and efficacy of
the implant-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 and Department of Bone and Cartilage
Regenerative Medicine are carrying forward theapplication procedures to obtain human ES cells from
Institute for Frontier Medical Sciences, Kyoto
University, which will be approved shortly.

Clinical Studies
Of particular note is clinical studies started in the four
departments as a result of basic research. In Projectfor Regenerative Medicine of Hematopoiesis, clinicalstudy 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
caused by peripheral vascular diseases (IRB approval
number #825 and #826) have been started andcontinued without causing major side effects. In
Department of Corneal Tissue Regeneration, clinicalstudies on transplantation of cultured autologous oral
mucous epithelial sheet on amniotic membrane forocular surface reconstruction, and corneal endothelial
stem cell transplantation for decrease in number ofcorneal endotheliums (IRB approval number #363 and#898) have been started. In Department of Bone &Cartilage Regenerative Medicine, a clinical study onbone implants into non-loading parts (IRB approval
number #1310) was conducted on 10 patients
successfully and a large-scale clinical trial was started
across the nation. In project for cartilage regeneration,
preparations for an investigator-initiated clinical trial“A clinical trial for the validation of safety andefficacy of the implant-type tissue-engineered
cartilage using autologous cells” have been started. As
stated above, we are proceeding translational researchaiming at clinical application of tissue engineering andregenerative medicine.

500

Contribution to the Hospital
Division of Tissue Engineering, as a cooperative
research facility in the Hospital, opens expensive
special machines that each laboratory cannot afford toequip with, such as a confocal laser scanningmicroscope, a cell analyzer and a cell sorter to the
Hospital staff, letting them use with cost sharing.
Department of Plastic Surgery is conducting researchusing this facility.

References
1. 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. doi: 10.2220/biomedres.36.21.
2. 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. doi: 10.1073/
pnas.1419699112.
3. Okada K, Fukai A, Mori D, Hosaka Y, Yano F,
Chung UI, Kawaguchi H, Tanaka S, Ikeda T, Saito
T. Identification of SCAN Domain Zinc-Finger
Gene ZNF449 as a Novel Factor of Chondrogenesis. PLoS One. 2014 Dec 29;9(12): e115169.
doi: 10.1371/journal.pone.0115169.
4. Yano F, Ohba S, Hosaka Y, Saito T, Chung UI.
Disease-modifying effects of TD-198946 on
progressed osteoarthritis in a mouse model. Ann
Rheum Dis. 2014 Nov;73(11):2062-4. doi: 10.
1136/annrheumdis-2014-205672.
5. Mori Y, Mori D, Chung UI, Tanaka S, Heierhorst
J, Buchou T, Baudier J, Kawaguchi H, Saito T.
S100A1 and S100B are dispensable for
endochondral
ossification
duringskeletaldevelopment. Biomed Res. 2014;35(4):243-50.
6. Mori Y, Chung UI, Tanaka S, Saito T.
Determination of differential gene expression
profiles in superficial and deeper zones of mature
rat articular cartilage using RNA sequencing oflaser microdissected tissue specimens. Biomed
Res. 2014;35(4):263-70.
7. Fujiwara S, Hoshikawa S, Ueno T, Hirata M,
Saito T, Ikeda T, Kawaguchi H, Nakamura K,
Tanaka S, Ogata T. SOX10 transactivates S100B
to suppress Schwann cell proliferation and topromote myelination. PLoS One. 2014 Dec 23;9(12):e115400. doi:10.1371/journal.pone. 0115400.
eCollection 2014.
8. Fujihara Y, Takato T, Hoshi K. Macrophageinducing FasL on chondrocytes forms immune
privilege in cartilage tissue engineering, enhancing in vivo regeneration. Stem Cells. 2014 May;32(5):1208-19.
9. Kawase-Koga Y, Saijo H, Hoshi K, Takato T,
Mori Y. Surgical management of odontogenic
myxoma: a case report and review of the literature.
BMC Res Notes. 2014 Apr 5;7:214.
10. Mori Y, Takato T, Hoshi K, Kanno Y, Sugiyama M,
Ohkubo K, Saijo H. Correction of upturned nasal
tip with a costal cartilage graft in bilateral cleft lip
patients. J Craniofac Surg. 2014 Sep; 25(5):e443-5.
11. Abe M, Mori Y, Inaki R, Ohata Y, Abe T, Saijo H,
Ohkubo K, Hoshi K, Takato T. A Case of
Odontogenic Infection by Streptococcus constellatus Leading to Systemic Infection in a Cogan's
Syndrome Patient. Case Rep Dent. 2014;2014:793174.

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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 2014, the Department of Child
Psychiatry consisted of 12 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 patientswith a broad 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 ObsessiveCompulsive Disorders (OCD).
Number of new patients in 2014 was 218 andalmost similar to that in 2013. A large part of the newpatients consisted of patients with ASD, tic disorder or
ADHD. Sixty-three patients were aged 11-15 years old,and 59 patients were aged 6-10 years old. In otherwords, more than half of the patients are students ofprimary school or junior high school. Thirty-fivepatients were younger than 6 years old, and 29
patients were older than 20 years old, suggesting
steady needs for assessment and treatment of bothpreschoolers and adults with developmental disorders.

502

The follow-up clinic consisted of general clinic andspecial clinics (high-functioning ASD clinic and
Tic/OCD clinic). At the general clinic, a rigorous
diagnosis based on detailed assessment and decision
about treatment course are provided for children andadolescents with any kinds of mental problems. After
fine adjustment of treatment course within a given
period, the patients are referred to community
hospitals/clinics or intervention/education facilities
with a detailed report. The special clinics meet a needfor high level services and work with research 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.
Interventions by psychologists include “psychology
outpatient services” and “group therapy”. Patients
involved in interventions are mainly individuals with
developmental disabilities, and individualized
treatment focusing on developmental viewpoint isplanned for each. “Psychology outpatient clinic”
usually provides 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
the disabled 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. “Grouptherapy” for preschool children with ASD consists of
10 sessions.
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 “group therapy” for preschool children.
Graduate students in clinical psychology course fromthe University of Tokyo participate in “short-termgroup therapy” for preschoolers 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 “group therapy” for preschoolers, andvisit to community 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 ofassessment about developmental disorders areprovided as opportunity to get knowledge andexperience of developmental disorders.
In response to the increasing interest to adults with
developmental disorders, a seminar of developmental
disorders was held in June 2014, and over 220 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 comparing individual treatment and“group therapy” is being undertaken.
Effectiveness of a program of group cognitive

503

behavior therapy for adults with high-functioning
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.
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 beginning genetic analysis of Tourette
syndrome also.
Neuroimaging
Studies include structural MRI, Near-Infrared
Spectroscopy (NIRS) and functional MRI with
exploring the pathogenesis of developmental disorders
such as ASD. One of the intensive study is theexamination of prefrontal blood flow in ASD and
ADHD by NIRS which is non invasive and easily
applicable to children and developmentally disabledindividuals. Possibility of NIRS as a predictor of
efficacy of methylphenidate for children with ADHD
is intensively examined also. Functional MRI study ofadults with ADHD and adults with Tourette syndromeby delayed reward task is in process.

References
1. Takizawa R, Fukuda M, Kawasaki S, Kasai K,
Mimura M, Pu S, Noda T, Niwa SI, Okazaki Y; onbehalf of the Joint Project for PsychiatricApplication of Near-Infrared Spectroscopy (JPSYNIRS) Group (Ishii-Takahashi A). Neuroimagingaided differential diagnosis of the depressive state.
Neuroimage 85 Pt1: 498-507, 2014.
2. 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 Pt1: 518-26, 2014.
3. 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,Ishii-Takahashi
A, Kawakubo Y, Kasai K. Genetic influences on
prefrontal activation during a verbal fluency task
in adults: a twin study based on multichannel
near-infrared spectroscopy. Neuroimage. 85 Pt 1:
508-17, 2014.
4. Watanabe T, Abe O, Kuwabara H, Yahata N,
Takano Y, Iwashiro N, Natsubori T,Aoki Y, Takao
H, Kawakubo Y, Kamio Y, Kato N, Miyashita Y,
Kasai K, Yamasue H. Mitigation of sociocommunicational deficits of autism throughoxytocin-induced recovery of medial prefrontal
activity: a randomized trial. JAMA Psychiatry.
71(2):166-75, 2014.
5. 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. Social Cognitive and Affective Neuroscience.
9(6):767-75, 2014.
6. 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 A, Kasai K, Yamasue H. Oxytocin

504

improves behavioural and neural deficits in
inferring others'social emotions in autism. Brain.
137(Pt 11):3073-86, 2014.
7. Itahashi T, Yamada T, Nakamura M, Watanabe H,
Yamagata B, Jimbo D, Shioda S, Kuroda M,
Toriizuka K, Kato N, Hashimoto R. Linked
alterations in gray and white matter morphology
in adults with high-functioning autism spectrum
disorder: a multimodal brain imaging study.
Neuroimage Clin. 3(7):155-69, 2014.
8. Kamio Y, Inada N, Koyama T, Inokuchi E,
Tsuchiya K, Kuroda M. Effectiveness of Using
the Modified Checklist for Autism in Toddlers in
Two-Stage Screening of Autism Spectrum
Disorder at the 18-Month Health Check-Up in
Japan. Journal of Autism and Developmental
Disorder. 44(1):194-203,2014.
9. Kuwabara H, Araki T, Yamasaki S, Ando S, Kano Y,
Kasai K. Regional differences in post-traumaticstress symptoms among children after the 2011
tsunami in Higashi-Matsushima, Japan. Brain Dev.
(in press)

505

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 2014, thenumber achieved to more than total 500 cases. To date
we have become to collaborate with almost all
departments treating cancer in our hospital. These
results indicate that the hospital understands thesignificance of 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

506

and palliative care team and attend the daily teamconference on weekdays.

information about diagnoses, recurrence, progression and prognosis of illness to his patients.

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.

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.

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 care of suchpatients concisely to the database. They acquire theoutline of data management of the palliative careconnected directly to a clinical research.
･ 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

507

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. Sumitani M, Yasunaga H, Uchida K, Horiguchi H,
Nakamura M, Ohe K, Fushima K, Matsuda S,
Yamada Y. Perioperative factors affecting theoccurrence of acute complex regional pain
syndrome following limb bone fracture surgery:
Data from the Japanese Diagnosis Procedure
Combination database. Rheumatology 2014; 53:
1186-93
2. Sumitani M, Misaki M, Kumagaya S, Ogata T,
Yamada Y, Miyauchi S. Dissociation in accessing
space and number representation in pathologic
pain patients. Brain and Cognition 2014; 90:
151-6
3. Sumitani M, Ueda H, Hozumi J, Inoue R, Kogure
T, Ogata T, Yamada Y. Minocycline does notdecrease intensity of neuropathic pain, but

4.

5.

6.

7.

8.

improves its affective dimension. J Pain Palliat
Care Pharmacother 2014 (in press)
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 2014
(in press)
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 2014 (in press)
Suka M, Odajima T, Okamoto M, Sumitani M,
Nakayama T, Sugimori H. Reading comprehension of health checkup reports and health literacy
in Japanese people. Environmental Health andPreventive Medicine 2014; 19: 295-306
Nakamura M, Nishiwaki Y, Sumitani M, Ushida T,
Yamashita T, Konno S, Taguchi T, Toyama Y.
Investigation of chronic musculoskeletal pain
(third report): with special reference to theimportance of neuropathic pain and psychogenic
pain. J Orthop Sci 2014; 19: 667-75
Kogure T, Sumitani M, Suka M, Ishikawa H,
Odajima T, Igarashi A, Kusama M, Okamoto M,
Sugimori H, Kawahara K. Validity and Reliabilityof the Japanese version of the Newest Vital Sign:
a preliminary study. Plos One 2014; 9: e94582(And, more than 30 Japanese articles)

508

Cancer Resource Center
Associate Professor
Sachiyo Nomura, M.D., Ph.D.

Assistant Professor
Takako Wakeda, M.D., Ph.D.

Homepage

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

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 Resource Center to provide consultations tocancer patients and their families as well as residents
in neighboring communities with aim of leading them
to appropriate departments and facilities.
The Center consists of a chief of the center, anassistant chief and two consultant nurses. In addition,
staff from the Cancer Board, an in-hospitalinterdisciplinary cancer treatment team, may join
consultations depending on issues to be discussed.

Clinical activities
1. Provision of information if patient contracts
cancer
If a person gets cancer, the first thing they need to
do is collect information on cancer. This Center
provides information and booklets on different
types of cancer. Furthermore, in order to select thebest treatment for oneself from among thetherapies presented by doctors, the person needs
to accurately understand the doctors’ explanations.
At the Center, we explain difficult medical terms
in simple language, and we help patients
understand their doctors’ advice.
2. Various kinds of advice on the medical care ofcancer

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 Center
provides patients with advice and support, so thatthey can resolve such worries.
3. Provision of information on second opinion
The Center provides information on how to get asecond opinion and on facilities that provide
second opinions.
4. Provision of general information and advice on
cancer
The Center sends out and provides information topeople who do not have cancer but who want tofind out about cancer, for instance, the treatment
and screening for it.

Scope
We are going to meet patients and their families not
only of our patients but also from all over Japan. We
will make effort to have many patients receive goodtherapies with their satisfaction.

509

Genome Informatics
Director & Professor
Takashi Kadowaki, M.D., Ph.D.

1. Organization
The Department of Genome Informatics started as a
special unit conducting research on clinicalepidemiology and human genetics in 2003. Our
section functions as the unit to establish/support
clinical and epidemiological data sampling/ management and to accomplish an appropriate and efficient
application of results of recently advanced human
genetics and genomics. In addition, as the unit oftraining and educating specialists of clinicalepidemiology and human genetics. It consists of one
professor and different specialties participating in thedepartment. They include cardiologists, diabetologists,
epidemiologists, and statisticians. Our section also
supported designing of clinical / genetic studies andprovided 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 to identify
variations conferring susceptibility to T2D in theJapanese population that were not detected in theprevious scans. We imputed 6,209,637 variants
derived from 286 East Asian subjects (November
2010 Release) in 5,976 cases and 20,829 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 that in addition to variants of the previously
reported loci, there were 3 loci harboring multiple
variants possibly associated with T2D. These findings
highlight the usefulness of conducting GWAS toclarify the genetic predisposition to T2D in East
Asians as well as in European-origin populations.

Our study highlights the benefits of using data
derived from next-generation sequencing of thehuman genome such as the 1000 Genomes Project to
explore T2D loci more comprehensively. We also took
part in the Asian Genetic Epidemiology Network(AGEN) consortium which conducted a large-scale
GWAS with several trans-ethnic consortium comprising up to 26,488 cases and 83,262 controls and found
7 novel T2D loci in East Asian, European, South
Asian and Mexican-American populations.
In cardiology and vascular medicine, we focused onatherosclerotic diseases such as coronary stenosis andmyocardial infarction. It is important to accumulate
and analyze data obtained in daily practice to gain
insight into a larger clinical picture. Thus, we
designed and developed a coronary angiography andintervention reporting system (CAIRS) to collect data
and analyze outcomes of coronary intervention. The
resulting advanced CAIRS can record detailed data on
coronary angiographic and interventional procedures.
We have also 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
provide detailed and timely insight into the 'real world'of coronary atherosclerotic diseases and their clinicaloutcome.
Concerning genetic analysis of monogenic diseases,
our department has provided service of genetic
analysis of Marfan syndrome (MFS), one of therepresentative connective tissue diseases. Approximately 70-80% of MFS is caused by genetic mutationsof FBN1 gene. We performed mutational analysis
using a high-throughput microarray-based resequencing system.

510

3．References
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Yasuda K, Horikoshi M, Peng C, Hu C, Ma RC,
Imamura M, Iwata M, Tsunoda T, Morizono T,
Shojima N, So WY, Leung TF, Kwan P, Zhang R,
Wang J, Yu W, Maegawa H, Hirose H;
DIAGRAM consortium, Kaku K, Ito C, Watada H,
Tanaka Y, Tobe K, Kashiwagi A, Kawamori R, Jia
W, Chan JC, Teo YY, Shyong TE, Kamatani N,
Kubo M, Maeda S, Kadowaki T, Genome-wide
association study identifies three novel loci for
type 2 diabetes. Human Molecular Genetics
23:239-246, 2014
2. DIAbetes Genetics Replication And Meta-analysis(DIAGRAM) Consortium; Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D)
Consortium; South Asian Type 2 Diabetes(SAT2D) Consortium; Mexican American Type 2
Diabetes (MAT2D) Consortium; Type 2 Diabetes
Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES)
Consortium, Mahajan A,… Yamauchi T,…
Kadowaki T,… Morris AP, Genome-wide transancestry meta-analysis provides insight into thegenetic architecture of type 2 diabetes
susceptibility. Nature Genetics 46:234-244, 2014
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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 (in press)
4. 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. European
Journal of Human Genetics (in press)

511

Department of Clinical Genomics,
Medical Genome Center
Director & Professor
Shoji Tsuji, M.D., Ph.D.

Vice-director & Associate Professor
Jun Goto, M.D., Ph.D.

Organization
The Department of Clinical Genomics started as a
special unit conducting genomic medicine or clinicalhuman genetics services in 2003. Our department
functions as the core unit to accomplish an appropriate
and efficient application of results of recently
advanced human genetics and genomics to clinicalpractice in the hospital and as the unit of training andeducating specialists of human genetics practice. It
consists of one professor and many different
specialties participate in the department. They include
pediatricians, obstetricians, internist (cardiologists,diabetologists, and neurologists), surgeons, and staffs
of the Departments of Clinical Laboratory Medicine,
Human Genetics and Nursing Science.

Activities
The exclusive consultation room (Room 200) is
allocated in the outpatient clinic. Consultation andcounseling is performed by a team of medical doctor
and non-M.D. staffs. All cases are reviewed anddiscussed at the conference which is held on the 1st
Monday every month.
Counseling of participants in researches including
genome or gene analysis is a duty with which thehospital and the faculty charge the department.
To build suitable clinical systems including
modern genomic medicine we are cooperating withother departments. We are participating in Marfan’sSyndrome Clinic which is managed 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, Takahashi Y, Hayashi T, Saito K,
Furuya H, Watanabe M, Murata M, Suzuki M,
Sugiura A, Sawai S, Shibuya K, Ueda N, Ichikawa
Y, Kanazawa I, Goto J, Tsuji S. Molecularepidemiology and clinical spectrum of hereditary
spastic paraplegia in the Japanese population
based on comprehensive mutational analyses. J
Hum Genet. 59:163-72, 2014.
2. Mitsui J, Tsuji S. Genomic aspects of sporadic
neurodegenerative diseases. Biochem Biophys
Res Commun. 452:221-5, 2014.
3. Tokushige S, Mitsui J, Goto R, Hatano K, Terao Y,
Kanda T, Nakano R and Tsuji S. Sensorimotor
neuropathy in late-onset Krabbe disease progressing over 40 years after onset. Neruol Clin
Neurosci. 2:114–116, 2014
4. Yamada M, Tanaka M, Takagi M, Kobayashi S,
Taguchi Y, Takashima S, Tanaka K, Touge T,
Hatsuta H, Murayama S, Hayashi Y, Kaneko M,
Ishiura H, Mitsui J, Atsuta N, Sobue G,
Shimozawa N, Inuzuka T, Tsuji S, Hozumi I.

512

Evaluation of SLC20A2 mutations that cause
idiopathic basal ganglia calcification in Japan.
Neurol. 82:705-12, 2014.

513

Department of Genome Analysis,
Medical Genome Center
Director & 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), which havebeen installed until now, include three Illumina
HiSeq2500s ， one Pacific Bioscience RS II, one
Illumina MiSeq, one Life Technologies 5500xl, and
one Roche GS Junior. Robotics for preparation ofsamples has also been installed. Computer servers forprocessing of massive amount of genome data havebeen installed in the server room, which are connected
to NGs via network system isolated from the internet.

Activities
The core facility offers genome sequencing
employing NGSs for other laboratories in the
University of Tokyo Hospital as well as for the
in-house projects. The core facility further offers
genome sequencing employing NGSs for laboratories
outside of the University of Tokyo. Starting in 2011,
exome and target sequencing of 5,964 samples (3,736
samples for the in-house project) and whole genome
sequencing of 121 samples (79 samples for the
in-house projects) have been accomplished.

Research Accomplishments
Kenny-Caffey syndrome (KCS) is a rare dysmorphologic syndrome characterized by proportionate
short stature, cortical thickening and medullarystenosis of tubular bones, delayed closure of anterior
fontanelle, eye abnormalities, and hypoparathyroidism.
Four unrelated Japanese patients with typical sporadic
KCS2 were recruited, and exome sequencing was
performed in three patients. The possible candidate

genes were explored by a de novo mutation detection
method. A single gene, FAM111A (NM_001142519.1),
was identified as the candidate gene. An identicalmissense mutation, R569H, was heterozygously
detected in all the three patients but not in theunaffected family members. This mutation was also
found in an additional unrelated patient (J Bone
Miner Res. 29:992-8, 2014.).
Long expansions of short tandem repeats (STRs)
are associated with some genetic diseases. A
enumerous number of short reads remains, however,largely unexplored, because of the difficulty in
elucidating STRs longer than 100 bp, the typicallength of short reads in massively parallel sequencers.
We propose ab initio procedures for detecting andlocating long STRs promptly by using the frequency
distribution of all STRs and paired-end read
information. This is the first proposed method for
rapidly finding disease-associated long STRs in
personal genomes using hybrid sequencing of shortand long reads (Bioinformatics. 30:815-22, 2014).

Publications
1. Doi K, Monjo T, Hoang PH, Yoshimura J, Yurino
H, Mitsui J, Ishiura H, Takahashi Y, Ichikawa Y,
Goto J, Tsuji S, Morishita S. Rapid detection of
expanded short tandem repeats in personal genomics using hybrid sequencing. Bioinformatics.
30:815-22, 2014.
2. Ishiura H, Takahashi Y, Hayashi T, Saito K,
Furuya H, Watanabe M, Murata M, Suzuki M,
Sugiura A, Sawai S, Shibuya K, Ueda N, Ichikawa
Y, Kanazawa I, Goto J, Tsuji S. Molecularepidemiology and clinical spectrum of hereditary

514

spastic paraplegia in the Japanese population
based on comprehensive mutational analyses. J
Hum Genet. 59:163-72, 2014.
3. Koh K, Ishiura H, Miwa M, Doi K, Yoshimura J,
Mitsui J, Goto J, Morishita S, Tsuji S andTakiyama Y. Exome sequencing shows a novel denovo mutation in ATL1. Neurol Clin Neurosci. 2:
1-4, 2014
4. 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 type 2. J Bone Miner
Res. 29:992-8, 2014.
5. Mitsui J, Tsuji S. Genomic aspects of sporadic
neurodegenerative diseases. Biochem Biophys
Res Commun. 452:221-5, 2014.
6. Mitsui J, Tsuji S. Mutant COQ2 in multiplesystem atrophy. N Engl J Med. 371:82-3, 2014.
7. Sasaki M, Ishii A, Saito Y, Morisada N, Iijima K,
Takada S, Araki A, Tanabe Y, Arai H, Yamashita S,
Ohashi T, Oda Y, Ichiseki H, Hirabayashi S,
Yasuhara A, Kawawaki H, Kimura S, Shimono M,
Narumiya S, Suzuki M, Yoshida T, Oyazato Y,
Tsuneishi S, Ozasa S, Yokochi K, Dejima S,
Akiyama T, Kishi N, Kira R, Ikeda T, Oguni H,
Zhang B, Tsuji S, Hirose S. Genotype-phenotype
correlations in alternating hemiplegia ofchildhood. Neurol. 82:482-90, 2014.
8. Shimazaki H, Honda J, Naoi T, Namekawa M,
Nakano I, Yazaki M, Nakamura K, Yoshida K,
Ikeda S, Ishiura H, Fukuda Y, Takahashi Y, Goto J,
Tsuji S, Takiyama Y. Autosomal-recessive
complicated spastic paraplegia with a novel
lysosomal trafficking regulator gene mutation. J
Neurol Neurosurg Psych. 85: 1024-8, 2014.
9. Tokushige S, Mitsui J, Goto R, Hatano K, Terao Y,
Kanda T, Nakano R and Tsuji S. Sensorimotor
neuropathy in late-onset Krabbe disease progressing over 40 years after onset. Neruol Clin
Neurosci. 2:114–116, 2014
10. Yamada M, Tanaka M, Takagi M, Kobayashi S,
Taguchi Y, Takashima S, Tanaka K, Touge T,
Hatsuta H, Murayama S, Hayashi Y, Kaneko M,
Ishiura H, Mitsui J, Atsuta N, Sobue G,
Shimozawa N, Inuzuka T, Tsuji S, Hozumi I.
Evaluation of SLC20A2 mutations that cause

idiopathic basal ganglia calcification in Japan.
Neurol. 82:705-12, 2014.

515

Cooperative Unit of Medicine andEngineering Research
Organization
The University of Tokyo Hospital
Cardiovascular Medicine, Nutrition and Metabolism, Surgical Oncology, Vascular Surgery,
Artificial Organ and Transplantation, Cardiac Surgery, Thoracic Surgery, Neurosurgery,
Urology, Orthopaedic Surgery, Oral and maxillofacial Surgery, Radiology, Tissue
Engineering Unit, Department of Clinical Epidemiology & Systems, Bone & Cartilage
Regenerative Medicine, Cartilage of Bone Regeneration, Department of
Immunotherapeutics (Medinet), Division of Science for Joint Reconstruction

Engineering and Pharmaceutical Research
Chemical System Engineering, Mechanical Engineering, Precision Engineering, Quantum
Engineering and System Science, Nuclear Engineering and Management, Chemistry andBiotechnology, Material Engineering, Information Science and Technology, Frontier
Sciences, Pharmaceutical Sciences Laboratory of Chemistry and Biology, Center for Disease
Biology and Integrative Medicine, Center for Disease Biology and Integrative Medicine
Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine
Clinical Biotechnology, Research Center for Advanced Science and Technology, Institute ofIndustrial Science

Homepage

http://plaza.umin.ac.jp/~ikourenk/

Introduction and Organization
The application of an advanced bioscience to a newtechnical development of clinical medicine has
become an important subject for research in the 21st
century. We’ve established Cooperative Unit ofMedicine and Engineering Research at The Universityof Tokyo Hospital to create a new research andeducation center, which cross-sectionally unites
medicine with engineering research for the development of a next generation medical technology.
2002 June. The establishment of Cooperative Unitof Medicine and Engineering Research was approvedby a hospital administration committee as a special
practice unit that belongs to The University of Tokyo
Hospital.
2002 September. A steering committee of Cooperative Unit of Medicine and Engineering Research

was organized by representative members of relevant
clinical departments. The committee made a decisionof the following basic principles; recruitment for theparticipation to this unit should be, as a general rule,
an open call for a joint project of clinical department
and engineering or pharmaceutical research group in
The University of Tokyo, an equipment/administration
expense of a laboratory should be a responsibility of
the user, and a basic participation period to this unit
should be three years and for the continued
participation in the unit, a review and approve of thesteering committee is indispensable.
2002 October. An open call for participants to thisunit started. There were 18 applications and thesteering committee approved all projects after review.
A liaison conference of Cooperative Unit of Medicine
and Engineering Research was organized by arepresentative member of each project. Configurationof each project in a space of 554.4m2 that is consisted

516

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.

517

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 /518

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

519

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.

520

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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
Y, Selective Ablation of β-Galactosidaseexpressing Cells with a Rationally Designed
Activatable Photosensitizer. Angew Chem Int Ed,
53(26): 6772-6775, 2014.
26. Uno S, Kamiya M, Yoshihara T, Sugawara K,Okabe K, Tarhan MC, Fujita H, Funatsu T, Okada
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
Y: Boron dipyrromethene as a fluorescent caging
group for single-photon uncaging with longwavelength visible light. ACS Chem Biol, 9:22422246, 2014.
29. Yoshida M, Kamiya M, Yamasoba T, Urano Y, A
highly sensitive, cell-membrane-permeable fluorescent probe for glutathione. Bioorg Med Chem
Lett, 24:4363-6, 2014.
30. Akihiro Haga, Taiki Magome, Shigeharu Takenaka,Toshikazu Imae, Akira Sakumi, Akihiro Nomoto,
Hiroshi Igaki, Kenshiro Shiraishi, Hideomi
Yamashita, Kuni Ohtomo, and Keiichi Nakagawa,“Independent Absorbed Dose Calculation Using theMonte Carlo Algorithm in Volumetric Modulated
Arc Therapy”, Radiation Oncology, 9:75, 2014, 1-9.
31. Kenshiro Shiraishi, Masahiko Futaguchi, Akihiro
Haga, Akira Sakumi, Katsutake Sasaki, Kentaro
Yamamoto, Hiroshi Igaki, Kuni Ohtomo, Kiyoshi
Yoda, and Keiichi Nakagawa, “Validation ofPlanning Target Volume Margins by Analyzing
Intrafractional Localization Errors for 14 Prostate
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CT and Intrafraction Cone-Beam CT during
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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
Hospital”, BioMed Research International,
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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Kato, “Natural and glucosyl flavonoids inhibit
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Hiroyuki Takahashi, Kazuhiro Tagi, Joichi
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523

Department of Disaster Medical
Management
Professor
Tadashi Iwanaka, 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.
Associate Professor, Dr. Hiroyuki Nakao, who
experienced disasters such as the Great Hanshin-Awaji
Earthquake in 1995 and studied and engaged indisaster medicine at the Disaster and Emergency
Medicine Course in Faculty of Medicine of Kobe
University, was assigned post as the first General
Manager of the Department of Disaster Medical
Management in July 2012 and was appointed as thechairman of the in-hospital Disaster Prevention
Committee. Also, in March 2013, Dr. Jun Tomio,
Assistant Professor of the Public Health Course of this
University, was assigned as the instructor of the
Department of Disaster Medical Management in orderto develop approaches by methods of public health.
Afterwards, Professor Dr. Tadashi Iwanaka, thehospital vice director in charge of crisis managementand disaster prevention, was assigned post as thesecond General Manager, and also Lecturer Dr.
Masataka Gunshin, the emergency medicine center
vice director, was assigned post as the Vice Manager

in January 2015.
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 forestablishing a system for the University of Tokyo
Hospital to lead disaster medicine and 3) developing asystem as a base of formation of organizations at thetime of disaster.

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 2014, drills of building hospital headquarterfor disaster control and of reporting in-hospitaldamage situation were held.

Teaching activities
We have started “Disaster Medicine System Lecture”
on a monthly basis for personnel of this hospital,
Hongou Fire Department and Moto-Fuji Police Station
since December 2012.
As educational activities outside of the University,
we are teaching in the Japan DMAT workshops,
Trauma Primary Care education and Disaster524

Medicine workshops 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. Hiroyuki Nakao, Hiroshi Kodaira, Shinichi Sato,
Shinichi Nakayama, Shuichi kozawa, Noboru
Ishii. Development of a triage system using
mobile phones and image recognition software on
the market. J.J.Disast. Med. 2012;17:345-350.
2. Yasuyuki Hayashi, Masato Nishino, Hiroyuki
Nakano, Yoshimi Kitagawa, Katsuhiko Sugimoto,Atsushi Katsumi, Naoto Morimura, Kazutoshi
Kuboyama, Tatsuro Kai. Actual situation of
medical relief dispatch services at events in Japan.
J.J.Disast. Med. 2012;17:372-376.
3. Kazutoshi Kuboyama, Noboru Ishii, Shuichi
Ozawa, Joji Kotani, Hiroyuki Nakao, Shinichi
Nakayama, Noriko Murakami, Kazumasa
Yoshinaga. Construction "of the support system
for the family of the study on disease in the" 2011
area and medical care investigation great disasterdead. Shinryoku society academic journal 2012;
28: 11-16.

525International 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 40,000
hits from 157 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.

526

Department of Clinical Nutrition
Therapy
Head of the Department
Naoto Kubota (Associate Professor)

Assistant Head of the Department
Kazuhiko Fukatsu (Associate Professor, Surgical Center)
Rie Sekine

Lectuer
Hideaki IjichiHomepage

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

Introduction and Organization
In 1922, a stall in the outpatient department of thehospital and hospital ward shop sold milk, baked
goods, cider and ice cream. In 1925, a service contract
between the hospital and the Kojinkai Foundation
resulted in the start of a patient food service. In 1936,
a “special therapeutic diet” approach for newborn
infants, diabetes, nephropathy in which a physician
prescribed the food composition individually for eachpatient was instituted for the first time in Japan. In
1950, a national-hospital complete food service
system was announced, and the nutrient content
provided was standardized. The nutrient content
provision for patient meals at the time was 2400
kcal/day. In 1952, the inpatient meal service wasofficially outsourced to a foundation.
In 1957, the first nationwide meeting of 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 apartial revision of the Nutritionists Act. In 1972,
nutritional guidance was actively provided to
inpatients and outpatients with the aim of obtaining
approval to charge fees, and in 1978 a medical dietcharge and nutrition guidance charge were established.
In 1988, a timely tray service achieved by using hot
and cold food-tray carts was instituted in order todispel the “too early, cold, unappetizing” reputation of
hospital meals.
In 1991, the name of the food service section waschanged to the “Department of Nutrition Management”, a change that had a long been sought bynationwide national-university-hospital managerial
dietitian staff members. At the same time, the nutrition
sections of the main hospital and branch hospital wereconsolidated, and the head of the Department of
Nutrition Management, who was a managerial
dietitian, assumed the section manager post to form asystem composed of 5 managerial dietitians at themain hospital and 3 managerial dietitians at the branchhospital.
In 1994, as a result of a partial revision of the
National Health Insurance Act, the standard foodservice approval system was abolished, and a diet

527

therapy notification system on admission was set up.
An on-admission nutrition guidance fee was alsoestablished.
In 1998, the first diet therapy exhibit organized by
the Department of Nutrition Management was
conducted as part of the diabetes week events that theTokyo Diabetes Association held to the side of the freespace in the vestibule of the outpatient department. In
the first year there were 3527 visitors a week.
In 2001, integration of the branch hospital with themain hospital resulted in an 8-managerial- dietitiansystem. In 2004, the Department of Nutrition
Management was separated from the medical service
division. In 2005, the introduction of the self-pay
system for inpatient meals meant that inpatients began
to be charged for their meals. During the same year
one managerial dietitian (limited-term employment)
was added to the staff.
In 2006, charges for the performance of nutrition
management were newly established, and that meant
providing nutrition management for all patients. The
increase in work was accompanied by the addition of
one managerial dietitian (limited-term employment) to
the staff. Team care was introduced the same year, andin-hospital activity in the form of an all-department
nutrition support team (NST) was inaugurated. Eachhospital ward was staffed with a physician, managerial
dietitian, and nurse in charge of an NST, andwhenever necessary members from other fields(pharmacists,
medicaltechnologists,
physicaltherapists) joined, and they held a hospital ward
meeting once a week. In 2010, an NST committee wascreated as a result of the establishment of charges for
NSTs. The NST director up until that time became amember of the committee and played an active role as
the center of in-hospital NST activities. The additionof one managerial dietitian to the staff (full time) as afull-time employee to calculate the billing charges for
the NST was approved. In 2011, the inauguration of anutritional guidance service for recipients of healthcheckups in the Department of Epidemiology andPreventive Medicine was accompanied by the additionof one managerial dietitian (limited-term employment)
to the staff. In 2012, charges for conducting nutrition
management were abolished. They were incorporated
into the basic hospital-admission fee, and the nutrition
management system by physicians, managerial

dietitians, and nurses was improved.
In 2013, the Department of Nutrition Management
was reorganized as the Department of ClinicalNutrition Therapy. A physician (Professor, the head of
the Central Clinical Services Administration) assumed
the concurrent post of head of the Department, and thehead of the Department of Nutrition Management
assumed the post of Assistant Head of the Department;
they undertook responsibility for managing the foodservice, maintaining activities of the NST, andstrengthening its functions. In 2014, with the adventof a full-time department head, improvements weremade to 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 been assigned
this fiscal year.

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 2013 show that
there were 2176 instances of inpatient nutritional
guidance (354 without charge) and 3268 instances of
outpatient nutritional guidance (166 without charge).
The results for group nutritional guidance showed thatduring the year there had been 438 outpatient diabetes
classes and 254 inpatient diabetes classes (for some ofwhich there was a charge), and that there had been 156
best-weight classes, classes after gastric cancer
operations for 115 patients, and mother’s classes for
208 mothers.
In July 2012, a physician, managerial dietitian, andnurse formed a dialysis prevention team, and began
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 in 2013
there were 199 guidance sessions.

528

Teaching Activities
The Department accepts managerial dietitian
clinical trainees. In 2013, the department accepted 39
trainees from 7 training schools: Ochanomizu
University, Tokyo Kasei University, Otsuma Women’s
University, Kagawa Education Institute of Nutrition,
Jissen Women’s Educational Institute, Japan Women’s
University, and Wayo Women’s University.
In 2011, the Department began accepting NST
trainees. From 1 to 4 or 5 terms are conducted a year
(5 days/week/term). Participants are mainly managerial dietitians, pharmacists, nurses, medical
technologists, and physical therapists, and candidates
are trainees whose aim is acquiring the qualifications
certified by academic societies or to become afull-time employee to calculate the billing charges for
the NST. There were 15 participants in 2013.

Research・Joint research with the Department of Stomach andEsophageal Surgery
Research topic: “Evaluation of nutrition indexes
after proximal gastrectomy”
・Research topic: “Multi-center randomized controlled
study of the effects of early post-gastrectomy oral
feeding support”
・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 pancreatoduodenectomy”

References<Academic meeting presentations, etc.>
1. Sekine R, Sasaki S, Nanjo Y: Luncheon Seminar“Total management of fecal incontinence according to a University of Tokyo care algorithm”, The
22nd Meeting of the Japanese Society of Wound,
Ostomy and Continence Management, 2013.5.24.
2. Togashi H, Hanafusa N, Nangaku M, Sekine R:
Background factors of patients who requiredietary potassium management from the standpoint of the presence or absence of potassium

3.

4.

5.

6.

7.

8.

9.

correction, The 58th Congress of the JapaneseSociety for Dialysis Therapy, 2013.6.
Kinoshita E, Sakurai M, Sekine R: Nutrition
approach to obese patients whose intake cannot be
evaluated, The 31st Congress of the JapaneseSociety for Treatment of Obesity, 2013.6.
Sekine R: NST medical staff session (introductory
edition) Complications of enteral nutrition andcountermeasures (in hospitals), The 17th Annual
Meeting of the Japan Society of Metabolism andClinical Nutrition, 2014.1.11.
Sekine R: Special program 1 “The role of thespecialist in clinical nutrition therapy at the
University of Tokyo Hospital”, the role of thespecialist in clinical nutrition therapy in clinicalpractice and future prospects, The 17th Annual
Meeting of the Japan Society of Metabolism andClinical Nutrition, 2014.1.12.
Sekine R: Diabetes TV Symposium “Nutritional
guidance in clinical practice; AstraZeneca (Corp.),2014.1.31.
Sekine R: Research engaged in by managerial
dietitians, 3. University of Tokyo Nursing
Research Symposium -Aiming for collaboration
among physicians, nurses, and researchers-,
Graduate School of Medicine and Faculty of
Medicine, The University of Tokyo, Research
Building, 14F, Tetsumon Memorial Hall. 2014.2.1
Sekine R: Hospital unit managerial dietitianstaffing, current status of hospital ward staffing at
the University of Tokyo Hospital, The 56th
Meeting of the Nutrition Research Group of theTokyo Branch of the Japan Hospital Association.
2014.03.14
Sekine R, Sawada M, Uehata Y, et al.: Effect of an
ONS (oral nutritional supplement) on the loss ofskeletal muscle mass after stomach cancer surgery,86th Annual Meeting of the Japanese Gastric
Cancer Association, 2014.03.22<Publications>
1. Sekine R, Sasaki S, Nanjo Y: Special issue “Total
management of fecal incontinence (diarrhea)”,
Expert Nurse, Oct issue, Vol.29, No.12.2013.
2. Sekine R, Ogawa S (eds.): 24 Points aboutsarcopenia, Fuji Medical Publishing, 2013.11.18

529

3. Sekine R: Special issue. Nutrition management
designed to improve the QOL of decubitus ulcer
patients “Key points in carbohydrate setting andadministration”：WOC Nursing,Vol.1.No.3.2013.
4. Kinoshita E: Need for an approach by managerial
dietitians to the psychosocial aspects of morbidly
obese patients -Experience with patients with low
self-esteem who refuse to disclose their foodrecords-： Prospects for Obesity Therapeutics, No.
2:3-3.2014.1

530

Department of Clinical Research
GovernanceDirector & Professor
Nobuhito Saito, M.D.,Ph.D. (Vice Director of the University of Tokyo Hospital,
Director of Department of Research Support)

Homepage

http://www.h.u-tokyo.ac.jp/about/ichiran/#02

History andOrganization

Overviewofthe

The Department of Clinical Research Governance
was established independently from the ClinicalResearch Support Center on January 1, 2015, for the
management of clinical research. It is aimed at
appropriately and quickly responding to various issues
surrounding clinical research of recent years, toprevent the occurrence of problems in research ethics
and research misconduct, and to promote highly
reliable clinical research. The Department of ClinicalResearch Governance is intended at establishing asystem that would enable the University of Tokyo
Hospital to take initiative in managing and promoting
clinical research, in order to ensure the reliability ofclinical research and compliance with the ethics ofclinical research promoted by university hospitals
which provide advanced medical care.
The Department of Clinical Research Governance iscomposed of three offices: 1) The Central Office forDevelopment of Advanced Medicine, 2) The Officefor Clinical Research Education, and 3) The Office ofClinical Quality Assurance & Compliance. These
offices mutually cooperate to promote and strengthen
the governance function within the hospital.
The following activities are carried out by theCentral Office for Development of Advanced
Medicine: (1) Formulation of comprehensive strategies for research and development at the University ofTokyo Hospital; (2) Playing the role of theadministrative headquarters when publicly applying

for large-scale research projects; (3) Serving as aliaison for consultation regarding the acquisition ofresearch funds and intellectual properties; (4)Examination of financial self-reliance strategies of theclinical research base; (5) Discovery of needs andseeds in clinical practice; (6) Investigation of research
activities of the University of Tokyo Hospital andcreation of a database; (7) Collection of clinicalresearch information from external organizations; (8)Activities related to conflicts of interest at the
University of Tokyo Hospital; (9) Clerical work
related to Advanced Medicine Development Support
Management Committee; (10) Clerical work related toSpecial Clinical Research Steering Committee.
The activities of the Office for Clinical Research
Education are as follows: (1) Educational activities forclinical researchers; (2) Dissemination of workshop
summaries.
The activities of the Office of Clinical Quality
Assurance & Compliance are as follows: (1) Quality
assurance-related activities, such as auditing ofclinical trials and clinical studies and administrative
structure/system audits as well as improvement
proposals; (2) Proposals related to the establishmentof 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 centralized managementof results; (5) Centralized management of audit
results; (6) Confirmation of implementation ofcorrective
andpreventive
measures
from

531

audit/inspection findings.
The Department of Clinical Research Governanceconsists of one manager (concurrent post) and two
staff members of the Central Office for Developmentof Advanced Medicine (one special researcher/URA
and one clerical staff [temporary]) as of March 2015.
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.
Therefore, the staff member became a member of the
Department of Clinical Research Governance as of
fiscal year 2015.

Medical Care and Activities
The Central Office for Development of Advanced
Medicine was established in May 2014 and undertakes
the following activities.
1) Organization coordination activities: Assistance forestablishment of the Department of Clinical Research
Governance, assistance for holding Clinical Research
Optimization Review Committee meetings, assistancefor holding Advanced Medicine Development Support
Management Committee meetings, and preparation for
the application for approval of clinical research core
hospitals under the Medical Service Law (to be
applied in fiscal year 2015).
2) Activities related to conflict-of-interest management: 10 cases of consultation regarding the researchadministrative structure, management of conflict-ofinterest documents for 145 studies (total number), and
110 cases of consultation regarding 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 4 casesof consultation regarding intellectual properties (2cases for patent, 1 case for trademarks, and 1 case forcopyright).
4) Others: 2 cases of review of the application forms
for Grants-in-Aid for Scientific Research and for the

University of Tokyo Research Grant, investigation on
research paper publication activities, holding of the“Forum for Development of Seeds for Advanced
Medicine, 2015” (administrative office), and support
for the Center of Innovation Program of the Universityof Tokyo (support for departmental cooperation,
support for holding a symposium once, and support
for holding a seminar twice).
The Office of Clinical Quality Assurance &Compliance, which was reorganized from the
Department of Quality Assurance established in
December 2014 in the Clinical Research Support
Center, has begun quality assurance activities. 1) The
audit procedures and protocols for two investigatorinitiated clinical trials have been approved by theInstitutional Review Board, and the audit scheduled
for the start of the trial has been completed for one of
the two trials (contracted out by another university);
2) Witnessing and supporting the GCP on-site
inspection and QMS inspection by the Pharmaceuticals and Medical Devices Agency after submission ofan application for an investigator initiated clinical trialof a medical device.; 3) Supervising the audit of a
medical institution by the audit department of theoutsourced CRO; 4) Providing advice and guidance
when consulted about various issues related toreliability by the central management unit and sitemanagement unit. Quality assurance activities will be
undertaken not only for investigator initiated clinical
trials, but also for independent clinical studies coveredby the new ethical guidelines.

Center for Disease Biology andIntegrative Medicine

533

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., Kento Kitada, Ph.D., Mayumi Mori, 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. Mainly, we focus on the following two
major projects.
1. 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-

534

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.
2. Finding new mechanisms of infertility
It has been suggested that the regulation of
apoptosis is crucially involved in tumor development.
Our recent analysis of knockout mice of the deatheffector domain (DED) containing element DEDD-1
has implied an important role of DEDD-1 in tumor
progression. DEDD molecules regulate the speed ofcell division by sensing the concentration of ribosomal
DNA and its proteins, causing to determine the size ofcell. Also, DEDD molecules seem to function as asensory system of nutrient level, affecting directly tothe cell division activity level.
Due to the fact that DEDD knockout mice (♀)
results in 100% infertility, we focused on finding its
pathological mechanism. We found that female micelacking DEDD are infertile owing to unsuccessful
decidualization: The uterine decidua, which differentiates from stromal cells after implantation in a process
known as decidualization, plays essential role insupporting embryonic growth before establishment of
the placenta. In human, the cause of 25% of infertility
is unknown. It can be suggested that malfunction of
DEDD molecules may be the factor causing infertility
in human; so we now seek the involvement of DEDD
molecules in human fertility.
Since our recent
studies suggest DEDD molecules also have an effecton permeability of blood vessel in uterine, we try
creating a new model mice to further understand themechanism of infertility and to develop a 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 Aso,
Kumamoto prefecture. Teaching staffs, graduate
students, researchers from the two University andgraduate students of Kyusyu Univ. attended themeetings. Participants enjoyed substantial presentations and lively discussions during the four-day
meeting.
Those two fruitful meetings were great
opportunities for all the participants, for they wereable to experience what they can rarely experience inother meetings. They could build relationships fortheir future research, through participating dinners andget-togethers as well as research sessions.
We plan to hold this kind of joint meetings
continuously, in future.
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. So

535

far, eleven lecturers have been invited from many
places including Kyoto Univ., Hokkaido Univ., Riken
Institute, Tokyo Univ. of Science, Washington Univ.
(USA), Univ. of Basel (Switzerland), and Weill
Medical College of Cornell University (USA).
DBELS-EXTRA
This is a lecture series on the latest experimental
techniques for medical research, founded as anextension of DBELS. We offer monthly lecture series,
each of which convenes twice to four times a month,aiming mostly at graduate students and juniorresearchers.
This series provides lectures by experts fromcompanies, universities and research institutions
specializing in a wide range of areas such as
molecular biology, cellular biology, genetics,
immunology and others.
DBELS WORKSHOPIn 2007, we had a workshop at Unzen, a great resort
place in Nagasaki prefecture. Along the policy for
DBELS, we invited 8 top scientists from Kyoto,
Tokyo, Hokkaido, Okinawa, and Boston as lecturers,
and many young participants as audiences. Staying ina beautiful resort hotel, we all had a scientifically andculturally fruitful time. The next workshop is
scheduled to be held in Switzerland, probably in 2010
summer.
Music and Science
On Jun 6, 2006, to commemorate the foundation of
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.

2.

3.

4.

5.

6.

Yamazaki, T., Mori, M., Arai, S., Tateishi, R.,
Abe, M., Ban, M., Nishijima, A., Maeda, M.,
Asano, T., Kai, T., Izumino, K., Takahashi, J.,
Aoyama, K., Harada, S., Takebayashi, T., Gunji,
T., Ohnishi, S., Seto, S., Yoshida, Y., Hiasa, Y.,
Koike, K., Yamamura, K., Inoue, K. & Miyazaki,
T. Circulating AIM as an Indicator of Liver
Damage and Hepatocellular Carcinoma in
Humans- PLoS One. 9, e109123 (2014).
Maehara, N., Arai, S., Mori, M., Iwamura, Y.,
Kurokawa, J., Kai, T., Kusunoki, S., Taniguchi,
K., Ikeda, K., Ohara, O., Yamamura, K. &Miyazaki, T. Circulating AIM Prevents
Hepatocellular Carcinoma through Complement
Activation- Cell Rep. 9, 61-74 (2014).
Kai, T., Yamazaki, T., Arai, S. & Miyazaki, T.
Stabilization and Augmentation of Circulating
AIM in Mice by Synthesized IgM-Fc- PLoS One.
9, e97037 (2014).
Martinez, V. G., Escoda-Ferran, C., Tadeu Simões,I., Arai, S., Orta Mascaró, M., Carreras, E.,
Martínez-Florensa, M., Yelamos, J., Miyazaki, T.
& Lozano, F. The macrophage soluble receptor
AIM/Api6/CD5L displays a broad pathogen
recognition spectrum and is involved in early
response to microbial aggression- Cell Mol.
Immunol. 11, 343-354 (2014).
Hamada, M., Nakamura, M., Tran, M. T.,
Moriguchi, T., Hong, C., Ohsumi, T., Dinh, T.T.,
Kusakabe, M., Hattori, M., Katsumata, T., Arai,
S., Nakashima, K., Kudo, T., Kuroda, E., Wu,
CH., Kao, P. H., Sakai, M., Shimano, H.,
Miyazaki, T., Tontonoz, P. & Takahashi, S. MafB
promotes atherosclerosis by inhibiting foam-cell
apoptosis- Nat. Commun. 5, 3147 (2014).
Arai, S. & Miyazaki, T.
Impacts of theapoptosis inhibitor of macrophage (AIM) on
obesity-associated inflammatory diseases- Semin
Immunopathol. 36, 3-12 (2014).

536

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Lecturer
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. 11) of this year in somedetail.

Teaching activities
We have 1 master course and 4 doctor course
students in 2014. We were also responsible forundergraduate education of physiology, and organized
all lectures, student experiments and examinations.
We gave all together 7 lectures of physiology forundergraduate students, and 5 lectures of physiology
and neuroscience for master course students. Twoundergraduate students join the activity of ourlaboratory for free quarter (FQ).

537

It has been over a century ago since Thorndike andPavlov discovered that rewards need to follow the
behaviors for conditioning, and many lines ofevidence now indicate that dopamine release in the
striatum serves as a reward signal and reinforces thepreceding behaviors. Nonetheless, no study has eversucceeded in demonstrating the temporal specificity of
dopamine action on synaptic plasticity, and themolecular basis of reinforcement learning has been
mysterious. This is because, electrical stimulation
cannot distinguish glutamatergic and dopaminergic
fibers.
We therefore established an all-optical method tostimulate glutamate and dopamine inputs by
two-photon glutamate uncaging and optogenetic
stimulation (channelrhodopsin-2, ChR2) of dopamine
fibers. We examined how dopamine affected the
spike-timing plasticity (STDP) of single dendritic
spines in the medium spiny neurons (MSNs) of thenucleus accumbens (ventral striatum), and found thatspine enlargement, representing synaptic potentiation,
was markedly enhanced only when dopamine wasreleased within a very narrow time window (0.3-2 s)following the onset of STDP, consistent with the
behavioral conditioning. We performed imaging
studies for Ca2+, CaMKII and protein-kinase A (PKA),
to clarify why slow kinetics of dopamine-regulated
kinases, ex. PKA, can detect such a narrow temporalsequence (Fig. S7d). We found that the sequence
detection was induced upstream of PKA: Sufficient
generation of cAMP occurred only when dopamine
was preceded by spike to prime adenylyl cyclase(AC1), otherwise cAMP was effectively removed bystrong activity of phosphodiesterase (PDE) in the thin
distal dendrites of MSNs (due to the surface-tovolume effect). Thus, PKA was activated only when
dopamine was preceded by spikes, and promoted
spine enlargement via CaMKII. Very interestingly,
spines are only present in the distal dendrites of MSNs,
and it is conceivable that dendritic structures of MSNs
are optimized for detection of precise reward timing
for conditioning.
Dopamine is now believed to carry reward signal or
reward-prediction error signals in the brain. Our work
indicates that dopamine acts as reward signal becauseof the cellular timing mechanisms embedded indendritic spines.

References
1. Lam, P.*, Ohno, M.*, , Subhankar, D.*, He, Y., Qin,
T., Lian, T., Zhu, D., Kang, Y., Liu, Y., Kauppi, M.,
Xie, L., Wan, W., Bin, N., Sugita, S., Olkkonen, V.,
Takahashi,N., Kasai, H.CA & Gaisano, H.Y.CA (2013).
Munc18b is a major mediator of insulin exocytosis
in rat pancreatic β-cells. Diabetes. 62:2416-2428.
(CACorresponding authors.)
2. Hira, R., Ohkubo, F., Ozawa, K., Isomura, Y.,
Kitamura, K., Kano, M., Kasai, H., & Matsuzaki,
M. (2013). Spatial and temporal reconfigurationof microcircuitry activity in the motor cortex forvoluntary movement. J. Neurosci. 33:1377-1390.
3. Hira, R., Ohkubo, F., Tanaka, Y.R., Masamizu, Y.,
Augustine, G.J., Kasai, H. & Matsuzaki, M.
(2013). In vivo optogenetic tracing of functional
corticocortical connections between motor
forelimb areas. Frontier in Neural Circuits 7:55.
4. Hayama, T., Noguchi, J., Watanabe, S.,
Ellis-Davies, G.C.R., Hayashi, A., Takahashi, N.,
Matsuzaki, M. & Kasai, H. (2013). GABA
promotes the competitive selection of dendritic
spines by controlling local Ca2+ signaling. Nature
Neurosci. 16:1409-1416.
5. Nuriya, M, Momotake, A, Kimura, Y., Yasui, M.,
Kasai, H. & Arai, T. (2013) Evaluation of
dialkylaminofluorene-based hemicyanine dyes forsecond harmonic generation imaging by the directcomparison approach. Bull. Chemical Soc. Jpn.
86:1190-1192.
6. Takehara, H., Nagaoka, A., Noguchi, J., Akagi, T.,
Sakai, T., Chung, U., Kasai, H. & Ichiki, T. (2013).
Implementation of tetra-poly (ethylene glycol)hydrogel with high mechanical strength into
microfluidic device technology. Biomicrofluidics
7, 054109.
7. 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

538

and in vivo during late adolescence. Proc. Natl.
Acad. Sci. U.S.A. 111, 6461-6.
8. 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.
9. Boinapally, S., Huang, B., Abe, M., Katan, C.,
Noguchi, J., Watanabe, S., Kasai, H., Xue, B. &Kobayashi, T. (2014) Caged Glutamates with πExtended 1,2-Dihydronaphthalene Chromophore:
Design, Synthesis, Two-Photon Absorption
Property, and Photochemical Reactivity. J.
Organic Chemistry 79: 7822-7830.
10. 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.
11. 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.

539

Laboratory of Regenerative
Medical Engineering
Professor
Takashi Ushida, 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 cellbiotechnology. Secondly, we try to elucidate
mechanisms of cellular responses to physicalstimulations such as hydrostatic pressure, shear stress,
stretch, through observing intracellular signaling, andto adopt those effects 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 ofEngineering. 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 biosystem engineering, separation
technology, and biotechnology at the Chemical
System Engineering course and Bioengineering course
at Graduate School of Engineering School.

5402) 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 areencapsulated in various materials which achieve ideal
release kinetics. The functions of these biomaterials
and phenomena inside and outside biomaterials invivo are complicated both in terms of chemistry andbiology. Ito Laboratory is trying to design and develop
novel biomaterials for tissue engineering and drugdelivery by the combination of medicine and chemicalsystem engineering. Especially we focus on hydrogels
which can be utilized for islet regeneration and drugdelivery in peritoneum.
1) 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) Kevin Montagne, Hiroki Uchiyama, Katsuko S.
Furukawa, Takashi Ushida, Hydrostatic pressure
decreases membrane fluidity and lipid desaturase
expression in chondrocyte progenitor cells, Journalof Biomechanics 47 (2) 354-9 (2014)(2) Chang Ho Seo, Heonuk Jeong, Takashi Ushida,
Kevin Montagne, Feng Yue, Yuji Suzuki and
Katsuko S. Furukawa, Micropit surfaces designed

for accelerating osteogenic differentiation of murine
mesenchymal stem cells via enhancing focal
adhesion and actin polymerization, Biomaterials
Feb;35(7): 2245-52 (2014)(3) Erna G Santoso; Keita Yoshida; Yasushi Hirota;
Masanori Aizawa; Osamu Yoshino; Akio Kishida;
Yutaka Osuga; Shigeru Saito; Takashi Ushida;
Katsuko S Furukawa, Application of detergents orhigh hydrostatic pressure as decellularization
processes in uterine tissues and their subsequenteffects on in vivo uterine regeneration in murine
models, PLosOne Jul 24;9(7):e103201 (2014)(4) S. Sawada, T. Akimoto, M. Takahashi, R. Sakurai, S.
Shinkai, T. Ushida, Y. Fujiwara, K. Suzuki. Effectof aging and sex on circulating microRNAs inhumans. Adv Aging Res, 3, 152-159, (2014)(5) Tatsuto Kageyama, Takahiro Kakegawa, Tatsuya
Osaki, Junko Enomoto, Taichi Ito, Tadashi Nittami,
Junji Fukuda., Rapid engineering of endothelial
cell-lined vascular-like structures in in situ
crosslinkable hydrogels. Biofabrication 2014(6)025006(6) Shigenobu Emoto, Hironori Yamaguchi, Takao
Kamei, Hironori Ishigami, Takashi Suhara,
Yukimitsu Suzuki, Taichi Ito, Joji Kitayama,
Toshiaki Watanabe., Intraperitoneal administrationof cisplatin via an in situ cross-linkable hyaluronic
acid-based hydrogel for peritoneal dissemination ofgastric cancer. Sugery Today 2014 (44)919-26(7) Atsushi Shimizu, Takashi Suhara, Taichi Ito,
Kiyohiko Omichi, Katsutoshi Naruse, Kiyoshi
Hasegawa,
Norihiro
Kokudo.,A
New
Hepatectomy-Induced Postoperative Adhesion
Model in Rats, and Evaluation of the Efficacy ofAnti-adhesion Material. Sugery Today, 2014(44)314-323.

541

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://www.bmw.t.u-tokyo.ac.jp/english/index.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" intranationallyand 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

542

prevents the effective development of revolutionary
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. H.-C. Yen, H. Cabral, P. Mi, K. Toh, Y.
Matsumoto, X. Liu, H. Koori, A. Kim, K.
Miyazaki, Y. Miura, N. Nishiyama, K. Kataoka,
Light-induced cytosolic activation of reductionsensitive camptothecin-loaded polymeric micelles
for spatiotemporally controlled in vivo chemotherapy. ACS Nano 8 (11) 11591-11602 (2014)
2. L. Nuhn, S. Tomcin, K. Miyata, V. Mailander, K.
Landfester, K. Kataoka, R. Zentel, Size-dependent
knockdown potential of siRNA-loaded cationicnanohydrogel particles. Biomacromolecules 15(11) 4111-4121 (2014)
3. H. -J. Kim, H. Takemoto, Y. Yi, M. Zheng, Y.
Maeda, H. Chaya, K. Hayashi, P. Mi, F. Pittella,
R. J. Christie, K. Toh, Y. Matsumoto, N.
Nishiyama, K. Miyata, K. Kataoka, Precise
engineering of siRNA delivery vehicles to tumors
using polyion complexes and gold nanoparticles.
ACS Nano 8 (9) 8979-8991 (2014)

543

4. H. Wu, H. Cabral, K. Toh, P. Mi, Y.-C. Chen, Y.
Matsumoto, N. Yamada, X. Liu, H. Kinoh, Y.
Miura, M. R. Kano, H. Nishihara, N. Nishiyama,
K. Kataoka, Polymeric micelles loaded withplatinum anticancer drugs target preangiogenic
micrometastatic niches associated with inflammation. J. Control. Release 189 1-10 (2014)
5. H. Uchida, K. Itaka, T. Nomoto, T. ishii, T. Suma,
M. Ikegami, K. Miyata, M. Oba, N. Nishiyama, K.
Kataoka, Modulated protonation of side chainaminoethylene repeats in N-substituted polyaspartamides promotes mRNA transfection. J. Am.
Chem. Soc. 136 (35) 12396-12405 (2014)
6. Y. Oe, R. J. Christie, M. Naito, S. A. Low, S.
Fukushima, K. Toh, Y. Miura, Y. Matsumoto, N.
Nishiyama, K. Miyata, K. Kataoka, Activelytargeted polyion complex micelles stabilized bycholesterol and disulfide cross-linking forsystemic delivery of siRNA to solid tumors.
Biomaterials 35 27 7887-7895 (2014)
7. S. Quader, H. Cabral, Y. Mochida, T. Ishii, X. Liu,
K. Toh, H. Kinoh, Y. Miura, N. Nishiyama, K.
Kataoka, Selective intracellular delivery ofproteasome inhibitors through pH-sensitive
polymeric micelles directed to effcient antitumor
therapy. J. Control. Release 188 67-77 (2014)
8. Y. Mochida, H. Cabral, Y. Miura, F. Albertini, S.
Fukushima, K. Osada, N. Nishiyama, K. Kataoka,
Bundled assembly of helical nanostructures inpolymeric micelles loaded with platinum drugs
enhancing therapeutic efficiency against pancreatic tumor. ACS Nano 8 (7) 6724-6738 (2014)
9. S. Chuanoi, Y. Anraku, M. Hori, A. Kishimura, K.
Kataoka, Fabrication of polyion complex vesicles
with enhanced salt and temperature resistance andtheir potential applications as enzymatic nanoreactors. Biomacromolecules 15 (7) 2389-2397(2014)
10. K. Furugaki, L. Cui, Y. Kunisawa, K. Osada, K.
Shinkai, M. Tanaka, K. Kataoka, K. Nakano,Intraperitoneal administration of a tumorassociated antigen SART3, CD40L, and GM-CSF
gene-loaded polyplex micelle elicits a vaccine
effect in mouse tumor models. PLOS ONE 9 7e101854 (2014)
11. Y. Maeda, F. Pittella, T. Nomoto, H. Takemoto, N.
Nishiyama, K. Miyata, K. Kataoka, Fine-tuning of

charge-conversion polymer structure for efficientendosomal escape of siRNA-loaded calcium
phosphate hybrid micelles. Macromol. Rapid
Commun. 35 13 1211-1215 (2014)
A. Dirisala, K. Osada, Q. Chen, T. A. Tockary, K.
Machitani, S. Osawa, X. Liu, T. Ishii, K. Miyata,
M. Oba, S. Uchida, K. Itaka, K. Kataoka,
Optimized rod length of polyplex micelles for
maximizing transfection efficiency and theirperformance in systemic gene therapy against
stroma-rich pancreatic tumors. Biomaterials 35(20) 5359-5368 (2014)
12. L. Nuhn, S. Gietzen, K. Mohr, K. Fischer, K. Toh,
K. Miyata, Y. Matsumoto, K. Kataoka, M.
Schmidt, R. Zentel, Aggregation behavior of
cationic nanohydrogel particles in human blood
serum. Biomacromolecules 15 (4) 1526-1533(2014)
13. T. Ueno, K. Endo, K. Hori, N. Ozaki, A. Tsuji, S.
Kondo, N. Wakisaka, S. Murono, K. Kataoka, Y.
Kato, T. Yoshizaki, Assessment of antitumor
activity and acute peripheral neuropathy of 1,2diaminocyclohexane platinum (II)-incorporating
micelles (NC-4016). Int. J. Nanomedicine 9 (1)3005-3012 (2014)
14. K. Nagata, K. Itaka, M. Baba, S. Uchida, T. Ishii,
K. Kataoka, Muscle-targeted hydrodynamic gene
introduction of insulin-like growth factor-1 using
polyplex nanomicelle to treat peripheral nerve
injury. J. Control. Release 183 27-34 (2014)15. S. Murayama, P. Kos, K. Miyata, K. Kataoka, E.
Wagner, M. Kato, Gene regulation by intracellulardelivery and photodegradation of nanoparticles
containing small interfering RNA. Macromol.
Biosci. 14 (5) 626-631 (2014)16. H. -J. Kim, K. Miyata, T. Nomoto, M. Zheng, A.
Kim, X. Liu, H. Cabral, R. J. Christie, N.
Nishiyama, K. Kataoka, siRNA delivery from triblock copolymer micelles with spatially-ordered
compartments of PEG shell, siRNA-loadedintermediate layer, and hydrophobic core.
Biomaterials 35 (15) 4548-4556 (2014)
A. Wibowo, K. Osada, H. Matsuda, Y. Anraku, H.
Hirose, A. Kishimura, K. Kataoka, Morphology
control in water of polyion complex nanoarchitectures of double-hydrophilic charged block
copolymers through composition tuning and544

thermal treatment. Macromolecules 47 (9) 30863092 (2014)
17. T. Nomoto, S. Fukushima, M. Kumagai, K.
Machitani, Arnida, Y. Matsumoto, M. Oba, K.
Miyata, K. Osada, N. Nishiyama, K. Kataoka,
Three-layered polyplex micelle as a multifunctional nanocarrier platform for light-induced
systemic gene transfer. Nat. Commun. 5 3545
(2014)
18. F. Pittella, H. Cabral, Y. Maeda, P. Mi, S.
Watanabe, H. Takemoto, H. -J. Kim, N.
Nishiyama, K. Miyata, K. Kataoka, SystemicsiRNA delivery to a spontaneous pancreatic tumor
model in transgenic mice by PEGylated calcium
phosphate hybrid micelles. J. Control. Release
178 18-24 (2014)
19. Z. Ge, Q. Chen, K. Osada, X. Liu, T. A. Tockary,
S. Uchida, A. Dirisala, T. Ishii, T. Nomoto, K.
Toh, Y. Matsumoto, M. Oba, M. R. Kano, K.
Itaka, K. Kataoka, Targeted gene delivery by
polyplex micelles with crowded PEG palisade andcRGD moiety for systemic treatment of pancreatictumors. Biomaterials 35 (10) 3416-3426 (2014)20. S. Uchida, K. Itaka, T. Nomoto, T. Endo, Y.
Matsumoto, T. Ishii, K. Kataoka, An injectablespheroid system with genetic modification for celltransplantation therapy. Biomaterials 35 (8) 24992506 (2014)
21. C. V. Synatschke, T. Nomoto, H. Cabral, M.
Fortsch, K. Toh, Y. Matsumoto, K. Miyazaki, A.
Hanisch, F. H. Schacher, A. Kishimura, N.
Nishiyama, A. H. E. Mueller, K. Kataoka,
Multicompartment micelles with adjustable poly
(ethylene glycol) shell for efficient in vivo
photodynamic therapy. ACS Nano 8 (2) 11611172 (2014)22. H. -J. Kim, T. Ishii, M. Zheng, S. Watanabe, K.
Toh, Y. Matsumoto, N. Nishiyama, K. Miyata, K.
Kataoka, Multifunctional polyion complex
micelle featuring enhanced stability, targetability,and endosome escapability for systemic siRNAdelivery to subcutaneous model of lung cancer.
Drug Deliv. Transl. Res. 4 (1) 50-60 (2014)23. S. Chuanoi, A. Kishimura, W. -F. Dong, Y.
Anraku, Y. Yamasaki, K. Kataoka, Structural
factors directing nanosized polyion complex
vesicles (Nano-PICsomes) to form a pair of block

aniomer/homo catiomers: Studies on the aniomer
segment length and the catiomer side-chain
structure. Polym. J. 46 (2) 130-135 (2014)
24. K. S. -Kato, K. Un, K. Nanjo, N. Nishiyama, H.
Kusuhara, K. Kataoka, T. Kawanishi, Y. Goda, H.
Okuda, Elucidating the molecular mechanism forthe intracellular trafficking and fate of block
copolymer micelles and their components.
Biomaterials 35 (5) 1347-1358 (2014)
25. P. Mi, D. Kokuryo, H. Cabral, M. Kumagai, T.
Nomoto, I. Aoki, Y. Terada, A. Kishimura, N.
Nishiyama,K.
Kataoka,
Hydrothermallysynthesized PEGylated calcium phosphate
nanoparticles incorporating Gd-DTPA for contrast
enhanced MRI diagnosis of solid tumors. J.
Control. Release 174 63-71 (2014)
26. H. Chen, L. Xiao, Y. Anraku, P. Mi, X. Liu, H.
Cabral, A. Inoue, T. Nomoto, A. Kishimura, N.
Nishiyama, K. Kataoka, Polyion complex vesicles
for photo-induced intracellular delivery ofamphiphilic photosensitizer. J. Am. Chem. Soc.
136 (1) 157-163 (2014)27. H. Cabral, K. Kataoka, 22. The impact of"Development of the polymer micelles carriersystem for doxorubicin" on the nanomedicine
realm: Original Research Article: Development of
the polymer micelle carrier system for doxorubicin, 2001. J. Control. Release 190 70-72 (2014)
28. H. Cabral, K. Kataoka, Progress of drug-loaded
polymeric micelles into clinical studies. J. Control.
Release 190 465-476 (2014)
A. Matsumoto, K. Kataoka, Y. Miyahara, New
directions in the design of phenylboronatefunctionalized polymers for diagnostic andtherapeutic applications. Polymer J. 46 (8) 483491 (2014)

545

Laboratory of Environmental
Health Sciences
Professor
Chiharu Tohyama, Ph.D., Dr.Med.Sci.

Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Assistant Professor
Eiki Kimura, Ph.D.

Homepage

http://env-health.m.u-tokyo.ac.jp

Introduction and Organization
Laboratory of Environmental Health Sciences was
newly established as a department of the Center for
Disease Biology and Integrative medicine in 2005
when Dr. Tohyama was transferred to the professor.
Since then, the laboratory activity in the research andeducation in the environmental toxicology has beenstimulated with approximately 25 laboratory members
including staff, postdoctoral fellows, graduate andundergraduate students.

Research activities
Children’s health problems of today include suchconditions as disorders in the reproductive andimmune functions, learning deficits, mental problem
and ‘metabolic syndrome’. Our research is carried out
on the recognition that the homeostasis is disrupted byvarious environmentally hazardous chemicals, towhich expectant mothers and their newborn babies are
exposed during their highly sensitive period of life,
and that the contamination with these chemicals maylead to various disease conditions in children after
birth. This laboratory has been tackling such problemsby the standpoint of environmental toxicology. For
this end, our experimental investigations have been
performed in (1) identifying and characterizing themolecular target, i.e., ‘molecular target toxicology’,(2) elucidating epigenetic mechanisms that alter thesusceptibility to chemicals, i.e., ‘epigenetic
mechanism, and (3) clarifying effects of chemicals on
the learning/memory, emotion and sociality of therodents, i.e, behavioral and cognitive toxicology.
Our research efforts are further directed to develop
methodologies for evaluating behavioral toxicities invivo and to establish in vitro toxicity techniques atcellular and molecular levels. In addition to thesebasic approaches to the environmental toxicology, we
aim to provide data for obtaining the safety standard
in environmental factors and food, and to contribute to
the development of research in life and clinicalsciences.
Among a variety of potentially toxic substances inthe environment, we focus especially on dioxin and its
related-compounds and heavy metals which react withspecific receptors and proteins.
As to a major study on the ‘molecular target
toxicology’, we have been studying how lactational
exposure to dioxin induces hydronephrosis. It has
been established that aryl hydrocarbon receptor (AhR)
is required to elicit the majority of dioxin toxicity.
However, it has not been clear how dioxin induces avariety of toxicity including carcinogenicity, immunotoxicity, reproductive toxicity, and disorder of higher
brain function. We previously elucidated that
cyclooxygenase-2 (COX-2) play a critical role in the546

onset of hydronephrosis in the mouse neonates. This
year, we have clarified that a kind of prostaglandin
synthase is a critical factor for the onset of dioxininduced hydronephrosis.
As to the study on ‘epigenetic toxicology’, we havebeen studying why mice born to dams that wereadministered dioxin during gestation are prone todevelop benzo[a]pyren-induced stomach cancer. We
found that the mice that were exposed to dioxin inutero had the enhanced demethylated status in CpG aswell as histone modifications in a specific region of
the promoter of cytochrome P450 1A1, the observation of which is thought to loosen the chromatinstricter. In another study, we found that low zincstatus during gestation affect the gene regulation of
metallothionein in adulthood. Using mouse andhuman ES cell lines, we have been also studying
possible programing abnormality by environmental
factors.
As to the study on ‘behavioral and cognitive
toxicology’, we have been extensively studying how
chemical exposure at a low-dose level during
gestation affects higher brain functions in later in
adulthood. The mice that were born to dams exposed
to dioxin during gestation were found to develop
behavioral inflexibility, compulsive repetitive
behavior, and low social dominance. In this study, we
found that neuronal activity makers, Arc and c-FOS,
support the observations in the behavioral experiments.
Furthermore, we have established a method todetermine mRNA abundance from specifically labeledcells, as small as 10 cells.
The outcomes of our research provide not only
fundamental information for human health risk
assessment that can lead to the establishment ofadequate margins of safety for human exposure toenvironmental chemicals.

Laboratory’s Research Themes
1. Elucidation of mechanisms involved in the
manifestation of toxicity at the molecular andcellular level due to exposure to environmental
pollutants, such as dioxin/PCBs and heavy metals.
2. Clarification of epigenetic mechanisms that altersusceptibility to environmental chemicals.
3. Development of methodologies for evaluating thetoxicity of chemicals to the learning and emotionof rodents and of in vitro toxicity techniques at
the molecular and cellular levels.
4. Development and application of techniques andmethodology for evaluating risks of toxic
substances in formulating safety standard for theenvironment and food.

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.
1. Undergraduate educationa. School of Medicine
Hygiene (Required): In charge of ‘Environmental Toxicology’
b. School of Health Sciences
Pharmacology and Toxicology (Required): In
charge of Toxicology
Food Safety Assessment (Opition):Laboratory Methods in Health Sciences(Required): In charge of Toxicology
2. 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)

547

Publications
1.

Tohyama Chiharu. Clarification of moleculartargets of dioxin toxicity. Nihon Eiseigaku Zasshi.
69(1):1-7, 2014.
2. Yoshioka Wataru, 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. Scientific Reports. 10;4:
4042, 2014.
3. Benner S, Endo T, Endo N, Kakeyama M,
Tohyama C. Early deprivation inducescompetitive subordinance in C57BL/6 male mice.
Physiol Behav. 137:42-52, 2014.
4. Aida-Yasuoka K, Yoshioka W, Kawaguchi T,
Ohsako S, Tohyama C. A mouse strain lessresponsive to dioxin-induced prostaglandin E2
synthesis is resistant to the onset of neonatalhydronephrosis. Toxicological Science 141(2):465-474, 2014.
5. Shiizaki K, Ohsako S, Kawanishi M, and Yagi T.
Identification of amino acid residues in theligand-binding domain of the aryl hydrocarbon
receptor causing the species-specific response toomeprazole: possible determinants for binding
putative endogenous ligands. Molecular Pharmacology. 85:279-289, 2014.
6. Alam MS, Ohsako S, Kanai Y, and Kurohmaru M.
Single administration of butylparaben induces
spermatogenic cell apoptosis in prepubertal rats.
Acta Histochemical 116:474-480, 2014.
7. Kakeyama M, Endo T, Yan Zhang, Miyazaki W,
Tohyama C. Disruption of paired-associate learning in rat offspring perinatally exposed to dioxins.
Archives of Toxicology. 88(3):789-98, 2014.
8. Sugai E, Yoshioka W, Kakeyama M, Ohsako S,
Tohyama C. In utero and lactational exposure to
2,3,7,8-tetrachlorodibenzo-p-dioxin
modulates
dysregulation of the lipid metabolism in mouseoffspring fed a high-calorie diet. Journal Applied
Toxicology. 34(3):296-306, 2014.

548

Laboratory of Animal Resources
Professor
Atsu Aiba, Ph.D.

Associate Professor
Kazuki Nakao, Ph.D.

Assistant Professor
Hidetoshi Kassai, Ph.D.,

Homepage

Michinori Koebis, Ph.D.,

Harumi Nakao, Ph.D.

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, 7 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 535 at the end of academic year 2014.
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/Cas
system.

549

1. Selective activation of mTORC1 signaling in
the brain
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 hypertrophy of Purkinjecells, leading to apoptosis. Synapse elimination ofclimbing fiber to Purkinje cells was also deficient in
L7-mTOR Tg. L7-mTOR Tg showed deficits in motor
coordination and reduced spontaneous activity in the
open field. However, L7-mTOR Tg did not show the
deficit in social behavior observed in Purkinjecell-specific Tsc1 KO mice. We will study the role ofmTORC1 activation in common marmoset.
2. Generation of knock-in mice by CRISPR/Cas
systemThe CRISPR/ CRISPR-associated (Cas) system has
rapidly emerged recently as a new tool for genome
engineering, and is expected to allow for controlled
manipulation of specific genomic elements in avariety of species. A number of recent studies havereported the use of CRISPR/CRISPR-associated (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 the CRISPR/Cas
system, targeted insertion of large DNA elements
remains an apparent challenge.
We generated
knock-in mice with successful targeted insertion oflarge donor DNA elements ranged from 3.0 to 7.1 kb
at the ROSA26 locus using the CRISPR/Cas system.
Five independent ROSA26 knock-in founder mice
were obtained by injection of Cas9 mRNA/sgRNA/donor vector mixtures into the cytoplasm of C57BL/6
pronuclear embryos when the injected embryos weretreated with an inhibitor of actin polymerization.
Successful germ line transmission of three of theseknock-in alleles was also confirmed.

References
1. Ohtani Y, Miyata M, Hashimoto K, Tabata T,
Kishimoto Y, Fukaya M, Kase D, Kassai H,
Nakao K, Hirata T, Watanabe M, Kano M, andAiba A. The synaptic targeting of mGluR1 by its
carboxyl-terminal domain is crucial for cerebellar
function. J Neurosci. 2014 Feb; 34(7):2702-2712.
2. Takenaka N, Izawa R, Wu J, Kitagawa K, Nihata
Y, Hosooka T, Noguchi T, Ogawa W, Aiba A,
and Satoh T. A critical role of the small GTPase
Rac1 in Akt2-mediated GLUT4 translocation inmouse skeletal muscle. FEBS J. 2014 Mar;281(5):1493-1504.
3. Ueyama T, Sakaguchi H, Nakamura T, Goto A,
Morioka S, Shimizu A, Nakao K, Hishikawa Y,
Ninoyu Y, Kassai H, Suetsugu S, Koji T, Bernd
Fritzsch B, Yonemura Y, Hisa Y, Matsuda M, Aiba
A, and Saito N. Maintenance of stereocilia andapical junctional complexes by Cdc42 in cochlear
hair cells. J Cell Sci. 2014 May; 127(Pt9):
2040-2052.
4. Uesaka N, Uchigashima M, Mikuni T, Nakazawa
T, Nakao H, Hirai H, Aiba A, Watanabe M, andKano M. Retrograde Semaphorin Signaling
Regulates Synapse Elimination in the Developing
Mouse Brain. Science. 2014 May; 344(6187):
1020-1023.
5. Kassai H, Sugaya Y, Noda S, Nakao K, Maeda T,
Kano M, and Aiba A. Selective Activation ofmTORC1 Signaling Recapitulates Microcephaly,
Tuberous Sclerosis, and Neurodegenerative
Diseases. Cell Reports. 2014 Jun; 7(5):16261639.
6. Ito TK, Yokoyama M, Yoshida Y, Nojima A,
Kassai H, Oishi K, Okada S, Kinoshita D,
Kobayashi Y, Fruttiger M, Aiba A, and Minamino
T. A crucial role for CDC42 in senescenceassociated inflammation and atherosclerosis.
PLoS One. 2014 Jul; 9(7);e102186.
7. Hamada S, Ogawa, I, Yamasaki M, Kiyama Y,
Kassai H, Watabe AM, Nakao K, Aiba A,
Watanabe M, and Manabe T. The glutamate
receptor GluN2 subunit regulates synaptic
trafficking of AMPA receptors in the neonatal
mouse brain. Eur J Neurosci. 2014 Oct; 40(8):3136-3146.

550

8. Takenaka N, Yasuda N, Nihata Y, Hosook T,
Noguchi T, Aiba A, and Satoh T. Role of theguanine nucleotide exchange factor in Akt2mediated plasma membrane translocation of
GLUT4 in insulin-stimulated skeletal muscle. Cell
Signal. 2014 Nov; 26(11):2460-2469.

551

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.

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. There is no remarkable change in themaintenance system and frequency of the use ofradioisotope this year.

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
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.
At Graduate School of Medicine, the education
molecular biology of 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
Before the present professor took the position, a vide
range of radiation biology, including biological effectsof low-dose irradiation, nonhomologous end joining(NHEJ) for DNA double-strand breaks, apoptosis that
responds to DNA damage, and radio-sensitization had
been topics in this department. Since 2005, homologous recombinational repair has been the main
subject.
RecA in E. coli and its homolog Rad51 in budding
yeast play a central role in homologous re-552

combinational repair. Historically, mechanism ofhomologous recombination was extensively studied inthese organisms, whereas homologous recombination
had been recognized as a minor pathway of DNA
double-strand break repair in higher organisms.
However, subsequent studies revealed that homologous recombination as well as NHEJ plays animportant role in DNA double-strand break repair inhigher organisms. There are two major differences
between these two pathways. NHEJ functions at any
stages of the cell cycle, whereas homologous
recombination is restricted to the S to M phases.
Another difference is that NHEJ is an error-prone
repair pathway and homologous recombination is anerror-free repair pathway.
We have tried to understand the significance ofhomologous recombination repair in genomic
instability underlying cancer pathology. Since theincidence of mutations in genes involved inhomologous recombination is low in cancer, we haverecently focused on its epigenetic aberrations.
Particularly, we are investigating the roles of cancer
testis antigens, which are expressed in meiosis and incancer, in somatic cells.
We identified biological functions of SYCP3, amember of the synaptonemal complex, which isformed between homologous chromosomes to ensure
their connection in meiosis. Expression of SYCP3 wasobserved in adrenal tumor, liver tumor, gastric tumor,
and kidney tumor, confirming that SYCP3 is a cancer
testis antigen. Treatment of SYCP3-nonexpressing
cells with a methylation inhibitor induced its
expression, indicating that methylation alteration incancer 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 homologous
recombination, we screened the molecule thatco-localizes with SYCP3 by immunofluorescence.
Consequently, we identified that the tumor suppressor
BRCA2, whose mutations are found in hereditarybreast and ovarian cancers, co-localizes with SYCP3.

We also confirmed that these proteins form a complex.
Furthermore, we found that binding of SYCP3 to
BRCA2 inhibits the homologous recombination repair
activity mediated by binding of BRCA2 to Rad51.
Since cells with BRCA2 mutations are hypersensitive to PARP inhibitors, their clinical trials areinternationally ongoing. However, the problem is thatthe application of the trial is limited due to low
incidence of their mutations. Our findings implicatethat SYCP3-expressing cancers, even if they do nothave BRCA mutations, are sensitive to PARP
inhibitors, providing novel insight into cancer therapy.
Thus, our study on homologous recombination
contributes to the establishment of principals of cancer
therapy. Radiation and many DNA-damaging
chemotherapeutic agents induce DNA double-strand
breaks, which can be normally repaired by the
intrinsic repair pathways. The induced breaks
therefore do not always lead to apoptosis. If we will
understand the details of the repair pathways, themolecules in this pathway will be the therapeutictargets. From the clinical point of view, we willdevelop the fundamental research in this field.
Furthermore, we found that Rad54B, a molecule
involved in homologous recombination repair,facilitates genomic instability by negatively regulatingcell-cycle checkpoints (Yasuhara et al. Nat Commun,2014). Since this finding suggests that the novel
mechanism links two fundamental cellular functions,
DNA repair and cell-cycle regulation, we are trying to
identify such network systems in cellular functions.

Publications
1. Hosoya N, Miyagawa K: Targeting the DNA
damage response in cancer therapy. Cancer Sci
105:370-388, 2014
2. Iimoto T, Hayashi E, Kimura K, Suzuki T,
Kobashi A, Tanaka S: Optimized safety management for X-ray irradiators with various levels ofpotential exposure risk used for researches. Radiat
Emergency Med 3:45-49, 2014
3. Miyasaka A, Oda K, Ikeda Y, Wada-Hiraike O,
Kashiyama T, Enomoto A, Hosoya N, Koso T,
Fukuda T, Inaba K, Sone K, Uehara Y, Kurikawa
R, Nagasaka K, Matsumoto Y, Arimoto T,
Nakagawa S, Kuramoto H, Miyagawa K, Yano T,

553

Kawana K, Osuga Y, Fujii T: Anti-tumor activityof olaparib, a poly (ADP-ribose) polymerase(PARP) inhibitor, in cultured endometrial
carcinoma cells. BMC Cancer 14:179, 2014
4. Yasuhara T, Suzuki T, Katsura M, Miyagawa K:
Rad54B serves as a scaffold in the DNA damage
response that limits checkpoint strength. Nat
Commun 5:5426, 2014

554

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 Faculty of
Medicine. Its three most important roles, as defined by
the Committee on International Academic Affairs, arei) international educational exchange, ii) international
contacts in research and scientific fields, and iii)
international cooperation in health care and medicine.

Activities
This document reports on the office's activities inthese areas over the academic year 2014 (April 1, 2014
through March 31, 2015).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2014, there were 101 foreign students (32countries) 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 62 suchinquiries.
Many currently enrolled foreign students received
counseling at this office concerning their studies andlife at the University of Tokyo and the requirements for
obtaining scholarships and degrees.

In addition, a large number of University of Tokyo
students wish to supplement their training with basic
clinical experience overseas before graduation, as wellas the type of short-term training (1-3 months)
frequently called clinical electives overseas. Inquiries
from these students were either answered by this officeor referred to appropriate centers.
Every year, 24 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 2014, 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 2014 Contest
foreign students gave oral presentations based on theirresearch papers to interested fellow students and faculty,
and the five best speakers were given awards.
A formal agreement for academic exchange between
the University of Pennsylvania and the University ofTokyo was renewed in May 2004. Since that time,
fourteen University of Tokyo students have taken
research electives at the University of Pennsylvania,

555

and two students from the University of Pennsylvania
have taken clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and Johns Hopkins University inDecember 2002. Since the start of the program in 2002,
twenty seven University of Tokyo students visited toattend clinical electives at Johns Hopkins University,and four students from Johns Hopkins University havetaken clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the University of Michigan
Medical School in January 2005. Since the start of the
program in 2005, seventeen University of Tokyo
students have attended clinical electives at the
University of Michigan Medical School, and sevenstudents 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,
thirteen University of Tokyo students visited to attend
research electives at Munich University, and six
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 University of Washington
Medical School in November 2005. Since the start ofthe program in 2005, six University of Tokyo students
have attended clinical electives at the University ofWashington Medical School, and one student from the
University of Washington Medical School has 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 Taipei Medical University inNovember 2005. Since the start of the program in 2005,
five University of Tokyo students visited to attend
clinical electives at Taipei Medical University andfourteen students from Taipei Medical University havetaken clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and Mahidol University in

September 2006. Since the start of the program in 2006,
five University of Tokyo students visited to attend
research electives at Mahidol University, and sevenstudents from Mahidol University have taken clinicalelectives 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 53 requests from students forcounseling regarding pre-graduation or post-graduation
studies abroad are received by the Office ofInternational Academic Affairs. The office responds tothese requests by providing information, advice, andletters of recommendation.

2. Education and research
3.1 Education
In 2014, Dr. Green taught a course open to allstudents in the Graduate School of Medicine:
Introduction to Scale Development.
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 2014, 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. 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 in Japan,
measured with the Japanese version of Cardiff
Fertility Knowledge Scale (CFKS-J). Reprod
Health 2015, 12:10 (doi:10.1186/1742-4755-12-10).
2. Kojima T, Green J, Barron JP. How Japanese
Medical Journals Manage Conflicts of Interest.
CHEST. 2015; 147(2): e60. doi: 10.1378/chest.142396

556

Museum of Health and Medicine
Director
Kazuhiko Ohe

Specially-appointed technical expert
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",
and the eighth "Forensic Medicine" followed.
Since the opening of the Museum, more than74,255 people had visited by the end of FY2014.

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 toresearchers through consultation and develops humanresources 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 organtransplantation manuals for the liver, kidney andheart transplants.
◇ Specific items reviewed and examined by each
Ethics Committee in fiscal year 2014
・Research Ethics Committee:
305 new applications, 516 minor alterations ofapproved studies, and 47 documentary examinations
・Human Genome, Gene Analysis Research Ethics
Committee:
20 new applications, 152 minor alterations ofapproved studies

559

Research activities

1100
1000
900
800
700
600
500
400
300
200
100
0

At present, ORES is a business section. For more
information about the research, see the contents of
Department of Biomedical ethics, which is acooperative department.

Document examination of the medical case
Human Genome, Gene Analysis Research Ethics Committee
Research Ethics Committee

Total number of ethics reviews in Graduate School of Medicine andFaculty of Medicine, The University of Tokyo

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 3 times
in fiscal year 2014 with 1508 people attended.
Thereafter, from fiscal year 2015, ethics seminars
were held monthly.
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.

560

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.

Lecturer
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 ofInternational Cooperative Study in Medical Education,
and Planning & Cooperation for International
Cooperative Projects and Information on Medical
Education. Names of two new departments are
Department of Medical Education Studies andDepartment of International Cooperation for Medical
Education.
The mission of 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561

department expands research to construct theories andemphasizes activities of educational practice or
improvement.
In the University, this department provides
information and member(s) as to the education ofFaculty of Medicine in such as academic affair
committee, medical education reform working group,and clinical clerkship 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

Publication
1. Ie K, Tahara M, Murata A, Komiyama M, Onishi
H. Factors associated to the career choice offamily medicine among Japanese physicians: thedawn of a new era. Asia Pac Fam Med 13(1): 11,2014
2. Oda Y, Onishi H, Sakemi T. Effectiveness ofStudent Tutors in Problem-Based Learning ofUndergraduate Medical Education. Tohoku J Exp
Med 232(3): 223-227, 2014
3. Oda Y, Onishi H, Sakemi T, Fujimoto K, Koizumi
S. Improvement in medical students’ communication and interpersonal skills as evaluated bypatient satisfaction questionnaire after curriculum
reform. J Clin Biochem Nutr 55(1): 72–77, 2014
4. Tyastuti D, Onishi H, Ekayanti F, Kitamura K.
Psychometric item analysis and validation of theIndonesian version of the Readiness for Interprofessional Learning Scale (RIPLS). J Interprof
Care 28(5): 426-432, 2014
5. Tyastuti D, Onishi H, Ekayanti F, Kitamura K.
Psychometric Item Analysis and Validation ofIndonesian Version of Intragroup Conflict andGroup Atmosphere Scale. J Stud Soc Sci 7.1,
2014
6. Sonoo T, Gunshin M, Son D, Nakajima S,
Kitamura K, Yahagi N, Wong JG.: Cerebral
venous thrombosis and "Dense Triangle Sign" onunenhanced head computed tomographic scan.
Am J Emerg Med. 32(2):192.e3-4, 2014